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Background Significance of monitoring adalimumab trough levels and anti-adalimumab antibodies ( AAA) for disease outcome in Crohn's disease ( CD) patients remained unclear. Aim To evaluate the association of adalimumab trough levels and AAA at week 26 with clinical remission at week 52, the effect of azathiopurine on AAA and factors influencing trough levels in CD patients in the DIAMOND trial. Methods We performed this study using adalimumab trough levels, AAA at week 26 and 6-thioguanine nucleotide ( TGN) in red blood cells at week 12. A multiple regression model and receiver operating analysis was performed to identify factors influencing adalimumab trough levels and AAA, and adalimumab thresholds for predicting disease activity. Results There was a significant difference of adalimumab trough level at week 26 between patients with disease remission and without at week 52 (7.7 ± 3.3 μg/ mL vs 5.4 ± 4.3 μg/ mL: P <.001). Adalimumab trough level of 5.0 μg/ mL yielded optimal sensitivity and specificity for remission prediction (80.2% and 55.6%, respectively). AAA development at week 26 significantly affected remission at week 52 ( P = .021), which was strongly associated with adalimumab trough levels. Female gender and increasing body weight were independently associated with low adalimumab trough levels, and female gender was associated with AAA development. A cut-off 6 TGN level of >222.5 p mol/8 ×108 RBCs yielded sensitivity (100%) and specificity (60.6%) for AAA negativity. Conclusion Adalimumab trough levels and AAA occurrence were significantly associated with clinical remission. Higher 6 TGN affected AAA negativity. The combination therapy is beneficial in some relevant aspects for CD patients. ( UMIN Registration No. 000005146) [ABSTRACT FROM AUTHOR]

Background Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms ( DIHS/ DRESS) and Stevens-Johnson syndrome ( SJS)/toxic epidermal necrolysis ( TEN) represent contrasting poles of severe drug eruptions, and sequential reactivations of several herpesviruses have exclusively been demonstrated in the former. No previous studies, however, were extended beyond the acute stage. We sought to investigate whether herpesvirus reactivations could also be observed in SJS/ TEN and beyond the acute stage of both diseases. Methods Patients with SJS ( n = 16), SJS/ TEN overlap ( n = 2), TEN ( n = 10), and DIHS/ DRESS ( n = 34) were enrolled. We performed a retrospective analysis of Epstein-Barr virus ( EBV), human herpesvirus 6 ( HHV-6), and cytomegalovirus ( CMV) DNA loads sequentially determined by real-time polymerase chain reaction during a 2-year period after onset. Results Persistently increased EBV loads were detected in SJS during the acute stage and long after resolution, but not in others. In contrast, high HHV-6 loads were exclusively detected in DIHS/ DRESS during the acute stage. The dynamics of herpesvirus reactivation varied in DIHS/ DRESS according to the use of systemic corticosteroids: While EBV loads were higher in patients not receiving systemic corticosteroids, CMV and HHV-6 loads were higher in those receiving them. Conclusions Distinct patterns of herpesvirus reactivation according to the pathological phenotype and to the use of systemic corticosteroids were observed during the acute stage and follow-up period, which may contribute, at least in part, to the difference in the clinical manifestations and long-term outcomes. Systemic corticosteroids during the acute stage may improve the outcomes in DIHS/ DRESS. [ABSTRACT FROM AUTHOR]

