Bronchiolitis obliterans in a patient with localized scleroderma treated with D-penicillamine

D-penicillamine-associated bronchiolitis obliterans (BO) is a rare but well-known pulmonary complication in patients with rheumatoid arthritis or progressive systemic sclerosis. It has been assumed that in most, if not all cases, BO is a complication of the underlying disease rather than a side-effect of treatment. We report the case of a 46 year old man with scleroderma localized to his lower legs (morphea), who received a daily dose of 750 mg D-penicillamine. During the treatment of 1 yr duration, he developed progressive shortness of breath due to a worsening obstructive ventilatory defect suggesting BO, which was confirmed by surgical lung biopsy (constrictive BO). Bronchial obstruction progressed over the next 5 yrs and did not respond to corticosteroids. The patient finally underwent a successful single left lung transplantation. The histological features of constrictive BO were confirmed in the explanted lung. This observation suggests that D-penicillamine may induce bronchiolitis obliterans in the absence of a systemic connective tissue disease.     

Prenatal ultrasonographic and molecular diagnosis of Apert syndrome

Apert syndrome is a rare craniosynostosis syndrome with significant bilateral syndactyly of the hands and feet. Usually it is detected by ultrasonography during the third trimester unless there is a family history. We present an interesting sporadic case with features consistent with Apert syndrome detected as early as the first trimester. A first-trimester ultrasound evaluation prior to chorionic villus sampling (CVS) for maternal age 41 was within normal limits except for the suggestion of a 'mitten-like' hand and proximally placed thumb. Mid-trimester ultrasound was not diagnostic; however, following the development of polyhydramnios in the third trimester, the evaluation of the digits and facial features were strongly suggestive of Apert syndrome. Amniocentesis was performed and a molecular diagnosis of Apert syndrome was made and confirmed on cord blood.     

A high-fat diet influences insulin-stimulated posttransport muscle glucose metabolism in rats

Because of a failure to detect significant quantities of intracellular glucose, it has been generally accepted that transport rather than phosphorylation is the rate-limiting process of muscle glucose metabolism under most (but not all) physiological conditions. Here, we have measured tissue free levels of the glucose analog 2-deoxy-D-glucose (2DG) in red quadriceps muscle of rats fed a high-fat diet (59% of energy from fat) for 3 weeks, to identify the barrier to insulin-stimulated glucose uptake previously seen in such animals. Measurements were performed on pentobarbital-anesthetized rats following exogenous infusion of radiolabeled 2DG. A glucose clamp was used to maintain plasma insulin at high physiological levels (approximately 120 mU/L). Three other treatment groups representing normal insulin action (chow-fed), extreme glucose uptake (maximal insulin stimulation + hyperglycemia), and insulin resistance with elevated free intracellular glucose (epinephrine infusion) were also studied for comparison. In chow-fed animals, no muscle free 2DG was detected, confirming transport as the rate-limiting process. In fat-fed animals, a significant elevation in muscle free 2DG was observed (P < .01 v chow-fed controls). The elevation was similar in magnitude to that in epinephrine-infused rats, and implied a limitation of insulin action at a posttransport step. This result was confirmed with a more complex modeling analysis. We conclude that posttransport steps influence insulin-stimulated in vivo muscle glucose metabolism in long-term high-fat-fed rats.     

Correlation of radiologic and pathologic-anatomical findings in dust-induced pneumoconiosis in former coal miners

The ILO classification of small and large opacities is the basis for the compensation of patients with pneumoconiosis. In order to validate the radiological findings, we compared the ILO classification with the gradings of pneumoconiosis in the post mortem investigation (n = 126). An ILO classification of 1/0 used as the threshold value for accepting the diagnosis of a pneumoconiosis was 100% sensitive with a specificity of 2%. With a value of 2/3 the sensitivity decreased to 60% and specificity increased to 74%. The grading of large opacities in the radiograph correlated well with the post mortem findings (rs = 0.71; p < 0.001). For accepting the diagnosis pneumoconiosis from the radiograph alone a threshold value of 1/0 is not specific. The ROC-plot revealed that specificity reached acceptable levels with an ILO classification of at least 2/3.     

Aetiology of skeletal muscle ''cramps'' during exercise: a novel hypothesis

Secretions of the tick salivary glands are essential to the successful completion of the prolonged feeding of these ectoparasites as well as the conduit by which most tick-borne pathogens are transmitted to the host. In ixodid ticks the salivary glands are the organs of osmoregulation, and excess water from the bloodmeal is returned via saliva into the host. Host blood must continue to flow into the feeding lesion as well as remain fluid in the tick mouthparts and gut. The host's haemostatic mechanisms are thwarted by various anti-platelet aggregatory, anticoagulatory and anti-vasoconstrictory factors in tick saliva. Saliva components suppress the immune and inflammatory response of the host permitting the ticks to remain on the host for an extended period of time and, adventitiously, enhancing the transmission and establishment of tick-borne pathogens. Over the years much work has been done on the numerous enzyme and pharmacological activities found in the tick saliva. The present article reviews the most recent work on salivary gland secretions with special emphasis on how they favour pathogen transmission.     

