bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiprotozoal Agents
Authors: Fries David S. , Fairlamb Alan H. 
Published: November 2003

Abstract

The chapter provides coverage of all drugs currently used for the treatment of human African trypanosomiasis (African sleeping sickness), American trypanosomiases (Chagas' disease), and leishmaniasis. Collectively, this group of diseases is caused by flagellated protozoan of the order Kinetoplastida. The drugs currently used to treat these diseases include melarsoprol, suramin, pentamidine, organic antimonials, and several nitroheterocyclic agents. The agents have all been in use for 25–75 years. They have a high degree of toxicity and the first four in the preceding list must be given by parenteral injection over a 2‐ to 6‐week time period. Tolerance has developed to most of the drugs in at least some geographical areas. Eflornithine is the only agent approved in the last 50 years for the treatment of African trypanosomiasis, although it is expensive, requires prolonged systemic dosage, and is effective only against
T. brucei gambiense
. Megazol, trybazine, DB289, and CGP 40215A have all yielded encouraging results in
in vivo
preclinical studies against African trypanosomiasis. All four of these agents have entered or are scheduled to enter clinical trials. Nifurtimox and benznidazole are the only agents approved to treat Chagas' disease. The agents are toxic, rarely produce long‐term cures, and resistance to them has developed. The third‐generation triazole antifungal agents posaconazole and UR‐9825 have given encouraging preclinical results against Chagas' disease. Meltefosine has been found to be orally active and to produce 98% cure rates of visceral leishmaniasis. New classes of experimental antitrypanosomal agents include the bisphosphonates, which disrupt lipid metabolism, and cysteine protease inhibitors. Agents from both of these mechanistic classes are being advanced as potential antitrypanosomal agents. Kinetoplastid biochemistry offers numerous opportunities for the development of chemotherapeutic agents having a high degree of selective toxicity. Trypanothione, the
N
1
,
N
8
‐bis(glutathionyl)spermidine metabolite that replaces glutathione in redox protection reactions in kinetoplastids, is one hopeful target for drug design. A second possible target is the kinetoplastid organelle named the glycosome. African trypanosomes and perhaps other kinetoplastids are highly dependent on glycolysis for energy production. Enclosing the enzymes for glycolysis in glycosomes increases the efficiency of glycolysis compared to its rate in mammalian cells. Any potent inhibitor of an enzyme contained in the glycosome, or of any of the biochemical processes associated with glycosomal function, might be an effective drug against these parasites.
Structure‐Based Drug Design
Authors: Hardy Larry W. , Abraham Donald J. , Safo Martin K. 
Published: November 2003

AbstractStructure‐based drug design is achievable by exploiting the three‐dimensional information intrinsic in structural models of proteins that are involved in human disease. Many other tools (biochemistry, cellular and whole‐animal biology, organic synthesis, pharmaceutics, and computational analysis) must by tightly integrated to fulfill the promise of the structure‐based approach, and the use of this approach does not automatically guarantee success. However, the successes that have been achieved make it clear that structure‐based methods provide an efficient, effective, and elegant approach to medicinal chemistry. Examples are described in this chapter of the use of structure‐based methods in designing compounds that have entered human clinical trials and, in many cases, were launched as products. Some of the lessons that have been learned about best practices in the application of structure‐based methods are summarized.
Phenotypic abnormalities: Terminology and classification
Authors: Merks Johannes H.M. , van Karnebeek Clara D.M. , Caron Hubert N. , Hennekam Raoul C.M. 
Published: November 2003

AbstractClinical morphology has proved essential for the successful delineation of hundreds of syndromes and as a powerful instrument for detecting (candidate) genes (Gorlin et al. [2001]; Syndromes of the Head and Neck; Oxford: Oxford University Press. 1 p]. The major approach to reach this has been careful clinical evaluations of patients, focused on congenital anomalies. A similar careful physical examination performed in patients, who have been treated for childhood cancer, may allow detection of concurrent patterns of anomalies and provide clues for causative genes. In the past, several studies were performed describing the prevalence of anomalies in patients with cancer. However, in most studies, it was not possible to indicate the biologic relevance of the recorded anomalies, or to judge their relative importance. Are the detected anomalies common variants, and should they thus be regarded as normal, or are they minor anomalies or true abnormalities, indicating a possible developmental cause? Classification of items in the categories of common variants (disturbances of phenogenesis with a prevalence >4%), minor anomalies (disturbances of phenogenesis with a prevalence ≤4%), and malformations (disturbances of embryogenesis) should allow weighing the importance of the scored items in the population under study, and should facilitate assessment of developmental disturbances (if any) in a study group. The lack of published consensus in the literature led us to produce a classification list with a twofold goal. First, we wanted to enhance uniformity in the scoring and classification of apparently abnormal physical findings by a nomenclature for errors of morphogenesis detectable on surface examination, and secondly a uniform classification system. This should allow investigators to evaluate systematically the presence of patterns in phenotypic anomalies, in the general population, and in patients with various disorders, suspected to be a developmental anomaly. Also, normal values may be obtained this way. Second, the list will allow a determination of the importance of the collected symptoms in a study population. We tested the feasibility of the application of the classification list in a study population: the list was piloted in a group of patients who have had cancer as a child, to detect patterns of anomalies related to specific types of tumors. © 2003 Wiley‐Liss, Inc.
Coloboma and other ophthalmologic anomalies in Kabuki syndrome: Distinction from charge association
Authors: Ming Jeffrey E. , Russell Karen L. , Bason Lynn , McDonald‐McGinn Donna M. , Zackai Elaine H. 
Published: November 2003

