bluuebunny/crossref_metadata_2025 huggingface dataset:
Soft tissue facial areas and volumes in subjects with Down syndrome
Authors: Sforza Chiarella , Dellavia Claudia , Zanotti Gianfranco , Tartaglia Gianluca M. , Ferrario Virgilio F.
Published: August 2004

The objective of this study was to supply quantitative information about the facial soft‐tissues of a group of subjects with Down syndrome. The three‐dimensional coordinates of 28 soft‐tissue facial landmarks were obtained by an electromechanic digitizer in 17 male and 11 female subjects with Down syndrome aged 12–45 years, and in 429 healthy individuals of the same age, ethnicity, and sex. From the landmarks, facial areas (eyes, ears, nose, and lips) and volumes (nose and lips) were calculated according to a geometrical model of face. Data were compared to those collected in the normal subjects by computing z‐scores. Male and female z‐scores were not significantly different. Most of the facial volumes were significantly (Student's t, P < 0.05) smaller in subjects with Down syndrome than in their normal controls. Ear areas were significantly reduced (mean z‐scores in males −2.07 right, −1.9 left; in females −2.11 right, −2.21 left), as well as nasal surface area (mean z‐score −1.53 in males, −2.45 in females). In women, age and some z‐scores were significantly correlated (P < 0.05): upper lip volume (r = 0.714), left and right eye area (r = 0.635, right; 0.604, left), nasal area (r = 0.603): with increasing age, the negative values of the z‐scores approached the 0 value of the reference population. In the pooled sample, age and the z‐score of the total lip area were significantly correlated (r = 0.423): increasing age corresponded to a larger z‐score value. The method allowed a simple, low cost, fast, and noninvasive examination of the subjects, and provided a quantitative assessment of the deviation from the norm. © 2004 Wiley‐Liss, Inc.
“The Lion, the Witch and the Wardrobe”: Impact on sibs of individuals with AAT deficiency
Authors: Fanos Joanna H. , Strange Charlie
Published: August 2004

Alpha1‐antitrypsin (AAT) deficiency is a genetic disorder that may cause serious pulmonary or liver impairment in children or adults. Although genetic sequencing of the AAT gene has only been available for 20 years, analysis of the amount and electrophoretic mobility of the AAT protein has allowed clinical phenotyping for more than 40 years. There have been no studies assessing the psychological impact of having a sib affected by AAT deficiency. Twenty‐five participants drawn from the Alpha‐1 Research Registry completed a questionnaire and semi‐structured interview. Respondents were supportive of testing prior to adulthood for AAT status; 18 thought it was a good idea to test a child, three did not know, and four said children should not be tested, primarily citing insurance concerns. Of those 18 who stated it was a good idea, 14 would test at birth. Knowledge of genetics of AAT deficiency was limited; only 44% of respondents understood the inheritance pattern. We recommend: (1) parents and sibs need help in mourning the loss of children with AAT deficiency; young sibs are at risk for trauma and long‐term developmental problems. (2) Teams evaluating donors for liver transplantation should be aggressive in ruling out AAT deficiency prior to invasive testing. (3) Testing should be offered to individuals with a family history of AAT deficiency to obtain the health benefits of lifestyle modification and limit the burden of disease discovery in symptomatic relatives. (4) Awareness of liver disease from AAT deficiency should be increased. © 2004 Wiley‐Liss, Inc.
Genetic significance of skewed X‐chromosome inactivation in premature ovarian failure
Authors: Sato Kazuyo , Uehara Shigeki , Hashiyada Masaki , Nabeshima Hiroshi , Sugawara Jun‐ichi , Terada Yukihiro , Yaegashi Nobuo , Okamura Kunihiro
Published: August 2004

To determine the relationship between premature ovarian failure (POF) and skewed X‐chromosome inactivation (XCI), karyotype, and XCI status in 43 patients with POF (group I) and 43 age‐matched control women with regular menstrual cycles (group II) were evaluated. Evaluation of XCI status was based on the CAG triplet repeat polymorphism assay in the androgen receptor gene after sodium bisulfite treatment of DNA samples, and XCI patterns were classified as random (XCI < 70% skewing) or skewed (≥70%). Furthermore, skewed XCI was classified under three different thresholds (≥70, ≥80, or ≥90%). Karyotyping by G‐banding and fluorescence in situ hybridization (FISH) on peripheral blood lymphocytes showed that one patient in group I had a deletion of Xq22, and another was 47,XXX. The frequency of low‐level 45,X/46,XX mosaicism was nearly equal in both groups. In women without any X‐chromosomal aberrations, the incidence of skewed XCI in group I was significantly higher than in group II on all threshold levels. Furthermore, extremely skewed XCI (≥90%) was observed only in group I. These results indicate that POF may be caused by some underlying genetic disorders, which may induce skewed XCI. © 2004 Wiley‐Liss, Inc.
Association of CYP17 with HLA‐B27‐negative seronegative spondyloarthropathy in Japanese males
Authors: Mori Kanji , Kizawa Hideki , Ushiyama Toshio , Chano Tokuhiro , Inoue Hisashi , Tsuchiya Naoyuki , Okabe Hidetoshi , Matsusue Yoshitaka , Ikegawa Shiro
Published: August 2004