A novel macrophage receptor enhances MHC II-peptide loading and surface expression of a hapten-protein conjugate

A receptor possessing specificity for fluorescein was previously identified on murine macrophage. The goal of the present study was to determine if this receptor influenced MHC II-peptide loading and surface expression of a hapten-protein conjugate within murine macrophage. Although inhibition of fluid-phase pinocytosis had no detectable effect, lower levels of intracellular MHC II-peptide complexes were observed upon inhibition of receptor-mediated endocytosis. Moreover, lower levels of surface expressed MHC II-fluoresceinated peptide complexes were also detected. Following subcellular fractionation experiments, it was revealed that the receptor altered the endocytic trafficking of the antigen within the cell. Namely, degraded antigen and MHC II-peptide complexes were not observed in dense transferrin receptor positive, cathepsin D positive, LAMP-1 positive organelles upon inhibition of the receptor. Previous studies also suggested that this receptor enhanced MHC II-peptide loading by concentrating high levels of antigen to endocytic organelles. The implications of these findings on subsequent development of the immune response were also discussed.     

Mixed-function oxidases of 25-hydroxycholecalciferol in isolated chick kidney glomeruli: evidence for nuclear localization

Pure chick kidney glomeruli and proximal tubular fragments have been isolated by graded sieving through nylon screens. Electron micrographs revealed that, in distinct contrast to proximal epithelial cells, the glomerular epithelial and endothelial cells are essentially devoid of mitochondria. Glomeruli as well as proximal tubular fragments contain the 1 alpha- and 24R-hydroxylases of 25-hydroxycholecalciferol. The level of 1 alpha-hydroxylase activity was the same in both segments of the nephron. However, the tubular fragments contained twice the 24R-hydroxylase activity found in glomeruli. Glomerular nuclei were purified by sucrose gradient sedimentation and used to confirm the association of the 1 alpha-hydroxylase with this kidney organelle. Almost all of the glomerular 1 alpha-hydroxylase activity was found in the nuclear fraction. Two metabolites, which are produced predominantly by the nuclei, are designated N-1 and N-2. Their structural identity remains unknown. The novel presence of the 1 alpha-hydroxylase in the glomerulus may be important in defining the etiology of bone diseases in patients with glomerulonephritis and similar disorders.     

Pth1/Vam3p is the syntaxin homolog at the vacuolar membrane of Saccharomyces cerevisiae required for the delivery of vacuolar hydrolases

We constructed hybrid proteins containing a plant alpha-galactosidase fused to various C-terminal moieties of the hypoxic Srp1p; this allowed us to identify a cell wall-bound form of Srp1p. We showed that the last 30 amino acids of Srp1p, but not the last 16, contain sufficient information to signal glycosyl-phosphatidylinositol anchor attachment and subsequent cell wall anchorage. The cell wall-bound form was shown to be linked by means of a beta1,6-glucose-containing side-chain. Pmt1p enzyme is known as a protein-O-mannosyltransferase that initiates the O-glycosidic chains on proteins. We found that a pmt1 deletion mutant was highly sensitive to zymolyase and that in this strain the alpha-galactosidase-Srp1 fusion proteins, an alpha-galactosidase-Sed1 hybrid protein and an alpha-galactosidase-alpha-agglutinin hybrid protein were absent from both the membrane and the cell wall fractions. However, the plasma membrane protein Gas1p still receives its glycosyl-phosphatidylinositol anchor in pmt1 cells, and in this mutant strain an alpha-galactosidase-Cwp2 fusion protein was found linked to the cell wall but devoid of beta1,6-glucan side-chain, indicating an alternative mechanism of cell wall anchorage.     

Bronchial manifestation of acute febrile neutrophilic dermatosis (Sweet''s syndrome)

Eighteen isolates of Blastomyces dermatitidis were evaluated for their in vitro susceptibilities to ketoconazole, itraconazole, and fluconazole. The MIC ranges were 0.1 to 0.4 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 2.5 to 4.0 microg/ml for fluconazole. The ranges for the minimal lethal concentrations were 0.2 to 0.8 microg/ml for ketoconazole, < or =0.018 to 0.07 microg/ml for itraconazole, and 10 to 40 microg/ml for fluconazole. Itraconazole was the most active agent against B. dermatitidis in vitro, while fluconazole was the least active. These results correlate with the clinical efficacies noted to date with doses of these agents used to treat blastomycosis.