Carcinoid Tumor of the Middle Ear Containing Serotonin and Multiple Peptide Hormones A Case Report and Review of the Pathology Literature

A 69-year old man complaining of longstanding hearing loss and mild otorrhea was found to have a mass obliterating the external auditory canal and polypous tympanic mucosa with accompanying absence of the tympanic membrane and ossicular chain. Tumors excised from the external auditory canal and tympanum showed histologic features essentially characteristic of a carcinoid tumor: a ribbon or festoon arrangement of tumor cells, formation of anastomosing cords and glandular spaces, presence of numerous argyrophilic as well as argentaffin secretory granules within many of the tumor cells, and ultrastructur-al evidence of neurosecretory granules in the tumor cell cytoplasm. Immunohistochemically, the tumor was found to contain not only neuronal marker substances such as neuron-specific enolase, S 100 protein and chromogranin A, but also serotonin and multiple peptide hormones such as pancreatic polypeptide, glucagon, cholecystokinin and leucine-enkephalin. A review of the pathology of 17 previous cases of carcinoid of the middle ear suggested that this type of carcinoid may have a variegated hormone profile among carcinoids of foregut origin, and hormonally may resemble ileal carcinoid arising from the midgut, although their histogenetic origins may differ, because of frequent production of serotonin. Acta Pathol Jpn 42: 614–620, 1992.     

Ichthyosis associated with widespread tinea corporis: report of three cases

Ichthyoses are a common group of keratinization disorders. A non-inflammatory generalized persistent skin desquamation is observed. It is characterized by increased cell turnover, thickening of the stratum corneum and functional changes of sebaceous and sweat glands. All of these favor fungal proliferation. Dermatophytes may infect skin, hair and nails causing ringworm or tinea. They have the ability to obtain nutrients from keratinized material. One of its most prevalent genera is Trichophyton rubrum. Although tineas and ichthyoses are quite common, the association of the two entities is rarely reported in the literature. Three cases of ichthyosis associated with widespread infection by T. rubrum are presented. Resistance to several antifungal treatments was responsible for worsening of ichthyosis signs and symptoms.     

Characterization of skin blister fluids from children with Epstein–Barr virus‐associated lymphoproliferative disease

Epstein–Barr virus (EBV)‐associated T‐ or natural killer (NK)‐cell lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by chronic proliferation of EBV‐infected lymphocytes. Patients may present with severe skin manifestations, including hypersensitivity to mosquito bites (HMB) and hydroa vacciniforme (HV)‐like eruption, which are characterized by blister formation and necrotic ulceration. Skin biopsy specimens show inflammatory reactions comprising EBV‐infected lymphocytes. However, blister fluids have not been fully assessed in patients with this disease. Blister fluids were collected from three patients with EBV‐associated LPD: two with HMB and one with HV. Immunophenotyping of blister lymphocytes and measurement of tumor necrosis factor (TNF)‐α in blister fluids were performed. The patients with HMB and HV exhibited markedly increased percentages of NK and γδ T cells, respectively, in both peripheral blood and blister fluids. These NK and γδ T cells strongly expressed the activation marker human leukocyte antigen‐DR and were considered to be cellular targets of EBV infections. TNF‐α was highly elevated in all blister fluids. Severe local skin reactions of EBV‐associated LPD may be associated with infiltrating EBV‐infected lymphocytes and a high TNF‐α concentration in blister fluids.     