Aims Ubiquilin-1 acts as an adaptor protein that mediates the translocation of polyubiquitinated proteins to the proteasome for degradation. Although previous studies suggested a key role of ubiquilin-1 in the pathogenesis of Alzheimer's disease ( AD), a direct relationship between ubiquilin-1 and Hirano bodies in AD brains remains unknown. Methods By immunohistochemistry, we studied ubiquilin-1 and ubiquilin-2 expression in the frontal cortex and the hippocampus of six AD and 13 control cases. Results Numerous Hirano bodies, accumulated in the hippocampal CA1 region of AD brains, expressed intense immunoreactivity for ubiquilin-1. They were much less frequently found in control brains. However, Hirano bodies did not express a panel of markers for proteasome, autophagosome or pathogenic proteins, such as ubiquilin-2, ubiquitin, p62, LC3, beclin-1, HDAC6, paired helical filament ( PHF)-tau, protein-disulphide isomerase ( PDI) and phosphorylated TDP-43, but some of them expressed C9orf72. Ubiquilin-1-immunoreactive deposits were classified into four distinct morphologies, such as rod-shaped structures characteristic of Hirano bodies, dystrophic neurites contacting senile plaques, fragmented structures accumulated in the lesions affected with severe neuronal loss, and thread-shaped structures located mainly in the molecular layer of the hippocampus. Conclusions Ubiquilin-1 immunoreactivity is concentrated on Hirano bodies and dystrophic neurites in AD brains, suggesting that aberrant expression of ubiquilin-1 serves as one of pathological hallmarks of AD. [ABSTRACT FROM AUTHOR]

Structured Abstract Objective To investigate whether low mechanical loading on the temporomandibular joint ( TMJ) when ingesting a liquid diet affects the response properties of neurons in the trigeminal spinal tract subnucleus caudalis (Sp5C) in growing rats. Materials and Methods Shortly after weaning, 2-week-old male rats were fed chow pellets (control) or a liquid diet (experimental). Firing activities of single sensory units were recorded from the Sp5C at 4, 5, 7, and 9 weeks. Neurons were functionally classified by their responsiveness to TMJ stimuli. The responses of Class II and III neurons to TMJ stimuli were investigated. Results In both neuron classes, the firing threshold in the experimental group was significantly lower than in the control group at all time points, but remained static in the control group throughout the experimental period, whereas it peaked in the experimental group at 4 weeks, decreased at 5 weeks, and remained stable thereafter until 9 weeks. Similarly, the initial firing frequency was significantly higher in the experimental group than in the control group, but remained static in the control group throughout the experimental period, whereas in the experimental group, it was at its lowest at 4 weeks, increased at 5 weeks, and stayed stable thereafter until 9 weeks. Conclusion Differences in TMJ loading arising from variable diet consistency during growth may affect the functional characteristics of Sp5C neurons. [ABSTRACT FROM AUTHOR]

J. Satoh, H. Tabunoki, T. Ishida, Y. Saito and K. Arima (2013) Neuropathology and Applied Neurobiology 39, 109-120 Accumulation of a repulsive axonal guidance molecule RGMa in amyloid plaques: a possible hallmark of regenerative failure in Alzheimer's disease brains Aims: RGMa is a repulsive guidance molecule that induces the collapse of axonal growth cones by interacting with the receptor neogenin in the central nervous system during development. It remains unknown whether RGMa plays a role in the neurodegenerative process of Alzheimer's disease (AD). We hypothesize that RGMa, if it is concentrated on amyloid plaques, might contribute to a regenerative failure of degenerating axons in AD brains. Methods: By immunohistochemistry, we studied RGMa and neogenin (NEO1) expression in the frontal cortex and the hippocampus of 6 AD and 12 control cases. The levels of RGMa expression were determined by qRT-PCR and Western blot in cultured human astrocytes following exposure to cytokines and amyloid beta (Aβ) peptides. Results: In AD brains, an intense RGMa immunoreactivity was identified on amyloid plaques and in the glial scar. In the control brains, the glial scar and vascular foot processes of astrocytes expressed RGMa immunoreactivity, while oligodendrocytes and microglia were negative for RGMa. In AD brains, a small subset of amyloid plaques expressed a weak NEO1 immunoreactivity, while some reactive astrocytes in both AD and control brains showed an intense NEO1 immunoreactivity. In human astrocytes, transforming growth factor beta-1 (TGFβ1), Aβ1-40 or Aβ1-42 markedly elevated the levels of RGMa, and TGFβ1 also increased its own levels. Coimmunoprecipitation analysis validated the molecular interaction between RGMa and the C-terminal fragment β of amyloid beta precursor protein (APP). Furthermore, recombinant RGMa protein interacted with amyloid plaques in situ. Conclusions: RGMa, produced by TGFβ-activated astrocytes and accumulated in amyloid plaques and the glial scar, could contribute to the regenerative failure of degenerating axons in AD brains. [ABSTRACT FROM AUTHOR]

