Hypertrophic cardiomyopathy：from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions.Hypertrophic cardiomyopathy(HCM)was the first cardiac disorder in which a genetic basis was identified and as such,has acted as a paradigm for the study of an inherited cardiac disorder.HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death.HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes.At least ten genes have now been identified,defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart,i.e.the sarcomere.While much is now known about which genes cause disease and the various clinical presentations,very little is known about how these gene defects cause disease,and what factors modify the expression of the mutant genes.Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM,and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function,and will therefore provide new avenues for treating cardiovascular disease in man.     

Hypertrophic muscle fibers with fissures in power-lifters; fiber splitting or defect regeneration?

Power-lifters have hypertrophic muscle fibers with fissures seen in cross-sections, called as fiber splitting.Whether this phenomenon is due to real splitting or defective regeneration has not been settled. To elucidate this matter,we have examined biopsies from the trapezius and vastus lateralis of power lifters (P group) and power lifters self-administrating anabolic steroids (PAS group). For this purpose, immunohistochemical staining of serial cross -sections was used. The PAS group had significantly more fibers with fissures than the P group in the vastus lateralis (1.2%±0.95% vs 0.35±0.34, P<0.05) but not in the trapezius muscle (1.7% in both groups). Serial sections revealed that the fibers with fissures changed their profile profoundly over short distances. Some such fibers had a mature staining profile, whereas other fibers indicated recent degeneration and/or regeneration. Activation of satellite cells and formation of aberrant segments were also evident. We conclude that the so-called split fibers are due to defect regeneration. Some fibers with fissures are the results of old events of segmental muscle fiber damage, whereas the others reflect an ongoing process. The normal regenerative process is most likely disturbed in power-lifters by their continuous training with repeated high mechanical stress on the muscles.     

How NOD2 mutations predispose to Crohn's disease?

NOD2 mutations are associated with the development of granulomatous inflammatory diseases, such as early-onset sarcoidosis (EOS), Blau syndrome (BS) and Crohn's disease (CD). As a pathogen-recognition molecule for muramyl dipeptide (MDP), NOD2 controls both innate and adaptive immune responses, through the regulation of cytokines, chemokines and antimicrobial peptides production. Notably, Nod2-deficient mice experienced increased susceptibility to enteric infection and to antigen-specific colitis. Furthermore, mutant mice bearing the orthologue of the major CD-associated NOD2^3020ins allele showed increased susceptibility to DSS-induced colitis. However, many questions remain open. (i) Is antimicrobial function deficiency sufficient to initiate the development of CD? (ii) How impaired and mutant NOD2 might lead to increased adaptive immune response? (iii) How do the other disease-associated NOD2 mutations contribute to the development of chronic intestinal inflammation? Whatever the relevant mechanism(s), it provides a casual link between abnormal bacterial sensing and development of inflammatory disorders. Further work should now focus on restoring abnormal NOD2 function by modulating antimicrobial function and regulatory mechanisms of the adaptive immune system.     

Is the ApoE polymorphism associated with dilated cardiomyopathy?

Apolipoprotein E (ApoE) is 34 kDa protein involved in the modulation of cholesterol transport and homeostasis. Polymorphism of the ApoE gene has been implicated in many chronic cardiovascular and neuronal diseases. ApoE epsilon4 allele has been reported to be associated with increased risk of cardiovascular diseases such as myocardial infarction, hypertension, coronary heart disease, etc. Fifty patients with the end-stage dilated cardiomyopathy (DCM) and advanced congestive heart failure were examined in our study. For evaluation of ApoE polymorphism, novel approach of fast screening of ApoE gene polymorphism by combination of PCR and blotting (CVD StripAssay) was used. Individual genotypes were correlated with basic cardiologic clinical parameters. The reported frequency of this allele in Caucasian population is 14.7 %. Our results showed that in patients with DCM frequency of the ApoE epsilon4 allele is 40 %. Frequency of the genotype epsilon2/4 was 58 % and epsilon3/4 was 22 %. Comparison with control Caucasian groups monitored by others clearly revealed that frequency of epsilon4 alelle is increased in patients with advanced stages of DCM. This observation suggests association of ApoE polymorphism with severe form of DCM. Physiological consequences of this observation remain to be clarified.     

