Electromyography of oral-facial musculature in craniocarpaltarsal dysplasia (Freeman-Sheldon syndrome)

Electromyography and biopsy of the oral-facial musculature of a patient with craniocarpaltarsal dysplasia (Freeman-Sheldon syndrome) supports the thesis that facial muscle hypoplasia is a significant component of this evolving syndrome complex.     

Deconvoluting lung evolution using functional/comparative genomics

Parathyroid Hormone-related Protein (PTHrP) is a highly evolutionarily conserved, stretch-regulated gene that is necessary for the embryonic transition from branching morphogenesis to alveolization of the lung. It is expressed throughout vertebrate phylogeny, beginning with its expression in the fish swim bladder as an adaptation to gravity; microgravity downregulates the expression of PTHrP by alveolar type II cells, and by bones from rats exposed to 0 x g, suggesting that PTHrP signaling has been exploited for adaptation to 1 x g. PTHrP/PTHrP receptor signaling is upregulated by stretching alveolar type II cells and intersitial lung fibroblasts, whereas overdistension downregulates PTHrP and PTHrP receptor mRNA, further suggesting an evolutionary adaptation. Both surfactant homeostasis and alveolar capillary perfusion are under PTHrP control, indicating that alveolization and ventilation/perfusion matching may have evolved under the influence of PTHrP signaling. Phylogenetic analysis of lung evolution reflects the concomitant increases in alveolar surface area and surfactant production by "amplifying" the PTHrP pathway signal. This mechanism is discussed as a function of increased evolutionary respiratory demand to keep up with the increased metabolic demand for oxygen, and the role of the PTHrP signaling mechanism in leveraging this process.     

Detection of clonal immunoglobulin gene rearrangements in the peripheral blood progenitor cells of patients with multiple myeloma: the potential role of purging with CD34 positive selection

Aims—To determine the extent of clonal cell contamination of peripheral blood progenitor cell (PBPC) collections in patients with multiple myeloma (MM) and to assess the purging efficacy of CD34 positive selection.     

No evidence that common allelic variation in the Amyloid Precursor Protein (APP) gene confers susceptibility to Alzheimer's disease

In order to test the hypothesis that allelic variation withinthe Amyloid Precursor Protein (APP) gene influences susceptibilityto common forms of Alzheimer's disease (AD) we screened theentire coding, promoter and 3' untranslated sequences of theAPP gene for DNA variations in 30 unrelated patIents and eightcontrols with probable AD by a combination of RT-PCR, PCR andchemical cleavage mismatch analysis. Although we were unableto detect commonly occurring allelic variants, we were ableto detect a novel mutation within the APP gene in one individualwith late-onset AD. This mutation resulted in the substitutionof a tryptophan residue for an arginine residue at codon 328wIthin exon 7 which encodes the so-called protease Inhibitordomain of the 751 residue APP Isoform. However, the pathologicalsignificance of this mutation is uncertain as neither this,nor any other mutation occurring within exon 7 of the APP genewas found in any of a further 102 AD patients and 86 age-matchedcontrols. In conclusion, it is unlikely that susceptibilityto AD results from commonly occurring allelic variants of theAPP gene and it is even less probable that mutations withinexon 7 of the APP gene are important risk factors for late-onsetAD.     

Blood and Marrow Transplant Clinical Trials Network State of the Science Symposium 2007.

Outcomes of hematopoietic cell transplantation are steadily improving. New techniques have reduced transplant toxicities, and there are new sources of hematopoietic stem cells from unrelated donors. In June 2007 the Blood and Marrow Transplant Clinical Trials Network convened a State of the Science Symposium of more than 200 participants in Ann Arbor to identify the most compelling clinical research opportunities in the field. This report summarizes the symposium's discussions and identifies eleven high priority clinical trials that the network plans to pursue over the course of the next several years.     

B cell early response gene expression coupled to B cell receptor,CD40 and interleukin-4 receptor co-stimulation: evidence for a role of the egr-2/krox20 transcription factor in B cell proliferation

B lymphocytes are activated following antigen stimulation of the B cell receptor but require co-stimulation with accessory molecules provided by interleukin (IL)-4/CD40 ligand for cell cycle progression and proliferation. By analyzing a panel of 11 early response genes induced by cross-linking of surface immunoglobulin, we show that CD40 signaling alone induces only 2 genes, c-myc together with an anonymous gene, 3L3, and that these are distinct from the set of genes induced in response to IL-4. Co-stimulation with the proliferative combination of anti-μ, IL-4 + CD40 signaling led to a fourfold enhancement of egr-2/krox20 expression over that seen with anti-μ alone. Egr-2 expression/activity was selectively inhibited by the immunosuppressive drug cyclosporin A, and antisense oligonucleotide blockade of Egr-2 activity elicited a dose-dependent inhibition of B cell proliferation. Taken together, these observations show that the early gene regulatory programs coupled to different surface receptors on B cells are largely distinct from each other, but that certain genes, exemplified by egr-2, may represent a point of convergence in the integration of different signaling pathways into the B cell proliferative response.     

Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the {alpha}1 subunit of the inhibitory glycine receptor

Startle disease, or hyperekplexia, is characterized by an exaggeratedstartle reflex and neonatal hypertonla. An autosomal dominantform of the disorder Is associated with mutations In the samecodon of the ¹ subunit of the inhibitory glycine receptor (GLRA1) resulting in the substitution of an uncharged amlno acidfor Arg271 in the mature protein. However, recessive transmissionIs seen in the mouse mutant spasmodic which resembles startledisease phenotypcially and is also associated with mutationsIn Glra 1. We have confirmed the finding of Arg271 mutationsIn individuals with startle disease in a UK family showing autosomaldominant transmission. In addition we describe an apparentlysporadic case, the offspring of a consanguineous mating, whoIs homozygous for a novel mutation (T1112A) in GLRA 1, whichresults In the substitution of asparagine for isoleucine atposition 244 of the mature protein. This suggests that humanstartle disease can display recessive as well as dominant inheritanceresulting from different mutations in GLRA 1.     

Study of the HLA gene and antigen frequency from a Saudi Arabian hospital

The HLA-A, -B, -C and DR loci antigen frequencies were determined, respectively, on 1145, 558 and 352 healthy nonrelated Saudi family members. B21, CW4, CW7, and Dr7 showed the highest gene frequencies, of 14.6%, 28.3%, 7.4% and 19.5%, when compared to other populations. Haplotypes A2-B5, A32-B51, A26-B8, A2-B21, A28-B35, Aw19-B21 and B21-CW4 showed the highest frequencies when compared to other populations. Gene frequencies of 14.6% and 20.2% for B21 and Aw19 antigens, respectively, are highest among Middle East populations. Gene frequencies for A1 (10.5%), A2 (24.9%), A3 (8.9%), A9 (16.7%) and A28 (7.9%) are similar to the 10.1%, 24.9%, 8.3%, 16.8% and 7.7%, respectively, reported for the Turkish population. Also, gene frequencies for B5 (18.5%), B21 (14.6%) and B35 (10.2%) are very close to 17.1%, 14.0% and 10.2%, respectively, reported in the Yemenite population. The above results suggest some influence of other populations on the 'pure' Arab population.