Susceptibility genes for seronegative spondyloarthropathy (SNSA) other than HLA‐B27 remain unclarified. Sex hormones are implicated in the pathogenesis of SNSA. Cytochrome P450c17a (CYP17) is a key regulator of androgen biosynthesis, and a single nucleotide polymorphism (SNP) in the 5′‐untranslated region of the CYP17 gene (CYP17), −34C > T, is associated with variety of diseases. We have investigated the association between the CYP17 SNP and SNSA in Japanese males. Genomic DNA was extracted from 149 Japanese male SNSA patients and 380 controls. The CYP17 SNP was genotyped using polymerase chain reaction‐restriction fragment length polymorphism analysis. Allelic and genotypic frequencies of the SNP were compared between SNSA patients and controls, and within SNSA patients. We also computed haplotype frequencies using an expectation‐maximization algorithm, analyzed the difference between SNSA and control groups, and examined the potential association of other known SNPs in the CYP17 gene. The frequency of the −34T allele was significantly increased in HLA‐B27‐negative SNSA, but not in total or HLA‐B27‐positive SNSA when compared to controls. The T allele was more prevalent in HLA‐B27‐negative SNSA than in HLA‐B27‐positive SNSA, and the T/T genotype was over‐represented in HLA‐B27‐negative SNSA. Haplotype analysis did not demonstrate more significant association. The CYP17 SNP is associated with SNSA in HLA‐B27‐negative Japanese males. © 2004 Wiley‐Liss, Inc.
BRCA1/2testing in hereditary breast and ovarian cancer families: Effectiveness of problem‐solving training as a counseling intervention
Authors: McInerney‐Leo Aideen , Biesecker Barbara Bowles , Hadley Donald W. , Kase Ronald G. , Giambarresi Therese R. , Johnson Elizabeth , Lerman Caryn , Struewing Jeffery P.
Published: August 2004

It remains uncertain whether members of hereditary breast and ovarian cancer (HBOC) families experience psychological distress with genetic testing and whether pre‐test counseling can have a moderating effect on client well‐being. One purpose of this study was to assess change in psychological well‐being from baseline to 6–9 months follow‐up and the effect of a problem‐solving training (PST) intervention on psychological well‐being. Two hundred and twelve members of 13 HBOC families were offeredBRCA1/2testing for a previously identified family mutation. Participants received education and were randomized to one of two counseling interventions; PST or client‐centered counseling. Psychological well‐being was assessed at baseline and again at 6–9 months following the receipt of test results, or at the equivalent time for those participants who chose not to undergo testing. Well‐being was assessed using measures of depressive symptoms (CESD), intrusive thoughts (IES), cancer worries, and self‐esteem. Comparisons were made between those who chose testing and those who did not as well as between those who received positive and negative test results. One hundred eighty one participants elected to undergo genetic testing (85%) and 47 of these (26%) were identified asBRCA1/2mutation carriers. Breast and ovarian cancer worries decreased significantly (p = 0.007 and 0.008, respectively) in those who tested negative while there was no appreciable change in psychological well‐being from baseline to follow‐up in either those who tested positive or in non‐testers. Among all participants, particularly testers, those randomized to PST had a greater reduction in depressive symptoms than those randomized to client‐centered counseling (p < 0.05 andp = 0.02, respectively). Regardless of the decision to test, individuals with a personal history of cancer (n = 22) were more likely to have an increase in breast cancer worries compared to those who had never been diagnosed with cancer (p < 0.001). Results suggest that a problem‐solving counseling intervention may help to enhance psychological well‐being following testing and that a personal history of cancer may increase psychological distress associated with genetic testing. Published 2004 Wiley‐Liss, Inc.
Homozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13
Authors: Narkis Ginat , Landau Daniella , Manor Esther , Elbedour Khalil , Tzemach Anna , Fishelson Ma'ayan , Geiger Dan , Ofir Rivka , Carmi Rivka , Birk Ohad S.
Published: August 2004

We have recently described a novel autosomal recessive disorder, lethal congenital contractural syndrome type 2 (LCCS2) (OMIM 607598), in a large Israeli Bedouin kindred. The phenotype, which is lethal in the neonatal period, is distinguished by the presence of a markedly distended urinary bladder. Association of LCCS2 to the known loci associated with arthogryposis was excluded. In the present study, we set out to determine the genetic locus harboring the gene defective in this disease. We performed genome‐wide linkage analysis, demonstrating linkage to a ∼6 cM (corresponding to ∼7.2 Mb) homozygosity region on chromosome 12q13 between markers D12S1604 and D12S83. Based on recombination events, the interval harboring the disease‐associated locus was further narrowed to a region spanning ∼6 cM (∼6.4 Mb) between D12S325 and D12S1072. Linkage of LCCS2 to that locus was established, with two significant maximum peaks at markers D12S1604 (Zmax = 10.56 at θ = 0.01) and D12S1700 (Zmax = 9.23 at θ = 0.00). © 2004 Wiley‐Liss, Inc.
Congenital arhinia with de novo reciprocal translocation, t(3;12)(q13.2;p11.2)
Authors: Hou Jia‐Woei
Published: August 2004

A female newborn suffering from congenital arhinia with complete airway obstruction is reported. In addition, she had hypertelorism, microphthalmia, high‐arched palate, and hypoplasia of the auditory canal and mastoid and facial bones, along with the absence of olfactory bulbs and tracts. She had a de novo reciprocal translocation between chromosomes 3q13.2 and 12p11.2. Certain gene(s) located at either of the breakpoints, 3q13.2 and 12p11.2, may be involved in the pathogenesis of her arhinia. © 2004 Wiley‐Liss, Inc.
Exploratory study of the feasibility and utility of the colored eco‐genetic relationship map (CEGRM) in women at high genetic risk of developing breast cancer
Authors: Peters June A. , Kenen Regina , Giusti Ruthann , Loud Jennifer , Weissman Nancy , Greene Mark H.
Published: August 2004

