Cologastric fistula with a foreign body in a patient with Crohn's disease

Although the medical management of fistulizing Crohn's disease is improving, a subset of patients does not respond to maximal medical therapy and is referred for surgical consultation. We report a case of Crohn's colitis with an ingested foreign body resulting in a cologastric fistula. The patient underwent segmental colectomy and takedown of the cologastric fistula. At the time of laparotomy, the foreign body was found in the fistulous colonic segment. The presence of an ingested foreign body likely contributed to a rare fistula that was refractory to medical management.     

Transcriptional regulation of matrix metalloproteinase-1 and collagen 1A2 explains the anti-fibrotic effect exerted by proteasome inhibition in human dermal fibroblasts

Introduction  

Extracellular matrix (ECM) turnover is controlled by the synthetic rate of matrix proteins, including type I collagen, and their enzymatic degradation by matrix metalloproteinases (MMPs). Fibrosis is characterized by an unbalanced accumulation of ECM leading to organ dysfunction as observed in systemic sclerosis. We previously reported that proteasome inhibition (PI) in vitro decreases type I collagen and enhances MMP-1 production by human fibroblasts, thus favoring an antifibrotic fibroblast phenotype. These effects were dominant over the pro-fibrotic phenotype induced by transforming growth factor (TGF)-β. Here we investigate the molecular events responsible for the anti-fibrotic phenotype induced in fibroblasts by the proteasome inhibitor bortezomib.     

Characterization of the damage of Spodoptera eridania (Cramer) and Spodoptera cosmioides (Walker) (Lepidoptera: Noctuidae) to structures of cotton plants

The cotton plant, Gossypium hirsutum, hosts various pests that damage different structures. Among these pests, Spodoptera cosmioides (Walker) and Spodoptera eridania (Cramer) (Lepidoptera: Noctuidae) are considered important. The objectives of this study were to characterize and to quantify the potential damage of S. eridania and S. cosmioides feeding on different structures of cotton plants. For this purpose, newly-hatched larvae were reared on the following plant parts: leaf and flower bud; leaf and boll; flower bud or boll; and leaf, flower bud and boll. The survival of S. cosmioides and S. eridania was greater than 80% and 70% for larvae fed on cotton plant parts offered separately or together, respectively. One larva of S. eridania damaged 1.7 flower buds, but did not damage bolls, while one larva of S. cosmioides damaged 5.2 flower buds and 3.0 cotton bolls. Spodoptera eridania and S. cosmioides can be considered species with potential to cause economic damage to cotton plants because they can occur throughout cotton developmental stages causing defoliation and losses of reproductive structures. Therefore, the results validate field observations that these two species of Spodoptera are potential pests for cotton.     

BiP Binding to the ER-Stress Sensor Ire1 Tunes the Homeostatic Behavior of the Unfolded Protein Response

The unfolded protein response (UPR) is an intracellular signaling pathway that counteracts variable stresses that impair protein folding in the endoplasmic reticulum (ER). As such, the UPR is thought to be a homeostat that finely tunes ER protein folding capacity and ER abundance according to need. The mechanism by which the ER stress sensor Ire1 is activated by unfolded proteins and the role that the ER chaperone protein BiP plays in Ire1 regulation have remained unclear. Here we show that the UPR matches its output to the magnitude of the stress by regulating the duration of Ire1 signaling. BiP binding to Ire1 serves to desensitize Ire1 to low levels of stress and promotes its deactivation when favorable folding conditions are restored to the ER. We propose that, mechanistically, BiP achieves these functions by sequestering inactive Ire1 molecules, thereby providing a barrier to oligomerization and activation, and a stabilizing interaction that facilitates de-oligomerization and deactivation. Thus BiP binding to or release from Ire1 is not instrumental for switching the UPR on and off as previously posed. By contrast, BiP provides a buffer for inactive Ire1 molecules that ensures an appropriate response to restore protein folding homeostasis to the ER by modulating the sensitivity and dynamics of Ire1 activity.     

