bluuebunny/crossref_metadata_2025 huggingface dataset:
LEARNING BAYESIAN NETWORKS IN THE SPACE OF ORDERINGS WITH ESTIMATION OF DISTRIBUTION ALGORITHMS
Authors: ROMERO TXOMIN , LARRAÑAGA PEDRO , SIERRA BASILIO
Published: June 2004

The search for the optimal ordering of a set of variables in order to solve a computational problem is a difficulty that can appear in several circumstances. One of these situations is the automatic learning of a network structure, for example, a Bayesian Network structure (BN) starting from a dataset. Searching in the space of structures is often unmanageable, especially if the number of variables is high. Popular heuristic approaches, like Cooper and Herskovits's K2 algorithm, depend on a given ordering of variables. Estimation of Distribution Algorithms (EDAs) are a new paradigm for Evolutionary Computation that have been used as a search engine in the BN structure learning problem. In this paper, we will use two different EDAs to obtain not the best structure, but the optimal ordering of variables for the K2 algorithm: UMDA and MIMIC, both of them in discrete and continuous domains. We will also check whether the individual representation and its relation to the corresponding ordering play important roles, and whether MIMIC outperforms the results of UMDA.
CLASSIFYING POLYGONAL CHAINS OF SIX SEGMENTS
Authors: CLARK THOMAS J. , VENEMA GERARD A.
Published: June 2004

A polygonal chain is the union of a finite number of straight line segments in ℝ3 that are connected end-to-end. Two chains are considered to be equivalent if there is an isotopy of ℝ3 that moves one chain to the other while keeping the segments rigid. Each segment must remain straight during the isotopy and the lengths of the segments may not change, but bending and twisting are allowed at the joints between the segments. Chains may be knotted and stuck in this category even though all chains are topologically trivial. Cantarella and Johnston have classified polygonal chains with five or fewer segments. In this paper we classify polygonal chains of six segments.
Structural Basis of Ion Pumping by Ca2+-ATPase of the Sarcoplasmic Reticulum
Authors: Toyoshima Chikashi , Inesi Giuseppe
Published: June 2004

▪ Abstract  The structures of the Ca2+-ATPase (SERCA1a) have been determined for five different states by X-ray crystallography. Detailed comparison of the structures in the Ca2+ bound form and unbound (but thapsigargin bound) form reveals that very large rearrangements of the transmembrane helices take place accompanying Ca2+ dissociation and binding and that they are mechanically linked with equally large movements of the cytoplasmic domains. The meanings of the rearrangements of the transmembrane helices and those of the cytoplasmic domains as well as the mechanistic roles of phosphorylation are now becoming clear. Furthermore, the roles of critical amino acid residues identified by extensive mutagenesis studies are becoming evident in terms of atomic structure.
Structural Aspects of Ligand Binding to and Electron Transfer in Bacterial and Fungal P450s
Authors: Pylypenko Olena , Schlichting Ilme
Published: June 2004

▪ Abstract  Cytochrome P450 enzymes are heme-containing monooxygenases that are named after an absorption band at 450 nm when complexed with carbon monoxide. They catalyze a wide variety of reactions and are unique in their ability to hydroxylate nonactivated hydrocarbons. P450 enzymes are involved in numerous biological processes, which include the biosynthesis of lipids, steroids, antibiotics, and the degradation of xenobiotics. In line with the variety of reactions catalyzed, the size of their substrates varies significantly. Some P450s have open active sites (e.g., BM3), and some have shielded active sites that open only transiently (e.g., P450cam), whereas others bind the substrate only when attached to carrier proteins (e.g., Oxy proteins). Structural aspects of both organic and gaseous ligand binding and electron transfer are described.
Lysophospholipid Receptors: Signaling and Biology
Authors: Ishii Isao , Fukushima Nobuyuki , Ye Xiaoqin , Chun Jerold
Published: June 2004

▪ Abstract  Lysophospholipids (LPs), such as lysophosphatidic acid and sphingosine 1-phosphate, are membrane-derived bioactive lipid mediators. LPs can affect fundamental cellular functions, which include proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesis. In recent years, identification of multiple cognate G protein-coupled receptors has provided a mechanistic framework for understanding how LPs play such diverse roles. Generation of LP receptor-null animals has allowed rigorous examination of receptor-mediated physiological functions in vivo and has identified new functions for LP receptor signaling. Efforts to develop LP receptor subtype-specific agonists/antagonists are in progress and raise expectations for a growing collection of chemical tools and potential therapeutic compounds. The rapidly expanding literature on the LP receptors is herein reviewed.
Roles of N-Linked Glycans in the Endoplasmic Reticulum
Authors: Helenius Ari , Aebi Markus
Published: June 2004

▪ Abstract  From a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition “tags” that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as α-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
Opioid Receptors
Authors: Waldhoer Maria , Bartlett Selena E. , Whistler Jennifer L.
Published: June 2004

