Lung hyaluronan and water content in preterm and term rabbit pups exposed to oxygen or air

Rabbit pups were delivered by cesarean section 1 or 2 d before term, or vaginally around term, and then reared in room air or exposed to intermittent or continuous hyperoxia (> 85%) for up to 9 d. Pups were killed at different ages, and lung hyaluronan (HA; microgram/g of dry lung weight) and lung water content, measured as wet/dry lung weight, were determined. Compared with the day of birth, the lung HA concentration did not change significantly on succeeding days in pups kept in air delivered 2 d (-2 d) or 1 d (-1 d) before term, whereas the water content decreased significantly. Continuous exposure to hyperoxia resulted in a significantly raised lung HA concentration 6 d postterm in both -2 d and -1 d pups, and intermittent exposure to hyperoxia resulted in a significantly raised HA concentration 6 d postterm in -1 d pups, compared with the groups exposed to room air. These increases were accompanied by significantly elevated wet/dry lung weight ratios. Microscopic examination revealed significantly increased HA staining scores in alveoli, arterioles, and bronchioli in both hyperoxia-exposed groups of -2 d pups 6 d postterm, and nonsignificantly higher scores in -1 d and vaginally delivered pups of comparable age, compared with the scores at birth. The results indicate that oxygen exposure neonatally may result in an increase in lung HA accompanied by an increase in lung water content. The increase in lung HA concentration in our study may be an effect of oxygen free radicals or of oxygen-induced stimulation of inflammatory mediators.     

Coronary artery bypass grafting in immune thrombocytopenic purpura

BACKGROUND: Reports of patients with idiopathic thrombocytopenic purpura undergoing cardiac operations are scarce and no recommendations exist regarding their management. We report 3 patients with idiopathic thrombocytopenic purpura and severe coronary artery disease who underwent uncomplicated coronary bypass grafting. METHODS: The case history of each patient with idiopathic thrombocytopenic purpura who underwent coronary artery bypass grafting and the literature were reviewed. RESULTS: All 3 patients underwent uncomplicated coronary artery bypass grafting after preoperative treatment with intravenous immunoglobulin and intraoperative platelet transfusions if needed. Prophylactic splenectomy was not performed. There was no increased incidence of bleeding complications. CONCLUSIONS: Coronary artery bypass grafting can be safely performed in patients with idiopathic thrombocytopenic purpura using conventional conduits after pretreating with immunoglobulin G and avoiding splenectomy.     

Microsatellites reveal heterosis in red deer

The fitness consequences of inbreeding and outbreeding are poorly understood in natural populations. We explore two microsatellite-based variables, individual heterozygosity (likely to correlate with recent inbreeding) and a new individual-specific internal distance measure, mean d2 (focusing on events deeper in the pedigree), in relation to two measures of fitness expressed early in life, birth weight and neonatal survival, in 670 red deer calves (Cervus elaphus) born on the Isle of Rum between 1982 and 1996. For comparison, we also analyse inbreeding coefficients derived from pedigrees in which paternity was inferred by molecular methods. Only 14 out of 231 calves (6.1%) had non-zero inbreeding coefficients, and neither inbreeding coefficient nor individual heterozygosity was consistently related to birth weight or neonatal survival. However, mean d2 was consistently related to both fitness measures. Low mean d2 was associated with low birth weight, especially following cold Aprils, in which foetal growth is reduced. Low mean d2 was also associated with low neonatal survival, but this effect was probably mediated by birth weight because fitting birth weight to the neonatal survival model displaced mean d2 as an explanatory variable. We conclude that in the deer population fitness measures expressed early in life do not show evidence of inbreeding depression, but they do show evidence of heterosis, possibly as a result of population mixing. We also demonstrate the practical problems of estimating inbreeding via pedigrees compared with a direct marker-based estimate of individual heterozygosity. We suggest that, together, individual heterozygosity and mean d2, estimated using microsatellites, are useful tools for exploring inbreeding and outbreeding in natural population.     

Efficacy of a 2-mm spot size lens for the treatment of superficial vascular lesions with a flashlamp-pumped dye laser

BACKGROUND: The flashlamp-pumped dye laser, using either a 3 or 5 mm spot size, is an excellent instrument for the treatment of port-wine stains and other superficial cutaneous vascular lesions. Problems exist with patient acceptance due to prominent and prolonged blue-black discoloration and the pain associated with the treatment. OBJECTIVE: To assess the effectiveness of a flashlamp-pumped dye laser equipped with a 2 mm spot size lens in the treatment of superficial vascular lesions. METHODS: Twenty-one patients with telangiectasias, cherry angiomas, and angiokeratomas were treated at a variety of fluences. RESULTS: Three of 21 patients had complete clearing of their superficial vascular lesions. An improvement of greater than 75% was noted by 11 patients, and six patients noted a 50%-75% improvement. One patient had less than 50% improvement. Less post-treatment discoloration and less pain were noted with the 2 mm spot size lens. CONCLUSIONS: The 2 mm spot size lens, used with the flashlamp-pumped dye laser is an effective instrument for the treatment of superficial cutaneous vascular lesions.     