Paresis and death in elk (Cervus elaphus) due to lichen intoxication in Wyoming

During February-April 2004, an estimated 400-500 free-ranging elk (Cervus elaphus) developed paresis, became recumbent, and died or were euthanized in the Red Rim Wildlife Habitat Management Area (RRWHMA), Wyoming, USA. Elk were found in sternal recumbency, alert and responsive, but unable to rise. Their condition progressed to lateral recumbency followed by dehydration, obtundation, and death. Gross lesions were limited to degenerative myopathy, with pallor and streaking in skeletal muscles. Microscopically, affected muscles had degenerative lesions of varying duration, severity, and distribution, some with early mineralization and attempts at regeneration. Diagnostic testing ruled out common infectious, inflammatory, toxic, and traumatic causes. Tumbleweed shield lichen (Xanthoparmelia chlorochroa) was found in the area and in the rumen of several elk. This lichen was collected and fed to three captive elk. Two of these elk exhibited signs of ataxia, which rapidly progressed to weakness and recumbency after 7 and 10 days on this diet, respectively, and a degenerative myopathy, consistent with lesions observed in the elk affected at RRWHMA, was observed. All remaining elk migrated from the RRWHMA during the spring and no subsequent losses have been documented.     

Genotyping and segregation analyses indicate the presence of only two functional MIC genes in rhesus macaques

MIC molecules are stress-inducible ligands of the activating receptor NKG2D, which is expressed on natural killer cells and subsets of T lymphocytes. In rhesus macaques (Macaca mulatta), three different MIC sequences (MIC1, MIC2, MIC3) have been described that are closely related to but, according to phylogenetic analysis, do not represent orthologues of the human MICA and MICB genes. Although a single haplotype of the rhesus macaque Mhc (Mamu) has been completely sequenced, it remained unknown so far whether these three sequences are derived from two or three Mamu-MIC genes. We genotyped a cohort of 115 rhesus macaque individuals for the presence of MIC1, MIC2, and MIC3 sequences and analysed the segregation in families. All individuals were positive for MIC2, whereas only 66.1 and 80.9 % were positive for MIC1 and MIC3, respectively. MIC1 and MIC3 sequences segregated in offspring, indicating that they behave as alleles. Thus, we conclude that two MIC genes are present in the rhesus macaque Mhc, which we propose to designate as Mamu-MICA (MIC1 and MIC3) and Mamu-MICB (MIC2). “MIC1” and “MIC3” are regarded as divergent allelic lineages of the Mamu-MICA gene. Mamu-MIC genotyping of DNA of a cohort of 68 experimentally simian immunodeficiency virus (SIV)-infected rhesus macaques revealed no significant association of either of the two Mamu-MICA allelic lineages with differences in progression to AIDS-like symptoms. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorize users. Anne Averdam and Sandra Seelke contributed equally.     

Elucidation of the ipso-substitution mechanism for side-chain cleavage of alpha-quaternary 4-nonylphenols and 4-t-butoxyphenol in Sphingobium xenophagum Bayram

Recently we showed that degradation of several nonylphenol isomers with alpha-quaternary carbon atoms is initiated by ipso-hydroxylation in Sphingobium xenophagum Bayram (F. L. P. Gabriel, A. Heidlberger, D. Rentsch, W. Giger, K. Guenther, and H.-P. E. Kohler, J. Biol. Chem. 280:15526-15533, 2005). Here, we demonstrate with 18O-labeling experiments that the ipso-hydroxy group was derived from molecular oxygen and that, in the major pathway for cleavage of the alkyl moiety, the resulting nonanol metabolite contained an oxygen atom originating from water and not from the ipso-hydroxy group, as was previously assumed. Our results clearly show that the alkyl cation derived from the alpha-quaternary nonylphenol 4-(1-ethyl-1,4-dimethyl-pentyl)-phenol through ipso-hydroxylation and subsequent dissociation of the 4-alkyl-4-hydroxy-cyclohexadienone intermediate preferentially combines with a molecule of water to yield the corresponding alcohol and hydroquinone. However, the metabolism of certain alpha,alpha-dimethyl-substituted nonylphenols appears to also involve a reaction of the cation with the ipso-hydroxy group to form the corresponding 4-alkoxyphenols. Growth, oxygen uptake, and 18O-labeling experiments clearly indicate that strain Bayram metabolized 4-t-butoxyphenol by ipso-hydroxylation to a hemiketal followed by spontaneous dissociation to the corresponding alcohol and p-quinone. Hydroquinone effected high oxygen uptake in assays with induced resting cells as well as in assays with cell extracts. This further corroborates the role of hydroquinone as the ring cleavage intermediate during degradation of 4-nonylphenols and 4-alkoxyphenols.