▪ Abstract  Opioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.
Eukaryotic mRNA Decapping
Authors: Coller Jeff , Parker Roy
Published: June 2004

▪ Abstract  Eukaryotic mRNAs are primarily degraded by removal of the 3′ poly(A) tail, followed either by cleavage of the 5′ cap structure (decapping) and 5′->3′ exonucleolytic digestion, or by 3′ to 5′ degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these steps is a demonstrated, or potential, site for the regulation of mRNA decay. We discuss the decapping process in the light of these central properties, which also suggest fundamental aspects of cytoplasmic mRNA physiology that connect decapping, translation, and storage of mRNA.
Structural Insights Into the Signal Recognition Particle
Authors: Doudna Jennifer A. , Batey Robert T.
Published: June 2004

▪ Abstract  The signal recognition particle (SRP) directs integral membrane and secretory proteins to the cellular protein translocation machinery during translation. The SRP is an evolutionarily conserved RNA-protein complex whose activities are regulated by GTP hydrolysis. Recent structural investigations of SRP functional domains and interactions provide new insights into the mechanisms of SRP activity in all cells, leading toward a comprehensive understanding of protein trafficking by this elegant pathway.
Structure and Function of TolC: The Bacterial Exit Duct for Proteins and Drugs
Authors: Koronakis Vassilis , Eswaran Jeyanthy , Hughes Colin
Published: June 2004

▪ Abstract  The bacterial TolC protein plays a common role in the expulsion of diverse molecules, which include protein toxins and antibacterial drugs, from the cell. TolC is a trimeric 12-stranded α/β barrel, comprising an α-helical trans-periplasmic tunnel embedded in the outer membrane by a contiguous β-barrel channel. This structure establishes a 140 Å long single pore fundamentally different to other membrane proteins and presents an exit duct to substrates, large and small, engaged at specific inner membrane translocases. TolC is open to the outside medium but is closed at its periplasmic entrance. When TolC is recruited by a substrate-laden translocase, the entrance is opened to allow substrate passage through a contiguous machinery spanning the entire cell envelope, from the cytosol to the external environment. Transition to the transient open state is achieved by an iris-like mechanism in which entrance α-helices undergo an untwisting realignment, thought to be stabilized by interaction with periplasmic helices of the translocase. TolC family proteins are ubiquitous among gram-negative bacteria, and the conserved entrance aperture presents a possible cheomotherapeutic target in multidrug-resistant pathogens.
Incorporation of Nonnatural Amino Acids Into Proteins
Authors: Hendrickson Tamara L. , Crécy-Lagard Valérie de , Schimmel Paul
Published: June 2004

▪ Abstract  The genetic code is established by the aminoacylation of transfer RNA, reactions in which each amino acid is linked to its cognate tRNA that, in turn, harbors the nucleotide triplet (anticodon) specific to the amino acid. The accuracy of aminoacylation is essential for building and maintaining the universal tree of life. The ability to manipulate and expand the code holds promise for the development of new methods to create novel proteins and to understand the origins of life. Recent efforts to manipulate the genetic code have fulfilled much of this potential. These efforts have led to incorporation of nonnatural amino acids into proteins for a variety of applications and have demonstrated the plausibility of specific proposals for early evolution of the code.
Flap Endonuclease 1: A Central Component of DNA Metabolism
Authors: Liu Yuan , Kao Hui-I , Bambara Robert A.
Published: June 2004

▪ Abstract  One strand of cellular DNA is generated as RNA-initiated discontinuous segments called Okazaki fragments that later are joined. The RNA terminated region is displaced into a 5′ single-stranded flap, which is removed by the structure-specific flap endonuclease 1 (FEN1), leaving a nick for ligation. Similarly, in long-patch base excision repair, a damaged nucleotide is displaced into a flap and removed by FEN1. FEN1 is a genome stabilization factor that prevents flaps from equilibrating into structures that lead to duplications and deletions. As an endonuclease, FEN1 enters the flap from the 5′ end and then tracks to cleave the flap base. Cleavage is oriented by the formation of a double flap. Analyses of FEN1 crystal structures suggest mechanisms for tracking and cleavage. Some flaps can form self-annealed and template bubble structures that interfere with FEN1. FEN1 interacts with other nucleases and helicases that allow it to act efficiently on structured flaps. Genetic and biochemical analyses continue to reveal many roles of FEN1.
Regulation of Telomerase by Telomeric Proteins
Authors: Smogorzewska Agata , de Lange Titia
Published: June 2004