Beyond sepsis pathophysiology with cytokines: what is their value as biomarkers for disease severity?

Sepsis is a major challenge in medicine. It is a common and frequently fatal infectious condition. The incidence continues to increase, with unacceptably high mortality rates, despite the use of specific antibiotics, aggressive operative intervention, nutritional support, and anti-inflammatory therapies. Typically, septic patients exhibit a high degree of heterogeneity due to variables such as age, weight, gender, the presence of secondary disease, the state of the immune system, and the severity of the infection. We are at urgent need for biomarkers and reliable measurements that can be applied to risk stratification of septic patients and that would easily identify those patients at the highest risk of a poor outcome. Such markers would be of fundamental importance to decision making for early intervention therapy or for the design of septic clinical trials. In the present work, we will review current biomarkers for sepsis severity and especially the use of cytokines as biomarkers with important pathophysiological role.     

Why homocysteine-lowering therapy does not have beneficial effects on patients with cardiovascular disease?

Homocysteine is a sulfur-containing amino acid produced during the metabolism of methionine and elevated plasma levels of homocysteine have been linked to an increased risk of atherosclerosis and cardiovascular ischemic events by numerous authors. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed including impairment of endothelial function and at least some of those mechanisms are induced via homocysteine-associated DNA hypomethylation. Oral administration of folic acid and B vitamins, required for remethylation of homocysteine to methionine, decreased plasma total homocysteine levels but clinical trials using folic acid and B vitamins did not confirm that the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk. In our view a plausible explanation for the discordance between the epidemiologic studies and the results of the clinical trials may be related to the homocysteine-associated global DNA hypomethylation which cannot easily be reversed by homocysteine-lowering therapy.     

Is serum fibroblast growth factor 21 associated with the severity or presence of coronary artery disease?

BackgroundRecent studies have shown that increased circulating concentrations of fibroblast growth factor 21 (FGF21) are associated with obesity, metabolic disorder, and atherosclerosis. However the relationship between FGF21 and coronary artery disease (CAD) is controversial This study was planned to investigate the role of FGF21 in CAD development and CAD severity.MethodsSeventy-eight patients with stable angina pectoris (SAP) (lesion positive) and 40 control patients (lesion negative) with similar cardiovascular risk factors were included in the study. Serum FGF21 levels were measured by ELISA method. CAD severity was evaluated by using SYNTAX and GENSINI risk scores.ResultsFGF21 concentrations were found significantly higher in the SAP group than in the control group. [101.18 ± 141.62 vs. 47.93 ± 58.74 pg/mL; p = 0.03], no correlation was found between the SYNTAX (r = 0.146 and p = 0.134) and GENSINI (r = 0.211 and p = 0.084) scores with serum FGF21 levels. There was a negative relationship between serum FGF21 and serum HDL-C levels in correlation analysis (r = - 0.272; p = 0.026).ConclusionsThe serum FGF21 levels are different between SAP and control patients. FGF21 is a marker for CAD diagnosis, but not for the evaluation of CAD severity.     

iPAD or PADi — ‘tablets’ with therapeutic disease potential?

The PAD enzymes.

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How does the host‐specialized aphid deal with food deficiency?

