Showing papers by "Baylor College of Medicine published in 2005"

A haplotype map of the human genome

Abstract: Inherited genetic variation has a critical but as yet largely uncharacterized role in human disease. Here we report a public database of common variation in the human genome: more than one million single nucleotide polymorphisms (SNPs) for which accurate and complete genotypes have been obtained in 269 DNA samples from four populations, including ten 500-kilobase regions in which essentially all information about common DNA variation has been extracted. These data document the generality of recombination hotspots, a block-like structure of linkage disequilibrium and low haplotype diversity, leading to substantial correlations of SNPs with many of their neighbours. We show how the HapMap resource can guide the design and analysis of genetic association studies, shed light on structural variation and recombination, and identify loci that may have been subject to natural selection during human evolution.

Towards a proteome-scale map of the human protein–protein interaction network

Abstract: Systematic mapping of protein-protein interactions, or 'interactome' mapping, was initiated in model organisms, starting with defined biological processes and then expanding to the scale of the proteome. Although far from complete, such maps have revealed global topological and dynamic features of interactome networks that relate to known biological properties, suggesting that a human interactome map will provide insight into development and disease mechanisms at a systems level. Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions. Using a stringent, high-throughput yeast two-hybrid system, we tested pairwise interactions among the products of approximately 8,100 currently available Gateway-cloned open reading frames and detected approximately 2,800 interactions. This data set, called CCSB-HI1, has a verification rate of approximately 78% as revealed by an independent co-affinity purification assay, and correlates significantly with other biological attributes. The CCSB-HI1 data set increases by approximately 70% the set of available binary interactions within the tested space and reveals more than 300 new connections to over 100 disease-associated proteins. This work represents an important step towards a systematic and comprehensive human interactome project.

The 2005 International Society of Urological Pathology (ISUP) consensus conference on Gleason grading of prostatic carcinoma

Abstract: Five years after the last prostatic carcinoma grading consensus conference of the International Society of Urological Pathology (ISUP), accrual of new data and modification of clinical practice require an update of current pathologic grading guidelines. This manuscript summarizes the proceedings of the ISUP consensus meeting for grading of prostatic carcinoma held in September 2019, in Nice, France. Topics brought to consensus included the following: (1) approaches to reporting of Gleason patterns 4 and 5 quantities, and minor/tertiary patterns, (2) an agreement to report the presence of invasive cribriform carcinoma, (3) an agreement to incorporate intraductal carcinoma into grading, and (4) individual versus aggregate grading of systematic and multiparametric magnetic resonance imaging-targeted biopsies. Finally, developments in the field of artificial intelligence in the grading of prostatic carcinoma and future research perspectives were discussed.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

Abstract: background The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella– zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. methods We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine (“zoster vaccine”). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. results More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. conclusions The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Practice parameters for the indications for polysomnography and related procedures: an update for 2005.

Abstract: These practice parameters are an update of the previously-published recommendations regarding the indications for polysomnography and related procedures in the diagnosis of sleep disorders. Diagnostic categories include the following: sleep related breathing disorders, other respiratory disorders, narcolepsy, parasomnias, sleep related seizure disorders, restless legs syndrome, periodic limb movement sleep disorder, depression with insomnia, and circadian rhythm sleep disorders. Polysomnography is routinely indicated for the diagnosis of sleep related breathing disorders; for continuous positive airway pressure (CPAP) titration in patients with sleep related breathing disorders; for the assessment of treatment results in some cases; with a multiple sleep latency test in the evaluation of suspected narcolepsy; in evaluating sleep related behaviors that are violent or otherwise potentially injurious to the patient or others; and in certain atypical or unusual parasomnias. Polysomnography may be indicated in patients with neuromuscular disorders and sleep related symptoms; to assist in the diagnosis of paroxysmal arousals or other sleep disruptions thought to be seizure related; in a presumed parasomnia or sleep related seizure disorder that does not respond to conventional therapy; or when there is a strong clinical suspicion of periodic limb movement sleep disorder. Polysomnography is not routinely indicated to diagnose chronic lung disease; in cases of typical, uncomplicated, and noninjurious parasomnias when the diagnosis is clearly delineated; for patients with seizures who have no specific complaints consistent with a sleep disorder; to diagnose or treat restless legs syndrome; for the diagnosis of circadian rhythm sleep disorders; or to establish a diagnosis of depression.

