Huntington's disease: a clinical review

Huntington disease (HD) is a rare neurodegenerative disorder of the central nervous system characterized by unwanted choreatic movements, behavioral and psychiatric disturbances and dementia. Prevalence in the Caucasian population is estimated at 1/10,000-1/20,000. Mean age at onset of symptoms is 30-50 years. In some cases symptoms start before the age of 20 years with behavior disturbances and learning difficulties at school (Juvenile Huntington's disease; JHD). The classic sign is chorea that gradually spreads to all muscles. All psychomotor processes become severely retarded. Patients experience psychiatric symptoms and cognitive decline. HD is an autosomal dominant inherited disease caused by an elongated CAG repeat (36 repeats or more) on the short arm of chromosome 4p16.3 in the Huntingtine gene. The longer the CAG repeat, the earlier the onset of disease. In cases of JHD the repeat often exceeds 55. Diagnosis is based on clinical symptoms and signs in an individual with a parent with proven HD, and is confirmed by DNA determination. Pre-manifest diagnosis should only be performed by multidisciplinary teams in healthy at-risk adult individuals who want to know whether they carry the mutation or not. Differential diagnoses include other causes of chorea including general internal disorders or iatrogenic disorders. Phenocopies (clinically diagnosed cases of HD without the genetic mutation) are observed. Prenatal diagnosis is possible by chorionic villus sampling or amniocentesis. Preimplantation diagnosis with in vitro fertilization is offered in several countries. There is no cure. Management should be multidisciplinary and is based on treating symptoms with a view to improving quality of life. Chorea is treated with dopamine receptor blocking or depleting agents. Medication and non-medical care for depression and aggressive behavior may be required. The progression of the disease leads to a complete dependency in daily life, which results in patients requiring full-time care, and finally death. The most common cause of death is pneumonia, followed by suicide.     

Direct experimental evidence for alternative stable states: a review

A large number of studies have presented empirical arguments for the existence of alternative stable states (ASS) in a wide range of ecological systems. However, most of these studies have used non-manipulative, indirect methods, which findings remain open for alternative explanations. Here, we review the direct evidence for ASS resulting from manipulation experiments. We distinguish four conclusive experimental approaches which test for predictions made by the hysteresis effect: (1) discontinuity in the response to an environmental driving parameter, (2) lack of recovery potential after a perturbation, (3) divergence due to different initial conditions and (4) random divergence. Based on an extensive literature search we found 35 corresponding experiments. We assessed the ecological stability of the reported contrasting states using the minimum turnover of individuals in terms of life span and classified the studies according to 4 categories: (1) experimental system, (2) habitat type, (3) involved organisms and (4) theoretical framework. 13 experiments have directly demonstrated the existence of alternative stable states while 8 showed the absence of ASS in other cases. 14 experiments did not fulfil the requirements of a conclusive test, mostly because they applied a too short time scale. We found a bias towards laboratory experiments compared to field experiments in demonstrating bistability. There was no clear pattern of the distribution of ASS over categories. The absence of ASS in 38% of the tested systems indicates that ASS are just one possibility of how ecological systems can behave. The relevance of the concept of ASS for natural systems is discussed, in particular under consideration of the observed laboratory bias, perturbation frequency and variable environments. It is argued, that even for a permanently transient system, alternative attractors may still be of relevance.     

Testing the immunocompetence handicap hypothesis: a review of the evidence

The immunocompetence handicap hypothesis was formulated 12 years ago in an attempt to offer a proximate mechanism by which female choice of males could be explained by endocrine control of honest signalling. The hypothesis suggested that testosterone has a dual effect in males of controlling the development of sexual signals while causing immunosuppression. Our purpose in this review is to examine the empirical evidence to date that has attempted to test the hypothesis, and to conduct a meta-analysis on two of the assumptions of the hypothesis, that testosterone reduces immunocompetence and increases parasitism, to ascertain any statistical trend in the data. There is some evidence to suggest that testosterone is responsible for the magnitude of trait expression or development of sexual traits, but this is by no means conclusive. The results of many studies attempting to find evidence for the supposed immunosuppressive qualities of testosterone are difficult to interpret since they are observational rather than experimental. Of the experimental studies, the data obtained are ambiguous, and this is reflected in the result of the meta-analysis. Overall, the meta-analysis found a significant suppressive effect of testosterone on immunity, in support of the hypothesis, but this effect disappeared when we controlled for multiple studies on the same species. There was no effect of testosterone on direct measures of immunity, but it did increase ectoparasite abundance in several studies, in particular in reptiles. A funnel analysis indicated that the results were robust to a publication bias. Alternative substances that interact with testosterone, such as glucocorticoids, may be important. Ultimately, a greater understanding is required of the complex relationships that exist both within and between the endocrine and immune systems and their consequences for mate choice decision making.     

