Ataxia‐telangiectasia (A‐T) is a pleiotropic recessive disorder characterized cerebellar ataxia, immunodeficiency, specific developmental defects, profound predisposition to cancer and acute radiosensitivity. Functional inactivation of single gene product, ATM, accounts for this compound phenotype. We suggest that ATM acts as a sensor of reactive oxygen species and/or oxidative damage cellular macromolecules, including DNA. In turn, ATM induces signalling through multiple pathways, thereby coordinating acute phase stress responses with cell cycle checkpoint control and repair of oxidative damage. Absence of (...) ATM is proposed to limit the repair of insidious oxidative damage that can occur under normal physiological conditions, ultimately leading to apoptosis of particularly sensitive cells, such as neurons and thymocytes. (shrink)

Ataxia‐telangiectasia (A‐T), an inherited disorder giving radiation sensitivity and cancer‐proneness, is discussed in terms of a defect in ability to repair DNA damage. A new assay using damaged recombinant DNA molecules suggests that the fidelity of repair of DNA double‐strand breaks is reduced in an A‐T cell line. Specific chromosomal changes in some A‐T patients appear to be associated with cancer induction, and it is suggested that these could be linked to a DNA repair‐fidelity defect. However, a general (...) correlation between radiosensitivity and cancer‐proneness is difficult to establish at present, partly because of diversity in radiosensitivity in the normal population. (shrink)

DNA double‐strand breaks (DSBs) are one of the most deleterious forms of DNA damage and can result in cell inviability or chromosomal aberrations. The Mre11‐Rad50‐Nbs1 (MRN) ATPase‐nuclease complex is a central player in the cellular response to DSBs and is implicated in the sensing and nucleolytic processing of DSBs, as well as in DSB signaling by activating the cell cycle checkpoint kinase ATM. ATP binding to Rad50 switches MRN from an open state with exposed Mre11 nuclease sites to a closed (...) state with partially buried nuclease sites. The functional meaning of this switch remained unclear. A new study shows that ATP binding to Rad50 promotes DSB recognition, tethering, and ATM activation, while ATP hydrolysis opens the nuclease active sites to promote processing of DSBs. MRN thus emerges as functional switch that may coordinate the temporal transition from signaling to processing of DSBs. (shrink)

Dysregulation of genes that control cell‐cycle progression and DNA repair is a hallmark of tumorigenesis. It is becoming increasingly apparent, however, that these defects also contribute to degeneration of post‐mitotic neurons under certain conditions. The gene for ataxia‐telangiectasia mutated (ATM) is a prototype for this dual mechanism of action, with loss‐of‐function mutations causing not only selective degeneration of cerebellar neurons but also increased susceptibility to breast cancer and hematologic malignancy. Increased dosage of amyloid precursor protein in Down syndrome (...) (trisomy 21) predisposes to dementia of Alzheimer type and may also contribute to acute leukemia and transient myeloproliferative disorder. The gene parkin, loss‐of‐function mutations in which account for about half of cases of early‐onset Parkinson disease, has been identified as a candidate tumor suppressor gene by several groups. Parkin is deleted or downregulated in several tumor types, and its re‐expression sensitizes derivative cell lines to inhibitors of cell‐cycle progression. The overlap of molecular pathways implicated in cancer and neurodegeneration challenges long‐held notions about differentiated cellular states and may open the door to novel therapeutic approaches to both groups of disorders. BioEssays 30:719–727, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

As recently as six years ago, three human diseases with similar phenotypes were mistakenly believed to be caused by a single genetic defect. The three diseases, Ataxia-telangiectasia, Nijmegen breakage syndrome, and an AT-like disorder are now known, however, to have defects in three separate genes: ATM, NBS1, and MRE11. Furthermore, new recent studies have shown now that all three gene products interact; the ATM kinase phosphorylates NBS1,1 which, in turn, associates with MRE11 to regulate DNA repair. Remarkably or (...) expectedly, depending on one's point of view, the similarity in disease phenotypes is evidently due to defects in a common DNA repair pathway. BioEssays 22:966–969, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Ataxia is a kind of external characteristics when the human body has poor coordination and balance disorder, it often indicates diseases in certain parts of the body. Many internal factors may causing ataxia; currently, observed external characteristics, combined with Doctor’s personal clinical experience play main roles in diagnosing ataxia. In this situation, different kinds of diseases may be confused, leading to the delay in treatment and recovery. Modern high precision medical instruments would provide better accuracy but the (...) economic cost is a non-negligible factor. In this paper, novel non-contact sensing technique is used to detect and distinguish sensory ataxia and cerebellar ataxia. Firstly, Romberg’s test and gait analysis data are collected by the microwave sensing platform; then, after some preprocessing, some machine learning approaches have been applied to train the models. For Romberg’s test, time domain features are considered, the accuracy of all the three algorithms are higher than 96%; for gait detection, Principal Component Analysis is used for dimensionality reduction, and the accuracies of Back Propagation neural Network, Support Vector Machine, and Random Forest are 97.8, 98.9, and 91.1%, respectively. (shrink)