Linezolid (LZD) is the first oxazolidinone antibiotic that is effective against drug-resistant gram-positive organisms. Hematological toxicities such as thrombocytopenia, anemia, and leukocytopenia are common in LZD therapy. However, LZD-induced pure red cell aplasia (PRCA) is very rare. A 56-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation from a human leukocyte antigen-matched and ABO blood type-matched unrelated male donor. He had bacteremia caused by Staphylococcus epidermidis after engraftment of neutrophils and red blood cells. We first administered vancomycin, but then changed to intravenous LZD because of kidney damage. Two weeks after LZD therapy, the patient's hemoglobin and reticulocyte levels were 6.8 g/dL and 0.3%, respectively. Bone marrow examination revealed red blood cell aplasia (myeloid/erythroid ratio was 402). The patient showed rapid recovery of normal erythropoiesis within 2 weeks of LZD cessation. It is important to be aware of the hematological effects associated with LZD in the setting of stem cell transplantation,particularly for those with pre-existing myelosuppression, renal insufficiency, and those receiving concomitant drugs that produce bone marrow suppression. We advocate that a reticulocyte count be performed periodically for detecting bone marrow suppression, including PRCA, during LZD therapy. [ABSTRACT FROM AUTHOR]

J. Satoh, H. Tabunoki, T. Ishida, Y. Saito and K. Arima (2012) Neuropathology and Applied Neurobiology 38, 132-141 Immunohistochemical characterization of γ-secretase activating protein expression in Alzheimer's disease brains Aims: A recent study showed that γ-secretase activating protein (GSAP), derived from a C-terminal fragment of pigeon homolog (PION), increases amyloid-β (Aβ) production by interacting with presenilin-1 (PS1) and the β-secretase-cleaved C-terminal fragment of amyloid precursor protein (APP-CTF). In the study, knockdown of GSAP reduces production of Aβ and plaque formation in the brain of APPswe and PS1ΔE9 double transgenic mice without affecting the Notch-dependent pathway. Therefore, GSAP is an ideal target for designing γ-secretase modulators with least side effects in Alzheimer's disease (AD). However, at present, the precise distribution of GSAP in AD brains remains to be characterized. Methods: By immunohistochemistry, we studied GSAP expression in the frontal cortex and the hippocampus of 11 aged AD and 17 age-matched control cases. Results: GSAP immunoreactivity exhibited distinct morphological features, such as fine granular cytoplasmic deposits, dense nodular and patchy deposits, beads and string-like deposits, and diffuse dot-like deposits. In both AD and control brains, a fairly small subset of cerebral cortical and hippocampal neurones expressed fine granular cytoplasmic deposits, while diffuse dot-like deposits were more frequently found in the neuropil and neuronal processes, particularly enriched in the hippocampal CA2 and CA3 regions. Among GSAP-immunoreactive deposits, dense nodular and patchy deposits, located in the neuropil and closely associated with PS1 expression and Aβ deposition, indicated the most distinguishing features of AD pathology. Conclusions: Aberrant regulation of GSAP expression plays a key role in acceleration of γ-cleavage of APP-CTF and accumulation of Aβ in AD brains. [ABSTRACT FROM AUTHOR]