Huntington's disease: revisiting the aggregation hypothesis in polyglutamine neurodegenerative diseases

After the successful cloning of the first gene for a polyglutamine disease in 1991, the expanded polyglutamine tract in the nine polyglutamine disease proteins became an obvious therapeutic target. Early hypotheses were that misfolded, precipitated protein could be a universal pathogenic mechanism. However, new data are accumulating on Huntington's disease and other polyglutamine diseases that appear to contradict the toxic aggregate hypothesis. Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers, and that the protein context of expanded polyglutamine is critical to understanding disease specificity. Here we discuss recent publications that define other important therapeutic targets for polyglutamine-mediated neurodegeneration related to the context of the expanded polyglutamine tract in the disease protein.     

Recovery from training: a brief review: brief review

Athletes spend a much greater proportion of their time recovering than they do in training. Yet, much attention has been given to training with very little investigation of recovery. The purpose of this review is to stimulate further research into this vital area of training. Recovery can be categorized in three terms: i) immediate recovery between exertions; ii) short-term recovery between repeats (e.g., between resistance sets or interval bouts); and iii) training recovery between workouts. The focus of this review is training recovery. Full training recovery is essential to optimal performance and improvement. This review includes an examination of extant research on recovery and a very brief review of some potential modalities and techniques for hastening recovery and the time course of recovery and responses to some treatments. Measures of recovery and practical considerations are discussed briefly. Much research is needed in this area, but there are obstacles to high quality research. Attention must be given to key issues in research on recovery, especially the individual response to recovery treatments.     

Salmonella, the host and disease: a brief review

Salmonella species cause substantial morbidity, mortality and burden of disease globally. Infections with Salmonella species cause multiple clinical syndromes. Central to the pathophysiology of all human salmonelloses is the induction of a strong host innate immune/inflammatory response. Whether this ultimately reflects an adaptive advantage to the host or pathogen is not clear. However, it is evident that both the host and pathogen have evolved mechanisms of triggering host responses that are detrimental to the other. In this review, we explore some of the host and pathogenic mechanisms mobilized in the two predominant clinical syndromes associated with infection with Salmonella enterica species: enterocolitis and typhoid.     

Evaluating the twin testosterone transfer hypothesis: a review of the empirical evidence

In this paper we review the evidence that fetuses gestated with a male co-twin are masculinized in development, perhaps due to the influence of prenatal androgens: the so-called twin testosterone transfer (TTT) hypothesis. Evidence from studies of behavioral, perceptual, cognitive, morphological and physiological traits in same- and opposite-sex human twins is considered. Apart from two studies reporting increases in aspects of sensation-seeking for females with a male rather than a female co-twin, there is sparse evidence supporting the TTT hypothesis in behavioral studies. Outcomes from studies of perception (in particular otoacoustic emissions) and cognition (in particular vocabulary acquisition and visuo-spatial ability) provide more consistent evidence in support of masculinized performance in twins with a male co-twin compared to twins with a female co-twin. The outcomes favorable to the TTT hypothesis for otoacoustic emissions and visuo-spatial ability are restricted to females. Studies of physiology and morphology (e.g., brain volume, tooth size and 2D:4D ratio) also show some influence of co-twin sex, but again these effects are often restricted to female twins. Because females produce little endogenous testosterone, the effects of gestation with a male co-twin may be more pronounced in females than males. Thus, while uneven, the evidence for the TTT hypothesis is sufficient to warrant further investigation, ideally using large samples of same- and opposite-sex twins, along with control groups of same- and opposite-sex siblings when the characteristics assessed are potentially open to social influences.     