Recently, βIII spectrins have been recognized as ataxia disease genes, with the identification by Ikeda and co‐workers of pathogenic mutations in the SPTBN2 gene in three large (and mapped) SCA5 families of American and European origin.(1) With their discovery, the large “Lincoln” family has been traced back to the underlying genetic defect for the slowly progressive cerebellar ataxia. In addition, the involvement of this component of the cytoskeleton directs attention towards the possible role of organelle stability during neurodegeneration. (...) The findings suggest that the mechanical properties of neurons and their dynamics may be as important as altered Ca2+ homeostasis, transcriptional dysregulation, and impaired protein degradation in neurodegeneration conditions. BioEssays 28: 785–787, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of (...) vermis and right cerebellum and structural changes in various brain regions of patients with gluten ataxia and compared it with healthy controls. Volumetric 3-D T1 and T1-weighted magnetic resonance imaging in the three planes of the whole brain and single-voxel 1H- magnetic resonance spectroscopy of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of ; reduction in the volumes of cerebellum lobe and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients. (shrink)

Evidence from optic ataxic patients with bilateral lesions to the superior parietal lobes does not support the view that there are separate planning and control mechanisms located in the IPL and SPL respectively. The aberrant reaches of patients with bilateral SPL damage towards extrafoveal targets seem to suggest a deficit in the selection of appropriate motor programmes rather than a deficit restricted to on-line control.

RESUMEN El presente trabajo de revisión expone cómo las prácticas de gestión en la anestesiología deben ser modificadas para encarar las cambiantes necesidades de pacientes, otros profesionales y sistemas sanitarios, a fin de mantener una función significativa en la atención sanitaria. Los servicios de anestesia han adoptado una amplia variedad de modelos para hacer frente a las necesidades del medio local, la relación entre los anestesiólogos y la comunidad, y los papeles desempeñados por los anestesiólogos en el tratamiento perioperatorio. El (...) sistema sanitario cubano se encuentra inmerso en un proceso de permanente adecuación de sus servicios a los problemas, demandas y necesidades de la población cubana y sus determinantes. Por ello, objetivo es exponer consideraciones teóricas en función del perfeccionamiento del servicio de Anestesiología y Reanimación. ABSTRACT This review paper presents how anesthesiology management practices must be modified in order to deal with the changing needs patients, other professionals and health systems have, in order to maintain a significant function in health care. Anesthesiology services have adopted a wide variety of models to face up to the needs the city, the relationship between anesthesiologists and the community and the role anesthesiologists play in perioperative treatment have. The Cuban health system services are in a process of permanent adaptation to the problems, demands and needs the Cuban population and its determinants have. For that reason, this paper aims at presenting theoretical considerations towards the improvement of the Anesthesiology and Resuscitation service. (shrink)

Evidence for a dichotomy between the planning of an action and its on-line control in humans is reviewed. This evidence suggests that planning and control each serve a specialized purpose utilizing distinct visual representations. Evidence from behavioral studies suggests that planning is influenced by a large array of visual and cognitive information, whereas control is influenced solely by the spatial characteristics of the target, including such things as its size, shape, orientation, and so forth. Evidence from brain imaging and neuropsychology (...) suggests that planning and control are subserved by separate visual centers in the posterior parietal lobes, each constituting part of a larger network for planning and control. Planning appears to rely on phylogenetically newer regions in the inferior parietal lobe, along with the frontal lobes and basal ganglia, whereas control appears to rely on older regions in the superior parietal lobe, along with the cerebellum. Key Words: action; apraxia; control; illusions; optic ataxia; PET; planning; reaching;. (shrink)