AbstractKabuki (Niikawa–Kuroki) syndrome is associated with growth retardation, developmental delay, congenital heart disease, cleft palate, and characteristic facial features. Although the external appearance of the eyes has been well‐described, the type and frequency of structural and functional eye anomalies has not been emphasized. We report three children with Kabuki syndrome who also had a retinal coloboma. A diagnosis of CHARGE association was initially suggested in two of the patients before the typical facial features of Kabuki syndrome emerged. A detailed review of reported cases of Kabuki syndrome shows that a variety of eye anomalies are associated with Kabuki syndrome. The incidence of coloboma is greatly increased in Kabuki syndrome. Thus, ophthalmologic abnormalities are frequently associated with Kabuki syndrome, and an ophthalmologic evaluation should be performed for each patient. Phenotypic overlap, including congenital heart, ear, and renal defects, can lead to the diagnosis of CHARGE association, especially since the typical facial features of Kabuki syndrome may not be apparent in early infancy. Thus, Kabuki syndrome should be considered in patients with coloboma if other features consistent with this condition are present, and follow‐up evaluations are indicated for establishing the proper diagnosis. © 2003 Wiley‐Liss, Inc.
RMRP mutations in Japanese patients with cartilage‐hair hypoplasia
Authors: Nakashima Eiji , Mabuchi Akihiko , Kashimada Kenichi , Onishi Toshikazu , Zhang Junwei , Ohashi Hirofumi , Nishimura Gen , Ikegawa Shiro 
Published: November 2003

AbstractWe examined 12 Japanese patients with metaphyseal chondrodysplasia (MCD) for mutations in the ribonuclease mitochondrial RNA processing gene (RMRP), and identified four novel mutations in two patients with typical and atypical cartilage‐hair hypoplasia (CHH), a form of MCD characterized by extra‐skeletal manifestations including hypoplastic hair and defective immunity. A patient with typical CHH had a 17‐bp duplication at +3 and a de novo 182G > A. The other patient with atypical CHH had a 17‐bp insertion at −20 and a 218A > G. Expression analysis revealed that the allele with this insertion mutation in the promoter region silenced the gene. Spectrum analysis of the mutations and polymorphisms in RMRP showed marked difference between the Japanese and other ethnic groups. Such ethnic and phenotypic difference should be taken into account in mutation analysis of the gene. © 2003 Wiley‐Liss, Inc.
Patient with trisomy 9p and a hypoplastic left heart with a tricentric chromosome 9
Authors: Morrissette Jennifer J.D. , Laufer‐Cahana Ayala , Medne Livija , Russell Karen L. , Venditti Charles P. , Kline Rochelle , Zackai Elaine H. , Spinner Nancy B. 
Published: November 2003

AbstractWe present a patient with a hypoplastic left heart (HLH), dislocations of the hips and knees, and minor dysmorphic features, who had an abnormal karyotype that resulted in trisomy for 9p and a portion of 9q: 46,((, dic(or tri?)(9)(9pter → 9q34::9q21 → 9pter).ish(WCP9++).ish(D9Z5X4 +/+++). The derivative chromosome consisted of an additional copy of the proximal q arm and p arm attached to 9qter in an inverted fashion. Fluorescence in situ hybridization (FISH) using a chromosome 9 β‐satellite probe revealed three signals on the abnormal chromosome 9, suggesting the presence of 3 pericentromeric regions on the der(9). The 9q subtelomere was present on both the normal and derivative chromosome 9, suggesting that very little material, if any, is deleted. © 2003 Wiley‐Liss, Inc.
Unreported manifestations in two Dutch families with Bartsocas–Papas syndrome
Authors: Veenstra‐Knol Hermine E. , Kleibeuker Arianne , Timmer Albertus , ten Kate Leo P. , van Essen Anthonie J. 
Published: November 2003

