bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spermatogenesis of mice lacking CK2α′: Failure of germ cell survival and characteristic modifications of the spermatid nucleus
Authors: Escalier Denise , Silvius Derek , Xu Xin 
Published: August 2003

AbstractCsnk2a2 encodes the CK2α′catalytic subunit of CK2 that is predominantly expressed in testis. Male mice in which Csnk2a2 has been disrupted were infertile and displayed oligozoospermia with an abnormal shape of the spermatid nucleus. In this study, Csnk2a2 null testes revealed extensive germ cell degenerative processes at all stages of spermatogenesis, including the first spermatogenesis wave. Nuclear envelope (NE) protrusions with loss of nuclear pores, swelling of the outer membrane, and disruption of the inner membrane were observed in cells ranging from spermatogonia to early spermatids. Most early round spermatids were depleted, and DNA‐specific fluorescent dyes showed a large chromatin‐free nuclear domain near the chromocenter. Spermatids that were not eliminated retained NE defects that could explain the acrosomal and nuclear abnormalities of Csnk2a2 null spermatozoa. Data suggest that CK2α′ deficiency could impair the phosphorylation of nuclear proteins of male germ cells leading to a particular cell‐death pathway characterized by NE protrusions and an unusual pattern of chromatin modifications in spermatids. Mol. Reprod. Dev. 66: 190–201, 2003. © 2003 Wiley‐Liss, Inc.
Association of C‐MYC amplification with progression from the in situ to the invasive stage in C‐MYC‐amplified breast carcinomas
Authors: Robanus‐Maandag Els C , Bosch Cathy AJ , Kristel Petra M , Hart Augustinus AM , Faneyte Ian F , Nederlof Petra M , Peterse Johannes L , van de Vijver Marc J 
Published: August 2003

AbstractHuman carcinoma in situ of the breast already demonstrates genomic changes found in invasive lesions. However, no specific genetic alterations have previously been identified that are associated with progression from the in situ to the invasive stage. By comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of an invasive breast carcinoma with a large associated in situ component, high‐level amplification of C‐MYC was found in the invasive component only. To determine the frequency of this correlation in a panel of 188 invasive breast carcinomas, 18 additional cases with C‐MYC amplification were identified. Nine of these cases had a detectable adjacent in situ component. FISH analysis demonstrated increased (>5) C‐MYC signals per nucleus in seven invasive components and increased (>4) C‐MYC/centromere 8 signal ratios in five of these. None of the associated in situ components demonstrated these increases. The minimal amplified region was defined at 8q24.13‐8qter. C‐MYC amplification was correlated with overexpression of C‐MYC and two of its target genes, TERT and FBL. Thus, C‐MYC amplification is the first identified genetic alteration that is associated with progression from the in situ to the invasive stage of breast carcinoma. Copyright © 2003 John Wiley & Sons, Ltd.
Adducin expression in cutaneous and oral lesions: α‐ and β‐adducin transcripts down‐regulate with keratinocyte differentiation in stratified epithelia
Authors: Bowen Sharn L , Bloor Balvinder K , Leigh Irene M , Waseem Ahmad 
Published: August 2003