▪ Abstract  Telomeres are essential for genome stability in all eukaryotes. Changes in telomere functions and the associated chromosomal abnormalities have been implicated in human aging and cancer. Telomeres are composed of repetitive sequences that can be maintained by telomerase, a complex containing a reverse transcriptase (hTERT in humans and Est2 in budding yeast), a template RNA (hTERC in humans and Tlc1 in yeast), and accessory factors (the Est1 proteins and dyskerin in humans and Est1, Est3, and Sm proteins in budding yeast). Telomerase is regulated in cis by proteins that bind to telomeric DNA. This regulation can take place at the telomere terminus, involving single-stranded DNA-binding proteins (POT1 in humans and Cdc13 in budding yeast), which have been proposed to contribute to the recruitment of telomerase and may also regulate the extent or frequency of elongation. In addition, proteins that bind along the length of the telomere (TRF1/TIN2/tankyrase in humans and Rap1/Rif1/Rif2 in budding yeast) are part of a negative feedback loop that regulates telomere length. Here we discuss the details of telomerase and its regulation by the telomere.
ZINC AND THE RISK FOR INFECTIOUS DISEASE
Authors: Walker Christa Fischer , Black Robert E.
Published: June 2004

▪ Abstract  Zinc is an essential micronutrient for human growth, development, and immune function. Zinc deficiency impairs overall immune function and resistance to infection. Mild to moderate zinc deficiency can be best detected through a positive response to supplementation trials. Zinc supplementation has been shown to have a positive effect on the incidence of diarrhea (18% reduction, 95% CI: 7–28%) and pneumonia (41% reduction, 95% CI: 17–59%), and might lead to a decrease in the incidence of malaria. Zinc has also proven to decrease the duration of diarrhea by 15% (95% CI: 5–24%). Maternal zinc supplementation may lead to a decrease in infant infections. Studies assessing the role of zinc supplementation among persons with HIV, tuberculosis, and the common cold have not been conclusive. Two studies have shown zinc supplementation to decrease child mortality by more than 50%. Zinc clearly has an important role in infant and childhood infectious diseases; programs to increase the intake of zinc among deficient populations are needed.
NUTRIENT REGULATION OF CELL CYCLE PROGRESSION
Authors: Bohnsack Brenda L. , Hirschi Karen K.
Published: June 2004

▪ Abstract  Cell replication is tightly controlled in normal tissues and aberrant during disease progression, such as in tumorigenesis. The replication of cells can be divided into four distinct phases: Gap 1 (G1), synthesis (S), gap 2 (G2), and mitosis (M). The progression from one phase to the next is intricately regulated and has many “checkpoints” that take into account cellular status and environmental cues. Among the modulators of cell cycle progression are specific nutrients, which function as energy sources or regulate the production and/or function of proteins needed to advance cells through a replicative cycle. In this review, we focus on the roles of specific nutrients (vitamin A, vitamin D, iron, folic acid, vitamin B12, zinc, and glucose) in the control of cell cycle progression and discuss how insights into the mechanisms by which these nutrients modulate this process can be and have been used to control aberrant cell growth in the treatment of prevalent pathologies.
ENVIRONMENTAL FACTORS THAT INCREASE THE FOOD INTAKE AND CONSUMPTION VOLUME OF UNKNOWING CONSUMERS
Authors: Wansink Brian
Published: June 2004

▪ Abstract  Package size, plate shape, lighting, socializing, and variety are only a few of the environmental factors that can influence the consumption volume of food far more than most people realize. Although such environmental factors appear unrelated, they generally influence consumption volume by inhibiting consumption monitoring and by suggesting alternative consumption norms. For researchers, this review suggests that redirecting the focus of investigations to the psychological mechanisms behind consumption will raise the profile and impact of research. For health professionals, this review underscores how small structural changes in personal environments can reduce the unknowing overconsumption of food.
RETINOIC ACID RECEPTORS AND CANCERS
Authors: Soprano Dianne Robert , Qin Pu , Soprano Kenneth J.
Published: June 2004

▪ Abstract  Studies utilizing experimental animals, epidemiological approaches, cellular models, and clinical trials all provide evidence that retinoic acid and some of its synthetic derivatives (retinoids) are useful pharmacological agents in cancer therapy and prevention. In this chapter, we first review the current knowledge of retinoic acid receptors (RARs) and their role in mediating the actions of retinoic acid. We then focus on a discussion of RARα and acute promyelocytic leukemia followed by a discussion of the role of RARs, in particular RARβ expression, in other cancer types. Loss of normal RAR function in the presence of physiological levels of RA (either due to alterations in the protein structure or level of expression) is associated with a variety of different cancers. In some cases treatment with pharmacological doses of RA can be effective.
ON BECOMING A NUTRITIONAL BIOCHEMIST
Authors: McCormick Donald B.
Published: June 2004

