Doubly heterozygous LMNA and TTN mutations revealed by exome sequencing in a severe form of dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is a heterogeneous disease; although 30 disease genes have been discovered, they explain only no more than half of all cases; in addition, the causes of intra-familial variability in DCM have remained largely unknown. In this study, we exploited the use of whole-exome sequencing (WES) to investigate the causes of clinical variability in an extended family with 14 affected subjects, four of whom showed particular severe manifestations of cardiomyopathy requiring heart transplantation in early adulthood. This analysis, followed by confirmative conventional sequencing, identified the mutation p.K219T in the lamin A/C gene in all 14 affected patients. An additional variant in the gene for titin, p.L4855F, was identified in the severely affected patients. The age for heart transplantation was substantially less for LMNA:p.K219T/TTN:p.L4855F double heterozygotes than that for LMNA:p.K219T single heterozygotes. Myocardial specimens of doubly heterozygote individuals showed increased nuclear length, sarcomeric disorganization, and myonuclear clustering compared with samples from single heterozygotes. In conclusion, our results show that WES can be used for the identification of causal and modifier variants in families with variable manifestations of DCM. In addition, they not only indicate that LMNA and TTN mutational status may be useful in this family for risk stratification in individuals at risk for DCM but also suggest titin as a modifier for DCM.     

Tooth loss in complying and non-complying periodontitis patients with different periodontal risk levels during supportive periodontal care

Clinical Oral Investigations - To evaluate yearly tooth loss rate (TLR) in periodontitis patients with different periodontal risk levels who had complied or not complied with supportive periodontal...     

Reciprocal translocations in myelodysplastic syndromes and chronic myelomonocytic leukemias: Review of 5,654 patients with an evaluable karyotype

The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent. © 2013 Wiley Periodicals, Inc.     

Analysis of oral risk factors for ventilator-associated pneumonia in critically ill patients

Clinical Oral Investigations - This a cross-sectional study to evaluate the association between oral health findings and ventilator-associated pneumonia (VAP) among critically ill patients in...     

Improved detection of synovial boundaries in ultrasound examination by using a cascade of active-contours

Rheumatoid arthritis (RA) is a chronic multisystemic autoimmune disease, with an unclear etiopathogenesis. Its early diagnosis and activity assessment are essential to adjust the proper therapy. Among the different imaging techniques, ultrasonography (US) allows direct visualization of early inflammatory joint changes as synovitis, being also rapidly performed and easily accepted by patients. We propose an algorithm to semi-automatically detect synovial boundaries on US images, requiring minimal user interaction. In order to identify the synovia-bone and the synovia-soft tissues interfaces, and to tackle the morphological variability of diseased joints, a cascade of two different active contours is developed, whose composition corresponds to the whole synovial boundary.The algorithm was tested on US images acquired from proximal interphalangeal (PIP) and metacarpophalangeal (MCP) finger joints of 34 subjects. The results have been compared with a consensus manual segmentation. We obtained an overall mean sensitivity of 85 ± 13%, and a mean Dice's similarity index of 80 ± 8%, with a mean Hausdorff distance from the manual segmentation of 28 ± 10 pixels (approximately 1.4 ± 0.5 mm), that are a better performance than those obtained by the raters with respect to the consensus.     

Determinants of Successful Weight Loss After Using a Commercial Web-Based Weight Reduction Program for Six Months: Cohort Study

Background

The Internet is widely available and commonly used for health information; therefore, Web-based weight loss programs could provide support to large parts of the population in self-guided weight loss. Previous studies showed that Web-based weight loss interventions can be effective, depending on the quality of the program. The most effective program tools are visual progress charts or tools for the self-monitoring of weight, diet, and exercises. KiloCoach, a commercial program currently available in German-speaking countries, incorporates these features. A previous investigation showed that the program effectively supports users in losing weight.

Objective

We investigated weight loss dynamics stratified by weight loss success after 6-month use of KiloCoach. Furthermore, we analyzed possible associations between intensity of program use and weight loss. The results are intended for tailoring user recommendations for weight-loss Internet platforms.