AbstractBartsocas–Papas syndrome (BPS) is a severe autosomal recessive syndrome characterized by neonatal or intrauterine death in most cases, severe popliteal webbing, oligosyndactyly, genital abnormalities, and typical face with short palpebral fissures, ankyloblepharon, hypoplastic nose, orofacial clefts, and small mouth. Until now at least 23 cases with this syndrome in 11 families were described, mostly from Mediterranean origin. We report on two Dutch families with six affected children having BPS. One of the patients was prenatally diagnosed by ultrasound examination. Additional unreported findings were omphalocele and aplasia of the urethra. The intrafamilial resemblance in severity is of importance for the genetic counseling of families and prenatal detection by ultrasound. We discuss possible pathogenic mechanisms and review similar cases from the literature. © 2003 Wiley‐Liss, Inc.
Incidence of the mucopolysaccharidoses in Western Australia
Authors: Nelson John , Crowhurst June , Carey Bill , Greed Lawrence 
Published: November 2003

AbstractAn epidemiological study of the mucopolysaccharidoses in Western Australia (WA) using multiple ascertainment sources was carried out and the incidence rate for the period 1969–1996 was estimated. An incidence of approximately 1 in 107,000 live births was obtained for MPS IH (Hurler phenotype); 1 in 320,000 live births (1 in 165,000 male live births) for MPS II (Hunter Syndrome); 1 in 58,000 for MPS III (Sanfilippo Syndrome); 1 in 640,000 for MPS IVA (Morquio Syndrome type A), and 1 in 320,000 for MPS VI (Maroteaux–Lamy Syndrome). The overall incidence for all types of mucopolysaccharidosis was approximately 1 in 29,000 live births. A comparison is made with incidence estimates obtained from other published studies. © 2003 Wiley‐Liss, Inc.
X chromosome inactivation patterns in Russell–Silver syndrome patients and their mothers
Authors: Beever Christy L. , Peñaherrera Maria S. , Langlois Sylvie , Robinson Wendy R. 
Published: November 2003

AbstractRussell–Silver syndrome (RSS) is a disorder characterized by pre‐ and post‐natal growth deficiency, triangular facies, relative macrocephaly, and body asymmetry. Maternal uniparental disomy for chromosome 7 has been found in approximately 10% of RSS cases, while the cause in the remaining cases is unknown. Although most cases of RSS are sporadic, at least 25 families have been reported with familial RSS and inheritance patterns of RSS consistent with an X‐linked dominant mutation. Thus, we hypothesized that skewed X‐chromosome inactivation (XCI) could be increased in some females with RSS as a consequence of a tendency to have the mutant allele on the predominantly active chromosome. Alternatively, unaffected mothers of children with RSS may tend to be skewed due to preferential inactivation of the mutant allele. In support of this last hypothesis, a significant increase in extremely skewed XCI (>95%) was found in mothers of children with RSS (4 of 21, 19%) compared to controls (2 of 101, 2%) (P = 0.008). However, an increase in skewed XCI was also observed in female patients who had unexplained short stature but did not fulfill the criteria for RSS (3 of 17, 18%) (P = 0.02), but not in those diagnosed as RSS (0 of 7, n.s.). Different mechanisms may underlie the increase in skewing in each group, possibly being due to different X‐linked mutations or growth restriction during very early in utero development. © 2003 Wiley‐Liss, Inc.
Costello syndrome and neurological abnormalities
Authors: Delrue Marie‐Ange , Chateil Jean‐François , Arveiler Benoit , Lacombe Didier 
Published: November 2003

AbstractCostello syndrome is a rare but increasingly recognized syndrome of unknown etiology. Neurological abnormalities are not rare in this syndrome and consist of structural and electrophysiological disorders. Ventricular dilatation is observed in more than 40% of cases. Other reported cerebral anomalies are brain atrophy, Chiari malformation and syringomyelia. Although there is insufficient data to propose strict guidelines, it seams reasonnable to have a low threshold for neuroimaging, in general, and particularly when neurologic signs or symptoms are present. Screening including cerebral MRI and EEG should be proposed after a diagnosis of Costello syndrome. The frequency of testing in such children should be guided by neurological follow‐up. © 2003 Wiley‐Liss, Inc.
Clinical, cytogenetic, and molecular observations in a patient with Pallister‐Killian‐syndrome with an unusual karyotype
Authors: Leube Barbara , Majewski Frank , Gebauer Jürgen , Royer‐Pokora Brigitte 
Published: November 2003