Recent evidence has shown that -aspartate modulates hormone secretion in the vertebral neuroendocrine system. Because only -aspartate oxidase (DDO) can degrade -aspartate, we determined DDO localisation in the pituitary and pineal glands to elucidate the control mechanisms of local -aspartate concentration. Brain tissues and pituitary and pineal glands of the female pigs contained a similar DDO activity of 0.38-0.66 U/g protein. However, approximately ten-fold higher concentrations of -aspartate (0.27-0.35 μmol/g protein) were found in both glands. To determine the distribution of immunoreactive DDO, we made a rabbit polyclonal antibody specific to porcine DDO using a recombinant porcine enzyme. DDO immunoreactivity was found in the cytoplasm of a subgroup of cells in the anterior and intermediate lobes, in a part of nerve processes and terminals in the posterior lobe, and in the cytoplasm of a small group of pinealocytes. We used dual-label immunocytochemistry to determine which pituitary hormones colocalise with DDO, and whether DDO and -aspartate immunoreactivity is reciprocal. In the pituitary gland, almost all proopiomelanocortin-positive cells colocalised DDO, whereas only growth hormone-positive cells colocalised -aspartate. -Aspartate immunoreactivity was not detected where DDO immunoreactivity was found. The present study suggests that DDO plays important roles to prevent undesirable off-target action of -aspartate by strictly controlling local -aspartate concentration in the pituitary and pineal glands. [ABSTRACT FROM AUTHOR]

M. Shioya, S. Obayashi, H. Tabunoki, K. Arima, Y. Saito, T. Ishida and J. Satoh (2010) Neuropathology and Applied Neurobiology 36, 320–330 Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3 Aims: MicroRNAs (miRNAs) are small non-coding RNAs that regulate translational repression of target mRNAs. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled that manner in the brain plays a key role in neuronal development. However, at present, the pathological implication of aberrant miRNA expression in neurodegenerative events remains largely unknown. To identify miRNAs closely associated with neurodegeneration, we performed miRNA expression profiling of brain tissues of various neurodegenerative diseases. Methods: We initially studied the frontal cortex derived from three amyotrophic lateral sclerosis patients by using a microarray of 723 human miRNAs. This was followed by enlargement of study population with quantitative RT-PCR analysis ( n = 21). Results: By microarray analysis, we identified up-regulation of miR-29a, miR-29b and miR-338-3p in amyotrophic lateral sclerosis brains, but due to a great interindividual variation, we could not validate these results by quantitative RT-PCR. However, we found significant down-regulation of miR-29a in Alzheimer disease (AD) brains. The database search on TargetScan, PicTar and miRBase Target identified neurone navigator 3 (NAV3), a regulator of axon guidance, as a principal target of miR-29a, and actually NAV3 mRNA levels were elevated in AD brains. MiR-29a-mediated down-regulation of NAV3 was verified by the luciferase reporter assay. By immunohistochemistry, NAV3 expression was most evidently enhanced in degenerating pyramidal neurones in the cerebral cortex of AD. Conclusions: These observations suggest the hypothesis that underexpression of miR-29a affects neurodegenerative processes by enhancing neuronal NAV3 expression in AD brains. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 68-year-old man with a nodular mass in the lower lobe of the left lung. The said nodule is indicated to have enlarged by 3.0 centimetre at its maximum diameter. A 21-gauge needle transbronchial needle aspiration was performed and a monophasic fibrous synovial sarcoma (SS) was confirmed. The article also discusses the primary pulmonary synovial sarcoma (PPSS)

Aim: Glucokinase (GK) in pancreatic β cells is thought to be involved in insulin secretion and glucose homeostasis. This study investigates whether the long-acting agonist of the glucagon-like peptide 1, namely exendin-4, mediates stimulatory effects on GK gene expression through the Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) cascade. Methods: GK expression was examined by real-time PCR, western blot analysis and reporter gene assay in rat insulin-secreting INS-1 cells incubated with exendin-4. CaMKIV activity was assessed by detection of activation loop phosphorylation (Thr196) of CaMKIV. We investigated the effect of the constitutively active form (CaMKIVc) of CaMKIV on GK promoter activity. Results: Increased expression level of GK protein was noted in response to rising concentrations of exendin-4 with maximum induction at 10 nM. Real-time PCR analysis showed a significant increase in the amount of GK mRNA in response to rising concentrations of exendin-4. Exendin-4 also stimulated GK promoter activity but failed to do so in the presence of STO-609, a CaMKK inhibitor. This result is consistent with the observations that the upregulation of CaMKIV phosphorylation (at Thr196) peaked after 15 min of exposure to exendin-4 and that CaMKIVc enhanced or upregulated GK promoter activity in INS-1 cells. Furthermore, STO-609 significantly suppressed the exendin-4 – upregulated the expression of the GK protein. Conclusion: Activation of the CaMKK/CaMKIV cascade might be required for exendin-4-induced GK gene transcription, indicating that exendin-4 plays an important role in insulin secretion in pancreatic β cells. [ABSTRACT FROM AUTHOR]