Methods

Datasets of KiloCoach users (January 1, 2008 to December 31, 2011) who actively used the platform for 6 months or more were assigned to this retrospective analysis. Users (N=479) were 42.2% men, mean age of 44.0 years (SD 11.7), with a mean body mass index (BMI) of 31.7 kg/m² (SD 3.2). Based on the weight loss achieved after 6 months, 3 success groups were generated. The unsuccessful group lost <5%, the moderate success group lost 5%-9.9%, and the high success group lost ≥10% of their baseline body weight. At baseline, the unsuccessful (n=261, 54.5%), moderate success (n=133, 27.8%), and high success (n=85, 17.8%) groups were similar in age, weight, BMI, and gender distribution.

Results

After 6 months, the unsuccessful group lost 1.2% (SD 2.4), the moderate success group lost 7.4% (SD 1.5), and the high success group lost 14.2% (SD 3.8) of their initial weight (P<.001). Multivariate regression showed that early weight loss (weeks 3-4), the total number of dietary protocols, and the total number of weight entries were independent predictors for 6-month weight reduction (all P<.001) explaining 52% of the variance in weight reduction. Sensitivity analysis by baseline carried forward method confirmed all independent predictors of 6-month weight loss and reduced the model fit by only 11%. The high success group lost weight faster and maintained weight loss more efficiently than the other groups (P<.001). Early weight loss was associated with weight maintenance after 1 year and 2 years (both P<.001). Weight dynamics did not differ between men and women over 6 months when adjusted for baseline and usage parameters (P=.91). The percentage of male long-term users was unusually high (42.2%).

Conclusions

Our results suggest that early weight loss and close program adherence (ie, 5 dietary protocols per week and weekly entering of current weight), especially in the early phase of program usage, can improve weight loss outcome.     

Comparison of pregnenolone sulfate,pregnanolone and estradiol levels between patients with menstrually-related migraine and controls: an exploratory study

BackgroundNeurosteroids affect the balance between neuroexcitation and neuroinhibition but have been little studied in migraine. We compared the serum levels of pregnenolone sulfate, pregnanolone and estradiol in women with menstrually-related migraine and controls and analysed if a correlation existed between the levels of the three hormones and history of migraine and age.MethodsThirty women (mean age ± SD: 33.5 ± 7.1) with menstrually-related migraine (MM group) and 30 aged- matched controls (mean age ± SD: 30.9 ± 7.9) participated in the exploratory study. Pregnenolone sulfate and pregnanolone serum levels were analysed by liquid chromatography-tandem mass spectrometry, while estradiol levels by enzyme-linked immunosorbent assay.ResultsSerum levels of pregnenolone sulfate and pregnanolone were significantly lower in the MM group than in controls (pregnenolone sulfate: P = 0.0328; pregnanolone: P = 0.0271, Student’s t-test), while estradiol levels were similar. In MM group, pregnenolone sulfate serum levels were negatively correlated with history of migraine (R² = 0.1369; P = 0.0482) and age (R² = 0.2826, P = 0.0025) while pregnenolone sulfate levels were not age-related in the control group (R² = 0.04436, P = 0.4337, linear regression analysis).ConclusionLow levels of both pregnanolone, a positive allosteric modulator of the GABAA receptor, and pregnenolone sulfate, a positive allosteric modulator of the NMDA receptor, involved in memory and learning, could contribute either to headache pain or the cognitive dysfunctions reported in migraine patients. Overall, our results agree with the hypothesis that migraine is a disorder associated with a loss of neurohormonal integrity, thus supporting the therapeutic potential of restoring low neurosteroid levels in migraine treatment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01231-9.     