Tidal volume and diaphragm muscle activity in rats with cervical spinal cord injury

[Purpose] The purpose of this study was to make an experimental model of cervical spinal cord injury (CSCI) using Wistar rats, in order to analyze the influence of CSCI on the respiratory function. [Subjects] Thirty-two male 12-week-old Wistar rats were used. [Methods] The CSCI was made at the levels from C3 to C7, and we performed pneumotachography and electromyography (EMG) on the diaphragm. Computed tomography was used to determine the level of spinal cord damage. [Results] After the operation, the tidal volume of the rats with a C3 level injury decreased to approximately 22.3% of its pre-injury value. In addition, in the same rats, the diaphragmatic electromyogram activity decreased remarkably. Compared with before CSCI, the tidal volume decreased to 78.6% of its pre-injury value in CSCI at the C5 level, and it decreased to 94.1% of its pre-injury value in CSCI at the C7 level. [Conclusion] In the rats that sustained a CSCI in this study, the group of respiratory muscles that receive innervation from the thoracic spinal cord was paralyzed. Therefore, the EMG signal of the diaphragm increased. These results demonstrate that there is a relationship between respiratory function and the level of CSCI.Key words: Cervical spinal cord injury, Respiratory function, Electromyography of diaphragm muscle     

Contribution of closed mitral commissurotomy in the surgery of rheumatic mitral stenosis

The objective of this work was to study the indications, techniques and results of closed heart mitral commissurotomy in patients with rheumatic mitral stenosis in Morocco.MethodsAll patients who had undergone closed heart mitral commissurotomy for rheumatic mitral stenosis, operated between 1999 and 2008 were collected in this study. Mitral stenosis was diagnosed and evaluated using Doppler echocardiography. Patients with commissural calcification, severe mitral regurgitation, and surgical tricuspid or aortic valvular disease were excluded from this study.ResultsSix hundred and twenty-five patients have been collected. 62.2% were young with an age between 18 and 35 years and 491 (78.8%) were female. Seventy-nine percent of patients had stage III or IV NYHA and were in sinus regular rhythm. The closed heart mitral commissurotomy was performed for all patients through a left thoracotomy using either digital or dual dilatation. The mitral area was significantly increased postoperatively to 2.11 ± 0.32 with 100% opening of the anterior commissure, while the posterior commissure was opened only for 93.7% of patients. There were nine perioperative deaths (4.9%) and all patients who died had severe mitral stenosis (< 0.8 cm²) with an elevated systolic pulmonary artery pressure (> 60 mmHg).ConclusionThe closed heart mitral commissurotomy provides excellent results in young patients with rheumatic mitral stenosis.     

Chitin-induced activation of immune signaling by the rice receptor CEBiP relies on a unique sandwich-type dimerization