Aphis gossypii Glover shows obvious host specialization, with cucurbit‐ and cotton‐specialized biotypes or host races in many regions. Because its annual natal host crops senesce earlier the cucurbit‐specialized biotype may suffer food deficiency. The method this biotype uses to overcome this challenge is still poorly understood. In order to understand the potential of the cucurbit‐specialized biotype aphids in host shift and usage, the performance of this biotype on cotton (Gossypium hirsutum), a common but poor quality host plant, was explored in this study. The cucurbit‐specialized aphids could establish populations on cotton only when these plants had at least nine leaves, and subsequent populations developed rather slowly. The presence of whitefly populations on cotton improved the success rate of cucurbit‐specialized aphids. The cucurbit‐specialized aphids were mainly distributed on the older leaves of cotton, with only a few settling on the upper leaves. The cucurbit‐specialized aphids reared on cotton for 40, 54 and 61 days still maintained strong preference for their natal host plant, cucumber (Cucumis sativus), rather than cotton, and their net reproductive rates and intrinsic rates of natural increase were dramatically lower when they were transferred onto new six‐leaf cotton plants or detached leaves. Therefore, we concluded that the cucurbit‐specialized aphids have the potential to utilize mature or whitefly‐stressed cotton plants, but that this feeding experience on cotton did not alter their specialization for cucurbits. Some cotton plants could act as a temporary host for the cucurbit‐specialized aphids to overcome food deficiency arising from senescing cucurbits.     

Are splicing mutations the most frequent cause of hereditary disease?

Disease-causing point mutations are assumed to act predominantly through subsequent individual changes in the amino acid sequence that impair the normal function of proteins. However, point mutations can have a more dramatic effect by altering the splicing pattern of the gene. Here, we describe an approach to estimate the overall importance of splicing mutations. This approach takes into account the complete set of genes known to be involved in disease and suggest that, contrary to current assumptions, many mutations causing disease may actually be affecting the splicing pattern of the genes.     

Autoimmunity in chagas disease cardiomyopathy: Fulfilling the criteria at last?

Here, Jorge Kalil and Edécio Cunha-Neto review the recent evidence for autoimmunity in chronic Chagas cardiomyopathy (CCC) involving molecularly defined antigens and immunopathological mechanisms. They also discuss the criteria for assignment of CCC as an organ-specific autoimmune disease.     

Neurodegeneration: how does parkin prevent Parkinson's disease?

Mutations in parkin cause Parkinson's disease due to the loss of the ubiquitin-protein ligase activity of Parkin protein. Recent data suggest we may be beginning to understand the nature of the proteins that are targeted by Parkin and how these cause neuronal damage.     

Is infertility a disease and does it matter?

Claims about whether or not infertility is a disease are sometimes invoked to defend or criticize the provision of state‐funded treatment for infertility. In this paper, I suggest that this strategy is problematic. By exploring infertility through key approaches to disease in the philosophy of medicine, I show that there are deep theoretical disagreements regarding what subtypes of infertility qualify as diseases. Given that infertility’s disease status remains unclear, one cannot uncontroversially justify or undermine its claim to medical treatment by claiming that it is or is not a disease. Instead of focusing on disease status, a preferable strategy to approach the debate about state‐funded treatment is to explicitly address the specific ethical considerations raised by infertility. I show how this alternative strategy can be supported by a recent theoretical framework in the philosophy of medicine which avoids the problems associated with the concepts of health and disease.     

NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C

Complementary and genomic DNAs isolated from the fibroblasts of 10 Japanese (7 late infantile, 2 juvenile, and 1 adult form of the disease) and one Caucasian patient with Niemann-Pick disease type C were analyzed for mutations in the NPC1 gene. Fourteen novel mutations were found including small deletions and point mutations. A one-base deletion and a point mutation caused splicing errors. The mutations were not clustered in any particular region of the gene and were found both in and out of the transmembrane domains. Three patients were homozygous, five were compound heterozygous, and the remaining three were suspected of being compound hetrozygous with an unknown error in one of their NPC1 alleles. Of the 14 mutations, the G1553A substitution that caused a splicing error of exon 9 appeared to be relatively common in Japanese patients, because two patients were homozygous and one patient was compound heterozygous for this mutation. Electronic Publication     

Novel <Emphasis Type="Italic">CHM</Emphasis> mutations in Polish patients with choroideremia – an orphan disease with close perspective of treatment

Background

Choroideremia (CHM) is a rare X-linked recessive retinal dystrophy characterized by progressive chorioretinal degeneration in the males affected. The symptoms include night blindness in childhood, progressive peripheral vision loss and total blindness in the late stages. The disease is caused by mutations in the CHM gene encoding Rab Escort Protein 1 (REP-1). The aim of the study was to identify the molecular basis of choroideremia in five families of Polish origin.