▪ Abstract  Much of the science underlying nutrition has come from biochemical studies. This certainly is true in our understanding of the metabolism and function of such micronutrient cofactors as vitamins and metal ions. My own interest stems from an early desire to understand the molecular events in an organism and ultimately to know the fate of those nutrients that are needed to maintain life. My training in chemistry, biochemistry, and nutrition was helpful in gaining knowledge about the interface among these disciplines. My interests followed an understandable trail, beginning with those factors that cause plant galls and continuing through carbohydrate metabolism to vitamins. After all, from studying such pentitols as ribitol with Professor Touster at Vanderbilt University through indoctrination with enzymes, vitamins, and coenzymes with Professor Snell at the University of California-Berkeley, it was rational to begin my independent academic life investigating the enzymes that convert a ribityl-containing vitamin, namely riboflavin, to its operational flavocoenzymes. While at Cornell University, I encountered Professor Wright, who shared an interest in biotin. My realization that there was a similar need to determine the metabolism of lipoate followed logically. Interactions with inorganic chemists such as Professor Sigel at Basel University, as well as inorganic chemists at Cornell, led to an interest in metal ions. As summarized in this article, my colleagues and I are pleased to have contributed to both basic knowledge about cofactors and to have utilized much of this information in extensions to applications. Along the way, I have served by teaching, researching, and administrating at the universities that provided my positions in academe, and I have worked to share the load of numerous public and professional duties that are summarized herein. Altogether it has been an enjoyable career to be a nutritional biochemist. I recommend it for those who follow.
STRUCTURE, FUNCTION, AND DIETARY REGULATION OF Δ6, Δ5, AND Δ9 DESATURASES
Authors: Nakamura Manabu T. , Nara Takayuki Y.
Published: June 2004

▪ Abstract  Fatty acid desaturases introduce a double bond in a specific position of long-chain fatty acids, and are conserved across kingdoms. Degree of unsaturation of fatty acids affects physical properties of membrane phospholipids and stored triglycerides. In addition, metabolites of polyunsaturated fatty acids are used as signaling molecules in many organisms. Three desaturases, Δ9, Δ6, and Δ5, are present in humans. Delta-9 catalyzes synthesis of monounsaturated fatty acids. Oleic acid, a main product of Δ9 desaturase, is the major fatty acid in mammalian adipose triglycerides, and is also used for phospholipid and cholesteryl ester synthesis. Delta-6 and Δ5 desaturases are required for the synthesis of highly unsaturated fatty acids (HUFAs), which are mainly esterified into phospholipids and contribute to maintaining membrane fluidity. While HUFAs may be required for cold tolerance in plants and fish, the primary role of HUFAs in mammals is cell signaling. Arachidonic acid is required as substrates for eicosanoid synthesis, while docosahexaenoic acid is required in visual and neuronal functions. Desaturases in mammals are regulated at the transcriptional level. Reflecting overlapping functions, three desaturases share a common mechanism of a feedback regulation to maintain products in membrane phospholipids. At the same time, regulation of Δ9 desaturase differs from Δ6 and Δ5 desaturases because its products are incorporated into more diverse lipid groups. Combinations of multiple transcription factors achieve this sophisticated differential regulation.
Glucose activates H+-ATPase in kidney epithelial cells
Authors: Nakamura Suguru
Published: June 2004

The vacuolar H+-ATPase (V-ATPase) acidifies compartments of the vacuolar system of eukaryotic cells. In renal epithelial cells, it resides on the plasma membrane and is essential for bicarbonate transport and acid-base homeostasis. The factors that regulate the H+-ATPase remain largely unknown. The present study examines the effect of glucose on H+-ATPase activity in the pig kidney epithelial cell line LLC-PK1. Cellular pH was measured by performing ratiometric fluorescence microscopy using the pH-sensitive indicator BCECF-AM. Intracellular acidification was induced with NH3/NH4+ prepulse, and rates of intracellular pH (pHi) recovery (after in situ calibration) were determined by the slopes of linear regression lines during the first 3 min of recovery. The solutions contained 1 μM ethylisopropylamiloride and were K+ free to eliminate Na+/H+ exchange and H+-K+-ATPase activity. After NH3/NH4+-induced acidification, LLC-PK1 cells had a significant pHi recovery rate that was inhibited entirely by 100 nM of the V-ATPase inhibitor concanamycin A. Acute removal of glucose from medium markedly reduced V-ATPase-dependent pHi recovery activity. Readdition of glucose induced concentration-dependent reactivation of V-ATPase pHi recovery activity within 2 min. Glucose replacement produced no significant change in cell ATP or ADP content. H+-ATPase activity was completely inhibited by the glycolytic inhibitor 2-deoxy-d-glucose (20 mM) but only partially inhibited by the mitochondrial electron transport inhibitor antimycin A (20 μM). The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (500 nM) abolished glucose activation of V-ATPase, and activity was restored after wortmannin removal. Glucose activates V-ATPase activity in kidney epithelial cells through the glycolytic pathway by a signaling pathway that requires PI3K activity. These findings represent an entirely new physiological effect of glucose, linking it to cellular proton secretion and vacuolar acidification.
Natural History of Frontotemporal Dementia: Comparison with Alzheimer’s Disease
Authors: Pasquier Florence , Richard Florence , Lebert Florence
Published: June 2004