AbstractAdducin is a heterodimer of α‐ with β‐ or γ‐subunits that regulates the assembly of the spectrin‐based membrane skeleton in erythrocytes. Although adducin has been identified in various non‐erythroid cells and tissues, it has been localized at intercellular junctions only in keratinocytes and epidermis. However, no data are available yet on the regulation of individual adducin genes in differentiating versus hyperproliferating keratinocytes. Due to the unavailability of mono‐specific antibodies for individual adducins, this study has used RT‐PCR and in situ hybridization to investigate the expression of α‐ and β‐adducins in cultured cells and in stratified epithelia including cutaneous and oral lesions. Using RT‐PCR, the α‐transcripts were consistently expressed in all cell lines tested, as well as in normal interfollicular epidermis, whereas the β‐transcripts were more variable and were strongly expressed in K562, A431, and primary keratinocytes. However, in normal skin, oral mucosa, and attached gingivae, the levels of α‐transcripts closely paralleled those for the β‐subunit. In most normal tissues, adducin expression was observed primarily in the proliferating compartments including the basal layer and lower suprabasal layers. Expression of both genes was also up‐regulated in skin diseases characterized by increased cell proliferation and keratinocyte activation, such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and psoriasis. It was observed that, in most cases, the expression of both α‐ and β‐adducin was accompanied by increased expression of the proliferation marker Ki‐67 and keratins K6 and K16. Differentiating keratinocytes in normal epithelia as well as in tumours appear to suppress the expression of adducin transcripts. The data suggest that the expression of adducin genes may be linked to cell proliferation and starts to down‐regulate at the onset of differentiation. Copyright © 2003 John Wiley & Sons, Ltd.
Monoclonal antibody 4C4‐mAb specifically recognizes keratan sulphate proteoglycan on human embryonal carcinoma cells
Authors: Fukuma Mariko , Abe Hitoshi , Okita Hajime , Yamada Taketo , Hata Jun‐ichi 
Published: August 2003

AbstractGerm cell tumours, the most common solid cancers in young males, display pluripotentiality for embryonal and somatic differentiation. Specific surface antigens are useful in the study of cellular differentiation and for clinical diagnosis. A mouse monoclonal antibody (4C4‐mAb) has been developed against a human embryonal carcinoma (EC) cell line (NCR‐G3) isolated from a combined form of testicular germ cell tumour. On immunohistological and immuno‐electron microscopic examination, the 4C4 antigen (4C4) was detected on the surface of NCR‐G3 and gold particles were exclusively detected on the microvilli of the cells. In both formalin‐fixed paraffin wax sections and touch‐smear specimens, 4C4 was detected specifically in EC, while the antigen was not expressed in other types of germ cell tumour or in the other solid tumours tested. Tunicamycin diminished the antigenicity of NCR‐G3 cells. In biochemical studies, 4C4 was found in a high molecular weight region ranging from 1 × 106 to 1 × 107 kD, which disappeared after periodate treatment. The density of 4C4 was 1.5 g/cm3 after equilibrium centrifugation. These results imply that 4C4 is a proteoglycan. Furthermore, endo‐ and exo‐glycosidase treatment revealed that 4C4 is a keratan sulphate proteoglycan that contains sialyl and fucosyl moieties. With EC‐specific and formalin‐resistant characteristics, 4C4 may be a specific marker for diagnosing EC among a variety of germ cell tumours. Copyright © 2003 John Wiley & Sons, Ltd.
Inter‐individual differences in anti‐proteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pretreatment renal damage
Authors: Kramer Andrea B , Laverman Gozewijn D , van Goor Harry , Navis Gerjan 
Published: August 2003