The conventional approach to developing disease‐modifying treatments for neurodegenerative conditions has been to identify drivers of pathology and inhibit such pathways. Here we discuss the possibility that the efficacy of such approaches may be increasingly attenuated as disease progresses. This is based on experiments using mouse models of spinocerebellar ataxia type 1 and Huntington's disease (HD), where expression of the dominantly acting mutations could be switched off, as well as studies in human HD, which suggest that the primary genetic (...) driver of age‐of‐onset of disease is a much weaker determinant of disease progression in affected individuals. The idea that one may approach a point in the disease course where such rational therapeutic strategies based on targets which determine onset of disease have minimal efficacy, suggests that one needs to consider other approaches to therapies and clinical trial design, including initiation of therapies in presymptomatic individuals. (shrink)

What representational state mediates between perception and action? Bence Nanay says pragmatic representations, which are outputs of perceptual systems. This commits him to the view that optic ataxics face difficulty in performing visually guided arm movements because the relevant perceptual systems output their pragmatic representations incorrectly. Here, I argue that it is not enough to say that pragmatic representations are output incorrectly; we also need to know why they are output that way. Given recent evidence that optic ataxia impairs (...) peripersonal space representation, I argue that pragmatic representations are output incorrectly because the organizing principle of the vision-for-action system is blocked by optic ataxia. I then show how this means that this principle, not pragmatic representations, is the representational state that mediates between perception and action, i.e. the principle, not pragmatic representations, is the immediate mental antecedent of action. (shrink)

The transcription factor Nrf2 is the master regulator of cellular stress response, facilitating the expression of cytoprotective genes, including those responsible for drug detoxification, immunomodulation, and iron metabolism. FDA‐approved Nrf2 activators, Tecfidera and Skyclarys for patients with multiple sclerosis and Friedreich's ataxia, respectively, are non‐specific alkylating agents exerting side effects. Nrf2 is under feedback regulation through its target gene, transcriptional repressor Bach1. Specifically, in Parkinson's disease and other neurodegenerative diseases with Bach1 dysregulation, excessive Bach1 accumulation interferes with Nrf2 activation. (...) Bach1 is a heme sensor protein, which, upon heme binding, is targeted for proteasomal degradation, relieving the repression of Nrf2 target genes. Ideally, a combination of Nrf2 stabilization and Bach1 inhibition is necessary to achieve the full therapeutic benefits of Nrf2 activation. Here, we discuss recent advances and future perspectives in developing small molecule inhibitors of Bach1, highlighting the significance of the Bach1/Nrf2 signaling pathway as a promising neurotherapeutic strategy. (shrink)

© 2015 Wong,Tassone,Rivera and Simon.Carriers of the fragile X premutation allele have an expanded CGG trinucleotide repeat size within the FMR1 gene and are at increased risk of developing fragile x-associated tremor/ataxia syndrome. Previous research has shown that male fXPCs with FXTAS exhibit cognitive decline, predominantly in executive functions such as inhibitory control and working memory. Recent evidence suggests fXPCs may also exhibit impairments in processing temporal information. The attentional blink task is often used to examine the dynamics of (...) attentional selection, but disagreements exist as to whether the AB is due to excessive or insufficient attentional control. In this study, we used a variant of the AB task and neuropsychological testing to explore the dynamics of attentional selection, relate AB performance to attentional control, and determine whether fXPCs exhibited temporal and/or attentional control impairments. Participants were adult male fXPCs, aged 18–48 years and asymptomatic for FXTAS and age-matched male controls. We found that fXPCs did not differ from controls in the AB task, indicating that the temporal dynamics of attentional selection were intact. However, they were impaired in the letter-number sequencing task, a test of executive working memory. In the combined fXPC and control group, letter-number sequencing performance correlated positively with AB magnitude. This finding supports models that posit the AB is due to excess attentional control. In our two-pronged analysis approach, in control participants we replicated a previously observed effect and demonstrated that it persists under more stringent theoretical constraints, and we enhance our understanding of fXPCs by demonstrating that at least some aspects of temporal processing may be spared. (shrink)

The anecdotal and historical literature describing intoxication in elephants from fermented fruit or alcoholic beverages is reviewed. Seven African elephants readily self-administered 7% unflavored alcohol solutions; the results included separation from herd groupings and changes in the frequency and/or duration of several behaviors as scored according to a quantitative observational system. Alcohol decreased feeding, drinking, bathing, and exploration for most animals. Inappropriate behaviors such as lethargy and ataxia increased for all elephants. Results are discussed in terms of stress-induced drinking (...) and intoxication. (shrink)