Disassembly of the cholinergic postsynaptic apparatus induced by axotomy in mouse sympathetic neurons: the loss of dystrophin and beta-dystroglycan immunoreactivity precedes that of the acetylcholine receptor

In mouse sympathetic superior cervical ganglion (SCG), cortical cytoskeletal proteins such as dystrophin (Dys) and beta1sigma2 spectrin colocalize with beta-dystroglycan (beta-DG), a transmembrane dystrophin-associated protein, and the acetylcholine receptor (AChR) at the postsynaptic specialization. The function of the dystrophin-dystroglycan complex in the organization of the neuronal cholinergic postsynaptic apparatus was studied following changes in the immunoreactivity of these proteins during the disassembly and subsequent reassembly of the postsynaptic specializations induced by axotomy of the ganglionic neurons. After axotomy, a decrease in the number of intraganglionic synapses was observed (t1/2 8 h 45'), preceded by a rapid decline of postsynaptic specializations immunopositive for beta-DG, Dys, and alpha3 AChR subunit (alpha3AChR) (t1/2 3 h 45', 4 h 30' and 6 h, respectively). In contrast, the percentage of postsynaptic densities immunopositive for beta1sigma2 spectrin remained unaltered. When the axotomized neurons began to regenerate their axons, the number of intraganglionic synapses increased, as did that of postsynaptic specializations immunopositive for beta-DG, Dys, and alpha3AChR. The latter number increased more slowly than that of Dys and beta-DG. These observations suggest that in SCG neurons, the dystrophin-dystroglycan complex might play a role in the assembly-disassembly of the postsynaptic apparatus, and is probably involved in the stabilization of AChR clusters.     

Granulocyte colony-stimulating factor improves host defense to resuscitated shock and polymicrobial sepsis without provoking generalized neutrophil-mediated damage

BACKGROUND: Granulocyte colony-stimulating factor (G-CSF) increases production and release of neutrophil precursors and activates multiple functions of circulating polymorphonuclear neutrophils (PMNs). G-CSF has therapeutic effects in many experimental models of sepsis; its actions with superimposed reperfusion insults are unknown. In traumatic conditions, G-CSF could exacerbate unregulated, PMN-dependent injury to otherwise normal host tissue or, it could partially reverse trauma-induced immune suppression, which may improve long-term outcome. This study tested whether stimulating PMN proliferation and function with G-CSF during recovery from trauma+sepsis potentiated reperfusion injury or whether it improved host defense. METHODS: Anesthetized swine were subjected to cecal ligation and incision, 35% hemorrhage, and 1 hr of hypotension. Resuscitation consisted of intravenous G-CSF (5 microg/kg) or placebo followed by shed blood and 40 mL/kg of lactated Ringer's solution. The control group received laparotomy only. G-CSF or placebo was given daily. Animals were killed at 4 days. Observers, blind to the protocol, graded autopsy samples for localization of infection and quality of abscess wall formation. Data included complete blood count, granulocyte oxidative burst after phorbol myristate acetate stimulation in vitro (GO2B), bronchoalveolar lavage (BAL) cell count, BAL noncellular protein, lipopolysaccharide-stimulated tumor necrosis factor production in whole blood in vitro (lipopolysaccharide-tumor necrosis factor), and lung tissue myeloperoxidase (MPO). RESULTS: Neutrophilia and localization of infection, were significantly improved by G-CSF. Variables altered by G-CSF, though not significantly, showed GO2B potential increased by 50%, lipopolysaccharide-tumor necrosis factor decreased by 50%, and improved survival versus placebo (100% vs. 70%). G-CSF did not increase lung MPO, BAL cell count, or BAL protein. Both arterial and venous O2 saturations were unaltered. CONCLUSIONS: Our data show that G-CSF initiated at the time of resuscitation reduced the sequelae of posttrauma sepsis by increasing PMN proliferation and function without potentiating PMN-mediated lung reperfusion injury.     

Crystal structure of the first three domains of the type-1 insulin-like growth factor receptor

The type-1 insulin-like growth-factor receptor (IGF-1R) and insulin receptor (IR) are closely related members of the tyrosine-kinase receptor superfamily. IR is essential for glucose homeostasis, whereas IGF-1R is involved in both normal growth and development and malignant transformation. Homologues of these receptors are found in animals as simple as cnidarians. The epidermal growth-factor receptor (EGFR) family is closely related to the IR family and has significant sequence identity to the extracellular portion we describe here. We now present the structure of the first three domains of IGF-IR (L1-Cys-rich-L2) determined to 2.6 A resolution. The L domains each consist of a single-stranded right-handed beta-helix. The Cys-rich region is composed of eight disulphide-bonded modules, seven of which form a rod-shaped domain with modules associated in an unusual manner. The three domains surround a central space of sufficient size to accommodate a ligand molecule. Although the fragment (residues 1-462) does not bind ligand, many of the determinants responsible for hormone binding and ligand specificity map to this central site. This structure therefore shows how the IR subfamily might interact with their ligands.     

Structure-activity relationship of 2-[[(2-pyridyl)methyl]thio]-1H- benzimidazoles as anti Helicobacter pylori agents in vitro and evaluation of their in vivo efficacy

A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 microg/mL. The structure-activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]-3-methyl-2-pyridyl)methyl]thio]-1H-be nzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felismodel (125 micromol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.