CARD15 was first identified as a susceptibility gene for Crohn’s disease. More recently, CARD15 mutations were shown to be associated with the pediatric granulomatous inflammatory diseases, Blau syndrome and early-onset sarcoidosis (EOS). The aim of the present study was to evaluate whether CARD15 variants also play a role in patients with ordinary sarcoidosis other than EOS. We enrolled 135 Japanese sarcoidosis patients with uveitis as well as 95 healthy individuals and performed mutation analysis by direct sequencing of CARD15 exon 4. Direct DNA sequencing in the sarcoidosis patients showed eight CARD15 variants, including five novel mutations (13402C>T, 13543C>T, 13775C>A, 13937G>A, and 14079C>T). Compared with healthy individuals, CARD15 mutations are not common in the Japanese patients with sarcoidosis. Based on the results, we examined the clinical manifestations in patients with sarcoidosis according to their CARD15 mutations. Sarcoidosis patients with these mutations have no specific clinical features with regard to course of the disease or disease severity. Our results indicate that in general, CARD15 mutations may not contribute to the risk of sarcoidosis. [ABSTRACT FROM AUTHOR]

Background Bronchial asthma is a chronic inflammatory disorder of the airways. Recently, it has been suggested that complement plays significant roles in asthma. Mannose-binding lectin (MBL) is one of the key molecules in complement activation pathways that are associated with several infectious and immune disorders. Subjects and method To investigate whether MBL plays roles in asthma, we analysed MBL2 polymorphisms (allele B, H/L and Y/X) and plasma MBL levels in a Japanese adult population including 232 healthy controls and 579 asthmatics. Results Although there was linkage disequilibrium among the three polymorphisms, each polymorphism significantly affects serum MBL levels independently. However, there were no significant differences between asthmatics and controls in MBL2 genotype distribution and in MBL concentrations [1.47±0.07(SE) mg/L for asthmatics and 1.66±0.14 mg/L for controls, P=0.2]. MBL levels and genotype have no significant relationship with serum IgE, pulmonary functions, and the severity of asthma. Conclusion Although plasma MBL levels depend on the MBL2 polymorphisms, these polymorphisms and plasma MBL levels are not associated with the asthma phenotype. [ABSTRACT FROM AUTHOR]

To estimate the species-specific mutation rates at the DRB1 locus in humans and chimpanzee, we analyzed the nucleotide sequence of a 37.6-kb chimpanzee chromosomal segment containing the entire Patr-DRB1*0701 allele and the flanking nongenic region and we compared it with two corresponding human sequences containing the HLA-DRB1*070101 allele using the sequence of HLA-DRB1*04011 as an outgroup. Because the allelic pair of HLA-DRB1*070101 and Patr-DRB1*0701 shows the lowest number of substitutions between the two species, it appears that these sequences diverged close to the time of the humans–chimpanzee divergence (6 million years ago). Alignment of the nucleotide sequences for HLA-DRB1*070101 and Patr-DRB1*0701 alleles showed that they share a high degree of similarity, suggesting that the studied chromosomal segments with these sequences have not been subjected to recombination since the humans–chimpanzee divergence. Comparison of the flanking 10.6 kb of nongenic sequences revealed an average of 41.5 and 83 single nucleotide substitutions in humans and chimpanzee, respectively. Thus, the species-specific nucleotide substitution rates in the flanking nongenic region were estimated to be 6.53 × 10−10 and 1.31 × 10−9 per site per year in humans and chimpanzee, respectively. Unexpectedly, the estimated rate in humans was twofold lower than in chimpanzee ( P < 10−3, Tajima’s relative rate test) and lower than the average substitution rate in the human genome. Because the nucleotide substitution rate in nongenic regions free from selection is expected to be equal to the mutation rate, the estimated substitution rate should correspond to the species-specific mutation rate at the DRB1 locus. Our results strongly suggest that the mutation rate at DRB1 locus differs among species. [ABSTRACT FROM AUTHOR]

