A prospective, randomized, assessor-blind, multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus Metrodin) in in-vitro fertilization

Urinary follicle stimulating hormone (FSH) is being used forthe treatment of human infertility. Recently, FSH manufacturedby means of recombinant DNA technology with a much higher purity(>99%) has become available. A prospective, randomized, assessor-blind,multicentre (n = 18) study was conducted in infertile womenundergoing in-vitro fertilization comparing recombinant FSH(Org 32489, Puregon®) and urinary FSH (Metrodin®). Eligiblesubjects were randomized (recombinant versus urinary FSH = 3:2)and pretreated with buserelin for pituitary suppression. FSHwas given until three or more follicles with a diameter of atleast 17 mm were seen. After oocyte retrieval, fertilizationroutines were applied according to local procedures. No morethan three embryos were replaced. In all, 585 subjects receivedrecombinant FSH and 396 urinary FSH. Significantly more oocyteswere retrieved after recombinant FSH treatment (mean adjustedfor centre 10.84 versus 8.95, P < 0.0001). Ongoing pregnancyrates per attempt and transfer in the recombinant FSH groupwere 22.17 and 25.97% respectively, and in the urinary FSH group,18.22 and 22.02% respectively (not significant). Ongoing pregnancyrates including pregnancies resulting from frozen-thawed embryocycles were 25.7% for recombinant and 20.4% for urinary FSH(P = 0.05). Compared to urinary FSH, the total dose of FSH wassignificantly lower with recombinant FSH (2138 versus 2385 IU,P < 0.0001) in a significantly shorter treatment period (10.7versus 11.3 days, P < 0.0001). No clinically relevant differencesbetween recombinant and urinary FSH were seen with respect tosafety variables. It is concluded that recombinant FSH (Puregon)is more effective than urinary FSH in inducing multifolliculardevelopment and achieving an ongoing pregnancy.     

Association of haplotypes in the beta-chemokine locus with multiple sclerosis

Linkage studies in multiple sclerosis (MS) identified several susceptibility loci. One of these regions includes chromosome 17q11 where a meta-analysis of data from three genome scans suggested linkage. This region encodes a cluster of genes for beta-chemokines or CC chemokine ligands (CCLs), which may be involved in the development of MS lesions. Here we aimed to test if CCL alleles and haplotypes are associated with MS. Using methods of linkage and association, we observed deviations from the expected 50% transmission of haplotypes from unaffected parents to their affected children at CCL2, CCL11-CCL8-CCL13 and CCL3 within the investigated 1.85 MB chromosomal segment. Analyses of the linkage disequilibrium map support that variants with possible relevance to MS can be located within these subregions. Identification of MS associated CCL variants may have direct clinical significance, as it can lead to the design of small competitive antagonists of these molecules with beneficial effects in the treatment of patients with early and active disease.     

Early steps of a thymic tumor in SV40 transgenic mice: hyperplasia of medullary epithelial cells and increased mature thymocyte numbers disturb thymic export

Bone marrow progenitors migrate to the thymus, where they proliferate and differentiate into immunologically competent T cells. In this report we show that mice transgenic for SV40 T and t antigens under the control of the L-pyruvate kinase promoter develop, in a first step, thymic hyperplasia of both thymocytes and epithelial cells. Morphological studies (histology, immunohistolabeling and electron microscopy) revealed modifications of the thymic microenvironment and gradual expansion of medullary epithelial cells in 1 month-old mice, taking over the cortical region. Then, a thymic carcinoma develops. Two-color labeling of frozen sections identified the transgene in medullary epithelial cells. Flow cytometry analysis demonstrated a marked increase in mature CD4+ and CD8+ thymocytes in adult mice (39 +/- 10 x 10(6) in transgenic mice and 12 +/- 5 x 10(6) in age-matched controls). Furthermore, thymocyte export was disturbed.     

IgG anti-tetanus toxoid antibody synthesis by human bone marrow. I. Two distinct populations of marrow B cells and functional differences between marrow and peripheral blood B cells

This investigation uses a system for inducing and detecting anti-tetanus toxoid antibody (anti-TT) synthesis to study specific antibody (Ab) synthesis by bone marrow mononuclear cells (MC). We measured the amounts of anti-TT secreted and the number of B cells secreting antibody (Ab). The ELISA plaque detects single B cells secreting specific Ab. The results show that (1) spontaneous anti-TT secretion by MC is higher than spontaneous anti-TT secretion by peripheral blood lymphocytes (PBL) using an ELISA plaque (P<0.01); (2) spontaneous anti-TT production by MC correlated with the serum anti-TT titers as measured by an ELISA (r=0.75,P=0.005); (3) two types of marrow B cells were identified—one that spontaneously secretes anti-TT and another that produces anti-TT after TT-stimulation; (4) the frequency of anti-TT-secreting B cells is higher in MC than in PBL; (5) the amount of Ab secreted per marrow B cell is not different from that secreted by a peripheral B cell; and (6) marrow B cells could be induced to produce anti-TTin vitro up to 10 months without added cytokines. These results show that bone marrow is a major repository for differentiated B cells that spontaneously produce Abs to maintain circulating Abs titers and for memory B cells that can be induced to produce specific Ab.     

Clinical Features of Fatal Familial Insomnia: Phenotypic Variability in Relation to a Polymorphism at Codon 129 of the Prion Protein Gene

Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake-sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio-dorsal and anterior-ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mai seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein-gene.     

