bluuebunny/crossref_metadata_2025 huggingface dataset:
Twin-to-Twin Transfusion Syndrome, Vein of Galen Malformation, and Transposition of the Great Arteries in a Pair of Monochorionic Twins: Coincidence or Related Association?
Authors: Steggerda Sylke , Lopriore Enrico , Sueters Marieke , Bartelings Margot , Vandenbussche Frank , Walther Frans
Published: July 2006

The pathogenetic mechanisms leading to the development of congenital heart disease and congenital intracranial arteriovenous malformation are still unclear. We report on a monochorionic twin pregnancy with twin-to-twin transfusion syndrome (TTTS), in which vein of Galen malformation (VGM) was diagnosed in the donor twin and transposition of the great arteries (TGA) in the recipient twin. The development of TTTS, VGM, and TGA in a single monochorionic pregnancy could be pure coincidence, but there might also be a causative link. We discuss the possible contribution of genetic factors, fetal flow fluctuations, vascular endothelial growth factors, and the process of twinning itself to the development of these congenital anomalies.
Pulmonary Atresia, Intact Ventricular Septum, Right Ventricle-Dependent Coronary Artery Circulation, and Systemic Collateral Arteries Supplying the Left Coronary Artery
Authors: Craver Randall D. , Caspi Joseph
Published: July 2006

We present a 14-day-old with pulmonary artery atresia with intact ventricular septum, right ventricle-dependent coronary circulation, a single aortic root coronary ostia (left), congenital collateral arterial supply to the left coronary artery from the left internal mammary artery, and bilateral paravertebral arteries, with obstructive coronary artery lesions.
Nonobstructive Neonatal Cholestasis: Clinical Outcome and Scoring of the Histopathological Changes in Liver Biopsies
Authors: Okçu-Heper Aylin , Erden Esra , Doganci Tümay , Kuloglu Zarife , Kansu Aydan , Genc Yasemin
Published: July 2006

The clinical outcome of nonobstructive neonatal cholestasis (NC) cases varies greatly and the prognosis is generally unpredictable. In this study, we aimed to evaluate the prognostic benefits of qualitative analysis of histopathological changes in nonobstructive NC cases. A total of 28 nonobstructive NC cases (18 neonatal hepatitis; 10 intrahepatic bile duct paucity) were studied. We analyzed the relationship between histopathological and clinical parameters. Hepatic inflammation, bridging necrosis, pericellular fibrosis, giant cell transformation, and extramedullary hematopoiesis were evaluated and scored according to their absence or presence in each case. The sum of the histopathological scores was accepted as “total pathological injury score.” The height percentiles, the presence and the degree of hepatomegaly and ascites, and serum alanine aminotransferase (ALT), albumin, and bilirubin levels and prothrombin time were also evaluated and scored. The patients were divided into 2 clinical course groups considered “good” or “bad” according to the total clinical scores. For statistical analysis, Pearson's chi-square test, Mann-Whitney U-test, and receiver operating characteristic curve were used. We found a statistically significant negative relation between the clinical course and total pathological injury score ( P = 0.042) and pericellular fibrosis ( P = 0.016). In conclusion, during the interpretation of liver biopsies of nonobstructive NC, scoring of histopathological changes should be done for assessing the clinical prognostic outcome.
Neonatal Hepatitis in 2 Siblings with Seckel Syndrome
Authors: Deniz Kemal , Kontaş Olgun , Akçakuş M.
Published: July 2006

Seckel syndrome was described as the prototype of the primordial bird-head type of dwarfism. We report 2 cases of Seckel syndrome in siblings. Both cases showed peculiar phenotypic features. Autopsy was performed and microscopic examination of the livers displayed histologic features of neonatal hepatitis. In addition, our younger patient had central nervous system anomalies such as agenesis of corpus callosum, cerebral cyst, and primitive convolutional pattern. No previous reports of liver disease exist in patients with Seckel syndrome. The pathologic findings of such an unusual association and a review of literature are presented.
Screening for RB1 Mutations in Tumor Tissue Using Denaturing High Performance Liquid Chromatography, Multiplex Ligation-Dependent Probe Amplification, and Loss of Heterozygosity Analysis
Authors: Sellner Loryn N. , Edkins Edward , Smith Nicholas
Published: July 2006

Retinoblastoma is a malignant retinal neoplasm arising in infancy as a result of inactivating mutations in both alleles of the retinoblastoma susceptibility gene, RB1. Identification of the causative RB1 mutations in a patient assists in the clinical management of the affected patient and risk assessment of family members, principally on the basis of whether there is a germline mutation. In this paper, we describe our experience with molecular analysis of RB1 mutations in tumor and nontumor samples from 18 retinoblastoma patients, using multiplex ligation dependent probe amplification (MLPA) to detect large deletions or duplications, microsatellite analysis to detect loss of heterozygosity (LOH), and denaturing high performance liquid chromatography (D-HPLC) analysis to detect point mutations and small insertions or deletions. We found LOH in 71% of all cases, and 83% of these were due to acquired isodisomy rather than chromosomal deletions. Small mutations identified by D-HPLC accounted for 78% of the non-LOH mutations, and large deletions/duplications detected by MLPA accounted for the remaining 22%. We give the first report of a large, multiexon duplication in RB1 of exons 8 to 18.
Pulmonary Intra-Alveolar Siderophages in SIDS and Suffocation: A San Diego SIDS/SUDC Research Project Report
Authors: Krous Henry F. , Wixom Christopher , Chadwick Amy E. , Haas Elisabeth A. , Silva Patricia D. , Stanley Christina
Published: July 2006