AbstractPallister‐Killian syndrome is a clinically recognizable syndrome, usually due to a tissue‐limited mosaicism for a supernumary 12p isochromosome (i12p). Here we report an unusual case with tetrasomy/trisomy/disomy 12p mosaic in fibroblasts and trisomy/disomy 12p mosaic in lymphocytes. The tetrasomy 12p was due to an i12p, the trisomy 12p to a single 12p marker. Both marker chromosomes were investigated with conventional cytogenetic techniques and fluorescent in situ hybridization (FISH). Stability under culturing conditions was studied. DNA‐analysis revealed prezygotic maternal origin of the extra 12p material. Clinically, the patient seems to have less retardation than most patients with Pallister‐Killian syndrome. © 2003 Wiley‐Liss, Inc.
Interstitial 1q25.3‐q31.3 deletion in a boy with mild manifestations
Authors: Höglund Pia , Jalkanen Reetta , Marttinen Eino , Alitalo Tiina 
Published: November 2003

AbstractWe describe a 4‐year‐old boy with an accessory right thumb, short and broad toes, cryptorchidism, micrognathia, abnormally modeled ears, and delayed speech development. The chromosome analysis of patient's peripheral blood lymphocytes by conventional GTG banding demonstrated a small deletion in the long arm of chromosome 1. Confirmation and defined localization of the deleted segment to chromosomal bands 1q25.3‐q31.3 was obtained by high resolution prometaphase analysis. Molecular studies, using a set of polymorphic chromosome 1q specific microsatellite markers, localized the deletion between the markers D1S2127 and D1S1727 on the paternally inherited chromosome 1. The maximum physical distance between these markers is approximately 21 Mb. The previously described two patients with 1q25‐q31 deletions both had severe clinical manifestations, just as the other 10 patients with the proposed “intermediate 1q deletion syndrome,” associated with 1q25‐q32 deletions. Distinct from all these patients, the clinical picture of our patient is markedly milder, i.e., without growth retardation, microcephaly, or clear mental retardation. © 2003 Wiley‐Liss, Inc.
Oculo‐facio‐cardio‐dental syndrome: Skewed X chromosome inactivation in mother and daughter suggest X‐linked dominant Inheritance
Authors: Hedera Peter , Gorski Jerome L. 
Published: November 2003

AbstractOculo‐facio‐cardio‐dental syndrome (OFCD) is an uncommon multiple congenital anomaly syndrome that is characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects, and dental anomalies including canine radiculomegaly and oligodontia. Although most cases of OFCD are sporadic, since all reported OFCD individuals have been female, it has been suggested that OFCD is an X‐linked dominant trait. Here we report two affected female patients with OFCD, a mother and daughter, who both had congenital cataracts, microphthalmia, characteristic dental anomalies, and typical facial dysmorphisms. These features were diagnostic for OFCD; thus, these cases represent the second documented instance of mother‐to‐daughter OFCD transmission. In addition to the clinical features typically seen in OFCD individuals, the affected daughter exhibited several additional congenital anomalies including intestinal malrotation and hypoplastic thumbs. Thus, these cases further define and expand the OFCD clinical phenotype. These two individuals also displayed a skewed pattern of X chromosome inactivation. Together, these data strongly support the hypothesis that OFCD is inherited as an X‐linked dominant condition. © 2003 Wiley‐Liss, Inc.
Idiopathic congenital central hypoventilation syndrome: Analysis of genes pertinent to early autonomic nervous system embryologic development and identification of mutations in PHOX2b
Authors: Weese‐Mayer Debra E. , Berry‐Kravis Elizabeth M. , Zhou Lili , Maher Brion S. , Silvestri Jean M. , Curran Mark E. , Marazita Mary L. 
Published: November 2003