The objective of this study was to reveal the problems related to interpersonal relationships which patients with obstinate diseases face, and consider the behavior, attitude and medical intervention that healthcare and healthcare-related professions should take in regards to these problems. Semi-structured individual interviews were conducted with patients with obstinate neurological diseases and observation of outpatient care was also conducted. Data were analyzed by qualitative content analysis. Patient diseases included Parkinson Disease , Amyotrophic Lateral Sclerosis , myasthenia gravis, spinocerebellar ataxia (...) , and progressive supranuclear palsy . Findings highlighted that patients’ disease and suffering was not understood fully by patients’ families, that patients feel a lack of family support and cooperation, and that society’s level of understanding of their disease was also insufficient. Again, findings revealed that patients recognized their inability to perform personal activities and to behave competently within the contexts of family and society. This lowered their self evaluation. These findings highlight three needs: “the need for empathy,” “the need for self the “the need for empathy” and “the need for self esteem.”This study was supported by a great-in-aid by Ministry of Health, Labor and Welfare in Japan, “Outcomes Research of Specific Diseases”（PI:S.Fukuhara）（Grand no: H14-44）. (shrink)

A case is described of a man who discovered years after donating sperm for artificial insemination, that he had a serious genetic disease, autosomal dominant cerebellar ataxia . This manifests itself only years after puberty and occurs in 50% of the progeny. The sperm had been used for the conception of 18 children in 13 women. The parents were only told three years after the insemination. This long time interval was unavoidable since many of the parents had to be (...) found and the hospital director wished first to discuss the matter with his legal advisors and other experts.In future, in agreement with the new law only 10 inseminations will take place with sperm from one donor. This will reduce still further the availability of donor sperm. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Family, Friends, and Cancer:The Overwhelming Effects of Brain Cancer on a Child’s LifeLynne ScheumannOur son was diagnosed with a medulloblastoma at the old age of 13. The “lucky” part for him was his brain was almost fully developed at this age as opposed to most “medullo” patients. While this was a benefit to him it was also one of the hardest things for him.He went into surgery a highly (...) intelligent, active, and left handed boy and came out unable to move his left side, could barely speak, and very much aware of what he just lost. We, as a family, were totally unprepared for how globally this would [End Page 23] affect the rest of his life. As we spent time in the hospital I would look at the children with other types of cancer and see them walking and talking and doing their schoolwork and God forgive me I would be jealous. The fact that the cancer was in his brain, the part of his body that makes him who he is changed everything forever.He lost all of his friends because 13–year–old boys communicate best through physical activity and that was not an option for him. He still has the same personality and sense of humor, but he will not be the architect or engineer he once dreamed of being. Math, that was once so easy for him was now like a foreign language, never to be mastered again. He was able to graduate from High School and takes classes at our local Junior College in Computer Assisted Drafting, but he can only manage one or two classes a semester due to the fatigue he still suffers from.What I most worry about and wish I had been forewarned about is his long–term quality of life. Physically he has come such a long way from how he was after the resection. It was a very slow process in which the first year of rehab was slowed by the fact that one of the chemo agents causes peripheral neuropathy. He developed contractures in his ankles and needed serial casting and ankle–foot orthotics (AFO) not just on the left leg, but now the right. He was able to switch his handedness fairly easily and his left hand will always be of limited usefulness because of ataxia. I would get angry at him that he gave up on his left side so quickly until it was finally explained to me years later that the ataxia would never get better.As far as his walking ability goes he has come a long way. At first he was unable to walk and once he started rehab he went back to learning to crawl and progressed to a walker. The first time I saw him walk with the walker brought tears to my eyes. It was so much more of an event for me than when he took his first steps as a toddler. This was so much more hard fought. He never complained, just always did what was asked of him. It had to have been such hard work and also somewhat embarrassing, as he needed help to literally do everything for months. He progressed to a cane and about two years ago decided not to use that or his AFO’s. He now wears high top boots that substitute for the AFO’s but don’t make him appear disabled. Recently he decided there are times when he would be safer if he had his cane and purchased one that looks more like a hiking stick than a cane. I think he has come to terms with the fact that physically he is as good as he is going to get and works hard to maintain what he did regain. He has a trainer and goes to the gym on a regular basis with no prompting from us. I do not know if he realizes that as he ages things will be harder for him than the average person. I think in some way he is aware of that because he did decided to use the cane if safety is an issue.His... (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Seeing the Best of MeJohn ScheumannHi I am John, I am 21 and live in Northern California. I was diagnosed with a brain tumor in March 2005. When I was diagnosed I was 13–year–old, in 7th grade, the school year was nearing its end. I was just starting to hit my stride with my youthful independence. Skipping forward to post surgery: right after, the effects from the surgery were (...) severe. My whole body was weak, I was temporarily paralyzed on the left side of my of my body, I could hardly speak or see. My recovery has been hard, relearning how to do many things again.Now eight years after, I have recovered very well (although it doesn’t always seem like that to me). My “disabilities” are physical and cognitive. My physical issues are that I have very poor balance. My coordination is also poor (especially on my left side). I get fatigued more easily, then that triggers the issues with my balance and coordination even more. Also when I’m fatigued my left arm, leg, and hand can get shaky (which is also know as ataxia). My cognitive issues are that I process information slower, have a bad memory, have trouble finding the right words to say, organizing thoughts, etc.To me I am disabled, I have things that happened to me that effected my body and impaired me in different ways. I am disabled but that’s not all I am, I am still a young growing adult who does things that most people my age do.There are times though were the term disability does not do me justice. The things that happened to me affect me everyday but I act and do things that most people my age do, I go to the gym, walk my dog, hang out with friend, watch sports, etc..... On the surface I appear to be an average able bodied person, my “disabilities” aren’t always visible sometimes till someone gets to know me or see me interact for a while. So people will sometimes not treat me in the way I would like to be treated because of their unknowing. People sometimes expect me or want me to do things I’m not capable of and that can be awkward and upsetting.Other times people see me as your average person my age and I’ll tell them I have a disability they don’t understand the complexity of it and that certain things are difficult for me and only in certain situations, not all the time. They don’t understand the disability is individual to me and one issue is not the same for everyone across the board. This can also be awkward and upsetting at times.Saying all this I understand people will misjudge me and most often people are not being ignorant they are acting the best way they know how and that given the chance they can see the best of me and truly understand who I am and forget the label “disabled.” [End Page E8]Copyright © 2013 The Johns Hopkins University Press... (shrink)