SPECIFICITY AND VERSATILITY IN TGF-β SIGNALING THROUGH SMADS

Abstract: The TGF-β family comprises many structurally related differentiation factors that act through a heteromeric receptor complex at the cell surface and an intracellular signal transducing Smad complex. The receptor complex consists of two type II and two type I transmembrane serine/threonine kinases. Upon phosphorylation by the receptors, Smad complexes translocate into the nucleus, where they cooperate with sequence-specific transcription factors to regulate gene expression. The vertebrate genome encodes many ligands, fewer type II and type I receptors, and only a few Smads. In contrast to the perceived simplicity of the signal transduction mechanism with few Smads, the cellular responses to TGF-β ligands are complex and context dependent. This raises the question of how the specificity of the ligand-induced signaling is achieved. We review the molecular basis for the specificity and versatility of signaling by the many ligands through this conceptually simple signal transduction mechanism.

Vitamin E and Donepezil for the Treatment of Mild Cognitive Impairment

Abstract: background Mild cognitive impairment is a transitional state between the cognitive changes of normal aging and early Alzheimer’s disease. methods In a double-blind study, we evaluated subjects with the amnestic subtype of mild cognitive impairment. Subjects were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of donepezil daily, or placebo for three years. The primary outcome was clinically possible or probable Alzheimer’s disease; secondary outcomes were cognition and function. results A total of 769 subjects were enrolled, and possible or probable Alzheimer’s disease developed in 212. The overall rate of progression from mild cognitive impairment to Alzheimer’s disease was 16 percent per year. As compared with the placebo group, there were no significant differences in the probability of progression to Alzheimer’s disease in the vitamin E group (hazard ratio, 1.02; 95 percent confidence interval, 0.74 to 1.41; P=0.91) or the donepezil group (hazard ratio, 0.80; 95 percent confidence interval, 0.57 to 1.13; P=0.42) during the three years of treatment. Prespecified analyses of the treatment effects at 6-month intervals showed that as compared with the placebo group, the donepezil group had a reduced likelihood of progression to Alzheimer’s disease during the first 12 months of the study (P=0.04), a finding supported by the secondary outcome measures. Among carriers of one or more apolipoprotein E e 4 alleles, the benefit of donepezil was evident throughout the three-year follow-up. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point, either among all patients or among apolipoprotein E e 4 carriers. conclusions Vitamin E had no benefit in patients with mild cognitive impairment. Although donepezil therapy was associated with a lower rate of progression to Alzheimer’s disease during the first 12 months of treatment, the rate of progression to Alzheimer’s disease after three years was not lower among patients treated with donepezil than among those given placebo.

Care of Children and Adolescents With Type 1 Diabetes A statement of the American Diabetes Association

Abstract: During recent years, the American Diabetes Association (ADA) has published detailed guidelines and recommendations for the management of diabetes in the form of technical reviews, position statements, and consensus statements. Recommendations regarding children and adolescents have generally been included as only a minor portion of these documents. For example, the most recent ADA position statement on “Standards of Medical Care for Patients With Diabetes Mellitus” (last revised October 2003) included “special considerations” for children and adolescents (1). Other position statements included age-specific recommendations for screening for nephropathy (2) and retinopathy (3) in children with diabetes. In addition, the ADA has published guidelines pertaining to certain aspects of diabetes that apply exclusively to children and adolescents, including care of children with diabetes at school (4) and camp (5) and a consensus statement on type 2 diabetes in children and adolescents (6). The purpose of this document is to provide a single resource on current standards of care pertaining specifically to children and adolescents with type 1 diabetes. It is not meant to be an exhaustive compendium on all aspects of the management of pediatric diabetes. However, relevant references are provided and current works in progress are indicated as such. The information provided is based on evidence from published studies whenever possible and, when not, supported by expert opinion or consensus (7). Several excellent detailed guidelines and chapters on type 1 diabetes in pediatric endocrinology texts exist, including those by the International Society of Pediatric and Adolescent Diabetes (ISPAD) (8), by the Australian Pediatric Endocrine Group (www.chw.edu/au/prof/services/endocrinology/apeg), in Lifshitz’s Pediatric Endocrinology (9–11), and by Plotnick and colleagues (12,13). Children have characteristics and needs that dictate different standards of care. The management of diabetes in children must take the major differences between children of various ages and …