We report here the results of an exploratory feasibility study of the colored eco‐genetic relationship map (CEGRM), a novel, recently‐developed psychosocial assessment tool, which incorporates features of the genetic pedigree, family systems genogram, and ecomap. The CEGRM presents a simple, concise, visual representation of the social interaction domains of information, services, and emotional support through the application of color‐coded symbols to the genetic pedigree. The interactive process of completing the CEGRM was designed to facilitate contemporary genetic counseling goals of: (a) understanding the client in the context of her/his social milieu; (b) bolstering client self‐awareness and insight; (c) fostering active client participation and mutuality in the counseling interaction; (d) eliciting illuminating social narratives; and (e) addressing outstanding emotional issues. Twenty women participating in a breast imaging study of women from families with BRCA1/2 mutations completed and evaluated various aspects of the CEGRM. We found that efficient construction of the CEGRM was feasible, and that compliance was excellent. Participants developed insights into their social milieu through observing the visual pattern of relationships illustrated by the CEGRM. The process of co‐constructing the CEGRM fostered the participant's active involvement in the session, marked by mutuality and increased empathy. In this clinical research context, the participants felt free to share poignant stories about their friends and families. Further studies are planned to refine the CEGRM and to examine its utility in cancer genetics research. Published 2004 Wiley‐Liss, Inc.
Do parents and grandparents of patients with achondroplasia have a higher cancer risk?
Authors: Stoll C. , Feingold J.
Published: August 2004

Several studies, performed according to hypotheses based on teratogenesis and carcinogenesis have tried to answer the question: Do parents of children with congenital anomalies have a higher cancer risk? If the general answer is no, however, a higher risk for cancer was reported in the parents of children with cleft lip/palate (Zhu et al. [2002: Br J Cancer 87:524–528]). In achondroplasia, the neo‐mutations are from paternal origin raising the hypothesis of the existence of a “mutator” gene acting in male meiosis and in somatic, mitotic cells in both sexes which may favor also the occurrence of cancer. In order to test this hypothesis, a questionnaire was sent to people with non‐familial achondroplasia, asking for cancer, lymphoma, and leukemia in their parents and grandparents. In the hypothesis tested, the maternal lineage was the control. One hundred forty eight answers were obtained from 76 males and 72 females with achondroplasia. Out of them 68 had parents and/or grandparents with cancer. Among the grandparents of people with achondroplasia there were 36 cancers including two lymphomas in the paternal grandparents, 20 cancers including two chronic myeloid leukemia (CML) in the paternal grandmothers, 22 cancers including two CML in the maternal grandfathers, and two cancers in the maternal grandmothers. Paternal grandfathers and grandmothers had significantly more cancers (56) than maternal grandfathers and grandmothers (24) (χ2‐test = 14.80, P < 0.001). In conclusion, paternal grandfathers and grandmothers of people with achondroplasia had significantly more cancers than maternal grandfathers and grandmothers. This result raises hypotheses in relationship with the paternal origin of neo‐mutations in achondroplasia. © 2004 Wiley‐Liss, Inc.
Nasal dimensions in normal subjects: Conventional anthropometry versus computerized anthropometry
Authors: Sforza Chiarella , Dellavia Claudia , Colombo Anna , Serrao Graziano , Ferrario Virgilio F.
Published: August 2004

The aim of the current investigation was to compare computerized measurements of nasal linear distances (nasal tip protrusion, height of the cutaneous upper lip, length of the nasal bridge) collected from 705 healthy individuals from Northern Italy (age range 6–60 years) using an electromagnetic digitizer with conventional anthropometric measurements: one set obtained on individuals of central European origin (Zankl et al. [2002: Am J Med Genet 111:388‐391]), and one set collected from North American Caucasians (Farkas et al. [1994: Anthropometry of the Head and Face 241–335]). On average, the present lengths of the nasal bridge were always significantly smaller than the European data (P < 0.01, Student's t for independent samples). Nevertheless, only in one sex and age group of 18 the discrepancy between the two mean values was larger than 10 mm. In other 10 groups, the mean values differed less than 5 mm. More limited differences (up to 6.5 mm) were found in comparison to the American data. For nasal tip protrusion, digital and conventional data were significantly different (up to 4 mm) in 18 instances of 30. On average, the present heights of the cutaneous upper lip were always smaller than the European data (up to 2.9 mm). The differences were statistically significant in 14 groups of 18. Minor discrepancies (less than 1 mm in nine groups of 12) were found in comparison to the American data. Statistical significance was reached only in seven comparisons. In conclusion, the conventional anthropometric and the digital data compared in the current study, though not superimposable, seemed sufficiently interchangeable, at least from a clinical point of view. © 2004 Wiley‐Liss, Inc.
Characterization of the phenotype and definition of the deletion in a new patient with ring chromosome 22
Authors: Battini R. , Battaglia A. , Bertini V. , Cioni G. , Parrini B. , Rapalini E. , Simi P. , Tinelli F. , Valetto A.
Published: August 2004