Pulmonary intra-alveolar siderophages (PS) have been suggested as a marker of previous attempts at imposed suffocation in infants dying suddenly and unexpectedly. The aims of this study were to (1) compare PS counts between cases of sudden infant death syndrome (SIDS) and a control group comprised of infants whose deaths were attributed to accidental or inflicted suffocation, (2) compare clinical variables in SIDS and control suffocation cases, and (3) review individual cases irrespective of the cause and manner of death with an average PS count greater than 200 per 20 high-power fields (hpf) per lung lobe. Retrospective assessment of siderophages in available iron-stained lung sections was undertaken in 91 SIDS cases and 29 cases of death due to suffocation (27 accidents and 2 homicides) from the San Diego SIDS and Sudden Unexplained Death in Childhood (SUDC) Research Project (SDSSRP) database. Neither the means of the log-transformed PS counts nor the medians of the raw PS counts were significantly different between the SIDS and control suffocation groups. The distributions of the PS data were different, however—the range was wider in the SIDS group. Only 6% of each group had a history of prior apparent life-threatening events. Approximately three fourths of the families from both groups had no prior referral to Child Protective Services. The number of PS varies widely in cases of sudden infant death caused by SIDS and accidental or inflicted suffocation and cannot be used as an independent variable to ascertain past attempts at suffocation.
Congenital Renal Rhabdoid Tumor with Placental Metastases: Immunohistochemistry, Cytogenetic, and Ultrastructural Findings
Authors: de Tar Michael , Biggerstaff Julie Sanford
Published: July 2006

Malignant congenital tumors of fetal origin are rare lesions, the most common type being congenital neuroblastoma. Although prenatal diagnosis is possible in large tumors, occasionally the tumor will be diagnosed first by its metastatic involvement of the placenta. Placental metastases can reflect either maternal or fetal primary sites, and each has relatively specific patterns of placental involvement. We describe the clinical and pathologic features of a widely metastatic congenital renal rhabdoid tumor with its placental and autopsy findings, and include the immunohistochemical, cytogenetic, and ultrastructural features. The pathologic features of the placenta in congenital renal rhabdoid tumor with placental metastasis have not been previously described. The examination of the placenta in this case led to the initial diagnosis and obviated the need for additional diagnostic procedures.
Umbilical Cord Hypercoiling and Thinning: A Rare Cause of Intrauterine Death in the Second Trimester of Pregnancy
Authors: Horn Lars-Christian , Faber Renaldo , Stepan Holger , Simon Eike , Robel Ralf , Wittekind Christian
Published: July 2006

Little attention has been paid to the pathologic features of the umbilical cord, which might fatally damage the fetus. We determined the association of hypercoiling (more than 1 coil per 5 cm) and thinning with consecutive constriction of the umbilical vessels (thin cord syndrome; TCS) and intrauterine fetal death (IUFD). Three hundred and three cases of consecutive fetal autopsies over a 5-year period, including spontaneous and induced abortions of the 2nd trimester of pregnancy, were examined using a standardized protocol. The mean maternal age was 28.5 years and the mean gestational age was 19.1 weeks (range: 12.6 to 24.5 weeks). Thirty-six percent of all cases were induced abortions because of congenital malformations, and 8.9% resulted from legal abortions, as regulated by German law. One hundred sixty-seven cases (55.1%) were spontaneous abortion specimens. The leading cause for IUFD in the spontaneous abortion group was an amnion infection (34.7%), followed by abruptio placentae (15.6%). In 25.1% of cases, placental dysmaturity with consecutive placental insufficiency was responsible for IUFD. Pathologies of the umbilical cord as the cause of IUFD were seen in 10.2% of the cases. Most of these cases (15/17) involved TCS. In 14.4% of all spontaneous abortion specimens the cause of IUFD could not be determined by autopsy. There was an apparent difference in the frequency of TCS in the spontaneous abortion group (15/167 = 9%) compared to the nonspontaneous group (2/136 = 1.5%). A remarkably high percentage (17/303 = 5.6%) of all cases showed TCS. In cases of spontaneous abortions, TCS was causative for intrauterine death in 9% of cases (15/167). Careful pathologic examination of the umbilical cord is recommended to detect TCS and to reduce the cases with unexplained intrauterine death.
Pediatric Undifferentiated Sarcoma of the Soft Tissues: A Clinicopathologic Study
Authors: Somers Gino R. , Gupta Abha A. , Doria Andrea S. , Ho Michael , Pereira Carlos , Shago Mary , Thorner Paul S. , Zielenska Maria
Published: July 2006