The genome of the social amoeba Dictyostelium discoideum

Abstract: The social amoebae are exceptional in their ability to alternate between unicellular and multicellular forms. Here we describe the genome of the best-studied member of this group, Dictyostelium discoideum. The gene-dense chromosomes of this organism encode approximately 12,500 predicted proteins, a high proportion of which have long, repetitive amino acid tracts. There are many genes for polyketide synthases and ABC transporters, suggesting an extensive secondary metabolism for producing and exporting small molecules. The genome is rich in complex repeats, one class of which is clustered and may serve as centromeres. Partial copies of the extrachromosomal ribosomal DNA (rDNA) element are found at the ends of each chromosome, suggesting a novel telomere structure and the use of a common mechanism to maintain both the rDNA and chromosomal termini. A proteome-based phylogeny shows that the amoebozoa diverged from the animal-fungal lineage after the plant-animal split, but Dictyostelium seems to have retained more of the diversity of the ancestral genome than have plants, animals or fungi.

Getting to know you : Reputation and trust in a two-person economic exchange

Abstract: Using a multiround version of an economic exchange (trust game), we report that reciprocity expressed by one player strongly predicts future trust expressed by their partner—a behavioral finding mirrored by neural responses in the dorsal striatum. Here, analyses within and between brains revealed two signals—one encoded by response magnitude, and the other by response timing. Response magnitude correlated with the “intention to trust” on the next play of the game, and the peak of these “intention to trust” responses shifted its time of occurrence by 14 seconds as player reputations developed. This temporal transfer resembles a similar shift of reward prediction errors common to reinforcement learning models, but in the context of a social exchange. These data extend previous model-based functional magnetic resonance imaging studies into the social domain and broaden our view of the spectrum of functions implemented by the dorsal striatum.

A review of family and social determinants of children's eating patterns and diet quality.

Abstract: With the growing problem of childhood obesity, recent research has begun to focus on family and social influences on children's eating patterns. Research has demonstrated that children's eating patterns are strongly influenced by characteristics of both the physical and social environment. With regard to the physical environment, children are more likely to eat foods that are available and easily accessible, and they tend to eat greater quantities when larger portions are provided. Additionally, characteristics of the social environment, including various socioeconomic and sociocultural factors such as parents' education, time constraints, and ethnicity influence the types of foods children eat. Mealtime structure is also an important factor related to children's eating patterns. Mealtime structure includes social and physical characteristics of mealtimes including whether families eat together, TV-viewing during meals, and the source of foods (e.g., restaurants, schools). Parents also play a direct role in children's eating patterns through their behaviors, attitudes, and feeding styles. Interventions aimed at improving children's nutrition need to address the variety of social and physical factors that influence children's eating patterns.

Leptin regulation of bone resorption by the sympathetic nervous system and CART

Abstract: Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.

Meta-analysis: obesity and the risk for gastroesophageal reflux disease and its complications.

Abstract: Obesity is associated with a 1.5- to 2.0-fold increase in the risk for symptoms of gastroesophageal reflux disease, erosive esophagitis, and esophageal adenocarcinoma. With increasing body weight, ...