Perception of microbe-associated molecular patterns (MAMPs) through pattern recognition receptors (PRRs) triggers various defense responses in plants. This MAMP-triggered immunity plays a major role in the plant resistance against various pathogens. To clarify the molecular basis of the specific recognition of chitin oligosaccharides by the rice PRR, CEBiP (chitin-elicitor binding protein), as well as the formation and activation of the receptor complex, biochemical, NMR spectroscopic, and computational studies were performed. Deletion and domain-swapping experiments showed that the central lysine motif in the ectodomain of CEBiP is essential for the binding of chitin oligosaccharides. Epitope mapping by NMR spectroscopy indicated the preferential binding of longer-chain chitin oligosaccharides, such as heptamer-octamer, to CEBiP, and also the importance of N-acetyl groups for the binding. Molecular modeling/docking studies clarified the molecular interaction between CEBiP and chitin oligosaccharides and indicated the importance of Ile₁₂₂ in the central lysine motif region for ligand binding, a notion supported by site-directed mutagenesis. Based on these results, it was indicated that two CEBiP molecules simultaneously bind to one chitin oligosaccharide from the opposite side, resulting in the dimerization of CEBiP. The model was further supported by the observations that the addition of (GlcNAc)₈ induced dimerization of the ectodomain of CEBiP in vitro, and the dimerization and (GlcNAc)₈-induced reactive oxygen generation were also inhibited by a unique oligosaccharide, (GlcNβ1,4GlcNAc)₄, which is supposed to have N-acetyl groups only on one side of the molecule. Based on these observations, we proposed a hypothetical model for the ligand-induced activation of a receptor complex, involving both CEBiP and Oryza sativa chitin-elicitor receptor kinase-1.Plants have the ability to detect potential pathogens through the recognition of microbe-associated molecular patterns (MAMPs; also known as pathogen-associated molecular patterns), such as flagellin, elongation factor Tu (EF-Tu), peptidoglycan, LPS, chitin, and β-glucan, which are typical molecular signatures for whole classes of microbes (1, 2). MAMP-triggered defense is the first barrier to prevent the invasion of pathogens and plays a major role in the basal resistance of plants against various pathogens. It is also well known that this defense system is strikingly similar to the innate immunity of animals (1, 3, 4).Leucine-rich repeat receptor-like kinases, flagellin-sensetive 2 (FLS2), and EF-Tu receptor, have been shown to recognize bacterial flagellin and EF-Tu, respectively, and serve as receptors for these MAMPs (5). On the other hand, two types of lysin motif (LysM) proteins, CEBiP (chitin-elicitor binding protein) and CERK1 (chitin-elicitor receptor kinase-1), were identified as the cell-surface receptor for chitin, a representative fungal molecular pattern (6–8). Knockout/-down experiments of these genes showed that both of these LysM proteins are required for chitin perception and signaling in rice, whereas CEBiP-type molecules are not involved in chitin signaling in Arabidopsis, indicating the difference between the chitin receptor systems in these model plants (8). Additionally, another LysM receptor-like kinase, LYK4, was also indicated to contribute to chitin signaling in Arabidopsis (9). In the case of rice, it was also shown that CEBiP and Oryza sativa (Os)CERK1 form a heterooligomeric receptor complex ligand dependently (10).Both CEBiP and OsCERK1 have LysMs, which have been known to bind peptidoglycan and chitin (11), in their ectodomains. In Arabidopsis, CERK1 was shown to bind chitin and trigger immune responses as a kind of “all-in-one” receptor. On the other hand, CEBiP seems to play a major role in the perception of chitin in rice, as the knockdown of CEBiP almost abolished the binding of a radio-labeled chitin oligosaccharide to the plasma membrane, whereas OsCERK1 was shown not to bind chitin (6, 12). Liu et al. recently reported that two other CEBiP homologs, OsLYP4 and -6, also bind chitin and contribute to chitin responses and disease resistance in rice (13), although it is not clear to what extent these proteins contribute as the cell surface receptor for chitin oligosaccharides.It was also shown that the perception of peptidoglycan in Arabidopsis requires CEBiP-like molecules (14). Arabidopsis homologs of CEBiP, LYM1 and LYM3, play a major role for the binding of peptidoglycan and activation of downstream defense responses through the receptor kinase, CERK1. These results showed that the receptor kinase CERK1 is required for both chitin and peptidoglycan signaling, at least in Arabidopsis. The peptidoglycan receptor system in Arabidopsis seems similar to the rice chitin receptor for the requirement of a binding protein and a receptor kinase, although the receptor complex formation by these two proteins was not confirmed.Thus, the detailed analysis of ligand recognition by these CEBiP-like molecules and succeeding formation and activation of receptor complex is critically important to understand the molecular mechanisms leading to the activation of downstream defense responses triggered by these MAMPs. Such information would also contribute to the design of novel receptor molecules suitable for future biotechnological application. We show herein the results obtained by biochemical studies on the binding site of CEBiP, epitope mapping of chitin oligosaccharides by saturation transfer difference (STD) NMR spectroscopy, and molecular modeling/docking studies combined with site-directed mutagenesis of the ectodomain of CEBiP. These results clearly indicated that two CEBiP molecules simultaneously bind to one N-acetylchitoheptaose/octaose, (GlcNAc)_7/8, through a binding site located in the central LysM region of the ectodomain, resulting in the dimerization of CEBiP. Based on these observations, we proposed a hypothetical model for the ligand-induced activation of a receptor complex, involving both CEBiP and OsCERK1.