Pediatric undifferentiated soft tissue sarcomas represent a major challenge for pathologists and clinicians. The goal of this study was to identify cases that warranted this diagnosis by current standards of analysis and then determine if there are clinicopathological commonalities that may be useful for diagnosis, management, and prognosis. Eighteen potential patients were identified using the institutional pathology database. Three cases were reclassified as specific sarcomas, and 2 cases had insufficient material for molecular analysis, leaving 13 cases for pathological review and 12 patients for radiological and clinical review. There were 7 males and 6 females. The median age at diagnosis was 11 years (1 month to 16 years). Tumors commonly involved the trunk (7 of 13; 54%) and ranged in size from 1.7 to 14.5 cm (mean, 6.7 cm). Eleven patients received ifosfamide/etoposide chemotherapy and 4 received irradiation. Five-year event-free and overall survival (EFS and OS) rates were 54% and 74%, respectively. The predominant histological pattern was round to plump spindled cells forming sheets (9 of 13; 69%) and severe atypia was associated with decreased survival ( P = 0.048). Immunohistochemistry showed positivity for vimentin (92%), CD117 (92%), and vascular endothelial growth factor (69%), and 8% to 23% showed focal positivity for epithelial, neural, or myogenic markers. Tumors were uniformly negative for translocations associated with pediatric sarcomas. The presence of certain common morphological and immunohistochemical features in the absence of specific molecular genetic abnormalities allows for a diagnosis of pediatric undifferentiated soft tissue sarcoma; however, whether this group of neoplasms forms a unique category of tumors or a common precursor pathway for a number of different sarcomas awaits further study.
Polar Spongioblastoma of the Spinal Cord: A Case Report
Authors: Fuller Christine , Helton Kathleen , Dalton James , Fouladi Maryam , Kun Larry , Burger Peter
Published: July 2006

“Rhythmic palisading” is a striking histologic pattern infrequently encountered in a variety of central nervous system (CNS) tumors. We present the case of an infant with a large spinal cord lesion wherein all sampled tissue showed columnar arrangements of palisaded cells, typical of polar spongioblastoma. The tumor was briskly proliferative, focally necrotic, and variably expressed S100, glial fibrillary acidic protein, neuron specific enolase, and p53 by immunohistochemistry. Fluorescence in situ hybridization failed to reveal isochromosome 17q, EGFR amplification, or deletions of 1p, 19q, 22q11.2, 10q, or p16. Despite chemotherapy and decadron, he developed lesional necrosis and intracranial metastases and died less than 1 mo from presentation. This case illustrates polar spongioblastoma as a distinctive histologic pattern that can occur in embryonal CNS tumors. Discrimination of these rare aggressive lesions from other CNS tumors with focal palisaded architecture is crucial as the treatment and prognosis of the latter may differ significantly.
Disordered Pulmonary Myofibroblast Distribution and Elastin Expression in Preterm Infants with Ureaplasma Urealyticum Pneumonitis
Authors: Viscardi Rose , Manimtim Winston , He Ju Ren , Hasday Jeffrey D. , Sun Chen-Chih J. , Joyce Belinda , Pierce Richard A.
Published: July 2006

Respiratory colonization of preterm infants with Ureaplasma urealyticum is a significant risk factor for bronchopulmonary dysplasia, a chronic lung disease characterized by arrest of alveolar development, variable interstitial fibrosis, and disordered elastic fibers in the distal airspaces. As indicated in previous studies, moderate to severe fibrosis is a hallmark of pathology in the Ureaplasma-infected preterm lung. To further characterize the preterm lung's response to Ureaplasma, lung specimens from 4 gestational controls (GC), 12 other pneumonia and 5 Ureaplasma-infected infants were analyzed by immunohistochemistry for α-smooth muscle actin (αSMA) and transforming growth factor β1 (TGFβ1), Hart's elastin staining, and in situ hybridization for tropoelastin (TE) expression. Cells positive for αSMA were observed in thickened, extensive bundles surrounding terminal airspaces in Ureaplasma and other pneumonia cases compared to individual myofibroblasts in GC. The myofibroblast pattern correlated with the severity of fibrosis, but not duration of ventilation. Transforming growth factor β1 immunostaining was primarily localized to alveolar macrophages and was increased in Ureaplasma more than in other pneumonia cases. Elastic fibers and TE-expressing cells were spatially limited to emerging septal tips in GC. In pneumonia cases, increased deposition of elastic fibers was observed surrounding terminal airspaces, but TE expression was similar to GC. In Ureaplasma specimens, accumulation of elastic fibers correlated with duration of ventilation, and TE expression was extensive throughout the walls of terminal airspaces. These findings suggest that Ureaplasma is associated with alveolar macrophage TGFβ1 immunostaining and myofibroblast proliferation contributing to abnormal septation, interstitial fibrosis, and a prolonged and strong elastogenic response in the preterm lung.
KAI-1 Expression in Pediatric High-Grade Osteosarcoma
Authors: Leavey Patrick J. , Timmons Charles , Frawley William , Lombardi Donald , Ashfaq Raheela
Published: July 2006

Recent evidence implicates cell surface proteins of the tetraspanin superfamily in the process of metastasis whereas the downregulation of KAI-1, a member of the tetraspanin family, is associated with an aggressive clinical phenotype in several types of human cancers. To determine if expression of KAI-1-1 is associated with any known prognostic marker or clinical outcome in high-grade osteosarcoma, we examined 91 nondecalcified archival samples from 47 patients for the expression of KAI-1. Archival, paraffin-embedded, and decalcified pathologic samples were examined by immunohistochemistry and results were correlated to clinical outcomes and known prognostic markers. There were 46 samples from diagnostic biopsies (1 diagnostic sample was not available), 32 tumor resection samples, and 13 metastasis samples. Thirty-three percent (n = 30) of the samples expressed KAI-1 (16 biopsies, 9 resections, and 5 metastasis). KAI-1 expression was not significantly related to known prognostic markers or to either tumor necrosis after neoadjuvant therapy or the incidence of metastasis at diagnosis. KAI-1 expression was not significantly different between paired diagnostic tumor samples and either resection or metastasis tumor samples. Twenty-five patients remain alive at a median follow-up of 95 months. The overall and progression-free survival percentages at 5 years were 62% and 47% for KAI-1-positive patients and 49% and 38% for KAI-1-negative patients, respectively. This difference was not statistically significant. We conclude that KAI-1 is expressed in a proportion of high-grade osteosarcoma but is not of clinical significance and cannot be used to stratify treatment groups for these patients.
Chronic lymphoproliferative disorder with regulatory T‐cell phenotype
Authors: Kikuchi Tomoko , Katayama Yoshio , Kubonishi Shiro , Watanabe Toshiyuki , Watanabe Yukari , Matsuoka Ken‐ichi , Maeda Yoshinobu , Namba Noriko , Masunari Taro , Nasu Ryusuke , Ikeda Kazuma , Tanimoto Mitsune
Published: July 2006