Discusses the drainage network analysis for regional partitions of alluvial paddy-field soils. Determination of soil chemical properties; Methods of clustering soil sampling points; Digital elevation model production and drainage network analysis; Clustering for soil sampling points; Correspondence between landform division and soil classification.

Dendritic cells (DCs) are the most important antigen-presenting cells. Many recent studies have compared the function of immature DCs (iDCs) and mature DCs (mDCs), but there have been few reports of the molecular changes that occur in DCs during maturation. Here, we report on differential gene expression in iDCs generated from peripheral blood monocytes compared with mDCs. Gene expression was evaluated using the differential display method after activation of iDCs with a low concentration of lipopolysaccharide (LPS) to induce maturation. Proteasome subunit alpha type 3 (PSMA3), transcription factor EC (TFEC) isoform and BTK region clone 2f10-rpi were transiently upregulated. Tryptophanyl-tRNA synthetase and CD63 antigen were upregulated for at least 24 h. Neuronal apoptosis inhibitory protein (NAIP) and transforming growth factor-β-induced 68 kDa protein were downregulated. This is the first report of NAIP expression in human DCs. By comparing the expression of NAIP with that of other members of the inhibitor of apoptosis protein (IAP) family and the Bcl -2 family, only NAIP was found to be strongly expressed in iDCs before stimulation by LPS. PSMA3 was also induced in the DCs stimulated with immune complex. These findings might contribute to our understanding of DC maturation and the effectiveness of DC-based vaccines. [ABSTRACT FROM AUTHOR]

Abstract: Ascidiacyclamide (ASC), cyclo(-Ile[sup 1]-Oxz[sup 2]-d-Val[sup 3]-Thz[sup 4]- )[sub 2] (Oxz=oxazoline and Thz=thiazole) has a C[sub 2]-symmetric sequence, and the relationships between its conformation and symmetry have been studied. In a previous study, we performed asymmetric modifications in which an Ile residue was replaced by Gly, Leu or Phe to disturb the symmetry [Doi et al. (1999) Biopolymers49, 459–469]. In this study, the modifications were extended. The Ile[sup 1] residue was replaced by Gly, Ala, aminoisobutyric acid (Aib), Val, Leu, Phe or d-Ile, and the d-Val[sup 3] residue was replaced by Val. The structures of these analogs were analyzed by X-ray diffraction, [sup 1]H NMR and CD techniques. X-Ray diffraction analyses revealed that the [Ala[sup 1]], [Aib[sup 1]] and [Phe[sup 1]]ASC analogs are folded, whereas [Val[sup 1]]ASC has a square form. These structures are the first examples of folded structures for ASC analogs in the crystal state and are similar to the previously reported structures of [Gly[sup 1]] and [Phe[sup 1]]ASC in solution. The resonances of amide NH and Thz CH protons linearly shift with temperature changes; in particular, those of [Aib[sup 1]], [d-Ile[sup 1]] and [Val[sup 3]]ASCs exhibited a large temperature dependence. DMSO titration caused nonlinear shifts of proton resonances for all analogs and largely affected [d-Ile[sup 1]] and [Val[sup 3]]ASCs. A similar tendency was observed upon the addition of acetone to peptide solutions. Regarding peptide concentration changes, amide NH and Thz CH protons of [Gly[sup 1]]ASC showed a relatively large dependence. CD spectra of these analogs indicated approximately two patterns in MeCN solution, which were related to the crystal structures. However, all spectra showed a similar positive Cotton effect in TFE solution, except that of [Val[sup 3]]ASC. In the cytotoxicity test using P388 cells, [Val[sup 1]]ASC exhibited the strongest activity, whereas the epimers of ASC ([d-Ile[sup 1]] and [Val[sup 3]]ASCs), showed fairly moderate activities. [ABSTRACT FROM AUTHOR]