The clinical phenotype of patients with ring chromosome 22 includes mental retardation with severe language impairment, hypotonia, and dysmorphic facial features. In recent years an increasing number of patients with microscopic as well as cryptic terminal deletion involving band 22q13 have been described and their phenotype shows clinical features overlapping with patients with ring chromosome 22. Loss of DNA in the 22q13.3 region may lead to a clinically recognizable syndrome named “22q13.3 deletion syndrome.” We report a patient with a ring chromosome 22 who has hypotonia, profound mental retardation, language impairment, dysmorphic features, and behavioral disorders. To check if the critical region responsible for “22q13.3 deletion syndrome” was absent in this ring, a fluorescent in situ hybridization (FISH) analysis using a probe corresponding to the ARSA locus was performed. In our patient, only one ARSA signal could be detected, indicating that the deletion encompassed the critical 22q13.3 region. A more detailed analysis of the deletion extent then was performed using a panel of fluorescent probes located within 22q13. These experiments allowed the identification of the breakpoint between CTA‐299D3 and RP5‐925J7 probe, located in 22q13.32. Deletion extent could be estimated to be about 2.5 Mb, and this larger deletion may explain the severity of clinical features observed in our patient. © 2004 Wiley‐Liss, Inc.
Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: An autosomal recessive syndrome
Authors: Zenker Martin , Tralau Tim , Lennert Thomas , Pitz Susanne , Mark Karlheinz , Madlon Henry , Dötsch Jörg , Reis André , Müntefering Horst , Neumann Luitgard M.
Published: August 2004

We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth that resulted in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis (DMS). Clinically obvious eye abnormalities were recognized in six of the eight patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large appearing corneae in some cases suggesting buphthalmos, and extremely narrow, nonreactive pupils (microcoria). Pathological examination of the eyes of two aborted fetuses revealed a more complex ocular maldevelopment including posterior lenticonus as well as anomalies of cornea and retina. On the basis of these observations and other cases in the literature, we delineate a previously unrecognized distinct entity characterized by congenital nephrotic syndrome, DMS, and eye abnormalities with microcoria as the leading clinical feature. Pedigrees of affected families with parental consanguinity support autosomal recessive inheritance. We propose that this syndrome should be designated microcoria‐congenital nephrosis syndrome or Pierson syndrome. Possible overlap with Galloway–Mowat syndrome and relations to other oculo‐renal syndromes are discussed. © 2004 Wiley‐Liss, Inc.
CAG repeat polymorphism within the KCNN3 gene is a significant contributor to susceptibility to anorexia nervosa: A case‐control study of female patients and several ethnic groups in the Israeli Jewish population
Authors: Koronyo‐Hamaoui Maya , Gak Eva , Stein Daniel , Frisch Amos , Danziger Yardena , Leor Shani , Michaelovsky Elena , Laufer Neil , Carel Cynthia , Fennig Silvana , Mimouni Marc , Apter Alan , Goldman Boleslav , Barkai Gad , Weizman Abraham
Published: August 2004

The human small‐conductance Ca2+‐activated potassium channel gene KCNN3 has been involved in mechanisms underlying neuronal function and plasticity. A multiallelic CAG repeat polymorphism within the KCNN3 has been associated with schizophrenia and bipolar disorder. We have previously reported in a family‐based study that longer CAG repeats are preferentially transmitted to patients with anorexia nervosa (AN). The present study extends the analysis of KCNN3 allele distribution to a larger series of AN female patients and control groups, incorporating information on ethnicity and co‐morbidities associated with AN. The data analysis is presented while considering separately the two alleles of each individual, namely a minor (shorter) and a major (longer) allele. This study has found that the KCNN3 allele distribution in the general Israeli population does not differ significantly in at least four Jewish ethnic groups of Ashkenazi, North African, Iraqi, and Yemenite origin. These have been used as control groups in a matched case‐control analysis that has demonstrated a significant over‐representation of KCNN3 alleles with longer CAG repeats among AN patients (P < 0.001 for the major allele and P = 0.035 for allele sum). Under dichotomization, a significantly higher prevalence of the L allele (>19 repeats) has been observed among AN patients (P < 0.001). While considering AN and co‐morbid phenotypes, a tendency towards longer (L) alleles has been observed in the subset of patients with obsessive‐compulsive disorder (OCD) co‐morbidity. These findings further implicate KCNN3 as a significant contributor to predisposition to AN. © 2004 Wiley‐Liss, Inc.
A linkage disequilibrium map of the 1‐Mb 15q12 GABAA receptor subunit cluster and association to autism
Authors: McCauley Jacob L. , Olson Lana M. , Delahanty Ryan , Amin Taneem , Nurmi Erika L. , Organ Edward L. , Jacobs Michelle M. , Folstein Susan E. , Haines Jonathan L. , Sutcliffe James S.
Published: August 2004