We report a case of T‐cell chronic lymphoproliferative disorder (CLPD) that shows neither features of T‐cell prolymphocytic leukemia nor disease progression for more than 34months. Flow cytometric analyses of the lymphocytes revealed high expression of CD4 and CD25. Up‐regulation of Foxp3, a master regulatory gene for developmental differentiation of regulatory T cells (Treg), was confirmed at mRNA and protein levels. To our knowledge, this is the first case of extremely indolent CLPD with Treg phenotype. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Is there a role for inhaled nitric oxide as a rescue therapy in respiratory failure associated with hematologic malignancies?
Authors: Keegan Mark T. , Nygren Eric , Afessa Bekele , Hogan William J. , Harrison Barry A.
Published: July 2006

Inhaled nitric oxide has been demonstrated to improve oxygenation in critically ill patients requiring mechanical ventilation. We therefore performed a retrospective review to determine the outcome of patients with hematological malignancies and acute respiratory failure who received inhaled nitric oxide (INO) in a multidisciplinary intensive care unit of a single tertiary referral medical center.

Thirteen patients with hematological malignancies who required endotracheal intubation and mechanical ventilation and received INO for acute respiratory failure between January 1998 and December 2002 were identified. Mean ± standard deviation (SD) age was 47.6 (±13.2) years. The mean ± SD Acute Physiology and Chronic Health Evaluation (APACHE) III score on the day of ICU admission was 94.1 ± 33.7 with a mean (SD) predicted probability of ICU death of 42.4% (±28.6). Mean APACHE III score on the day of initiating INO was 107.6 (±34.4) with a predicted mortality in the intensive care unit of 72.7% (±23.3). Mean PaO2 to FiO2 (PF) ratios (±SD) prior to, and immediately after, the initiation of INO were 62.6 (±28.2) and 111 (±65.1), respectively (P < 0.001). The median duration of INO therapy was 41.8 h (interquartile range, 6.3–98.2). Patients with hematological malignancies and acute respiratory failure to whom INO was administered had clinical deterioration since ICU admission. Despite a marked initial improvement in arterial oxygen tension, all patients ultimately died in the intensive care unit, 8 of them within 48 h of initiating INO. Therefore, despite initial improvement in oxygenation, we did not observe any survival benefit to INO in this setting. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
Identification of Flt3 internal tandem duplications downstream targets by high‐throughput immunoblotting protein array system
Authors: Takahashi Shinichiro
Published: July 2006

The receptor tyrosine kinase Flt3 plays an important role in proliferation and survival of hematopoietic cells. Flt3 is the most frequently mutated gene (20–30%) in cases of acutemyeloid leukemia (AML). The majority of Flt3 mutations are internal tandem duplications (ITD) in the juxtamembrane domain of Flt3 receptor. This mutation results in the constitutive activation of STAT5 and Ras/mitogen‐activated protein kinase pathways, leading to the aberrant growth of AML cells. In this study, to better understand the mechanisms of Flt3‐ITD to the downstream pathways, a high‐throughput immunoblotting protein array system was employed. As a result, c‐Jun and c‐Raf were markedly induced, suggesting that these factors are functional downstream targets of Flt3‐ITD. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
EBV negative Richter's syndrome from a coexistent clone after salvage treatment with alemtuzumab in a CLL patient
Authors: Janssens Ann , Berth Mario , De Paepe Pascale , Verhasselt Bruno , Van Roy Nadine , Noens Lucien , Philippé Jan , Offner Fritz
Published: July 2006

Transformation of B cell chronic lymphocytic leukemia (B‐CLL) to large cell lymphoma or Hodgkin's disease is known as a Richter's syndrome (RS). According to the literature, 1–10% of B‐CLL patients develop this high‐grade lymphoid malignancy. The relationship between the immunosuppressive effect of nucleoside analogues (NA) and monoclonal antibodies and the development of large cell transformation still remains a controversial issue. We describe a CLL patient who developed a large B cell lymphoma 94 months after diagnosis and 3 months after the start of alemtuzumab. The CLL immunophenotype was retained by the transforming cells although a different light chain was expressed. Molecular analysis of the immunoglobulin heavy chain confirmed that the CLL and the RS had a different clonal origin. Subsequent molecular analyses of stored samples showed that the clone with transforming capacity already appeared two years before the clinical appearance of the RS. We hypothesize that alemtuzumab promoted the uncontrolled growth of the latest clone by eradicating the initial B‐CLL clone efficiently, and by inducing a strong T cell depletion with consequent impairment of the immunosurveillance. We also ruled out that the RS was EBV driven. In conclusion, we report a case of EBV negative RS after alemtuzumab as salvage therapy. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
An efficient chemical method to generate repetitive sequences depleted DNA probes
Authors: Lucas Joe N. , Wu Xiaoyan , Guo Emily , Chi Loretta E. , Chen Zhong
Published: July 2006

