The molecular basis of familial hypercholesterolemia in the Czech Republic: Spectrum of LDLR mutations and genotype-phenotype correlations

BackgroundFamilial hypercholesterolemia (FH), a major risk for coronary heart disease, is predominantly associated with mutations in the genes encoding the low-density lipoprotein receptor (LDLR) and its ligand apolipoprotein B (APOB).ResultsIn this study, we characterize the spectrum of mutations causing FH in 2239 Czech probands suspected to have FH. In this set, we found 265 patients (11.8%) with the APOB mutation p.(Arg3527Gln) and 535 patients (23.9%) with a LDLR mutation. In 535 probands carrying the LDLR mutation, 127 unique allelic variants were detected: 70.1% of these variants were DNA substitutions, 16.5% small DNA rearrangements, and 13.4% large DNA rearrangements. Fifty five variants were novel, not described in other FH populations. For lipid profile analyses, FH probands were divided into groups [patients with the LDLR mutation (LDLR+), with the APOB mutation (APOB+), and without a detected mutation (LDLR?/APOB?)], and each group into subgroups according to gender. The statistical analysis of lipid profiles was performed in 1722 probands adjusted for age in which biochemical data were obtained without FH treatment (480 LDLR+ patients, 222 APOB+ patients, and 1020 LDLR?/APOB? patients). Significant gradients in i) total cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients) ii) LDL cholesterol (LDLR+ patients > APOB+ patients = LDLR?/APOB? patients in men and LDLR+patients > APOB+ patients >LDLR?/APOB? patients in women), iii) triglycerides (LDLR?/APOB? patients > LDLR+ patients > APOB+ patients), and iv) HDL cholesterol (APOB+ patients > LDLR?/APOB? patients = LDLR+ patients) were shown.ConclusionOur study presents a large set of Czech patients with FH diagnosis in which DNA diagnostics was performed and which allowed statistical analysis of clinical and biochemical data.     

Pathology of myocardial infarction

Myocardial infarction (MI) is an increasing problem, worldwide. An appreciation of its causes and morphology helps provide a basis for development of new interventions, as well as its management, and in the future prevention. Studies have shown that the myocardium does not suffer sudden and complete permanent damage, but rather that it takes time for the damage to start and to progress. It is this interval that is used to salvage myocardium, post ischaemic myocardial events, thus improving patient outcomes. This paper discusses the morphological findings at different time points and illustrates them.     

Histological evaluation of human intrabony periodontal defects treated with an unsintered nanocrystalline hydroxyapatite paste

Objectives

The aim of the study was to clinically and histologically evaluate the healing of human intrabony defects treated with open flap surgery (OFD) and application of a new, resorbable, fully synthetic, unsintered, nanocrystalline, phase-pure hydroxyapatite (nano-HA).

Materials and methods

Six patients, each of them displaying very advanced intrabony defects around teeth scheduled for extraction due to advanced chronic periodontitis and further prosthodontic considerations, were included in the study. Following local anaesthesia, mucoperiosteal flaps were reflected; the granulation tissue was removed, and the roots were meticulously debrided by hand and ultrasonic instruments. A notch was placed at the most apical extent of the calculus present on the root surface or at the most apical part of the defect (if no calculus was present) in order to serve as a reference for the histological evaluation. Following defect fill with nano-HA, the flaps were sutured by means of mattress sutures to allow primary intention healing. At 7 months after regenerative surgery, the teeth were extracted together with some of their surrounding soft and hard tissues and processed for histological analysis.

Results

The postoperative healing was uneventful in all cases. At 7 months following surgery, mean PPD reduction and mean CAL gain measured 4.0?±?0.8 and 2.5?±?0.8 mm, respectively. The histological analysis revealed a healing predominantly characterized by epithelial downgrowth. Limited formation of new cementum with inserting connective tissue fibers and bone regeneration occurred in three out of the six biopsies (i.e. 0–0.86 and 0–1.33 mm, respectively). Complete resorption of the nano-HA was found in four out of the six biopsies. A few remnants of the graft particles (either surrounded by newly formed mineralized tissue or encapsulated in connective tissue) were found in two out of the six biopsies.

Conclusion

Within their limits, the present results indicate that nano-HA has limited potential to promote periodontal regeneration in human intrabony defects.

