Aims To examine the heritability of atrial fibrillation (AF) in Icelanders, utilizing a nationwide genealogy database and population-based data on AF. AF is a disorder with a high prevalence, which ...has been known to cluster in families, but the heritability of the common form has not been well defined. Methods and results The study population included 5269 patients diagnosed since 1987 and age-sex-matched controls randomly selected from the genealogy database. Kinship coefficients (KC), expressed as genealogical index of familiality (GIF=average KC×100 000), were calculated before and after exclusion of relatives separated by one to five meiotic events. Risk ratios (RR) were calculated for first- to fifth-degree relatives. The average pairwise GIF among patients with AF was 15.9 (mean GIF for controls 13.9, 95%CI=13.3, 14.4); this declined to 15.4 (mean GIF for controls 13.6, 95%CI=13.1, 14.2) after exclusion of relatives separated by one meiosis and to 13.7 (mean GIF for controls 12.6, 95%CI=12.1, 13.2), 12.7 (mean GIF for controls 11.9, 95%CI=11.4, 12.4), and 11.3 (mean GIF for controls 10.6, 95%CI=10.1, 11.1) after exclusion of relatives within two, three, and four meioses, respectively (all P<0.00001). RRs among relative pairs also declined incrementally, from 1.77 in first-degree relatives to 1.36, 1.18, 1.10, and 1.05 in second- through fifth-degree relatives (all P<0.001), consistent with the declining proportion of alleles shared identically by descent. When the analysis was limited to subjects diagnosed with AF before the age of 60, first-degree relatives of the AF cases were nearly five times more likely to have AF than the general population. Conclusion AF shows strong evidence of heritability among unselected patients in Iceland, suggesting that there may be undiscovered genetic variants underlying the risk of the common form of AF.
Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a ...genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1x10(-10)). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3 x 10(-23)) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0 x 10(-17)) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0 x 10(-6)), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7 x 10(-5)).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The contribution of low-penetrant susceptibility variants to cancer is not clear. With the aim of searching for genetic factors that contribute to cancer at one or more sites in the body, we have ...analyzed familial aggregation of cancer in extended families based on all cancer cases diagnosed in Iceland over almost half a century.
We have estimated risk ratios (RRs) of cancer for first- and up to fifth-degree relatives both within and between all types of cancers diagnosed in Iceland from 1955 to 2002 by linking patient information from the Icelandic Cancer Registry to an extensive genealogical database, containing all living Icelanders and most of their ancestors since the settlement of Iceland. We evaluated the significance of the familial clustering for each relationship separately, all relationships combined (first- to fifth-degree relatives) and for close (first- and second-degree) and distant (third- to fifth-degree) relatives. Most cancer sites demonstrate a significantly increased RR for the same cancer, beyond the nuclear family. Significantly increased familial clustering between different cancer sites is also documented in both close and distant relatives. Some of these associations have been suggested previously but others not.
We conclude that genetic factors are involved in the etiology of many cancers and that these factors are in some cases shared by different cancer sites. However, a significantly increased RR conferred upon mates of patients with cancer at some sites indicates that shared environment or nonrandom mating for certain risk factors also play a role in the familial clustering of cancer. Our results indicate that cancer is a complex, often non-site-specific disease for which increased risk extends beyond the nuclear family.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increased prosthetic hip to toe distance and insufficient mid swing toe clearance of a prosthetic foot is a well-recognized inadequacy for lower limb prosthesis users with wide and possible grave ...consequences on their ambulation capabilities. Most important are increased risk of falls and abnormal compensatory gait patterns with secondary unwanted physical effect like generally deceased mobility, muscular-skeletal pain and joint degeneration, i.e. osteoarthritis, with possible significant health economic effect. Even though insufficient toe clearance can be device related and technically or even intentionally induced for attaining equal length of the lower extremities in a neutral standing position or the stance phase, it is important to be aware of available technical solutions that can counteract the problem, like swing phase dorsiflexing feet, vacuum suspension systems, polycentric axis knees rather than single-axis knees and adequate knee flexion in early swing and swing-flexion assistance in the case of bionic knees.
Article PDf Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/30813/23259
How to cite: Lechler K, and Kristjansson K. The importance of additional mid swing toe clearance for amputees. Canadian Prosthetics & Orthotics Journal. Volume1, Issue2, No.1, 2018. DOI: https://doi.org/10.33137/cpoj.v1i2.30813
Gene expression profiles were examined in freshly isolated peripheral blood mononuclear cells (PBMC) from two independent cohorts (training and test sets) of glucocorticoid (GC)-sensitive (n = 64) ...and GC-resistant (n = 42) asthma patients in search of genes that accurately predict responders and nonresponders to inhaled corticosteroids. A total of 11,812 genes were examined with high-density oligonucleotide microarrays in both resting PBMC (106 patients) and cells treated in vitro with IL-1β and TNF-α combined (88 patients), with or without GC. A total of 5,011 genes were expressed at significant levels in the PBMC, and 1,334 of those were notably up-regulated or down-regulated by IL-1β/TNF-α treatment. The expression changes of 923 genes were significantly reversed in GC responders in the presence of GC. The expression pattern of 15 of these 923 genes that most accurately separated GC responders (n = 26) from the nonresponders (n = 18) in the training set, based on the weighted voting algorithm, predicted the independent test set of equal size with 84% accuracy. The expression accuracy of these genes was confirmed by real-time-quantitative PCR, wherein 11 of the 15 genes predicted GC sensitivity at baseline with 84% accuracy, with one gene predicting at 81% in an independent cohort of 79 patients. We conclude that we have uncovered gene expression profiles in PBMC that predict clinical response to inhaled GC therapy with meaningful accuracy. Upon validation in an independent study, these results support the development of a diagnostic test to guide GC therapy in asthma patients.