AbstractACE inhibition (ACEi) reduces proteinuria and provides reno‐protection, but not all subjects benefit from ACEi. Individual differences in the reduction in proteinuria at the onset of treatment and in residual proteinuria during therapy predict differences in renal outcome. The present study investigated whether individual differences in the anti‐proteinuric efficacy of ACEi are explained by differences in the severity of pretreatment renal structural damage and whether differences in the level of residual proteinuria during therapy are explained by the severity of renal structural damage at that time, in adriamycin nephrosis in the rat. Pretreatment renal structural damage was assessed in biopsies 6 weeks after exposure to adriamycin (2 mg/kg iv). Then ACEi (75 mg/l lisinopril,n= 23) or vehicle (n= 10) was administered; renal biopsies were repeated after stabilization of the anti‐proteinuric response (week 8). Early renal damage (interstitial α‐smooth muscle actin expression and macrophage accumulation) and established lesions [focal glomerulosclerosis (FGS) and interstitial fibrosis] were scored. During ACEi, proteinuria fell from 834 (487–851) mg/24 h pretreatment to 153 (66–265) mg/24 h at week 8 (p< 0.05); FGS stabilized from 27 (4–70) arbitrar units (AU) pretreatment to 26 (4–84) at week 12, whereas the vehicle did not affect proteinuria, resulting in progressive FGS: 18 (10–26) AU pretreatment versus 88 (46–130) at week 12 (p< 0.05). All parameters of pretreatment damage significantly predicted the anti‐proteinuric response. Residual proteinuria during ACEi correlated significantly with renal structural damage parameters at that time. Pretreatment renal damage also predicted renal outcome during extended treatment. Thus, in this experimental setting, in rats with the same renal disorder and the same duration of disease, individual differences in pretreatment renal damage, albeit relatively modest, explain individual differences in renal responsiveness to ACEi. This implies that the limits of the efficacy of ACEi are set by prevalent renal damage. Further studies into the mechanisms of individual resistance to the anti‐proteinuric action of ACEi are needed to develop additive intervention strategies. Copyright © 2003 John Wiley & Sons, Ltd.
Stromal cells of fibrodysplasia ossificans progressiva lesions express smooth muscle lineage markers and the osteogenic transcription factor Runx2/Cbfa‐1: clues to a vascular origin of heterotopic ossification?
Authors: Hegyi Laszlo , Gannon Francis H , Glaser David L , Shore Eileen M , Kaplan Frederick S , Shanahan Catherine M 
Published: August 2003

AbstractFibrodysplasia ossificans progressiva (FOP) is a rare heritable genetic disorder, which is characterized pathologically by sporadic episodes of explosive growth of mesenchymal cells in skeletal muscle followed by cellular differentiation to heterotopic bone through an endochondral process. This study examined the histological origin and differentiation state of stromal cells in early FOP lesions and investigated the association between the phenotype of these FOP cells and bone formation. Interestingly, FOP lesional stromal cells were found to display characteristics of the smooth muscle (SM) cell lineage and are therefore potentially of vascular origin. These cells co‐express multiple SM lineage markers along with multiple proteins associated with bone formation including the obligate osteogenic transcription factor Runx2/Cbfa‐1. It is hypothesized that the stromal cells of early FOP lesions may be locally recruited vascular cells or cells of the bone marrow stroma and that these cells maintain the potential (given the correct environmental stimuli) to differentiate along an endochondral ossification pathway. Copyright © 2003 John Wiley & Sons, Ltd.
Infrequent somatic Fas mutations but no evidence of Bcl10 mutations or t(11;18) in primary cutaneous MALT‐type lymphoma
Authors: Grønbæk Kirsten , Ralfkiaer Elisabeth , Kalla Jörg , Skovgaard Gunhild L , Guldberg Per 
Published: August 2003

AbstractGenetic alterations that allow tumour cells to evade apoptosis have recently been identified as key features of extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue type (MALT‐type lymphoma). The t(11;18), which produces the putative anti‐apoptotic fusion protein API2‐MALT1, has been identified in a large proportion of extracutaneous MALT‐type lymphomas and a smaller fraction of tumours harbour mutations that inactivate the pro‐apoptotic functions of Fas and Bcl10. The present study has examined the status of these genes in 19 primary cutaneous B‐cell lymphomas (PCBCLs), 12 of which were MALT‐type lymphomas according to the WHO classification. None of the 19 PCBCLs carried the t(11;18) and tumour‐specific Bcl10 alterations were not identified at the genomic level or at the mRNA level. Somatic Fas mutations causing truncation of the Fas receptor were identified in two MALT‐type lymphomas. Both patients with Fas mutant PCBCL exhibited benign conditions of dysregulated lymphoproliferation. One had autoimmune diabetes and rheumatoid arthritis and the other had a 25‐year history of recurrent cutaneous pseudo‐lymphomas. It is suggested that Fas mutation permits the survival and hence the accumulation of autoreactive B cells. This expansion of autoreactive B cells is analogous to the expansion of B cells chronically stimulated by exogenous antigens in the development of MALT‐type lymphoma. Copyright © 2003 John Wiley & Sons, Ltd.
Pathogenese der Rheumatoiden Arthritis: Die pathologische Basis
Authors: Burkhardt Harald , Möller Burkhard 
Published: August 2003