Introduction: Frontotemporal dementia (FTD) is a more common cause of dementia than previously recognised. Few data are available regarding the natural course of FTD in terms of survival, nursing home admission and causes of death. Methods: An observational study of all consecutive patients referred to the memory centre of Lille, France, between 1995 and 1999, and examined at least twice in this centre, with a diagnosis of FTD (frontal or behavioural variant) or of Alzheimer’s disease (AD) was performed. Kaplan-Meyer analysis allowing for delayed entry was used to compare the survival functions in FTD and AD. Results: 552 patients were included, of whom 49 (8.9%) were lost to follow-up at 3 years. FTD patients were younger (mean age at onset 59 years), had more often a family history of psychiatric disorders (20%), had a longer delay between first symptoms and first visit (5.9 years) and a higher Mini-Mental State Examination (MMSE) score at first visit (24.5) than patients with AD (19.9). The mean annual MMSE score decline was 0.9 point in FTD vs. 2.0 points in AD (p < 0.0004). Fewer patients with FTD than with AD entered an institution (RR: 0.20, 95% CI 0.05–0.81). After adjustment for sex, age at first visit, level of education and MMSE score at first visit, survival rates in FTD and AD did not differ significantly. Patients with FTD often had a sudden death, the cause of which could not be found. The earlier the first visit after onset, the longer the survival rate, whatever the diagnosis (RR: 0.76, 95% CI 0.67–0.86, p < 0.0001 per year of earlier first visit). Conclusion: This large study showed that the mean duration of FTD was 2 years longer than that of AD, but the risk of death after adjustment for age and sex was similar in FTD and in AD. Sudden and unexplained causes of death were frequent and need further study. Early management increases the life span of demented patients.
Phenotypic Variation in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17
Authors: van Swieten John C. , Rosso Sonia M. , van Herpen Esther , Kamphorst Wouter , Ravid Rivka , Heutink Peter
Published: June 2004

Hereditary frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) caused by mutations in the tau gene shows a wide range in age at onset, several distinct clinical presentations, and a spectrum of tau pathology. Although the clinical and pathological phenotype often correlate with the location of the mutation, there also exists considerable interfamilial and intrafamilial phenotypical variation. Not all families with FTDP-17 do have mutations and deposition of hyperphosphorylated tau in the brain, but show ubiquitin-positive, tau-negative inclusions. Future research should focus on the role of other genetic and environmental factors in this form of FTDP-17, whereas the responsible gene defect(s) has still to be identified for hereditary FTD without tau mutations.
Frontotemporal Dementia Linked to Chromosome 3
Authors: Brown Jerry , Gydesen Susanne , Johannsen Peter , Gade Anders , Skibinski Gaia , Chakrabarti Lisa , Brun Arne , Spillantini Maria , Yancopoulou Despina , Thusgaard Tove , Sorensen Asger , Fisher Elizabeth , Collinge John
Published: June 2004

A large pedigree with autosomal dominant frontotemporal dementia has been identified. Positional cloning has linked the disease gene to the pericentromeric region of chromosome 3. Clinical, neuropsychological, imaging, pathological and molecular genetic data are presented. The genetic mutation responsible for the disease has not been identified.
The Tau R406W Mutation Causes Progressive Presenile Dementia with Bitemporal Atrophy
Authors: Ostojic Jovanka , Elfgren Christina , Passant Ulla , Nilsson Karin , Gustafson Lars , Lannfelt Lars , Froelich Fabre Susanne
Published: June 2004

Frontotemporal dementia (FTD) and Alzheimer’s disease (AD) are two frequent causes of dementia that share both clinical and neuropathological features. Common to both disorders are the neurofibrillary tangles consisting of aggregations of hyperphosphorylated tau protein. Recently, a number of different pathogenic mutations in the tau gene have been identified in families with FTD and parkinsonism linked to chromosome 17 (FTDP-17). In the present study, a Swedish family with presenile degenerative dementia with bitemporal atrophy was screened for mutations in the tau gene. As a result, the R406W mutation in exon 13 was identified in all affected cases. This mutation has previously been reported in two different FTDP-17 families of Dutch and Midwestern American origin. Common features to these two kindreds and our family are the late age at onset and long duration of the disease. Our pedigree as well as the American one show early memory impairment and pronounced temporal lobar atrophy similar to AD, while the Dutch cases show more FTD features. This further illustrates the large clinical variability among cases with tau mutations and stresses the importance of genetic classification in addition to the traditional clinical classification of neurodegenerative disorders.
Longitudinal Patterns of Regional Change on Volumetric MRI in Frontotemporal Lobar Degeneration
Authors: Whitwell Jennifer L. , Anderson Valerie M. , Scahill Rachael I. , Rossor Martin N. , Fox Nick C.
Published: June 2004