Mutations in the methyl‐CpG‐binding protein 2 (MeCP2) cause Rett syndrome, a severe neurodevelopmental disease associated with ataxia and other post‐natal symptoms similar to autism. Much research interest has focussed on the implications of MeCP2 in disease and neuron physiology. However, little or no attention has been paid to how MeCP2 turnover is regulated. The post‐translational control of MeCP2 is of critical importance, especially as subtle increases or decreases in MeCP2 amounts can affect neuron morphology and function. The latter point (...) is of particular importance for gene therapeutic approaches in which exogenous wild‐type MeCP2 is being introduced into diseased neurons. Further to this, we propose two hypotheses. The first hypothesis discusses the poly‐ubiquitin‐mediated post‐translational regulation of MeCP2 through its two PEST domains. The second hypothesis explores the use of histone deacetylase inhibitors to modulate the amounts of MeCP2 expressed in conjunction with the aforementioned therapeutic approaches. (shrink)

Tremor of the upper extremity is a significant cause of disability in some patients with multiple sclerosis. The MS tremor is complex because it contains an ataxic intentional tremor component due to the involvement of the cerebellum and cerebellar outflow pathways by MS plaques, which makes the MS tremor, in general, less responsive to medications or deep brain stimulation than those associated with essential tremor or Parkinson's disease. The cerebellar component has been thought to be the main reason for making (...) DBS less effective, although it is not clear whether it is due to the lack of suppression of the ataxic tremor by DBS or else. The goal of this study was to clarify the effect of DBS on cerebellar tremor compared to non-cerebellar tremor in a patient with MS. By wearing an accelerometer on the index finger of each hand, we were able to quantitatively characterize kinetic tremor by frequency and amplitude, with cerebellar ataxia component on one hand and that without cerebellar component on the other hand, at the beginning and end of the hand movement approaching a target at DBS Off and On status. We found that cerebellar tremor surprisingly had as good a response to DBS as the tremor without a cerebellar component, but the function control on cerebellar tremor was not as good due to its distal oscillation, which made the amplitude of tremor increasingly greater as it approached the target. This explains why cerebellar tremor or MS tremor with cerebellar component has a poor functional transformation even with a good percentage of tremor control. This case study provides a better understanding of the effect of DBS on cerebellar tremor and MS tremor by using a wearable device, which could help future studies improve patient selection and outcome prediction for DBS treatment of this disabling tremor. (shrink)