AbstractDie Integration verschiedener pathogenetischer Aspekte der RA ergibt das komplexe Bild einer Erkrankung, deren individuelle Ausprägung unter multiplen genetischen Einflüssen im zeitlichen Verlauf großen Variationen unterworfen ist (Abb. 5). Initial mag ein exogener Faktor, evtl. ein infektiöses Agens, einen Autoimmunprozess anstoßen, der in seiner T‐Zell‐Antwort in Richtung eines Th1‐Phänotyps polarisiert ist und sich primär gegen gelenkspezifische Antigene wendet. Die sekundäre Ausweitung der Immunantwort im Rahmen eines so genannten “Epitope spreadings” kann auch extraartikuläre Antigene erfassen und im Rahmen einer Immunkomplexvaskulitis zu systemischen Manifestationen führen. Die persistierende Freisetzung proinflammatorischer Zytokine im Gelenk fördert die Transformation der Synovialfibroblasten in einen aggressiven Phänotyp, der schließlich nur noch bedingt parakrinen Regulationsmechanismen unterliegt. Sich verstärkende Rückkopplungsmechanismen auf verschiedenen Ebenen bewirken die Stabilisierung des Prozesses in Richtung auf die gewebedestruierende Endstrecke des chronischen Entzündungsprozesses.
Rekombinante Wirkstoffe bei Rheumatoider Arthritis: Kineret®, Enbrel®, Remicade® und Co.
Authors: Zündorf Ilse , Dingermann Theodor 
Published: August 2003

AbstractFür die Therapie der Rheumatoiden Arthritis stehen bereits einige sehr potente rekombinante Wirkstoffe zur Verfügung, und das Potenzial an weiteren Wirkstoffoptionen ist bei weitem noch nicht ausgeschöpft. Die genauere Kenntnis der Pathogenese liefert dazu die Grundlagen, und mit den gentechnischen Methoden stehen die Techniken zur Umsetzung zur Verfügung. Allerdings bleiben die Probleme, dass diese Wirkstoffe parenteral zu applizierende und sehr kostenintensive Proteine sind — Probleme, auf die an anderer Stelle in diesem Heft eingegangen wird.
Galenische Formulierung rekombinanter Wirkstoffe: Problem Arzneistoffstabilität
Authors: Zimmer Andreas 
Published: August 2003

AbstractDie galenische Formulierung von rekombinanten Wirkstoffen zur Behandlung der RA beschränkt sich auf parenteral zu applizierende Darreichungsformen. Es werden kleinvolumige, s. c. zu applizierende Injektionslösungen bis hin zu Infusionslösungen monoklonaler Antikörper eingesetzt. Als Herausforderung gilt es nach wie vor, die Stabilität der Proteine über einen Zeitraum von 2 bis 3 Jahren in der Arzneiform zu gewährleisten. Heute gilt die Lyophilisation als Technik der Wahl, um diesen Anforderungen gerecht zu werden.
Stellenwert rekombinanter Wirkstoffe in der Therapie der RA: Beurteilung der Studien
Authors: Kaltwasser Joachim Peter 
Published: August 2003