The aim of this study was to assess the longitudinal patterns of regional change in the different syndromic variants of frontotemporal lobar degeneration (FTLD). Ten patients with semantic dementia, 7 with progressive non-fluent aphasia and 29 with frontotemporal dementia had two serial volumetric MR scans. Fluid registration was used to match serial scans from each individual. Voxel-level analysis of change across subject groups was performed using statistical parametric mapping. The analysis showed patterns of increased rates of volume loss (atrophy) in frontal, temporal and parietal regions in the whole FTLD group compared with controls. The different FTLD syndromes displayed different patterns of change. This technique gives an insight into disease evolution over time in these disorders and may be useful as a method of tracking change in clinical trials.
Clinicopathological Staging of Frontotemporal Dementia Severity: Correlation with Regional Atrophy
Authors: Kril Jillian J. , Halliday Glenda M.
Published: June 2004

The pattern and degree of brain atrophy in frontotemporal dementia (FTD) has the potential for use as an aid in the diagnosis of this disorder and its differentiation from other neurodegenerative diseases. However, before this can occur, the sequence and progression of atrophy needs to be fully elucidated. Recently, we have described a four-point scheme for staging the severity of degeneration in FTD, which correlates with both duration of disease and severity of dementia [Broe M., et al.: Neurology 2003;60:1005–1011]. When volumetric analysis is performed in post-mortem-confirmed cases of FTD, atrophy of all lobes is present by stage 2 and then progresses with successive stages. Within each lobe, there is variation in the degree of atrophy between different functionally discreet brain regions with some regions showing marked atrophy and others showing little. Much of the frontal lobe, the amygdala and hippocampus are severely atrophic by stage 2, suggesting that they are some of the earliest areas affected in FTD.
MRI with Diffusion Tensor Imaging Post-Mortem at 3.0 T in a Patient with Frontotemporal Dementia
Authors: Larsson Elna-Marie , Englund Elisabet , Sjöbeck Martin , Lätt Jimmy , Brockstedt Sara
Published: June 2004

The formalin-fixed brain of a patient with clinically diagnosed frontotemporal dementia (FTD) was examined post-mortem using magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) at 3.0 T. Frontotemporal atrophy as well as bilateral frontal white matter abnormalities were seen. The white matter changes were slightly more extensive on DTI than on conventional MRI. Correlation with histopathology of the corresponding regions revealed typical frontal lobe degeneration of non-Alzheimer type, with mild frontotemporal degeneration in the outer cortical layers and a moderate frontal white matter gliosis with demyelination. Post-mortem MRI/DTI with histopathologic correlation will enhance our understanding of the basis of white matter changes observed in dementia patients and may improve the in vivo MRI/DTI diagnostic assessment in FTD.
Confrontation Naming and Morphometric Analyses of Structural MRI in Frontotemporal Dementia
Authors: McMillan Corey , Gee James , Moore Peachie , Dennis Kari , DeVita Chris , Grossman Murray
Published: June 2004

We studied the neural basis for confrontation naming difficulty in 29 patients with frontotemporal dementia (FTD) by correlating naming with voxel-based morphometric analyses of gray matter volume in structural MRI. We found that naming is significantly impaired in FTD, including patients with semantic dementia (SD), progressive nonfluent aphasia (PNFA), and nonaphasic patients (NON-APH) with a disorder of social and executive functioning. Significant cortical atrophy was found in the left anterior temporal cortex in all three FTD subgroups relative to healthy seniors. We also found significant cortical atrophy in unique anatomic distributions in each FTD subgroup. This included: lateral, ventral, and parahippocampal regions of the left temporal lobe in SD; inferior, orbital, dorsolateral, and premotor regions of the left frontal lobe in PNFA, and bilateral frontal regions in NON-APH. Direct correlations between confrontation naming and gray matter volume revealed distinct patterns in each FTD subgroup. SD patients showed a significant correlation in the left lateral temporal cortex, PNFA patients in several left frontal regions, and NON-APH patients in the right dorsolateral prefrontal cortex. These findings suggest that confrontation naming is supported by a large-scale neural network, and that naming is compromised in FTD due to interruption of the network in several different ways.
Neuronal Intranuclear Inclusions Distinguish Familial FTD-MND Type from Sporadic Cases
Authors: Mackenzie Ian R.A. , Feldman Howard
Published: June 2004

Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are characteristically found in the extramotor cortex in patients with motor neuron disease (MND) and dementia (MND-dementia) and in a subset of patients with frontotemporal dementia (FTD) without motor symptoms (FTD-MND type). Recently, ub-ir neuronal intranuclear inclusions have been described in a small number of patients with familial FTD-MND type. To better define the sensitivity and specificity of this pathological change, we examined postmortem tissue from 14 patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5 familial, 5 sporadic) and 19 cases of MND with no history of cognitive dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare intranuclear inclusions were present in the hippocampal dentate granule cells in 1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions. These findings suggest that intranuclear inclusions are specific for familial FTD and may identify a subset of families with a common genetic basis. Although intranuclear inclusions are most characteristic of families with pure FTD, they may also be found in some pedigrees with both FTD and MND, further supporting the hypothesis that FTD-MND type and MND-dementia represent a clinicopathological spectrum of disease.
Negative Neurofilament Light and Tau Immunostaining in Frontotemporal Dementia
Authors: Sjögren Magnus , Englund Elisabet
Published: June 2004