Autism is a complex genetic neuropsychiatric condition characterized by deficits in social interaction and language and patterns of repetitive or stereotyped behaviors and restricted interests. Chromosome 15q11.2‐q13 is a candidate region for autism susceptibility based on observations of chromosomal duplications in a small percentage of affected individuals and findings of linkage and association. We performed linkage disequilibrium (LD) mapping across a 1‐Mb interval containing a cluster of GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) which are good positional and functional candidates. Intermarker LD was measured for 59 single nucleotide polymorphism (SNP) markers spanning this region, corresponding to an average marker spacing of 17.7 kb−1. We identified haplotype blocks, and characterized these blocks for common (>5%) haplotypes present in the study population. At this marker resolution, haplotype blocks comprise <50% of the DNA in this region, consistent with a high local recombination rate. Identification of haplotype tag SNPs reduces the overall number of markers necessary to detect all common alleles by only 12%. Individual SNPs and multi‐SNP haplotypes were examined for evidence of allelic association to autism, using a dataset of 123 multiplex autism families. Six markers individually, across GABRB3 and GABRA5, and several haplotypes inclusive of those markers, demonstrated nominally significant association. These results are positively correlated with the position of observed linkage. These studies support the existence of one or more autism risk alleles in the GABAA receptor subunit cluster on 15q12 and have implications for analysis of LD and association in regions with high local recombination. This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website athttp://www.interscience.wiley.com/jpages/0148‐7299:1/suppmat/index.html. © 2004 Wiley‐Liss, Inc.
Neural connections between the hypothalamus and the liver
Authors: Uyama Naoki , Geerts Albert , Reynaert Hendrik
Published: August 2004

After receiving information from afferent nerves, the hypothalamus sends signals to peripheral organs, including the liver, to keep homeostasis. There are two ways for the hypothalamus to signal to the peripheral organs: by stimulating the autonomic nerves and by releasing hormones from the pituitary gland. In order to reveal the involvement of the autonomic nervous system in liver function, we focus in this study on autonomic nerves and neuroendocrine connections between the hypothalamus and the liver. The hypothalamus consists of three major areas: lateral, medial, and periventricular. Each area has some nuclei. There are two important nuclei and one area in the hypothalamus that send out the neural autonomic information to the peripheral organs: the ventromedial hypothalamic nucleus (VMH) in the medial area, the lateral hypothalamic area (LHA), and the periventricular hypothalamic nucleus (PVN) in the periventricular area. VMH sends sympathetic signals to the liver via the celiac ganglia, the LHA sends parasympathetic signals to the liver via the vagal nerve, and the PVN integrates information from other areas of the hypothalamus and sends both autonomic signals to the liver. As for the afferent nerves, there are two pathways: a vagal afferent and a dorsal afferent nerve pathway. Vagal afferent nerves are thought to play a role as sensors in the peripheral organs and to send signals to the brain, including the hypothalamus, via nodosa ganglia of the vagal nerve. On the other hand, dorsal afferent nerves are primary sensory nerves that send signals to the brain via lower thoracic dorsal root ganglia. In the liver, many nerves contain classical neurotransmitters (noradrenaline and acetylcholine) and neuropeptides (substance P, calcitonin gene‐related peptide, neuropeptide Y, vasoactive intestinal polypeptide, somatostatin, glucagon, glucagon‐like peptide, neurotensin, serotonin, and galanin). Their distribution in the liver is species‐dependent. Some of these nerves are thought to be involved in the regulation of hepatic function as well as of hemodynamics. In addition to direct neural connections, the hypothalamus can affect metabolic functions by neuroendocrine connections: the hypothalamus‐pancreas axis, the hypothalamus‐adrenal axis, and the hypothalamus‐pituitary axis. In the hypothalamus‐pancreas axis, autonomic nerves release glucagon and insulin, which directly enter the liver and affect liver metabolism. In the hypothalamus‐adrenal axis, autonomic nerves release catecholamines such as adrenaline and noradrenaline from the adrenal medulla, which also affects liver metabolism. In the hypothalamus‐pituitary axis, release of glucocorticoids and thyroid hormones is stimulated by pituitary hormones. Both groups of hormones modulate hepatic metabolism. Taken together, the hypothalamus controls liver functions by neural and neuroendocrine connections. © 2004 Wiley‐Liss, Inc.
Anatomy and function of sensory hepatic nerves
Authors: Berthoud Hans‐Rudolf
Published: August 2004

Vagal and spinal afferent innervation of the portal hepatic area has not been studied as thoroughly as the innervation of other important organs. It is generally agreed that unlike noradrenergic sympathetic efferent nerve fibers, sensory nerve fibers of either vagal or dorsal root/spinal origin do not directly innervate hepatocytes, but are restricted to the stroma surrounding triades of hepatic vasculature and bile ducts, and to extrahepatic portions of the portal vein and bile ducts. For vagal afferent innervation, retrograde and anterograde tracing studies in the rat have clearly shown that only a minor portion of the common hepatic branch innervates the liver area, while the major portion descends in the gastroduodenal branch toward duodenum, pancreas, and pylorus. Hepatic paraganglia, bile ducts, and portal vein receive the densest vagal afferent innervation. Calretinin may be a relatively specific marker for vagal afferent innervation of the portal‐hepatic space. Calcitonin gene‐related peptide (CGRP) is a specific marker for dorsal root afferents, and CGRP‐immunoreactive fibers are mainly present near the intrahepatic vascular bundles and bile ducts, and in the same extrahepatic compartments that contain vagal afferents. Because of the specific anatomical organization of hepatic nerves, selective hepatic denervation, whether selective for the vagal or sympathetic division, or for efferents and afferents, is nearly impossible. Great caution is therefore necessary when interpreting functional outcomes of so‐called specific hepatic denervation studies. © 2004 Wiley‐Liss, Inc.
Innervation of the extrahepatic biliary tract
Authors: Balemba Onesmo B. , Salter Matthew J. , Mawe Gary M.
Published: August 2004