AbstractSowohl die diagnostischen Möglichkeiten zur sicheren und vor allem frühen Erkennung der Rheumatoiden Arthritis als auch die Kriterien für den therapeutischen Effekt als Grundlage klinischer Arzneimittelprüfungen haben sich in den letzten Jahren erheblich verbessert. Basierend auf diesen besser systematisierten Kriterien sind Verbesserungen in der sinnvollen Auswahl konventioneller Antirheumatika und in der objektiven Bewertung neu entwickelter Arzneimittel erreicht worden. Völlig neue Dimensionen in der Arzneimitteltherapie der Rheumatoiden Arthritis haben die in jüngster Zeit eingeführten rekombinanten Wirkstoffe mit der spezifischen Zielrichtung einer Inhibition proinflammatorischer, bei der RA pathogenetisch relevanter Zytokine eingeführt. Bislang liegen ausgedehnte Erfahrungen aus großen klinischen Studien für die TNF‐α‐inhibierenden monoklonalen Antikörper Infliximab und Adalimumab, das TNF‐α‐Rezeptor‐Fusionsprotein Etanercept und den rekombinant hergestellten, natürlichen IL‐1‐Rezeptorantagonisten Anakinra vor.Alle vier Wirkstoffe weisen bisher nicht gekannte Effektivitätsdaten auf, die erstmals in relevantem Umfang anhaltende weitgehende Teilremissionen bei RA unter Einschluss des knochendestruierenden Prozesses ermöglichen. Die vorhandene Datenlage erlaubt eine sinnvolle Indikationsabgrenzung für diese neue, sehr vielversprechende Wirkstoffgruppe. Allerdings stehen hohe Arzneimittelpreise — unabhängig von den medizinischen Gesichtspunkten — häufig einer Anwendung noch im Wege.
Gestufte Verfahren zur Behandlung der RA: Wann welches Arzneimittel?
Authors: Bolten Wolfgang W. 
Published: August 2003

AbstractDie Rheumatoide Arthritis ist eine chronisch entzündliche Systemerkrankung, die mit Schmerzen, Funktionsstörungen, Verminderung der Lebensqualität und Lebenszeitverkürzung einhergeht. Die symptomatische Behandlung erfolgt mit nichtsteroidalen Antirheumatika (NSAR) oder ggf. Paracetamol. Das höhere gastrointestinale Risiko der NSAR kann durch die Kombination mit Protonenpumpenhemmern oder den Austausch des NSAR gegen COX‐2‐selektive Antirheumatika verringert werden. Corticosteroide werden bei entzündlichen Krankheitsschüben und niedrig dosiert bei geeigneten Patienten auch in der Langzeittherapie eingesetzt. Herkömmliche kostengünstige Basistherapeutika (Hydroxychloroquin, Goldsalze, Methotrexat, Leflunomid, Sulfasalazin) werden je nach Krankheitsaktivität, individueller Wirksamkeit und Verträglichkeit einzeln oder in Kombination zur Begrenzung des Krankheitsfortschritts eingesetzt. Wenn Methotrexat und andere Basistherapeutika keine ausreichende Wirkung haben oder unverträglich sind, dann müssen Biologika (TNF‐α‐Antagonisten, IL‐1‐Rezeptor‐Blocker) eingesetzt werden. In der Schwangerschaft reicht meist die symptomatische Behandlung mit NSAR oder Corticosteroiden aus.
Rheumatiker unter der Therapie mit rekombinanten Arzneimitteln: Fragen und Antworten
Authors: Karger Thomas , Missler‐Karger Barbara 
Published: August 2003

AbstractDie neuen Behandlungsoptionen auf molekularer Ebene („molekulare Chirurgie”︁) eröffnen neue, bisher nie erreichte therapeutische Möglichkeiten. In der Phylogenese haben aber Mechanismen, die wir unter einseitiger Betrachtungsweise als „pathophysiologisch”︁ betrachten, teleologisch eine Bedeutung, die wir nicht kennen. Hätte die Evolution sie sonst entwickelt? Wenn wir derartige — biologisch gesehen sinnvolle — Prozesse isoliert blockieren, sind neue, uns noch nicht bekannte Risiken zu erwarten.Die wissenschaftliche Fachgesellschaft hat dezidierte Empfehlungen erarbeitet, die klarstellen, wer Indikation und Therapie durchführt (internistische Rheumatologen), welche Qualitäts‐ und Sicherheitskontrollen erforderlich sind (DAS 28, ggf. auch HAQ oder FFbH, Tuberkulose‐Screening, Labor‐ und Röntgenverlaufskontrollen) und somit die Verantwortlichkeit klargestellt. Der Umgang mit rekombinanten Arzneimitteln in der täglichen Praxis erfordert den Spezialisten, der mit den Instrumenten und den Risiken vertraut ist.
Kleine RNA‐Moleküle — ganz groß
Authors: Gießen Hannelore 
Published: August 2003

