Relative contributions of innate and acquired host responses to bacterial control and arthritis development in Lyme disease

TLR2(-/-)/scid double-mutant mice were infected with B. burgdorferi to assess the relative importance of acquired and innate host defenses. Although spirochete levels at 4 weeks were lower in TLR2(-/-) mice than in TLR2(-/-)/scid mice, the increased arthritis severity of TLR2 (Toll-like receptor 2)-deficient mice was reduced by the presence of the scid mutation.     

The haemotoxicity of mitomycin in a repeat dose study in the female CD-1 mouse

Mitomycin (MMC), like many antineoplastic drugs, induces a predictable, dose-related, bone marrow depression in man and laboratory animals; this change is generally reversible. However, there is evidence that MMC may also cause a late-stage or residual bone marrow injury. The present study in female CD-1 mice investigated the haematological and bone marrow changes induced by MMC in a repeat dose study lasting 50 days. Control and MMC-treated mice were dosed intraperitoneally on eight occasions over 18 days with vehicle, or MMC at 2.5 mg/kg, autopsied (n = 6-12) at 1, 7, 14, 28, 42 and 50 days after the final dose and haematological changes investigated. Femoral nucleated bone marrow cell counts and levels of apoptosis were also evaluated and clonogenic assays carried out; serum levels of FLT3 ligand (FL) were assessed. At day 1 post-dosing, MMC induced significant reductions in RBC, Hb and haematocrit (HCT) values, and there were decreases in reticulocyte, platelet, and femoral nucleated cell counts (FNCC); neutrophil, lymphocyte and monocyte values were also significantly reduced. On days 7 and 14 post-dosing, all haematological parameters showed evidence of a return towards normal values, but at these times, and at day 28, values for RBC and FNCC remained significantly reduced in comparison with controls. At days 42 and 50 post-dosing, many haematological parameters in MMC-treated mice had returned to control levels; however, there remained evidence of late-stage effects on RBC, Hb and HCT values, and FNCC also continued to be significantly decreased. Results for granulocyte-macrophage colony-forming units and erythroid colonies showed a profound decrease immediately post-dosing, but a return to normal values was evident at day 50. Serum FL concentrations demonstrated very significant increases in the immediate post-dosing period, but a return to normal was seen at day 50 post-dosing; a relatively similar pattern was seen in the number of apoptotic femoral marrow nucleated cells. The histopathological examination of kidney tissues from MMC animals at day 42 and 50 post-dosing showed evidence of hydronephrosis with cortical glomerular/tubular atrophy and degeneration. It is therefore concluded that MMC administered on eight occasions over 18 days to female CD-1 mice at 2.5 mg/kg induced profound changes in haematological and bone marrow parameters in the immediate post-dosing period with a return to normal levels at day 50 post-dosing; however, there was evidence of mild but significant late-stage/residual effects on RBC and FNCC, and on cells of the erythroid lineage in the bone marrow.     

Microstructural disassembly of calcium phosphates

Microstructural factors may play a role in the osseointegration of calcium phosphates. In this paper, direct microstructural interactions between crystalline calcium phosphates and the biological milieu are reported. Degradation via exposure to osteoblast culture closely resembles in vivo interactions with subcutaneous tissues in a bovine model at early time periods. That these interactions were common to both experiments constitutes one of the few known examples of in vitro-in vivo correspondence. Interestingly, the degradation of phase pure hydroxyapatite (HA) in vitro was more rapid than that of biphasic HA in vivo. In both cases, grain extraction/pullout was frequently observed. This suggests a connection to smaller-scale observations of epitaxial CHA nucleation and growth on pre-existing HA grains. A microstructure in which the grain boundary is dissolving/corroding can apparently be disassembled by forces transmitted through biological structures. These observations are distinct from those of simple non-biological solutions and prove that biological environments can interact with the material beneath the ceramic-cell/ceramic-tissue interface. Many often ignored microstructural factors-grain size, shape, grain boundary strength and the presence of impurity phases-may in fact control degradation. We also suggest that even relatively modest initial grain sizes will, in combination with the mild/absent foreign body response to calcium phosphates, result in lengthy in vivo particle resistence.     