Methods

Six male patients from five unrelated families of Polish ethnicity, who were clinically diagnosed with choroideremia, were examined in this study. An ophthalmologic examination performed in all the probands included: best-corrected visual acuity, slit-lamp examination, funduscopy, fluorescein angiography and perimetry. The entire coding region encompassing 15 exons and the flanking intronic sequences of the CHM gene were amplified with PCR and directly sequenced in all the patients.

Results

Five variants in the CHM gene were identified in the five families examined. Two of the variants were new: c.1175dupT and c.83C?>?G, while three had been previously reported.

Conclusions

This study provides the first molecular genetic characteristics of patients with choroideremia from the previously unexplored Polish population.

     

How does parkin ligate ubiquitin to Parkinson's disease?

Recessive mutations in the human PARKIN gene are the most common cause of hereditary parkinsonism, which arises from the degeneration of dopaminergic neurons in the substantia nigra. However, the molecular mechanisms by which the loss of parkin causes dopaminergic neurodegeneration are not well understood. Parkin is an enzyme that ubiquitinates several candidate substrate proteins and thereby targets them for proteasomal degradation. Hypothesis-driven searches have led to the discovery of aggregation-prone protein substrates of parkin. Moreover, the enzyme is upregulated when under unfolded protein stress. Thus, loss-of-function mutations of parkin might impair the removal of potentially toxic protein aggregates. However, the limited neuropathological information that is available from parkin-proven patients, as well as the recent knockout of the parkin gene in fruit flies and mice, may indicate a more complex disease mechanism, possibly involving the misfolding of parkin itself or of additional substrates. The risk factors that predispose dopaminergic neurons to degenerate on parkin failure are yet to be identified.     

Network dysfunction in Alzheimer's disease: does synaptic scaling drive disease progression?

Accumulation of beta-amyloid protein (Abeta) in the brain is a key feature of Alzheimer's disease (AD). The build-up of aggregated forms of Abeta leads to synaptic loss and to cognitive dysfunction. Although the pathways controlling production and aggregation of Abeta are well studied, the mechanisms that drive the spread of neurodegeneration in the brain are unclear. Here, the idea is presented that AD progresses as a consequence of synaptic scaling, a type of neuronal plasticity that helps maintain synaptic signal strength. Recent studies indicate that brain-derived neurotrophic factor, tumour necrosis factor-alpha and alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) regulate synaptic scaling in the AD brain. It is suggested that further studies on synaptic scaling in AD could reveal new targets for therapeutic drug development.     

How does doxorubicin interfere with actin polymerization?

It is well known that doxorubicin (adriamycin), an antibiotic with an antitumoral action, has some undesirable side effects. Among these, the most serious is, undoubtedly, damage to myocardial tissue (progressive cardiomyopathy). We have for some time focused our attention on the effect of this drug on cellular contractile systems and, more specifically, on the process of actin polymerization, which we consider to be an extremely delicate key point for the economy of most cellular motor manifestations. In the present study, using capillary viscometry, spectrofluorometry and electron microscopy, we have shown a negative action of doxorubicin on various important chemical events which contribute to the transformation of G-actin into F-actin. Specifically, we found that the drug mainly acts by reducing the polymer size. A possible action mechanism of the antibiotic is proposed and a plausible correlation among the events described in vitro and those observed in vivo is advanced.