The extrahepatic biliary tract is innervated by dense networks of extrinsic and intrinsic nerves that regulates smooth muscle tone and epithelial cell function of extrahepatic biliary tree. Although these ganglia are derived from the same set of precursor neural crest cells that colonize the gut, they exhibit structural, neurochemical, and physiological characteristics that are distinct from the neurons of the enteric nervous system. Gallbladder neurons are relatively inexcitable, and their output is driven by vagal inputs and modulated by hormones, peptides released from sensory fibers, and inflammatory mediators. Gallbladder neurons are cholinergic and they can express a number of other neural active compounds, including substance P, galanin, nitric oxide, and vasoactive intestinal peptide. Sphincter of Oddi (SO) ganglia, which are connected to ganglia of the duodenum, appear to be comprised of distinct populations of excitatory and inhibitory neurons, based on their expression of choline acetyltransferase and substance P or nitric oxide synthase, respectively. While SO neurons likely receive vagal input and their activity is modulated by release of neuropeptides from sensory fibers, a significant source of excitatory synaptic input to these cells arise from the duodenum. This duodenum‐SO circuit is likely to play an important role in the coordination of SO tone with gallbladder motility in the process of gallbladder emptying. Now that we have gained a relatively thorough understanding of the innervation of the biliary tree under healthy conditions, the way is paved for future studies of altered neural function in biliary disease. © 2004 Wiley‐Liss, Inc.
Hepatic nervous system development
Authors: Delalande Jean‐Marie , Milla Peter J. , Burns Alan J.
Published: August 2004

During embryonic development, the liver emerges from the foregut as a thickening of the ventral endodermal epithelium. The embryonic liver then develops into a bud of cells that proliferates and differentiates to eventually form the largest gland of the body. Prior to birth, the primary function of the liver is hematopoietic, and the organ receives little innervation during early development. Postnatally, the role of the liver changes and many different nerve types modulate its function. Although the liver shares a common embryonic origin with other foregut derivatives, such as the gallbladder and the pancreas, the development of its innervation exhibits distinct characteristics. In this review, we summarize what is known about the development of the hepatic innervation, draw comparisons with the intrinsic innervation of the gastrointestinal tract and associated organs, and discuss the potential role of molecular signals in guiding the nerves that innervate the liver. © 2004 Wiley‐Liss, Inc.
Innervation of the sinusoidal wall: Regulation of the sinusoidal diameter
Authors: Ueno Takato , Bioulac‐Sage Paulette , Balabaud Charles , Rosenbaum Jean
Published: August 2004

In the livers of humans, cats, guinea pigs, and tupaia, nerve endings are distributed all over the hepatic lobules. Nerve endings in the intralobular spaces are localized mainly in the Disse spaces and are oriented toward the hepatic stellate cells (HSCs), sinusoidal endothelial cells, and hepatocytes. They are especially closely related to HSCs. Various neurotransmitters such as substance P exist in the nerve endings. In addition, HSCs possess endothelin (ET) and adrenergic receptors and contract in response to the corresponding agonists. In contrast, nitric oxide (NO) inhibits the contraction of HSCs. HSCs thus appear to be involved in the regulation of hepatic sinusoidal microcirculation by contraction and relaxation. In the cirrhotic liver, intralobular innervation is decreased, but ET, ET receptors, and NO are overexpressed in the HSCs. These findings indicate that HSCs in cirrhotic liver may play an important role in the sinusoidal microcirculation through agents such as ET or NO rather than through intralobular innervation. © 2004 Wiley‐Liss, Inc.
Neural control of hepatic osmolytes and parenchymal cell hydration
Authors: Häussinger Dieter
Published: August 2004

Liver cell function is strongly influenced by cell hydration and osmolyte content via osmosensing and osmosignaling pathways. Electrical stimulation of hepatic nerves increases the hepatocellular hydration state via an α‐adrenergic mechanism, promotes taurine release from parenchymal cells and myo‐inositol release from hepatic stellate cells. Although changes in liver cell hydration and osmolyte content are known regulators of liver cell function, the functional relevance and integration of nerve‐stimulation‐dependent alterations of liver cell volume and osmolyte content in the overall hepatic response to towards signals from the nervous system remains to be established. © 2004 Wiley‐Liss, Inc.
Neuroregulation of the neuroendocrine compartment of the liver
Authors: Roskams Tania , Cassiman David , De Vos Rita , Libbrecht Louis
Published: August 2004

Liver progenitor cells as well as hepatic stellate cells have neuroendocrine features. Progenitor cells express chromogranin‐A and neural cell adhesion molecule, parathyroid hormone‐related peptide, S‐100 protein, neurotrophins, and neurotrophin receptors, while hepatic stellate cells express synaptophysin, glial fibrillary acidic protein, neural cell adhesion molecule, nestin, neurotrophins, and their receptors. This phenotype suggests that these cell types form a neuroendocrine compartment of the liver, which could be under the control of the central nervous system. We recently showed that the parasympathetic nervous system promotes progenitor cell expansion after liver injury, since selective vagotomy reduces the number of progenitor cells after chemical injury in the rat. Similarly, after transplantation, which surgically denervates the liver, human livers that develop hepatitis have fewer progenitor cells than native, fully innervated livers with similar degrees of liver injury. There is also accumulating experimental evidence linking the autonomic system, in particular the sympathetic nervous system (SNS), with the pathogenesis of cirrhosis and its complications. Recently, it has been shown that hepatic stellate cells themselves respond to neurotransmitters. Moreover, inhibition of the SNS reduced fibrosis in carbon tetrachloride‐induced liver injury. In view of the denervated state of transplanted livers, it is very important to unravel the neural control mechanisms of regeneration and fibrogenesis. Moreover, since there is a shortage of donor organs, a better understanding of the mechanisms of regeneration could have therapeutic possibilities, which could even obviate the need for orthotopic liver transplantation. © 2004 Wiley‐Liss, Inc.
Transplanted liver: Consequences of denervation for liver functions
Authors: Colle Isabelle , Van Vlierberghe Hans , Troisi Roberto , De Hemptinne Bernard
Published: August 2004