Practice Parameters for Clinical Use of the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test

Abstract: Characterization of excessive sleepiness is an important task for the sleep clinician, and assessment requires a thorough history and in many cases, objective assessment in the sleep laboratory. These practice parameters were developed to guide the sleep clinician on appropriate clinical use of the Multiple Sleep Latency Test (MSLT), and the Maintenance of Wakefulness Test (MWT). These recommendations replace those published in 1992 in a position paper produced by the American Sleep Disorders Association. A Task Force of content experts was appointed by the American Academy of Sleep Medicine to perform a comprehensive review of the scientific literature and grade the evidence regarding the clinical use of the MSLT and the MWT. Practice parameters were developed based on this review and in most cases evidence based methods were used to support recommendations. When data were insufficient or inconclusive, the collective opinion of experts was used to support recommendations. These recommendations were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. The MSLT is indicated as part of the evaluation of patients with suspected narcolepsy and may be useful in the evaluation of patients with suspected idiopathic hypersomnia. The MSLT is not routinely indicated in the initial evaluation and diagnosis of obstructive sleep apnea syndrome, or in assessment of change following treatment with nasal continuous positive airway pressure (CPAP). The MSLT is not routinely indicated for evaluation of sleepiness in medical and neurological disorders (other than narcolepsy), insomnia, or circadian rhythm disorders. The MWT may be indicated in assessment of individuals in whom the inability to remain awake constitutes a safety issue, or in patients with narcolepsy or idiopathic hypersomnia to assess response to treatment with medications. There is little evidence linking mean sleep latency on the MWT with risk of accidents in real world circumstances. For this reason, the sleep clinician should not rely solely on mean sleep latency as a single indicator of impairment or risk for accidents, but should also rely on clinical judgment. Assessment should involve integration of findings from the clinical history, compliance with treatment, and, in some cases, objective testing using the MWT. These practice parameters also include recommendations for the MSLT and MWT protocols, a discussion of the normative data available for both tests, and a description of issues that need further study.

The Metabolic Syndrome and 11-Year Risk of Incident Cardiovascular Disease in the Atherosclerosis Risk in Communities Study

Abstract: OBJECTIVE — To assess the magnitude of the association between the National Cholesterol Education Program’s Third Adult Treatment Panel Report (ATP III) definition of the metabolic syndrome and cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS — Cox regression was used to estimate the relative risk of incident coronary heart disease (CHD) and stroke among 12,089 black and white middle-aged individuals in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS — The metabolic syndrome was present in ∼23% of individuals without diabetes or prevalent CVD at baseline. Over an average of 11 years of follow-up, 879 incident CHD and 216 ischemic stroke events occurred. Among the components of the metabolic syndrome, elevated blood pressure and low levels of HDL cholesterol exhibited the strongest associations with CHD. Men and women with the metabolic syndrome were ∼1.5 and 2 times more likely to develop CHD than control subjects after adjustment for age, smoking, LDL cholesterol, and race/ARIC center (sex interaction P < 0.03). Similar associations were found between the metabolic syndrome and incident ischemic stroke. Comparison of receiver operating characteristic curves indicated that the metabolic syndrome did not materially improve CHD risk prediction beyond the level achieved by the Framingham Risk Score (FRS). CONCLUSIONS — Individuals without diabetes or CVD, but with the metabolic syndrome, were at increased risk for long-term cardiovascular outcomes, although statistical models suggested that most of that risk was accounted for by the FRS. Nevertheless, identification of individuals with the metabolic syndrome may provide opportunities to intervene earlier in the development of shared disease pathways that predispose individuals to both CVD and diabetes.

Measuring diagnoses: ICD code accuracy.