Clinical relevance

The clinical outcomes obtained following surgery with OFD?+?nano-HA may not reflect true periodontal regeneration.     

Assessment of Hemodialysis Adequacy by Ionic Dialysance: Comparison to Standard Method of Urea Removal

Background. The hemodialysis adequacy is one of the most important issues influencing the survival of patients on maintenance hemodialysis (HD). Assessment of measuring the delivered dialysis dose using clearance × time/volume (Kt/V) index requires multiple blood sampling. New methods for assessment of dialysis dose based on ionic dialysance (ID) have been suggested. Online conductivity monitoring (using sodium flux as a surrogate for urea) allows the repeated noninvasive measurement of Kt/V on each HD treatment. In this study we have compared this method with the standard method of estimating Kt/V. Methods. We studied 24 established HD patients over a 4 week time period. Patients were dialyzed using Fresenius 4008S dialysis monitors, equipped with modules to measure ID. Data were manually collected and analyzed using the appropriate statistical software. Urea removal (UR) was measured once a week by a two-pool calculation, estimating an eKt/V. Results. The Kt/V measured by ID highly correlated with the one derived from the measurement of the UR (r = 0.8959, p< 0.0001). The ID underestimated UR by the mean of 6%. The ID varied greatly within individual patients with a median of 1.29 ± 0.22. If the eKt/V ≥ 1.2 is considered adequate, 33% of the patients would have been inadequately dialyzed. The mean HD duration to achieve an adequate dialysis was 4 hours and 47 minutes with high interpatient variability. Conclusion. The ID seems to be an easily obtained measure of the delivered dialysis dose, correlating well with standard UR method. Substantial individual variations imply that repeated measures (ideally for all treatments) are necessary to obtain a real answer to the mean treatment dose being delivered to the patients.     

The effects of microenvironment in mesenchymal stem cell–based regeneration of intervertebral disc

Background contextRecent studies have demonstrated new therapeutic strategy using transplantation of mesenchymal stem cells (MSCs), especially bone marrow–derived MSCs (BM-MSCs), to preserve intervertebral disc (IVD) structure and functions. It is important to understand whether and how the MSCs survive and thrive in the hostile microenvironment of the degenerated IVD. Therefore, this review majorly examines how resident disc cells, hypoxia, low nutrition, acidic pH, mechanical loading, endogenous proteinases, and cytokines regulate the behavior of the exogenous MSCs.PurposeTo review and summarize the effect of the microenvironment in biological characteristics of BM-MSCs for IVD regeneration; the presence of endogenous stem cells and the state of the art in the use of BM-MSCs to regenerate the IVD in vivo were also discussed.Study designLiterature review.MethodsMEDLINE electronic database was used to search for articles concerning stem/progenitor cell isolation from the IVD, regulation of the components of microenvironment for MSCs, and MSC-based therapy for IVD degeneration. The search was limited to English language.ResultsStem cells are probably resident in the disc, but exogenous stem cells, especially BM-MSCs, are currently the most popular graft cells for IVD regeneration. The endogenous disc cells and the biochemical and biophysical components in the degenerating disc present a complicated microenvironment to regulate the transplanted BM-MSCs. Although MSCs regenerate the mildly degenerative disc effectively in the experimental and clinical trials, many underlying questions are in need of further investigation.ConclusionsThere has been a dramatic improvement in the understanding of potential MSC-based therapy for IVD regeneration. The use of MSCs for IVD degeneration is still at the stage of preclinical and Phase 1 studies. The effects of the disc microenvironment in MSCs survival and function should be closely studied for transferring MSC transplantation from bench to bedside successfully.     

Social participation in early and established rheumatoid arthritis patients

Purpose: The aim of the study was to examine whether rheumatoid arthritis (RA) patients with different levels of restriction in social participation differ in disease related as well as psychosocial variables and whether a similar pattern can be found among early and established RA patients.