Human beings begin life as quadrupeds, crawling on all fours, but none has ever been known to retain this gait and develop it into a proficient replacement for adult bipedality. We report the case of a family in which five siblings, who suffer from a rare form of cerebellar ataxia, are still quadrupeds as adults - walking and running on their feet and wrists. We describe the remarkable features of this gait, discuss how it has developed in the members (...) of this family, and consider whether a similar gait may have been used by human ancestors. (shrink)

A case is described of a man who discovered years after donating sperm for artificial insemination, that he had a serious genetic disease, autosomal dominant cerebellar ataxia (ADCA). This manifests itself only years after puberty and occurs in 50% of the progeny. The sperm had been used for the conception of 18 children in 13 women. The parents were only told three years after the insemination. This long time interval was unavoidable since many of the parents had to be (...) found and the hospital director wished first to discuss the matter with his legal advisors and other experts.In future, in agreement with the new law only 10 inseminations will take place with sperm from one donor. This will reduce still further the availability of donor sperm. (shrink)

A substantial portion of the human genome has been found to consist of simple sequence repeats, including microsatellites and minisatellites. Microsatellites, tandem repeats of 1–6 nucleotides, form the template for dynamic mutations, which involve heritable changes in the lengths of repeat sequences. In recent years, a large number of human disorders have been found to be caused by dynamic mutations, the most common of which are trinucleotide repeat expansion diseases. Dynamic mutations are common to numerous nervous system disorders, including Huntington's (...) disease, various spinocerebellar ataxias, fragile X syndrome, fragile X tremor/ataxia syndrome, Friedreich ataxia and other neurodegenerative disorders. The involvement of dynamic mutations in brain disorders will be reviewed, with a focus on the large group caused by CAG/glutamine repeat expansions. We will also outline a proposed role of tandem repeat polymorphisms (TRPs), with unique ‘digital’ genetic distributions, in modulating brain development and normal function, so as to generate additional mutational diversity upon which natural selection may act. BioEssays 29:525–535, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Trinucleotide repeat expansions are now a well‐established mutational mechanism in human genetic disease. An unstable CAG repeat is known to be responsible for three neurodegenerative disorders: Huntington's disease, spinal and bulbar musclar atrophy and spinocerebellar ataxia type 1. Similarities in the genetics of these diseases, the size of the repeat expansions and the position of the unstable repeat within the gene (when known) suggest a common basis to the observed phenotypes. The cloning of two regions at which chromosome breakage (...) can be induced (FRAXA and FRAXE) has in each case uncovered an unstable CG‐rich triplet repeat which becomes methylated when fully expanded. In addition to these two classes of mutation, the presence of an expanded CTG repeat in the 3′ untranslated region of a protein kinase causes myotonic dystrophy. The size of the respective expansions, repeat stability, mutational origins and possible mechanisms of action are discussed. (shrink)

Polyglutamine (polyQ) diseases are genetically inherited neurodegenerative disorders. They are caused by mutations that result in polyQ expansions of particular proteins. Mutant proteins form intranuclear aggregates, induce cytotoxicity and cause neuronal cell death. Protein interaction data suggest that polyQ regions modulate interactions between coiled‐coil (CC) domains. In the case of the polyQ disease spinocerebellar ataxia type‐1 (SCA1), interacting proteins with CC domains further enhance aggregation and toxicity of mutant ataxin‐1 (ATXN1). Here, we suggest that CC partners interacting with the (...) polyQ region of a mutant protein, increase its aggregation while partners that interact with a different region reduce the formation of aggregates. Computational analysis of genetic screens revealed that CC‐rich proteins are highly enriched among genes that enhance pathogenicity of polyQ proteins, supporting our hypothesis. We therefore suggest that blocking interactions between mutant polyQ proteins and their CC partners might constitute a promising preventive strategy against neurodegeneration. (shrink)