Abstract: Nosology (the systematic classification of diseases) has always fascinated the sick and their would-be healers. Western societies developed an interest in nosology in the seventeenth and eighteenth centuries when they began to track the causes of sickness and death among their citizens. In the twentieth century, when medical insurance programs made payers other than patients responsible for medical care, nosology became a matter of great interest to those public and private payers. The most commonly used nosologies include International Classification of Diseases (ICD), the American Medical Association's Current Procedural Terminology, 4th Edition (CPT-4); the Health Care Financing Administration (HCFA, now known as the Centers for Medicare and Medicaid Services) Health Care Common Procedural Coding System (HCPCS); the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 4th Revision (DSM-IV); Europe's Classification of Surgical Operations and Procedures, 4th Revision (OPCS-4); and the Agency for Healthcare Research and Quality's Clinical Classification Software (CCS). This paper focuses on the International Classification of Diseases, now in its ninth and soon to be tenth iteration; the most widely used classification of diseases. Beginning in 1900 with the ICD-1 version, this nosology has evolved from 179 to over 120,000 total codes in ICD-10-CM (ICD-10 2003; ICD-10-CM 2003). The use of codes has expanded from classifying morbidity and mortality information for statistical purposes to diverse sets of applications, including reimbursement, administration, epidemiology, and health services research. Since October 1 1983, when Medicare's Prospective Payment System (PPS) was enacted, diagnosis-related groups (DRGs) based on ICD codes emerged as the basis for hospital reimbursement for acute-care stays of Medicare beneficiaries (U.S. Congress 1985). Today the use of ICD coding for reimbursement is a vital part of health care operations. Health care facilities use ICD codes for workload and length-of-stay tracking as well as to assess quality of care. The Veterans Health Administration uses ICD codes to set capitation rates and allocate resources to medical centers caring for its 6 million beneficiaries. Medical research uses ICD codes for many purposes. By grouping patients according to their diagnoses, clinical epidemiologists use ICD codes to study patterns of disease, patterns of care, and outcomes of disease. Health services researchers use the codes to study risk-adjusted, cross-sectional, and temporal variations in access to care, quality of care, costs of care, and effectiveness of care. Medical and health services researchers commonly use ICD codes as inclusion and exclusion criteria to define sampling frames, to document the comorbidities of patients, report the incidence of complications, track utilization rates, and determine the case fatality and morbidity rates (see Calle et al. 2003 for a recent example) (Steinman, Landefeld, and Gonzales 2000; Calle et al. 2003; Charbonneau et al. 2003; Jackson et al. 2003; Martin et al. 2003; Studdert and Gresenz 2003). The widespread and diverse use of ICD codes demonstrates the central role nosology plays in health care. Increased attention to code accuracy has occurred both as a result of the application of ICD codes for purposes other than those for which the classifications were originally designed as well as because of the widespread use for making important funding, clinical, and research decisions. Code accuracy, defined as the extent to which the ICD nosologic code reflects the underlying patient's disease, directly impacts the quality of decisions that are based on codes, and therefore code accuracy is of great importance to code users. Accuracy is a complicated issue, however, as it influences each code application differently. Using the codes for reporting case fatality rates in persons hospitalized for influenza, for example, might require a different level of accuracy than using codes as the basis for reimbursing hospitals for providing expensive surgical services to insured persons. Therefore, users of disease classifications, just as users of any measure, must consider the accuracy of the classifications within their unique situations. An appreciation of the measurement context in which disease classifications take place will improve the accuracy of those classifications and will strengthen research and health care decisions based on those classifications. Researchers studying errors in the code assignment process have reported a wide range of errors. Studies in the 1970s found substantial errors in diagnostic and procedure coding. These error rates ranged from 20 to 80 percent (Institute of Medicine 1977; Corn 1981; Doremus and Michenzi 1983; Johnson and Appel 1984; Hsia et al. 1988). Studies in the 1980s reported slightly increased accuracy with average error rates around 20 percent, and most below 50 percent (Lloyd and Rissing 1985; Fischer et al. 1992; Jolis et al. 1993). Studies in the 1990s found rates similar to those of the 1980 studies, with error rates ranging from 0 to 70 percent (Benesch et al. 1997; Faciszewski, Broste, and Fardon 1997; Goldstein 1998). The inconsistency in the error rates and wide range of reported amounts of error is due largely to differences across study methods (i.e., different data sets, versions of the ICD classifications, conditions studied, number of digits compared, codes examined, etc.) (Bossuyt et al. 2004). However, variation in error rates is also influenced by the many different sources of errors that influence code accuracy (Green and Wintfeld 1993). By clearly specifying the code process and the types of errors and coding inconsistencies that occur in each study, researchers can begin to understand which errors are most common and most important in their situation. They can then institute steps for reducing those errors. If we think of the assignment of ICD codes as a common measurement process, then the person's true disease and the assigned ICD code represent true and observed variables, respectively. One approach to evaluating ICD code accuracy is to examine sources of errors that lead to the assignment of a diagnostic code that is not a fair representation of the patient's actual condition. Errors that differentiate the ICD code from the true disease include both random and systematic measurement errors. By understanding these sources of error, users can evaluate the limitations of the classifications and make better decisions based on them. In this manuscript, we (1) present the history of ICD code use, (2) summarize the general inpatient ICD coding process (from patient admission to the assignment of diagnostic codes), (3) identify potential sources of errors in the process, and (4) critique methods for assessing these errors.