Abstract Objective Night-to-night variability of periodic leg movements (PLMs) in restless legs syndrome (RLS) was examined to define the range of intra-subject values, impact upon diagnosing RLS, ...and clinical correlates. Methods Twenty RLS patients were monitored for 10–15 nights using a validated, tri-axial accelerometer worn on the ankle. Results The mean difference in PLMs index (PLMI) between the lowest and highest night was 25.1/h (range: 3.9–73.8). Inter-subject differences accounted for nearly five times the variance in PLMI relative to between nights within an individual. Based on a single night of recording, PLMI criterion thresholds of 5, 10, and 15/h were exceeded on approximately 70.1%, 51.9% and 34.1% of individual nights among these patients. Based on five randomly sampled nights of recordings, the likelihood that such thresholds were met on at least a single night increased to 91.2%, 80.8% and 62.7%, respectively. Women exhibited greater variability. Conclusions Variability in PLMs within RLS subjects was substantial, yet individuals’ characteristic PLM level represented a quantitative trait. Variability was unrelated to age or scores on scales of RLS severity, sleepiness, functional status, and mood. A larger number of recording nights increased the likelihood that any criterion was reached.
This study was designed to investigate the feasibility and the potential effects on walking performance of a short gait training with a novel impairment-specific hip assistance (iHA) through a ...bilateral active pelvis orthosis (APO) in patients with acquired brain injury (ABI). Fourteen subjects capable of independent gait and exhibiting mild-to-moderate gait deficits, due to an ABI, were enrolled. Subjects presenting deficit in hip flexion and/or extension were included and divided into two groups based on the presence (group A, n = 6) or absence (group B, n = 8) of knee hyperextension during stance phase of walking. Two iHA-based profiles were developed for the groups. The protocol included two overground gait training sessions using APO, and two evaluation sessions, pre and post training. Primary outcomes were pre vs. post-training walking distance and steady-state speed in the 6-min walking test. Secondary outcomes were self-selected speed, joint kinematics and kinetics, gait symmetry and forward propulsion, assessed through 3D gait analysis. Following the training, study participants significantly increased the walked distance and average steady-state speed in the 6-min walking tests, both when walking with and without the APO. The increased walked distance surpassed the minimal clinically important difference for groups A and B, (respectively, 42 and 57 m > 34 m). In group A, five out of six subjects had decreased knee hyperextension at the post-training session (on average the peak of the knee extension angle was reduced by 36%). Knee flexion during swing phase increased, by 16% and 31%, for A and B groups respectively. Two-day gait training with APO providing iHA was effective and safe in improving walking performance and knee kinematics in ABI survivors. These preliminary findings suggest that this strategy may be viable for subject-specific post-ABI gait rehabilitation.
Most prosthetic limbs can autonomously move with dexterity, yet they are not perceived by the user as belonging to their own body. Robotic limbs can convey information about the environment with ...higher precision than biological limbs, but their actual performance is substantially limited by current technologies for the interfacing of the robotic devices with the body and for transferring motor and sensory information bidirectionally between the prosthesis and the user. In this Perspective, we argue that direct skeletal attachment of bionic devices via osseointegration, the amplification of neural signals by targeted muscle innervation, improved prosthesis control via implanted muscle sensors and advanced algorithms, and the provision of sensory feedback by means of electrodes implanted in peripheral nerves, should all be leveraged towards the creation of a new generation of high-performance bionic limbs. These technologies have been clinically tested in humans, and alongside mechanical redesigns and adequate rehabilitation training should facilitate the wider clinical use of bionic limbs.
Migraine is a common form of headache and has a significant genetic component. Here, we report linkage results from a study in Iceland of migraine without aura (MO). The study group comprised ...patients with migraine recruited by neurologists and from the registry of the Icelandic Migraine Society, as well as through the use of a questionnaire sent to a random sample of 20,000 Icelanders. Migraine diagnoses were made and confirmed using diagnostic criteria established by the International Headache Society. A genomewide scan with multipoint allele-sharing methods was performed on 289 patients suffering from MO. Linkage was observed to a locus on chromosome 4q21 (
LOD=
2.05;
P=.001). The locus reported here overlaps a locus (MGR1) reported elsewhere for patients with migraine with aura (MA) in the Finnish population. This replication of the MGR1 locus in families with MO indicates that the gene we have mapped may contribute to both MA and MO. Further analysis indicates that the linkage evidence improves for affected females and, especially, with a slightly relaxed definition of MO (
LOD=
4.08;
P=7.2×10
−6).
Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 ...missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.
The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio OR = 1.82, 95% confidence interval CI 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.
Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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