AbstractLange Zeit hat man in der RNA nur einen Vermittler für die Umsetzung des genetischen Codes gesehen. Jetzt mehren sich die Hinweise, dass sie in der Zelle noch ganz andere Aufgaben erfüllt. In den letzten Jahren wurde entdeckt, dass kurze RNA‐Moleküle bei der Zellteilung für Ordnung auf den einzelnen Chromosomen sorgen. Verschiedene Gene kann die small RNA ein‐ und ausschalten und, wenn nötig, Teile des Erbmaterials sogar ganz löschen.
Wie kann man Resistenzen aufheben?
Authors: Holzgrabe Ulrike 
Published: August 2003

AbstractAntibiotika‐Resistenzen entstehen unter anderem dadurch, dass das Bakterium den Wirkstoff chemisch modifiziert. Prominentestes Beispiel sind die β‐Lactam‐Antibiotika, deren Lactamring mittels der von den Bakterien gebildeten Lactamasen hydrolysiert wird.
Symptomatic postural hypotension in diabetes: aetiology and management
Authors: Winkler AS , Bosman DR 
Published: August 2003

AbstractThis review explores the problem of symptomatic postural hypotension in diabetes, a condition that is fortunately rare but increasingly prevalent in an ageing population. The diverse aetiology and pathophysiology are discussed and relevant investigations and existing therapies are described. New areas of research, which may have therapeutic implications, such as recombinant erythropoietin and octreotide, are also explored. Copyright © 2003 John Wiley & Sons, Ltd.
Cultural aspects of diabetes mellitus in Sudan
Authors: Ahmed AM 
Published: August 2003

AbstractDiabetes is an increasingly important problem in Sudan, being responsible for 10% of hospital admissions and mortality. This review aims to study the impact of cultural factors on diabetic patients. The impact of the following factors are discussed: fatalism, religious practices, cultural misconceptions, family and gender issues and cultural dietary aspects. Sudan is a multicultural society, with African, Arab, Islamic and Christian roots. Examining the cultural aspects of a common disease such as diabetes is the first step in setting up culture‐sensitive management programmes, and ultimately improving diabetes care. Copyright © 2003 John Wiley & Sons, Ltd.
Effect of posture on respiratory function and drive in preterm infants prior to discharge
Authors: Leipälä J.A. , Bhat R. Y. , Rafferty G.F. , Hannam S. , Greenough A. 
Published: August 2003

AbstractOur objective was to determine the effect of posture on respiratory function and drive in prematurely born infants immediately prior to discharge. Twenty infants (6 oxygen‐dependent), median gestational age 29 weeks (range, 25–32), were studied at a median postconceptional age (PCA) of 36 weeks (range, 33–39). On 2 successive days, infants were studied both supine and prone; each posture was maintained for 3 hr. The order on each day in which postures were studied was randomized between infants. At the end of each 3‐hr period, tidal volume (Vt), inspiratory (Ti) and expiratory (Te) time, respiratory rate, and minute ventilation were measured. In addition, respiratory drive was assessed by measuring the pressure generated in the first 100 msec of an imposed airway occlusion (P0.1), and respiratory muscle strength was assessed by recording the maximum inspiratory pressure (Pimax) generated against an occlusion which was maintained for at least five breaths. Overall, tidal volume was higher (P < 0.05), but respiratory rate (P < 0.05), P0.1 (P < 0.05), and Pimax (P < 0.05) were lower in the prone compared to the supine position. There were no significant differences in Ti or Te between the two postures. In oxygen‐dependent infants only, minute volume was higher in the prone position (P < 0.05). In conclusion, posture‐related differences in respiratory function are present in prematurely born infants studied prior to neonatal unit discharge. Pediatr Pulmonol. 2003; 36:295–300. © 2003 Wiley‐Liss, Inc.