We describe an efficient method to remove repetitive sequences from DNA of microdissected whole chromosomes, chromosome arms, locus specific probes, and specific bands. The chemical approach described removes human repetitive DNA sequences from a source DNA, eliminating the need for blocking such sequences when the source DNA used as a probe is hybridized with a target DNA. It employs subtracting hybridized biotin‐labeled repetitive‐sequence DNA complex with phenol and chloroform after incubation of hybridized products with avidin. The method produces unique products that are formed after such repetitive sequences have been removed from the DNA. We have applied our newly designed subtraction strategy to microdissected chromosomes in generating whole chromosome painting (e.g., chromosome 4), chromosome arm (e.g., 1q and 15q), and band (e.g., 3q26) specific probes, and we have demonstrated its utility using flow‐sorted chromosome. FISH analyses using these probes show consistent strong signals with no cross‐hybridization, and optimal hybridization results can be obtained relatively quickly. © 2006 Wiley‐Liss, Inc.
Mosaic ring 20 with no detectable deletion by FISH analysis: Characteristic seizure disorder and literature review
Authors: Zou Ying S. , Van Dyke Daniel L. , Thorland Erik C. , Chhabra Harinderpal S. , Michels Virginia V. , Keefe Jeannette G. , Lega Melanie A. , Feely Molly A. , Uphoff Timothy S. , Jalal Syed M.
Published: July 2006

Ring chromosome 20 is a rare chromosome disorder characterized by a typical seizure phenotype consisting of complex partial seizures, frequent progression to generalized tonic or tonic‐clonic seizures, and nocturnal frontal lobe seizures with frequent episodes of non‐convulsive status epilepticus. Development may be normal or mildly delayed, followed by cognitive and behavioral decline after seizure onset. Here, we describe a patient with a typical severe seizure phenotype and a mosaic ring chromosome 20 without loss of p or q subtelomere regions or telomeric sequences. The ring had a longer telomere length than either of the telomere ends of its homologous chromosome 20 by quantitative fluorescence in situ hybridization analysis, suggesting that it might be derived from telomere–telomere fusion. The phenotypic comparison of this patient and other chromosome 20 cases that had terminal deletions of 20qter (n = 1) and 20pter (n = 7), shows that the epilepsy phenotype and electroencephalographic abnormalities are characteristic in patients with ring chromosome 20. Several hypotheses have been proposed to address the elusive mechanisms underlying the seizure disorder in ring chromosome 20. These possibilities include haploinsufficiency of two epilepsy genes CHRNA4 and KCNQ2 located at 20qter, silencing of these genes by a telomere position effect, or microdeletions or rearrangements of genetic material during the ring formation. © 2006 Wiley‐Liss, Inc.
Deletion at 14q22‐23 indicates a contiguous gene syndrome comprising anophthalmia, pituitary hypoplasia, and ear anomalies
Authors: Nolen Leisha D. , Amor David , Haywood Ashley , St. Heaps Luke , Willcock Chris , Mihelec Marija , Tam Patrick , Billson Frank , Grigg John , Peters Greg , Jamieson Robyn V.
Published: July 2006

Anophthalmia and pituitary gland hypoplasia are both debilitating conditions where the underlying genetic defect is unknown in the majority of cases. We identified a patient with bilateral anophthalmia and absence of the optic nerves, chiasm and tracts, as well as pituitary gland hypoplasia and ear anomalies with a de novo apparently balanced chromosomal translocation, 46,XY,t(3;14)(q28;q23.2). Translocation breakpoint analysis using FISH and high‐resolution microarray comparative genomic hybridization (CGH) has identified a 9.66 Mb deleted region on the long arm of chromosome 14 which includes the genes BMP4, OTX2, RTN1, SIX6, SIX1, and SIX4. Three other patients with interstitial deletions involving 14q22‐23 have been described, all with bilateral anophthalmia, pituitary abnormalities, ear anomalies, and a facial phenotype similar to our patient. OTX2 is involved in ocular developmental defects, and the severity of the ocular phenotype in our patient and the other 14q22‐23 deletion patients, suggests this genomic region harbors other gene/s involved in ocular development. BMP4 haploinsufficiency is predicted to contribute to the ocular phenotype on the basis of its expression pattern and observed murine mutant phenotypes. In addition, deletion of BMP4 and SIX6 is likely to contribute to the abnormal pituitary development, and SIX1 deletion may contribute to the ear and other craniofacial features. This indicates that contiguous gene deletion may contribute to the phenotypic features in the 14q22‐23 deletion patients. © 2006 Wiley‐Liss, Inc.
Opitz trigonocephaly C syndrome in a boy with a de novo balanced reciprocal translocation t(3;18)(q13.13;q12.1)
Authors: Chinen Yasutsugu , Kaname Tadashi , Yanagi Kumiko , Saito Nakamichi , Naritomi Kenji , Ohta Takao
Published: July 2006