Semantic dementia with category specificity:acomparative case-series study

Patients with semantic dementia, the temporal variant of frontotemporal dementia, are relevant to both the neuroanatomical and neuropsychological debates in the category-specific literature. These patients present with a selective and progressive semantic deficit consequent on circumscribed atrophy of the inferolateral polar temporal lobes bilaterally, including the inferotemporal gyrus. In this study, a patient KH with a significant advantage for artefacts over living things was compared to five other semantic dementia patients with commensurate levels of semantic impairment. KH demonstrated a consistent category difference in favour of artefacts across all the expressive and receptive semantic tests. This difference was reliable even when familiarity, frequency, and other potential confounding factors were controlled. While KH demonstrated an association between poor knowledge of sensory attributes and a consistently greater impairment on living things than artefacts, the other patients did not. As observed in a number of previous studies, all five of the patients, contrasted to KH, exhibited an advantage for functional/associative over sensory attributes but without demonstrating the category-specific deficit that the sensory-functional theory (and the locus of their atrophy) might predict. The results of this and other studies are discussed in relation to four accounts of category specificity: the sensory-functional theory, domain-specific knowledge systems, intercorrelated features, and individual differences.     

Intestinal Spirochetosis and Acquired Immunodeficiency Syndrome: Ultrastructural Studies of Two Cases

Two cases of intestinal spirochetosis (IS) with acquired immunodeficiency syndrome are reported. In case 1, a 48-year-old homosexual black man presented with a 1-month history of alternating watery diarrhea and constipation, which dissipated following the removal of two colonic hyperplastic polyps containing IS. In case 2, a 26-year-old homosexual black man presented with a 3-month history of persistent bloody diarrhea and was found to have chronic shigellosis and IS. Pathologic findings of IS were similar in both cases. Basophilic fringes typical of IS covered the surfacing colonic epithelium and consisted of dense growths of spirochetes adherent to and oriented perpendicular to the plasma membranes of the surfacing epithelium. The spirochetes measured 3 to 5 μm in length and 0.2 (im in width, contained four to eight axial fibrils, and closely resembled Brachyspira aalborgi ultrastructurally. These cases are notable because the histopathologic changes of IS were more extensive than generally described. There was involvement of both the right colon and rectum by IS in case 2, and in both cases there was extension of the IS down into the crypts of Lieberkiihn, spirochetal invasion of the colonic mucosa, and a conspicuous inflammatory response by macrophages in the underlying lamina propria.     

Urofacial (Ochoa) syndrome

Between 1965 and 1986 we saw 36 children with enuresis and urinary tract infection in association with “inversion” of facial expression when laughing. Urologic work-up of these patients disclosed characteristic findings of mild neuropathic bladder in all cases, with severe urinary tract damage in most of them. The clear association of distortion in facial expression and neuropathic bladder with resultant damage to the genitourinary tract should prompt urological evaluation of individuals with “inversion” of facial expression. About two thirds of the patients also had moderate to severe constipation. We suggest the term urofacial syndrome for this disorder. The occurrence of the disorder in multiple sibs, normal parents, increased parental consanguinity, and equal sex ratio indicate autosomal recessive inheritance.     

Retinal dehydrogenase-2 is inhibited by compounds that induce congenital diaphragmatic hernias in rodents

Currently, the etiology of the serious developmental anomaly congenital diaphragmatic hernia (CDH) is unknown. We have used an animal model of CDH to address this issue. We characterized four separate teratogens that produced diaphragmatic defects in embryonic rats that are similar to those in infants with CDH. We then tested the hypothesis that all these agents share the common mechanism of perturbing the retinoid-signaling pathway. Specifically, inhibition of retinal dehydrogenase-2 (RALDH2), a key enzyme necessary for the production of retinoic acid and that is expressed in the developing diaphragm, was assayed by measuring retinoic acid production in cytosolic extracts from an oligodendrocyte cell line. The following compounds all induce posterolateral defects in the rat diaphragm; nitrofen, 4-biphenyl carboxylic acid, bisdiamine, and SB-210661. Importantly, we demonstrate that they all share the common mechanism of inhibiting RALDH2. These data provide an important component of mounting evidence suggesting that the retinoid system warrants consideration in future studies of the etiology of CDH.     

Applications of a rat multiple tissue gene expression data set

With the sequencing and assembly of the rat genome comes the difficult task of assigning functions to genes. Tissue localization of gene expression gives some information about the potential role of a gene in physiology. Various examples of the utility of multiple tissue gene expression data sets are illustrated here. First, we highlight their use in finding genes that might play an important role in a particular tissue on the basis of exclusive expression in that tissue or coexpression with a gene or genes with known function. Second, we show how this data might be used to explain known phenotypic differences between strains. Third, we show how expression patterns of genes in a genomic interval might identify candidate genes in quantitative trait loci (QTL) mapping studies. Lastly, we show how multiple tissue and species data can help researchers prioritize follow up studies to microarray experiments. All of these applications of multiple tissue gene expression data sets will play a role in functionally annotating the rat genome.