We investigated the immunohistochemical stainability of phosphorylated tau and the light (NFL), intermediate (NFM), and heavy (NFH) neurofilament proteins in postmortem brain tissue from 8 patients with frontotemporal dementia (FTD), for comparison with 6 patients with Alzheimer’s disease (AD), and 6 normal controls. In the FTD group, the neuropathological diagnosis was pure frontal-lobe degeneration of non-Alzheimer type (FLD) in 6 cases and in the remaining 2 cases mixed FLD-AD and frontal AD, respectively. The staining for tau was negative in 5 of the FLD cases and faintly positive in 1, but positive in all AD cases. The antibodies against NFM and NFH stained positive in FLD, AD, and controls, whereas the staining for NFL was negative in all FLD cases and positive in 1 AD case and in the controls. These findings regarding NFL and tau staining may be useful in the differential diagnosis of FLD and AD.
Strategies and Clinical Implications of Chimerism Diagnostics after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Thiede Christian , Bornhäuser Martin , Ehninger Gerhard
Published: June 2004

Analysis of donor chimerism has become a routine method for the documentation of engraftment after allogeneic hematopoietic stem cell transplantation (HSCT). In recent years several groups have also focused on the application of this technique for the detection of relapsing disease after allogeneic HSCT. This review addresses technical issues (sensitivity, specificity) and discusses the advantages and limitations of methods currently used for chimerism analysis and their usefulness for the detection of MRD. In addition, the potential impact of novel procedures, e.g. subset chimerism or real-time PCR-based procedures, is discussed.
FLT3 Length Mutations as Marker for Follow-Up Studies in Acute Myeloid Leukaemia
Authors: Schnittger Susanne , Schoch Claudia , Kern Wolfgang , Hiddemann Wolfgang , Haferlach Torsten
Published: June 2004

Length mutations within the FLT3 gene (FLT3-LM) can be found in 23% of acute myeloid leukaemia (AML) and thus are the most frequent mutations in AML. FLT3-LM are highly correlated with AML with normal karyotype and other cytogenetic aberrations of the prognostically intermediate group. This group is supposed to be a mixed group of AML with differences in the underlying pathogenesis. For more individualized treatment options it would be helpful to better characterize this large AML group not only by molecular mutations but also use these markers for the definition of minimal residual disease (MRD). However, so far the cytogenetically intermediate AML has been lacking suitable markers for PCR-based MRD detection like the fusion genes in the prognostically favourable subgroups. The suitability of the FLT3-LM as a target for PCR-based MRD was discussed controversially as it seemed to be a rather unstable marker. Thus, we aimed at the evaluation of FLT3-LM as a marker for residual disease in a large cohort of AML. Paired samples of 97 patients with AML at diagnosis and at relapse were analyzed. It could be shown that in only four cases a loss of the length mutation was detected. This is in the range of other well-characterized AML relapsing with a different geno- and/or phenotype. In contrast, a change in the ratio of the mutated allele in comparison to the wild-type allele was frequently observed. In detail, the FLT3-LM showed a tendency to accumulate during disease progression and was found more frequently at relapse than at diagnosis. In addition, 45 patients were analyzed at different time points during and after therapy. Using conventional PCR it clearly could be shown that for most of the patients positive at presentation FLT3-LM is a reliable PCR marker for monitoring treatment response. Even an early detection of relapse was possible in some cases.
WT1 as a Universal Marker for Minimal Residual Disease Detection and Quantification in Myeloid Leukemias and in Myelodysplastic Syndrome
Authors: Cilloni Daniela , Saglio Giuseppe
Published: June 2004

Monitoring of acute leukemia patients during and after treatment for the presence of remaining leukemic cells (minimal residual disease, MRD) has been shown to give major insight into the effectiveness of treatment. However, so far the applicability of this strategy has been limited to those leukemia subsets characterized by genetic markers amenable to sensitive detection by PCR. Although PCR for immunoglobulin and T cell receptor gene rearrangement represents the gold standard for MRD detection in most cases of ALL without any fusion gene transcripts as molecular markers available, the situation in AML is more complicated because, at present, more than 50% of them lack any sort of clonality markers suitable for MRD monitoring. Thus, a number of studies have been performed in an attempt to identify cytogenetic and molecular abnormalities associated with leukemic transformation. In this paper we describe the effectiveness of the quantitative assessment of the Wilms tumor gene (WT1) transcript as a molecular marker for the detection of the leukemic clone useful for monitoring the presence of MRD in all the patients affected by acute and chronic leukemias as well as myelodysplastic syndromes.
Molecular Surveillance of Chronic Myeloid Leukemia Patients in the Imatinib Era – Evaluation of Response and Resistance
Authors: Paschka Peter , Merx Kirsten , Hochhaus Andreas
Published: June 2004