Opitz trigonocephaly C syndrome (OTCS) is a multiple congenital anomaly syndrome characterized by trigonocephaly, mental retardation, a typical facial appearance, redundant skin, joint and limb abnormalities, and visceral anomalies. We describe a patient with the manifestations of OTCS who also had a de novo balanced reciprocal translocation t(3;18)(q13.13q12.1). His phenotype is a mild form with mild developmental delay and no severe visceral anomalies. Our findings suggest the possible existence of a new locus responsible for OTCS either on 3q13.13 or 18q12.1. © 2006 Wiley‐Liss, Inc.
Normal values for morphological abnormalities in school children
Authors: Merks Johannes H.M. , Özgen Heval M. , Cluitmans Theresia L.M. , van der Burg‐van Rijn Jaqueline M. , Cobben Jan Maarten , van Leeuwen Flora E. , Hennekam Raoul C.M.
Published: July 2006

Clinical morphology has proven to be a strong tool in the delineation of many syndromes and a helpful instrument in molecular studies. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for phenotypic abnormalities are essential. So far, only few studies on the frequency of phenotypic abnormalities in the normal population have been done having one thing in common: all were performed in newborn infants. We studied morphological characteristics in a group of 1,007 school children, representative for the Dutch population, through a body surface examination using detailed definitions for all morphological findings. The region of study and distribution of children over various school types was chosen in such a way that it represented the general Dutch population. The median age of the studied children was 11 years (range 8–14 years), sex ratio (M:F) was 0.93. Nine hundred twenty‐three children were of Caucasian descent, 84 others of mixed ethnic backgrounds. The reliability of the examinations was tested by independent scoring of 111 children by two observers, showing a kappa score of 0.85. Normal values for the morphological findings are presented together with their age‐adjusted classification. These normal values provide a valuable source for validation of classifications of phenotypic abnormalities, especially those that are depending on frequency, that is, minor anomalies and common variants. Furthermore, they will allow a proper evaluation of patterns of phenotypic abnormalities found in patient groups with specific disorders. © 2006 Wiley‐Liss, Inc.
The molecular etiologies and associated phenotypes of amelogenesis imperfecta
Authors: Wright J. Timothy
Published: July 2006

The amelogenesis imperfectas (AIs) are a clinically and genetically diverse group of conditions that are caused by mutations in a variety of genes that are critical for normal enamel formation. To date, mutations have been identified in four genes (AMELX, ENAM, KLK4, MMP20) known to be involved in enamel formation. Additional yet to be identified genes also are implicated in the etiology of AI based on linkage studies. The diverse and often unique phenotypes resulting from the different allelic and non‐allelic mutations in these genes provide an opportunity to better understand the role of these genes and their related proteins in enamel formation. Understanding the AI phenotypes also provides an aid to clinicians in directing molecular studies aimed at delineating the genetic basis underlying these diverse clinical conditions. Our current knowledge of the known mutations and associated phenotypes of the different AI subtypes are reviewed. © 2006 Wiley‐Liss, Inc.
Looking different: Understanding diversity in facial form
Authors: Brugmann S.A. , Kim J. , Helms J.A.
Published: July 2006

The face is perhaps the most distinguishing feature of the vertebrate body. Six billion human faces decorate the earth, each of them unique and exceptional in their own way. Likewise, facial variation is the cornerstone of species‐specific diversity within the animal kingdom. Yet despite this multiplicity in form, the underlying architecture of the vertebrate face is remarkably conserved. If early embryos of different species first resemble one another, then how is this facial diversity generated? Our primary goal is to elucidate the molecular origins of species‐specific craniofacial morphogenesis. We examined one facial primordia, the frontonasal prominence, of phylogenetically related (chick vs. quail vs. duck) and distant (mouse vs. chick) embryos and asked how such drastically different forms (e.g., beak, bill, or muzzle) could be generated from a once‐similar entity. We examined the morphological ontogeny and a number of molecular expression patterns in an attempt to shed light on when species‐specific variations occur and what molecules (BMPs, FGFs, etc.) are implicated in its differential growth. We hypothesize that subtle changes in the signaling of these morphogens can reproducibly alter the morphology of the frontonasal prominence. Taken together, these data facilitate our fledgling understanding of the process by which facial morphogenesis is regulated. © 2006 Wiley‐Liss, Inc.
Clinical dividends from the molecular genetic diagnosis of craniosynostosis
Authors: Wilkie Andrew O.M. , Bochukova Elena G. , Hansen Ruth M. S. , Taylor Indira B. , Rannan‐Eliya Sahan V. , Byren Jo C. , Wall Steven A. , Ramos Lina , Venâncio Margarida , Hurst Jane A. , O'Rourke Anthony W. , Williams Louise J. , Seller Anneke , Lester Tracy
Published: July 2006

A dozen years have passed since the first genetic lesion was identified in a family with craniosynostosis, the premature fusion of the cranial sutures. Subsequently, mutations in the FGFR2, FGFR3, TWIST1, and EFNB1 genes have been shown to account for ∼25% of craniosynostosis, whilst several additional genes make minor contributions. Using specific examples, we show how these discoveries have enabled refinement of information on diagnosis, recurrence risk, prognosis for mental development, and surgical planning. However, phenotypic variability can present a significant challenge to the clinical interpretation of molecular genetic tests. In particular, the difficulty of analyzing the complex interaction of genetic background and prenatal environment in determining clinical features, limits the value of identifying low penetrance mutations. © 2006 Wiley‐Liss, Inc.
Analysis of the dopamine beta hydroxylase gene in Gilles de la tourette syndrome
Authors: Ozbay Fatih , Wigg Karen G. , Turanli Eda Tahir , Asherson Phil , Yazgan Yanki , Sandor Paul , Barr Cathy L.
Published: July 2006