Method: Two samples of RA patients with early (n?=?97; age?=?53?±?12.3 years; disease duration?= 2.8?±?1.2 years; 76% women) and established (n?=?143; age?=?58?±?10.3 years; disease duration?= 16.1?±?3.6 years; 86% women) were collected. The pattern of differences for the patients with different level of participation restriction (no restriction, mild, moderate or high restriction) was explored by the Jonckheere–Terpstra test. Results: Significant differences were found between patients with different levels of social participation restrictions in both samples in pain, fatigue, functional disability, anxiety, depression and mastery. Generally, it was found that patients with higher restrictions experienced more pain and fatigue, more anxiety and depression and reported lower mastery. Similar pattern of differences concerning disease activity and self-esteem was found mainly in the established group. Conclusions: The study shows that the level of perceived restrictions in social participation are highly relevant regarding the disease related variables such as pain, fatigue and functional disability as well as psychological status and personal resources in both early and established RA.

• Implications for Rehabilitation

• Supporting involvement and participation of individuals with rheumatoid arthritis is important for decreasing the impact of RA symptoms on everyday life.

• Recognition and empowerment of individual resources such a mastery and self-esteem of RA patients could be beneficial for overcoming restrictions in participation.

     

Peculiarities of vasomotor reaction of cerebral vessels in arterial hypertension

We studied vasomotor activity of rat cerebral vessels. Peculiarities of endothelium-dependent reactions of cerebral arteries in induced arterial hypertension were revealed. Quantitative and qualitative relationships between the parameters of the vasomotor apparatus of cerebral arteries and parameters of circulatory homeostasis were determined. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 144, No. 7, pp. 36–38, July, 2007     

Phenotypic and population differences in the association between CILP and lumbar disc disease

Background

Lumbar disc disease (LDD) is one of the leading causes of disability in the working‐age population. A functional single‐nucleotide polymorphism (SNP), +1184T→C, in exon 8 of the cartilage intermediate layer protein gene (CILP) was recently identified as a risk factor for LDD in the Japanese population (odds ratio (OR) 1.61, 95% CI 1.31 to 1.98), with implications for impaired transforming growth factorβ1 signalling.

Aim

To validate this finding in two different ethnic cohorts with LDD.

Methods

This SNP and flanking SNPs were analysed in 243 Finnish patients with symptoms of LDD and 259 controls, and in 348 Chinese subjects with MRI‐defined LDD and 343 controls.

Results and conclusion

The results showed no evidence of association in the Finnish (OR = 1.35, 95% CI 0.97 to 1.87; p = 0.14) or the Chinese (OR = 1.05, 95% CI 0.77 to 1.43; p = 0.71) samples, suggesting that cartilage intermediate layer protein gene is not a major risk factor for symptoms of LDD in Caucasians or in the general population that included individuals with or without symptoms.Lumbar disc disease (LDD) is one of the leading causes of disability in the working‐age population. Radiological changes indicative of LDD are common, but only a proportion develops complications such as disc herniation and sciatica. Although the aetiology of LDD is not well understood, there is strong evidence for the involvement of both genetic and environmental factors.^1,2A recent study reported an association between LDD and a functional single‐nucleotide polymorphism (SNP) (rs2073711), +1184T→C, in exon 8 of the cartilage intermediate layer protein gene (CILP) in a Japanese group (odds ratio (OR) 1.61, 95% CI 1.31 to –1.98).³ The allelic change resulted in amino acid substitution Ile395Thr. CILP is expressed widely in intervertebral discs and its expression increases as disc degeneration progresses.³ CILP interacts directly with transforming growth factor (TGF)β1, inhibiting the TGFβ1‐mediated induction of extracellular matrix proteins such as aggrecan and collagen II.³ Functional studies showed that the C allele (coding for Thr395) increased binding and inhibition of TGFβ1, suggesting that regulation of TGFβ1 signalling by CILP plays a crucial role in the aetiology and pathogenesis of LDD.³Argument for a causal role would be strengthened if the same association could be replicated in a distinct population, and in clinical cases of LDD defined by MRI changes indicative of LDD in general. Therefore, we investigated the association between CILP polymorphisms and LDD in a Finnish sample with symptoms of LDD, and in a Chinese sample with only MRI‐defined LDD. These samples were informative in previous studies demonstrating association of LDD with the vitamin D receptor gene⁴ and the Gln326Trp (Trp2) allele of COL9A2⁵ in Chinese and the Arg103Trp (Trp3) allele of COL9A3 in Finns.⁶ Thus, the Chinese sample is comparable with the Finnish dataset, and a correlation can then be drawn with the Japanese dataset.