Residual disease in chronic myeloid leukemia patients may be assessed by various molecular methods. After imatinib treatment a significant proportion of patients achieve complete cytogenetic remission (CCR) and a sensitive method is necessary to monitor treatment response and to detect early signs of relapse. Reverse-transcriptase polymerase chain reaction (RT-PCR) is by far the most sensitive approach to assess residual disease in this group of patients. Qualitative PCR methods give only limited information about the residual leukemic mass. Quantitative RT-PCR (Q-PCR) assays enable to monitor the kinetics of residual BCR-ABL transcripts over time in patients with a good response to imatinib. Early Q-PCR results on imatinib treatment can help to identify individuals who are likely to have a good response. In chronic phase patients after CCR, Q-PCR may identify patients who are likely to continue with their CCR or to relapse and may help to optimize treatment for this group of patients. The definition of molecular surrogate endpoints beyond CCR for studies which are currently planned demands standardization of the nomenclature and of technologies to measure these targets.
Molecular and Clinical Follow-Up after Treatment of Multiple Myeloma
Authors: Rasmussen Thomas , Knudsen Lene M. , Huynh Tuan K. , Johnsen Hans E.
Published: June 2004

Multiple myeloma (MM) is a B cell malignancy characterized by accumulation of plasma cells (PCs) in the bone marrow. Traditional methods for the detection of minimal residual disease (MRD) measure the presence of monoclonal immunoglobulin protein secreted by the malignant PCs. However, changes in the level of MRD in MM may span 6 logs, and methods with a high sensitivity and dynamic range are necessary for quantitating MRD in MM. The two main technologies used in MRD detection are flow cytometry and patient-specific reverse transcription (RT) PCR. Patient-specific RT-PCR has high sensitivity and may be beneficial in monitoring patients receiving allogeneic transplantation. However, for the MRD evaluation of autotransplants, where few patients achieve molecular remission, flow cytometry monitoring seems to be sufficient.
T-Cell Modulation for the Treatment of Chronic Plaque Psoriasis with Efalizumab (Raptiva™): Mechanisms of Action
Authors: Jullien D. , Prinz J.C. , Langley R.G.B. , Caro I. , Dummer W. , Joshi A. , Dedrick R. , Natta P.
Published: June 2004

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis.
Drug-Induced Depression: A Systematic Review to Inform Clinical Practice
Authors: Patten Scott B. , Barbui Corrado
Published: June 2004

Background: Certain medications may contribute to the etiology of depressive symptoms and disorders. Research in this area, however, has been hampered by methodological and conceptual problems. This review had two objectives: to identify evidence linking medical drugs to depressive symptoms and disorders, and to summarize this evidence in a clinically meaningful way. Methods: Electronic literature searches were performed and studies were reviewed with reference to critical methodological features. Results: No medications causing the typical major depressive syndrome were identified. Evidence was found linking corticosteroids, interferon-α, interleukin-2, gonadotropin-releasing hormone agonists, mefloquine, progestin-releasing implanted contraceptives and propranolol to the etiology of atypical depressive syndromes. Conclusions: A small number of drugs have been shown capable of inducing depressive symptoms. Drug-induced depression appears to differ symptomatically from classical major depression.
The Sesto Fiorentino Study: Background, Methods and Preliminary Results
Authors: Faravelli Carlo , Abrardi Luca , Bartolozzi Daniela , Cecchi Cristiana , Cosci Fiammetta , D’Adamo Donato , Lo Iacono Beatrice , Ravaldi Claudia , Scarpato Maria Alessandra , Truglia Elisabetta , Rosi Simone
Published: June 2004

Background: This paper presents lifetime prevalences and estimated risks of DSM-IV psychiatric disorders from a community survey conducted in Sesto Fiorentino, Italy, using psychiatric interviewers with clinical experience and clinical instruments. Methods: Two thousand five hundred subjects aged 14 or more were randomly selected from the lists of 15 general practitioners (GPs) regardless of wheter or not they had consulted the GP. A three-phase design was adopted, with the GPs using the Mini International Neuropsychiatric Interview (MINI) for the first stage. All positive cases at the MINI and a probability sample of 123 negative cases were re-interviewed by psychiatrists or trained residents in psychiatry using the Florence Psychiatric Interview (FPI) at the second stage. During phase III, the subjects were administered the rating scales specific to the pathology detected by the FPI. Results: Two thousand three hundred and sixty-three subjects were interviewed (response rate 94.5%) by their own GP; 623 were found positive for any psychiatric disorder. The psychiatrists could re-interview 605 of these, along with a random sample of 123 negatives. Almost twenty-five percent (24.4%; 15.7% males, 31.7% females) of the population was found positive for any DSM-IV disorder during their lives. The most common diagnosis was major depressive episode, followed by anxiety not otherwise specified. Women had higher rates for most disorders. Conclusions: The prevalence rates for most of the disorders considered are generally comparable with the range identified by previous studies conducted in other Western countries, even though they were using different methodologies. Exceptions are represented by the high prevalence of residual categories and the lower prevalence of phobias.