Neurectodermal differentiation of extraskeletal myxoid chondrosarcoma: a classical feature?

Extraskeletal myxoid chondrosarcoma (EMC) is a phenotypically and genotypically distinct entity with a protracted course. A documented case of an extraskeletal myxoid chondrosarcoma characterized by a t(9; 17) (q22; q11) translocation with a neuroendocrine and neural differentiation is reported.     

Analysis of the genomic sequence of a human metapneumovirus

We recently described the isolation of a novel paramyxovirus from children with respiratory tract disease in The Netherlands. Based on biological properties and limited sequence information the virus was provisionally classified as the first nonavian member of the Metapneumovirus genus and named human metapneumovirus (hMPV). This report describes the analysis of the sequences of all hMPV open reading frames (ORFs) and intergenic sequences as well as partial sequences of the genomic termini. The overall percentage of amino acid sequence identity between APV and hMPV N, P, M, F, M2-1, M2-2, and L ORFs was 56 to 88%. Some nucleotide sequence identity was also found between the noncoding regions of the APV and hMPV genomes. Although no discernible amino acid sequence identity was found between two of the ORFs of hMPV and ORFs of other paramyxoviruses, the amino acid content, hydrophilicity profiles, and location of these ORFs in the viral genome suggest that they represent SH and G proteins. The high percentage of sequence identity between APV and hMPV, their similar genomic organization (3'-N-P-M-F-M2-SH-G-L-5'), and phylogenetic analyses provide evidence for the proposed classification of hMPV as the first mammalian metapneumovirus.     

On the various manifestations of spontaneous autoimmune diabetes in rodent models

Autoimmune (type 1) diabetes mellitus in mouse, rat, and humans shares several features, including T lymphocyte infiltration into pancreatic islets and a dependence on permissive class II major histocompatibility complex (MHC) alleles. We report here on an experimental model involving mice that express influenza hemagglutinin (HA) under the control of the insulin promoter and, at the same time, a transgenic class II MHC-restricted T cell receptor (TcR) specific for an HA peptide. These mice spontaneously develop islet infiltrates resembling those found in NOD mice and most animals become diabetic within 8 weeks of age. Because of the availability of a clonotypic TcR antibody, we can be confident that the Ins-HA transgene does not induce any measurable alterations in the vast majority of T cells with the transgenic TcR in primary and secondary lymphoid organs. Continuous export of large numbers of HA-specific lymphocytes from the thymus was not required for the manifestation of the disease since mice thymectomized at 3 days after birth still developed the disease albeit with smaller infiltrates.     

Acute fibrinous and organizing pneumonia: a histological pattern of lung injury and possible variant of diffuse alveolar damage

CONTEXT: The histologic patterns of diffuse alveolar damage (DAD), bronchiolitis obliterans with organizing pneumonia (BOOP), and eosinophilic pneumonia (EP) are well-recognized histologic patterns of lung injury associated with an acute or subacute clinical presentation. We have recognized acute fibrinous and organizing pneumonia (AFOP) as a histologic pattern, which also occurs in this clinical setting but does not meet the classic histologic criteria for DAD, BOOP, or EP and may represent an underreported variant. OBJECTIVE: To investigate the clinical significance of the AFOP histologic pattern and to explore its possible relationship to other disorders, including DAD and BOOP. DESIGN: Open lung biopsy specimens and autopsy specimens were selected from the consultation files of the Armed Forces Institute of Pathology, which showed a dominant histologic pattern of intra-alveolar fibrin and organizing pneumonia. Varying amounts of organizing pneumonia, type 2 pneumocyte hyperplasia, edema, acute and chronic inflammation, and interstitial widening were seen. Cases with histologic patterns of classic DAD, BOOP, abscess formation, or eosinophilic pneumonia were excluded. To determine the clinical behavior of patients with this histologic finding, clinical and radiographic information and follow-up information were obtained. Statistical analysis was performed using Kaplan-Meier and chi(2) analysis. RESULTS: Seventeen patients (10 men, 7 women) with a mean age of 62 years (range, 33-78 years) had acute-onset symptoms of dyspnea (11), fever (6), cough (3), and hemoptysis (2). Associations believed to be clinically related to the lung disease included definitive or probable collagen vascular disease (3), amiodarone (1), sputum culture positive for Haemophilus influenza (1), lung culture positive for Acinetobacter sp. (1), lymphoma (1), hairspray (1), construction work (1), coal mining (1), and zoological work (1). Six patients had no identifiable origin or association. Follow-up revealed 2 clinical patterns of disease progression: a fulminate illness with rapid progression to death (n = 9; mean survival, 0.1 year) and a more subacute illness, with recovery (n = 8). Histologic analysis and initial symptoms did not correlate with eventual outcome, but 5 of the 5 patients who required mechanical ventilation died (P =.007). CONCLUSIONS: Acute fibrinous and organizing pneumonia is a histologic pattern associated with a clinical picture of acute lung injury that differs from the classic histologic patterns of DAD, BOOP, or EP. Similar to these patterns of acute lung injury, the AFOP pattern can occur in an idiopathic setting or with a spectrum of clinical associations. The overall mortality rate is similar to DAD and therefore may represent a histologic variant; however, AFOP appears to have 2 distinct patterns of disease progression and outcome. The need for mechanical ventilation was the only parameter that correlated with prognosis. None of the patients with a subacute clinical course required mechanical ventilation.