Following liver transplantation, all hepatic nerves are transected; thus, liver allografts are completely isolated from neural control of their hosts. Despite this absolute denervation, liver allograft function does not appear to be significantly impaired after successful transplantation. In experimental animal models, hepatic denervation has no major effects on bile acid production and biotransformation, while it increases blood pressure and salt retention; decreases the number of hepatic progenitor cells, cholangiocyte proliferation, and liver regeneration; and influences the hepatic microcirculation, diet behavior, and glycemic control. In humans, hepatic denervation after liver transplantation has no major deleterious effects on bile secretion, liver regeneration, and hepatic blood flow. Insulin resistance and postprandial hyperglycemia, changes in ingestion behavior, and reduced stimulation of hepatic progenitor cells in the canals of Hering are the major side effects of absent liver innervation. Despite these abnormalities, patients can lead a new life with improved quality of life. © 2004 Wiley‐Liss, Inc.
When is “enough” enough? Modeling the information‐seeking and stopping behavior of senior arts administrators
Authors: Zach Lisl
Published: August 2004

Among managers, those who are responsible for nonprofit organizations in general and arts organizations in particular have been an understudied group. These managers have much in common with their for‐profit counterparts, but their environment also differs in significant ways. The goal of this exploratory research effort was to identify how senior administrators in fine arts museums and symphony orchestras go about identifying and acquiring the information they want to complete a range of management tasks. Deciding when and where to look for information, obtaining the “right” information at the time it is needed, evaluating its credibility and utility, and determining when “enough” information has been collected are challenges facing this group of information users every day. A multiple‐case studies design involving a replication strategy was selected to structure the research process. Data were collected from 12 arts administrators using a pretested interview protocol that included the Critical Incident Technique. Patterns in the data were identified, and the data were further reviewed for disconfirming evidence. The study resulted in a list of the types and sources of information that arts administrators use as well as a list of the factors or “stopping criteria” that influence them to end their information‐seeking process. A model describing the way in which arts administrators go about acquiring the information they want was also developed. The main findings of the study are (a) arts administrators do not consider information seeking to be a discrete management task, (b) they rely heavily on direct personal experience to fill their information‐seeking needs, and (c) they are “satisficers” when it comes to seeking information. Based on Simon's alternative to rational choice theory, satisficers are people who are willing to pursue a “good enough” option rather than the best possible option (maximizers) (Simon, 1956). Since arts administrators have not been studied in the context of LIS research before, understanding more about where they go for information, what factors influence the level of effort they are willing to invest in seeking information, and how they decide when they have “enough” information provides insights into the information‐seeking behavior of a new user group. Furthermore, although this research effort is focused on specific users in a specific field, the results from this study may be compared to what we already know about other user groups to confirm and expand existing models of information‐seeking behavior.
Pharmacokinetics and safety of oral almotriptan in healthy male volunteers
Authors: McEwen J. , Salva M. , Jansat J.M. , Cabarrocas X.
Published: August 2004

Almotriptan (LAS 31416) is a new, oral, specific 5‐hydroxytryptamine1B/1D receptor agonist for the treatment of migraine. The pharmacokinetics and safety of a range of oral doses were assessed in 23 healthy male volunteers. Peak plasma concentrations were reached between 1.5 and 4 h after dosing. The maximum plasma concentration and area under the curve showed dose proportionality over the dose range 5–200 mg. The elimination half‐life was constant at approximately 3 h across all dose levels. A substantial proportion of the initial dose was excreted in urine (27%–39%) during 12 h post‐dose and the main excretory product was unchanged drug. Three major urinary metabolites were detected, all of which were pharmacologically inactive. The most common events following almotriptan administration were headache, tiredness and mild nausea. Nine events (18%) were classed as probably related to almotriptan and these were all at the highest dose level of 200 mg. The maximum tolerated dose of almotriptan was, therefore, determined as 150 mg. In conclusion, almotriptan is well tolerated following single, oral doses up to 150 mg and has predictable pharmacokinetics. Copyright © 2004 John Wiley & Sons, Ltd.
Enhancement of tyrosinase inhibition of the extract of Veratrum patulum using cellulase
Authors: Kim Dong Hyun , Kim Jin Hee , Baek Seung Hwa , Seo Jin Ho , Kho Yung Hee , Oh Tae Kwang , Lee Choong Hwan
Published: August 2004