Glycerol is a suberin monomer. New experimental evidence for an old hypothesis

The monomer composition of the esterified part of suberin can be determined using gas chromatography-mass spectroscopy technology and is accordingly believed to be well known. However, evidence was presented recently indicating that the suberin of green cotton (Gossypium hirsutum cv Green Lint) fibers contains substantial amounts of esterified glycerol. This observation is confirmed in the present report by a sodium dodecyl sulfate extraction of membrane lipids and by a developmental study, demonstrating the correlated accumulation of glycerol and established suberin monomers. Corresponding amounts of glycerol also occur in the suberin of the periderm of cotton stems and potato (Solanum tuberosum) tubers. A periderm preparation of wound-healing potato tuber storage parenchyma was further purified by different treatments. As the purification proceeded, the concentration of glycerol increased at about the same rate as that of α,ω-alkanedioic acids, the most diagnostic suberin monomers. Therefore, it is proposed that glycerol is a monomer of suberins in general and can cross-link aliphatic and aromatic suberin domains, corresponding to the electron-translucent and electron-opaque suberin lamellae, respectively. This proposal is consistent with the reported dimensions of the electron-translucent suberin lamellae.     

Inter-locus interactions: A review of experimental evidence

In quantitative genetics, experiments designed to elucidate the nature of gene action and hence the importance of epistasis, have included analysis of genetic differences among individuals in random mating populations (partitioning of genetic variation, analysis of selection responses), of differences among inbred lines or selected populations (variance components in crosses among lines, chromosome analysis using genetic markers and crossover suppression), of the effects of inbreeding, and of population structure. Evidence in population genetic studies has come from studies of linkage disequilibrium and co-adaptation in natural populations, and of multilocus fitness estimation and linkage disequilibrium and associative overdominance in experimental populations. While it is clear that epistasis does contribute to the genetic variation in some quantitative characters, and in particular reproductive fitness, much of the evidence is equivocal and unsatisfying.     

Huntington's disease: Dancing in a dish

In a recent landmark paper, the Huntington''s disease (HD) iPSC Consortium reports on the establishment and characterization of a panel of iPSC lines from HD patients, and more importantly, the successful modeling of HD in vitro. In the same issue of Cell Stem Cell, An et al. reports on the successful targeted gene correction of HD in human iPSCs. Both advances are exciting, provide new resources for current and future HD research, and uncover new challenges to better understand and, most importantly, treat this devastating disease in the near future.Modeling human diseases using induced pluripotent stem cells (iPSCs) has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. Combined with advanced gene correction technology, human iPSCs hold great promise to provide patient-specific and mutation-free cells for potential cell replacement therapy. Huntington''s disease (HD) is an autosomal dominant neurodegenerative disorder, which causes motor dysfunction, psychiatric disturbances and cognitive impairment¹. HD is caused by an expanded cystosine adenine guanine (CAG) tri-nucleotide repeat encoding polyglutamine in the first exon of the Huntingtin (HTT) gene. To date, there is no effective therapy for preventing the onset or slowdown of this disorder. Preliminary clinical trials using fetal neural grafts had shown long-lasting functional benefits in patients². Though only effective in limited cases, these results suggest that cell-based therapy could be a potential treatment if a reliable and consistent cell source is available. For this purpose, an alternative cell source to overcome the logistical and biological hurdles of this disease had been actively explored in the past decade. With recent advancement in human iPSCs technology, HD patient-specific iPSCs coupled with an efficient directed cell differentiation protocol offers hope for an unlimited supply of autologous cells. Since HD is a monogenic disease, with a very well-established correlation between the number of CAG repeats and the age of disease onset, it provides an ideal target for iPSC-based gene correction that will allow for the production of disease-free cells for potential autologous cell therapy, and at the same time provide a much needed, valuable platform to further study the pathogenesis of the disease^3,4.This is in fact what has been recently accomplished in two reports published in Cell Stem Cell^5,6. The HD iPSC Consortium reports on the generation of HD patient-specific iPSC lines that showed CAG-repeat-expansion-associated phenotypes⁵. The study from An et al.⁶ reports on the successful targeted correction of expanded CAG repeat in HD patient iPSCs and the reversion of disease phenotypes.In the study reported from the HD iPSC Consortium, the authors generated 14 iPSC lines from HD patients and controls (listed in Open in a separate window