BackgroundSonographic mesenteric pattern in celiac disease (CD) suggests a hyperdynamic circulation. Despite the well-known CD-related neurological involvement, no study has systematically explored the cerebral hemodynamics to transcranial Doppler sonography.Materials and methodsMontreal Cognitive Assessment (MoCA) and 17-item Hamilton Depression Rating Scale (HDRS) were assessed in 15 newly diagnosed subjects with CD and 15 age-, sex-, and education-matched healthy controls. Cerebral blood flow (CBF) velocities and indices of resistivity (RI) and pulsatility (PI) from the middle cerebral artery (MCA), bilaterally, and the basilar (...) artery (BA) were recorded. We also assessed cerebral vasomotor reactivity (CVR) through the breath-holding test (BHT).ResultsWorse scores of MoCA and HDRS were found in patients compared to controls. Although patients showed higher values of CBF velocity from MCA bilaterally compared to controls, both at rest and after BHT, no comparison reached a statistical significance, whereas after BHT both RI and PI from BA were significantly higher in patients. A significant negative correlation between both indices from BA and MoCA score were also noted.ConclusionThese treatment-naïve CD patients may show some subtle CVR changes in posterior circulation, thus possibly expanding the spectrum of pathomechanisms underlying neuroceliac disease and in particular gluten ataxia. Subclinical identification of cerebrovascular pathology in CD may help adequate prevention and early management of neurological involvement. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Roadmap Needed:How to Help Parents Navigate the Worst Day of Their LivesCheryl KilpatrickOn January 14, 2010, our 3–year–old daughter, Maggie, was rushed to an emergency room at a satellite medical center. I am an occupational therapist and was actually scheduled to work at a hospital that day. I was wearing my purple scrubs. Maggie had been showing “strange” symptoms all week that I thought might be a sign that (...) she was getting a cold or the flu. She had been extremely tired, having morning headaches and ataxia (balance problems). When I dropped Maggie off at preschool the morning of January 14, 2010 she began to have trouble using her left arm. The teacher noticed that her smile was crooked. I did a quick neurological assessment and saw that her [End Page E9] left arm was much weaker than her right arm. I thought to myself, “My kid looks as if she is having a stroke. But she is only 3–years–old. This doesn’t make any sense.” The teacher gave me a look as if to say, “Are you going to take Maggie to the hospital or am I going to have to do it?” I just stood there. I suppose I was in the first stages of shock. I turned to the teacher and said, “We are going to the hospital.”As we walked toward the ER admissions desk I was surprised to see that we were the only people in the waiting area. It didn’t take long before we were called into the examination room. The ER doctor did a neurological assessment on Maggie like I had done only 30 minutes earlier and said that a CAT scan was needed. He thought that we would most likely be transferred to a local children’s hospital. The CAT scan revealed that Maggie had a large mass in her thalamus. I just looked at the ER doctor and said, “Just tell me what I need to do and I will do it.” No tears, no screams, no emotion. I just went into “mommy mode” and made sure that my child felt safe every step of the way. My husband was on his way home from a business trip when I called to tell him the news. He had no idea what he would find when he finally got to us.As expected, we were transported by ambulance to the local children’s hospital. I remember sitting in the front seat with the driver and feeling like this was all a dream. It was all very surreal. Maggie calmly chatted with the EMS personnel in the back of the ambulance as if nothing was happening. I had no idea how our lives would change once we reached the hospital. This ride to the hospital began our journey into uncharted territory. Nothing in my life had prepared me for what was about to happen.We arrived at the children’s hospital around 11:00 a.m. As we walked into ER department, I could feel the eyes of the ER staff following us. I turned to look at them and they smiled. The look on their faces told me that something was very wrong with my daughter. I felt like we were a sideshow at the carnival. I hated those looks. I didn’t want their smiles. I wanted to know what was happening. I wanted information.My husband arrived about an hour after our arrival. He walked into the room and found his little girl looking very spacey and unable to walk to him without falling. When Maggie and I stepped out into the hallway to find the restroom, I turned to look back into the room and saw my husband with his face in his hands. He was crying. I was not. I was still in “mommy mode” or just plain shock. I knew that my daughter was not well. But then again, neither was I. I was not crying. I was not screaming. I was numb. What I needed was someone to take my “emotional pulse.”We waited patiently in that small room watching the hours pass by as each doctor came... (shrink)

This book explains the key concepts that surround the issue as well as the nature of the hard problem and the several approaches to it. It gives a comprehensive treatment of the phenomenon, incorporating its main metaphysical and epistemic aspects as well as recent empirical findings, such as the phenomena of blindsight, change blindness, visual-form agnosia and optic ataxia, mirror recognition in other primates, split-brain cases, and visual extinction.