Secondary prevention of cryptogenic stroke in patients with patent foramen ovale: a systematic review and meta-analysis

The aim of our study is to compare patent foramen ovale (PFO) closure versus medical treatment and antiplatelet versus anticoagulant therapy in patients with cryptogenic stroke (CS) and PFO. We conducted a systematic review and meta-analysis with trial sequential analysis (TSA) of randomized trials. Primary outcomes are stroke or transient ischemic attack (TIA) and all-cause mortality. Secondary outcomes are peripheral embolism, bleeding, serious adverse events, myocardial infarction and atrial dysrhythmias. We performed an intention to treat meta-analysis with a random-effects model. We include six trials (3677 patients, mean age 47.3 years, 55.8% men). PFO closure is associated with a lower recurrence of stroke or TIA at a mean follow-up of 3.88 years compared to medical therapy [risk ratio (RR) 0.55, 95% CI 0.38–0.81; I²?=?40%]. The TSA confirms this result. No difference is found in mortality (RR 0.74, 95% CI 0.35–1.60; I²?=?0%), while PFO closure is associated with a higher incidence of atrial dysrhythmias (RR 4.55, 95% CI 2.16–9.60; I²?=?25%). The rate of the other outcomes is not different among the two groups. The comparison between anticoagulant and antiplatelet therapy shows no difference in terms of stroke recurrence, mortality and bleeding. There is conclusive evidence that PFO closure reduces the recurrence of stroke or TIA in patients younger than 60 years of age with CS. More data are warranted to assess the consequences of the increase in atrial dysrhythmias and the advantage of PFO closure over anticoagulants.     

Bone mineral density improvement after lung volume reduction surgery for severe emphysema

BACKGROUND: In patients with severe emphysema, bone mineral density (BMD) is reduced and the risk of osteoporosis is increased. STUDY OBJECTIVES: To identify the impact of lung volume reduction surgery on BMD. DESIGN: Prospective cohort study. SETTING: University hospital. PATIENTS AND INTERVENTIONS: Forty emphysematous patients, all receiving oral steroid therapy, underwent bilateral lung volume reduction surgery. Thirty similar patients, who refused the operation, followed a standard respiratory rehabilitation program. MEASUREMENTS: All subjects were evaluated pretreatment and 12 months posttreatment for respiratory function, nutritional status, and bone-related biochemical parameters. BMD was assessed by dual-energy radiograph absorptiometry. RESULTS: After surgery, we observed significant improvements in respiratory function (FEV1, + 18.8% [p < 0.01]; residual volume [RV], -29.6% [p < 0.001]; diffusing capacity of the lung for carbon monoxide [Dlco], + 21.6% [p < 0.01]) nutritional parameters (fat-free mass, + 6.0% [p < 0.01]), levels of bone-related hormones (free-testosterone, + 20.5% [p < 0.01]; parathormone, -11.2% [p < 0.01]), bone turnover markers (osteocalcin, -12.7% [p < 0.05]; bone-alkaline-phosphatase, -14.0% [p < 0.05]; beta-crosslaps, -33.6% [p < 0.001]), BMD (lumbar, + 8.8% [p < 0.01]; femoral, + 5.5% [p < 0.01]), and T-score (lumbar, + 21.0% [p < 0.01]; femoral, + 12.4% [p < 0.01]) with reduction in osteoporosis rate (50 to 25%). Nineteen patients who had undergone surgery were able to discontinue treatment with oral steroids. These subjects showed a more significant improvement in BMD (lumbar, + 9.6%; femoral, + 6.8%; p < 0.001) and T-score (lumbar, + 27.3%; femoral, + 14.3%; p < 0.001). The remaining 21 patients who had undergone surgery experienced significant improvement compared to respiratory rehabilitation subjects despite continued therapy with oral steroids (BMD: lumbar, + 4.5% vs -0.7%, respectively [p < 0.01]; femoral, + 2.7% vs -1.1%, respectively [p < 0.05]; T-score: lumbar, + 14 vs -2.1, respectively [p < 0.01]; femoral, + 7.4 vs -2.7, respectively [p < 0.01]). The increase in lumbar BMD was correlated with the surgical reduction of RV (p = 0.02) and with the increase in Dlco (p = 0.01) and fat-free mass (p = 0.01). CONCLUSIONS: Lung volume reduction surgery significantly improves BMD compared to respiratory rehabilitation therapy, even in patients requiring oral steroids. The increase in BMD correlates with RV, Dlco, and fat-free mass, suggesting that the restoration of respiratory dynamics, gas exchange, and nutritional status induces improvement in bone metabolism and mineral content.