Cell-based therapies for experimental chronic kidney disease: a systematic review and meta-analysis

Cell-based therapy is a promising strategy for treating chronic kidney disease (CKD) and is currently the focus of preclinical studies. We performed a systematic review and meta-analysis to evaluate the efficacy of cell-based therapy in preclinical (animal) studies of CKD, and determined factors affecting cell-based therapy efficacy in order to guide future clinical trials. In total, 71 articles met the inclusion criteria. Standardised mean differences (SMD) and 95% confidence intervals (CI) were calculated for outcome parameters including plasma urea, plasma creatinine, urinary protein, blood pressure, glomerular filtration rate, glomerulosclerosis and interstitial fibrosis. Sub-analysis for each outcome measure was performed for model-related factors (species, gender, model and timing of therapy) and cell-related factors (cell type, condition and origin, administration route and regime of therapy). Overall, meta-analysis showed that cell-based therapy reduced the development and progression of CKD. This was most prominent for urinary protein (SMD, 1.34; 95% CI, 1.00–1.68) and urea (1.09; 0.66–1.51), both P<0.001. Changes in plasma urea were associated with changes in both glomerulosclerosis and interstitial fibrosis. Sub-analysis showed that cell type (bone-marrow-derived progenitors and mesenchymal stromal cells being most effective) and administration route (intravenous or renal artery injection) were significant predictors of therapeutic efficacy. The timing of therapy in relation to clinical manifestation of disease, and cell origin and dose, were not associated with efficacy. Our meta-analysis confirms that cell-based therapies improve impaired renal function and morphology in preclinical models of CKD. Our analyses can be used to optimise experimental interventions and thus support both improved preclinical research and development of cell-based therapeutic interventions in a clinical setting.KEY WORDS: Cell-based therapy, Chronic kidney disease, Meta-analysis     

Juvenile neuronal ceroid-lipofuscinosis (Batten disease): a brief review and update

Juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, Spielmeyer-Vogt-Sjogren disease, CLN3) is the most common inherited, autosomal recessive, neurodegenerative disorder in man. Like the other neuronal ceroid-lipofuscinoses, it is characterized by progressive loss of vision, seizures, and loss of cognitive and motor functions, leading to premature demise. JNCL is caused by mutations of CLN3, a gene that encodes a hydrophobic transmembrane protein, which localizes to membrane lipid rafts in lysosomes, endosomes, synaptosomes, and cell membrane. While the primary function of the CLN3 protein (CLN3P) may be debated, its absence affects numerous cellular functions including pH regulation, arginine transport, membrane trafficking, and apoptosis. We have recently suggested that the unifying primary function of CLN3P may be in a novel palmitoyl-protein Delta-9 desaturase (PPD) activity that in our opinion could explain all of the various functional abnormalities seen in the JNCL cells. Another group of researchers has recently shown a correlation between the CLN3P expression and the synthesis of bis(monoacylglycerol)phosphate (BMP) and suggested that CLN3P may play a role in the biosynthesis of BMP. In this review, following an introduction to the neuronal ceroid-lipofuscinoses, we provide a brief overview and an update of the most recent research in JNCL, specifically that related to the function of CLN3P.     

Edwardsiellosis in fish: a brief review

Edwardsiellosis is one of the most important bacterial diseases in fish. Scientific work on this disease started more than forty years ago and numerous workers around the world are continually adding to the knowledge of the disease. In spite of this, not a single article that reviews the enormous scientific data thus generated is available in the English language. This article briefly discusses some of the recent research on edwardsiellosis, describing the pathogen's interaction with the host and environment, its pathogenesis and pathology as well as diagnostic, preventive and control measures.     

Edwardsiellosis in fish: a brief review

Edwardsiellosis is one of the most important bacterial diseases in fish. Scientific work on this disease started more than forty years ago and numerous workers around the world are continually adding to the knowledge of the disease. In spite of this, not a single article that reviews the enormous scientific data thus generated is available in the English language. This article briefly discusses some of the recent research on edwardsiellosis, describing the pathogen’s interaction with the host and environment, its pathogenesis and pathology as well as diagnostic, preventive and control measures.