Prevalence and patterns of cognitive impairment in sporadic ALS.

Abstract: Objective: To investigate the prevalence and nature of cognitive changes associated with sporadic amyotrophic lateral sclerosis (ALS) using a large scale study. Methods: Consecutive patients with sporadic ALS (n = 279) underwent comprehensive neurologic evaluation and neuropsychological testing. Testing data from normal controls (n = 129) were used for classification and comparison purposes. Results: On non-motor, non-speed-dependent tasks, 51% of patients with ALS had evidence of cognitive impairment compared to 5% of controls. Cluster analysis suggested four patient subgroups: 49% intact, 32% with mild impairment, 13% with moderate impairment, and 6% with severe impairment. Forty-one patients (15%) met criteria for frontotemporal dementia (FTD). ALS patient subgroups, excluding the intact group, performed significantly lower on tests of executive function and memory than normal controls. Patients with more severe disease also had deficits in confrontation naming. Although memory function declined with increasing severity of overall cognitive impairment, only two patients had the severe memory loss typical of Alzheimer disease. Cognitive impairment was correlated with clinical measures of word-finding, phrase length, and motor programming. Cognitive impairment was not correlated with depression scores or severity or duration of motor or bulbar symptoms. Patients with bulbar vs limb-onset ALS were not different in either level of impairment or pattern of performance. Conclusions: These data confirm the presence of cognitive impairment in 50% of patients with ALS and particularly implicate executive dysfunction and mild memory decline in the disease process. More severe impairment occurs in a subset of patients with ALS and has features consistent with FTD.

Diseases of unstable repeat expansion: mechanisms and common principles.

Abstract: The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.

Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

Abstract: Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells1. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure2. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.

FoxM1 is required for execution of the mitotic programme and chromosome stability

Abstract: Transcriptional induction of cell-cycle regulatory proteins ensures proper timing of subsequent cell-cycle events. Here we show that the Forkhead transcription factor FoxM1 regulates expression of many G2-specific genes and is essential for chromosome stability. Loss of FoxM1 leads to pleiotropic cell-cycle defects, including a delay in G2, chromosome mis-segregation and frequent failure of cytokinesis. We show that transcriptional activation of cyclin B by FoxM1 is essential for timely mitotic entry, whereas CENP-F, another direct target of FoxM1 identified here, is essential for precise functioning of the mitotic spindle checkpoint. Thus, our data uncover a transcriptional cluster regulated by FoxM1 that is essential for proper mitotic progression.

Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function.

Abstract: CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.

Epigenetic mechanisms in memory formation

Abstract: Discoveries concerning the molecular mechanisms of cell differentiation and development have dictated the definition of a new sub-discipline of genetics known as epigenetics Epigenetics refers to a set of self-perpetuating, post-translational modifications of DNA and nuclear proteins that produce lasting alterations in chromatin structure as a direct consequence, and lasting alterations in patterns of gene expression as an indirect consequence The area of epigenetics is a burgeoning subfield of genetics in which there is considerable enthusiasm driving new discoveries Neurobiologists have only recently begun to investigate the possible roles of epigenetic mechanisms in behaviour, physiology and neuropathology Strikingly, the relevant data from the few extant neurobiology-related studies have already indicated a theme — epigenetic mechanisms probably have an important role in synaptic plasticity and memory formation