Numerous lines of evidence support the role of the catecholamines in the development of tics and Gilles de la Tourette syndrome (GTS). Dopamine‐β‐hydroxylase (DBH) is the key enzyme in the conversion of dopamine to norepinephrine and the alleles of several polymorphisms of the DBH gene are correlated with individual variation in serum levels of the enzyme. We investigated the genetic relationship of the gene for DBH to GTS in two samples, one collected in Canada and one collected in Turkey. In total 106 affected probands and siblings in 71 nuclear pedigrees and 40 affected individuals and 71 family members in five multi‐generational pedigrees were genotyped for three polymorphisms in the DBH locus. In the Canadian pedigrees we found no convincing evidence for linkage either in the multi‐generational pedigrees or association in the nuclear families. We found significant evidence for association in the Turkish pedigrees (n = 29) for the 19 bp insertion/deletion markers; however, there was no supporting evidence for association with the other two markers. Based on the small sample size and low number of informative transmissions, we conclude that the results from the 19 bp insertion/deletion markers may be a chance false positive finding. These findings, in total, suggest that the DBH locus is unlikely to be a major gene influencing the susceptibility to DBH. © 2006 Wiley‐Liss, Inc.
Neurobehavioral disorders in children, adolescents, and young adults with Down syndrome
Authors: Capone George , Goyal Parag , Ares William , Lannigan Emily
Published: July 2006

The term dual‐diagnosis refers to a person with mental retardation and a psychiatric disorder. Most children with Down syndrome (DS) do not have a psychiatric or neurobehavioral disorder. Current prevalence estimates of neurobehavioral and psychiatric co‐morbidity in children with DS range from 18% to 38%. We have found it useful to distinguish conditions with a pre‐pubertal onset from those presenting in the post‐pubertal period, as these are biologically distinct periods each with a unique vulnerability to specific psychiatric disorders. Due to the increased recognition that psychiatric symptoms may co‐occur with mental retardation, and are not inextricably linked to cognitive impairment, these conditions are considered treatable, in part, under a medical model. Improvement in physiologic regulation, emotional stability, and neurocognitive processing is one of the most elusive but fundamental goals of pharmacologic intervention in these disorders. © 2006 Wiley‐Liss, Inc.
Current dilemmas in Down syndrome clinical care: Celiac disease, thyroid disorders, and atlanto‐axial instability
Authors: Cohen William I.
Published: July 2006

This study will discuss our current understanding of celiac disease (CD), thyroid disorders, and atlanto‐axial instability, three important areas of medical management in individuals with Down syndrome (DS). In this study, we highlight our current knowledge, as well as what we need to study in order to gather the necessary data to refine the empirically based screening protocols which are now in place. © 2006 Wiley‐Liss, Inc.
Clinical trials in children with Down syndrome: Issues from a cognitive research perspective
Authors: Heller James H. , Spiridigliozzi Gail A. , Crissman Blythe G. , Sullivan‐Saarela Jennifer A. , Li Jennifer S. , Kishnani Priya S.
Published: July 2006

Clinical and translational research play a key role in the transition of basic research discoveries to effective therapies. In Down syndrome (DS), these research approaches are not well utilized or developed to test new therapies to improve cognitive and/or adaptive function in this population. This article reviews the history of clinical trial research in children with DS from a cognitive research perspective and discusses important issues relevant to the conduct of well designed clinical trials for this population. Specific issues addressed include: funding, study design, study medication, subject recruitment and retention, safety, and efficacy challenges. The Duke Down Syndrome Research Team's program of clinical research of cholinesterase inhibitors for individuals with DS serves as the model application for the identified research principles. It is hoped that this article will raise awareness of the unmet need for clinical research in the cognitive and adaptive function of individuals with DS, especially children with DS. © 2006 Wiley‐Liss, Inc.
Three‐dimensional reconstruction of urogenital tract from Visible Korean Human
Authors: Uhl Jean‐François , Park Jin Seo , Chung Min Suk , Delmas Vincent
Published: July 2006

The three‐dimensional (3D) modeling from anatomical images is revealed to be a remarkable learning tool in anatomy. This is particularly true for the pelvis area and the urogenital tract. The authors present here a 3D reconstruction of the male urogenital tract from the Visible Korean Human data. The segmentation of 440 anatomical images was arranged in a pile and processed by the SURFdriver software to build an interactive 3D model. Forty‐two anatomical structures were reconstructed, including kidneys, ureters, urinary bladder (outer and inner boundaries), urethra, testes, epididymides, ducti deferens, seminal vesicles, prostate, rectum, anal canal, abdominal aorta, superior mesenteric artery, renal arteries, inferior vena cava, renal veins, lumbar vertebrae, intervertebral discs, sacrum, hip bones, femurs, and skin. Three‐dimensional models of 42 anatomical structures can be individually and interactively manipulated. In addition, the use is able to control the transparency of the model. The aim of this computerized modeling is to present a learning tool for students and patients. In the near future, it could be the basis of new simulation tools for surgeon's training. Anat Rec Part A, 288A:893–899, 2006. © 2006 Wiley‐Liss, Inc.
Staging of intestinal development in the chick embryo
Authors: Southwell Bridget R.
Published: July 2006