AbstractIdiopathic congenital central hypoventilation syndrome (CCHS) has been linked to autonomic nervous system dysregulation and/or dysfunction (ANSD) since it was first described in 1970. A genetic basis of CCHS has been proposed because of the reports of four families with two affected children, because of mother–child transmission, and because of a recent report of a polyalanine expansion mutation in PHOX2b in a subset of CCHS subjects. We, therefore, studied genes pertinent to early embryologic development of the ANS including mammalian achaete‐scute homolog‐1 (MASH1), bone morphogenic protein‐2 (BMP2), engrailed‐1 (EN1), TLX3, endothelin converting enzyme‐1 (ECE1), endothelin‐1 (EDN1), PHOX2a, and PHOX2b in 67 probands with CCHS, and gender‐ and ethnicity‐matched controls. No disease‐defining mutations were identified in MASH1, BMP2, EN1, TLX3, ECE1, EDN1, or PHOX2a.The 65/67 CCHS probands (97%) were found to be heterozygous for the exon 3 polyalanine expansion mutation identified previously in PHOX2b. Further, there was an association between repeat mutation length and severity of the CCHS/ANSD phenotype. Of the two probands who did not carry the expansion mutation, one had a nonsense mutation in exon 3 which truncated the protein and the other had no mutation in PHOX2b but had a previously reported EDN3 frameshift point mutation. The polyalanine expansion mutation was not found in any of 67 matched controls. Of 54 available families (including 97 unaffected parents), whose child carried the PHOX2b mutation, 4 parents demonstrated mosaicism for an expansion mutation identical to that seen in the CCHS cases, suggesting that not all mutations in affected probands with unaffected parents are de novo. We also studied four women with CCHS who were heterozygous for the PHOX2b mutation, each with one child. Three of the four children were also affected and had the same mutation, demonstrating autosomal dominant inheritance of the mutation. Assay of the PHOX2b polyalanine repeat mutation represents a highly sensitive and specific technique for confirming the diagnosis of CCHS. Identification of the CCHS mutation will lead to clarification of the phenotype, allow for prenatal diagnosis for parents of CCHS probands and adults with CCHS in future pregnancies, and potentially direct intervention strategies for the treatment of CCHS. © 2003 Wiley‐Liss, Inc.
Correlation of GDF5 and connexin 43 mRNA expression during embryonic development
Authors: Coleman Cynthia M. , Loredo Grace A. , Lo Cecilia W. , Tuan Rocky S. 
Published: November 2003

AbstractGrowth/differentiation factor 5 (GDF5) regulates connexin expression and enhances embryonic chondrogenesis in a gap junction‐dependent manner, suggesting that GDF5 action on developmental skeletogenesis is coordinated with gap junction activities. The results shown here demonstrate concordance between the mRNA expression profiles of GDF5 and the gap junction gene, Cx43, in the mouse embryonic limb, spine, and heart, consistent with coordinated functions for these gene products during developmental organogenesis. Anat Rec Part A 275A:1117–1121, 2003. © 2003 Wiley‐Liss, Inc.
Endothelial nitric oxide synthase gene polymorphisms in giant cell arteritis
Authors: Salvarani Carlo , Casali Bruno , Nicoli Davide , Farnetti Enrico , Macchioni Pierluigi , Catanoso Maria Grazia , Chen Qingquan , Bajocchi Gianluigi , Boiardi Luigi 
Published: November 2003

AbstractObjectiveTo examine potential associations of the Glu/Asp298 polymorphism in exon 7 and the 4a/b polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene with susceptibility to and clinical expression of giant cell arteritis (GCA), particularly in patients with versus those without ischemic complications.MethodsNinety‐one consecutive patients with biopsy‐proven GCA, who were residents of Reggio Emilia, Italy, and 133 population‐based controls from the same geographic area were genotyped by polymerase chain reaction and allele‐specific oligonucleotide techniques for eNOS polymorphisms in exon 7 and intron 4. The patients were separated into 2 subgroups according to the presence or absence of ischemic complications (visual loss and/or jaw claudication and/or aortic arch syndrome).ResultsThe distribution of the Glu/Asp298 genotype differed significantly between GCA patients and controls (corrected P [Pcorr] = 0.003). Carriers of the Asp298 allele (Asp/Asp or Glu/Asp) were significantly more frequent among the GCA patients than among the controls (Pcorr = 0.0002, odds ratio 3.3, 95% confidence interval 1.7–6.3). The distribution of the 4a/b genotype was similar in GCA patients and controls. No significant associations were found when GCA patients with and without ischemic complications were compared.ConclusionOur findings show that the Glu/Asp298 polymorphism of the eNOS gene is associated with GCA susceptibility.
Stereoselective Synthesis of anti‐1,4‐Diols by a BH3⋅THF‐Mediated Rearrangement of 1,2‐Disubstituted Cyclobutenes
Authors: Knapp Kolja M. , Goldfuss Bernd , Knochel Paul 
Published: November 2003

AbstractA new stereoselective rearrangement of cyclobutylboranes, obtained by the hydroboration of 1,2‐disubstituted cyclobutenes, provides anti‐1,4‐diols with good‐to‐excellent diastereoselectivity. The mechanism of the rearrangement is discussed based on theoretical calculations.