Inhibitors of melanin biosynthesis were screened by using three different methods. The extract of Veratrum patulum contains hydroxystilbene compounds that are potent tyrosinase inhibitors. We evaluated the enzyme inhibitory property on the mushroom tyrosinase of hydroxystilbene compounds including resveratrol, oxyresveratrol, and their analogs. Biotransformation using cellulase of the whole extract brought about an increase in the inhibitory activity of the products on mushroom tyrosinase. The enhancement of tyrosinase inhibition is supposed to increase the concentration of aglycon, which has superior inhibitory activity to its glycoside. Eventually, melanin biosynthesis was inhibited by the enhanced tyrosinase inhibitory activity of the extract. This result indicated that deglycosylation of stilbene compounds has exerted more effective inhibition on the enzyme than that of the unprocessed plant extract. © 2004 Wiley Periodicals, Inc.
Thermodynamic analysis of product formation in mesophilic acidogenesis of lactose
Authors: Yu Han‐Qing , Mu Yang , Fang Herbert H. P.
Published: August 2004

Thermodynamic analysis on the acidogenesis of lactose was performed to evaluate the different acidogenic patterns and mechanisms by using Gibbs free energy calculation. Batch acidogenesis of lactose was investigated by using an enriched culture at 37°C, pH 5.5 and varied substrate levels. In addition to usual acidogenic products, i‐butyrate, valerate, i‐valerate, caproate, and propanol were also produced at a significant level. Thermodynamic analysis shows that valerate might be formed through the reaction requiring hydrogen as electron donor and consuming of propionate and carbon dioxide. Caproate was most likely produced directly from butyrate, hydrogen, and carbon dioxide. The minimum amount of Gibbs free energies needed to sustain isomerization of butyrate and valerate were approximately 5.7–5.8 and 4.5–4.6 kJ/mol, respectively. Propanol was produced from acetate, hydrogen, and carbon dioxide with a minimum amount of Gibbs free energy of 41.8–42.0 kJ/mol. Formation of butanol was controlled more by substrate level or population dynamics than by thermodynamics. © 2004 Wiley Periodicals, Inc.
Real‐time detection of 13C NMR labeling kinetics in perfused EMT6 mouse mammary tumor cells and βHC9 mouse insulinomas
Authors: Mancuso A. , Beardsley N.J. , Wehrli S. , Pickup S. , Matschinsky F.M. , Glickson J.D.
Published: August 2004

A method was developed for obtaining high signal‐to‐noise 13C NMR spectra of intracellular compounds in metabolically active cultured cells. The method allows TCA cycle labeling kinetics to be determined in real time without significant oxygen transport limitations. Cells were immobilized on the surface of nonporous microcarriers that were either uncoated or coated with polypeptides and used in a 12‐cm3 packed bed. The methods were tested with two EMT6 mouse mammary tumor cell lines, one strongly adherent and the other moderately adherent, and a weakly adherent mouse insulinoma line (βHC9). For both EMT6 lines, NTP and oxygen consumption measurements indicated that the number of cells in the spectrometer ranged from 6 × 108 to 1 × 109. During infusion of [1‐13C]glucose, labeling in C‐4 glutamate (indicative of flux into the first half of the TCA cycle) could be detected with 15‐min resolution. However, labeling for C‐3 and C‐2 glutamate (indicative of complete TCA cycle activity) was fivefold lower and difficult to quantify. To increase TCA cycle labeling, cells were infused with medium containing [1,6‐13C2]glucose. A 2.5‐fold increase was observed in C‐4 glutamate labeling and C‐3 and C‐2 glutamate labeling could be monitored with 30‐min resolution. Citrate synthase activity was indirectly detected in real time, as [3,4‐13C2]glutamate was formed from [2‐13C]oxaloacetate and [2‐13C]acetate (of acetyl‐CoA). Cell mass levels observed with βHC9 cells were somewhat lower. However, the 13C S/N was sufficient to allow real‐time monitoring of the response of intracellular metabolite labeling to a step change in glucose and a combined glutamine/serum pulse. © 2004 Wiley Periodicals, Inc.
Hybrid pancreatic tissue substitute consisting of recombinant insulin‐secreting cells and glucose‐responsive material
Authors: Cheng S‐Y. , Gross J. , Sambanis A.
Published: August 2004

Insulin‐dependent diabetes is a serious pathological condition, currently treated by blood glucose monitoring and daily insulin injections, which, however, do not prevent long‐term complications. A tissue‐engineered pancreatic substitute has the potential to provide a more physiologic, less invasive, and potentially less costly treatment of the disease. A major issue in developing such a substitute is the cells being used. Nonpancreatic cells, retrieved from the same patient and genetically engineered to secrete insulin constitutively or with some glucose responsiveness, offer the significant advantages of being immune‐acceptable and relaxing the tissue availability limitations, which exist with islets from cadaveric donors. These cells, however, do not have insulin secretion dynamics appropriate for restoration of euglycemia in higher animals and, eventually, humans. In this study, we present the concept of a hybrid pancreatic substitute consisting of such cells sequestered in a material exhibiting glucose‐dependent changes of its permeability to insulin. A Concanavalin A‐glycogen material sandwiched between two polycarbonate membranes and exhibiting glucose‐dependent sol‐gel transformations was used. Rates of insulin transport through this material in gel and sol forms were characterized for both FITC‐labeled insulin in solution and insulin secreted by βTC3 mouse insulinoma cells. Effective diffusivities through sol were found to be up to 3.5‐fold higher than through the gel state of the material. A mathematical model of a hybrid construct was formulated and analyzed to simulate the secretory behavior in response to step ups and downs in the surrounding glucose concentration. The experimental and modeling studies indicate that a hybrid pancreatic substitute consisting of constitutively secreting cells and glucose‐responsive material has the potential to provide a more physiologic regulation of insulin release than the cells by themselves or in an inert material. © 2004 Wiley Periodicals, Inc.