Comparisons between developmental studies rely on embryonic staging systems. It is important for comparison of molecular, immunohistochemical, and physiological studies of the developing chick intestine that the developmental stage of embryos is reliably determined. Good staging systems exist for the external features of the chick embryo but not for development of internal organs. To facilitate precise comparisons of chick embryo intestine development, we prepared an intestinal staging system. Embryos were fixed, other tissues dissected away, and the intestine and associated organs were then drawn to scale using a camera lucida. This produced black‐and‐white drawings with features of the gut clearly visible. The detailed drawings of intestine from chick embryos aged 2.5 to 10 days were correlated with age of embryos and developmental stages described in three common staging systems, Hamilton and Hamburger, Thompson and Fitzharris, and Allan and Newgreen. Descriptions of key changes in gut morphology and position are given for each stage. This staging of chick gut development will allow future studies to quote and compare development of the gut rather than external features or incubation time. This will allow much more precise reporting and comparisons in developmental studies of cell migration and gene expression. Anat Rec Part A, 288A:909–920, 2006. © 2006 Wiley‐Liss, Inc.
Human ceruminous gland: Ultrastructure and histochemical analysis of antimicrobial and cytoskeletal components
Authors: Stoeckelhuber Mechthild , Matthias Christoph , Andratschke Michaela , Stoeckelhuber Beate M. , Koehler Claudia , Herzmann Sabine , Sulz Astrid , Welsch Ulrich
Published: July 2006

The ceruminous glands in the skin of the human external auditory canal are modified apocrine glands, which, together with sebaceous glands, produce the cerumen, the ear wax. Cerumen plays an important role in the protection of the ear canal against physical damage and microbial invasion. We studied the morphology of the glandular cells by light and electronmicroscopy. Antimicrobial and cytoskeletal components of the ceruminous glands were investigated by immunohistochemical methods. Numerous antimicrobial proteins and peptides are present in the ceruminous glandular cells: β‐defensin‐1, β‐defensin‐2, cathelicidin, lysozyme, lactoferrin, MUC1, secretory component of IgA. These data indicate a crucial role in the innate host defense against diverse pathogens. The apocrine secretion mechanism is a special mode of secretion by which the apical part of the cell cytoplasm surrounded by a membrane is pinched off. We could show that the presence of actin filaments, CK 19 and CK 7, seems to play a role in the pinching‐off mechanism. Finally, we showed the secretion of lipid vesicles from the ceruminous gland. We could extend the number of detected antimicrobial peptides and proteins in human ceruminous glandular cells that protect the surface of the external auditory meatus. In addition, we detected proteins involved in the apocrine secretion mode of the ceruminous gland. Anat Rec Part A, 288A:877–884, 2006. © 2006 Wiley‐Liss, Inc.
Conus arteriosus of the teleost heart: Dismissed, but not missed
Authors: Icardo José M.
Published: July 2006

The heart outflow tract (OFT) of primitive fish is formed by two portions: a proximal conus arteriosus and a distal bulbus arteriosus. The OFT of modern teleosts is considered to be formed by a single component, the bulbus, the conus having been lost through evolution. This article challenges the concept of the disappearance of the conus arteriosus in the teleost heart. A total of 28 teleost species belonging to 19 families and 10 orders were analyzed. The hearts were divided into two large groups: those having entirely trabeculated ventricles, and those possessing a compacta. In the hearts having entirely trabeculated ventricles, the conus arteriosus appears as a distinct segment interposed between the ventricle and the bulbus arteriosus, being formed by compact vascularized myocardium. However, the conus of several species lacks vessels. In these cases, the conus presents large intercellular spaces bounded by collagen. In the hearts possessing a ventricular compacta, the conus either appears as a muscular ring of variable length connecting the ventricle and the bulbus or forms a crown or ring of myocardium apposed to the ventricular base. In all the teleosts studied, the conus can be recognized as an anatomic entity different from the ventricle. Furthermore, the conus appears as a distinct heart segment in the developing fish. Therefore, the conus arteriosus has not been lost in evolution and constitutes a fundamental part of the teleost OFT. In all the species studied, the conus supports the OFT valves, which should properly be named conus valves. Anat Rec Part A, 288A:900–908, 2006. © 2006 Wiley‐Liss, Inc.
Looking for the lunate sulcus: A magnetic resonance imaging study in modern humans
Authors: Allen John S. , Bruss Joel , Damasio Hanna
Published: July 2006

The position of the lunate sulcus in fossil endocasts (when it can be determined) may serve as a potential marker of cognitive development in extinct hominid species. While the lunate sulcus is reliably present in the brains of great apes and forms the anterolateral boundary of the primary visual cortex, in humans its presentation is much more variable, and even if present, it does not correspond to a functional region. Grafton Elliot Smith, who named the lunate sulcus, claimed that it was homologous in humans and the great apes. Using high‐resolution MRI, we assessed the presence/absence and course of the lunate sulcus in 110 adult subjects. We found that in the vast majority of cases, lunate sulci identified on the surface of the occipital lobe are actually composed of smaller sulcal segments that converge into an apparently continuous composite lunate sulcus. We found only 3 examples in 220 hemispheres (1.4%) of continuous lunate sulci that resembled ape lunates in form (albeit in a more posterior position). Composite lunate sulci were found in 32.7% of left hemispheres and 26.4% of right hemispheres. These results, combined with those from histological and functional imaging studies, indicate that human and ape lunate sulci are not homologous structures. We suggest that the extent of functional reorganization of the occipital region during hominid evolution has been underestimated, and that changes in this region were not just passively shaped by expansion of parietal association cortex. Anat Rec Part A, 288A:867–876, 2006. © 2006 Wiley‐Liss, Inc.