The purpose of the present study was to clarify the relationship between the flow of a bolus and occlusal condition during mastication. First, the characteristics of a bolus under mastication was measured in subjects having different occlusal conditions. Secondly, the flow of a bolus between the upper and lower first molars under mastication was simulated using finite element non-linear dynamic analysis. Measurement of the elasticity of the bolus clarified the phenomenon of its communition. The measurement of the viscosity of the bolus clarified the phenomenon of its mixing with saliva. In addition, a relationship between the elasticity and the viscosity of the bolus at the point of just before swallowing was investigated. The flow of the bolus under mastication was revealed to vary according to the occlusal condition. These results suggest a close relationship between the occlusal condition, the flow of the bolus and its characteristics. [ABSTRACT FROM AUTHOR]

RANTES, a member of C-C chemokine, is known to be produced at sites of granulomatous reactions in the lung of sarcoidosis. RANTES is a potent eosinophil and lymphocyte attractant with particular preference for CD45RO+ T cells and eosinophils. Polymorphism of the RANTES promoter has recently been shown to be related to allergic and infectious diseases; atopic dermatitis, asthma, and polymyalgia rheumatica. Considering that this might affect sarcoidosis, we studied polymorphism of the RANTES gene in 114 patients with sarcoidosis and 136 healthy control subjects. Their genotypes were determined using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). Although no difference in the genotype distribution between healthy control subjects and sarcoidosis patients was identified, the difference in the frequencies of the patients with three or more organ involvement was significant (P <0.01) with the frequency of those in AA genotype being elevated (P <0.05). BAL findings in 48 out of 114 patients who underwent bronchoscopy were reviewed. The CD4/8 ratio of lymphocytes in bronchoalveolar lavage fluid in the patients with AA genotype was significantly increased (P <0.05). From the results, we suggest that in RANTES gene polymorphism the homozygous A allele might be a genetic risk factor for extent disease of sarcoidosis. [ABSTRACT FROM AUTHOR]

In order to make clear the structural role of the C-terminal amide group of endomorphin-2 (EM2, H-Tyr-Pro-PhePhe-NH[sub 2]), an endogenous μ-receptor ligand, in the biological function, the solution conformations of endomorphin-2 and its C-terminal free acid (EM2OH, H-Tyr-Pro-Phe-Phe-OH), studied using two-dimensional ¹H NMR measurements and molecular modeling calculations, were compared. Both peptides were in equilibrium between the cis and trans isomers around the Tyr-Pro ω bond in a population ratio of ≈ 1 : 2. The lack of significant temperature and concentration dependence of NH protons suggested that the NMR spectra reflected the conformational features of the respective molecules themselves. Fifty possible 3D structures for the each isomer were generated by the dynamical simulated annealing method under the proton-proton distance constraints derived from the ROE cross-peaks. These energy-minimized conformers, which were all in the φ torsion angles estimated from J[sub NHCαH] coupling constants within ± 30°, were then classified in groups one or two according to the folding backbone structures. All trans and cis EM2 conformers adopt an open conformation in which their extended backbone structures are twined at the Pro²-Phe³ moiety. In contrast, the trans and cis conformers of EM2OH show conformational variation between the 'bow'-shaped extended and folded backbone structures, although the cis conformers of its zwitterionic form are refined into the folded structure of the close disposition of C- and N-terminal groups. These results indicate clearly that the substitution of carboxyl group for C-terminal amide group makes the peptide flexible. The conformation requirement for μ-receptor activation has been discussed based on the active form proposed for endomorphin-1 and by comparing conformational features of EM2 and EM2OH. [ABSTRACT FROM AUTHOR]

Background: Alloimmune neonatal neutropenia (ANN) is caused by a reaction of maternal alloantibodies with paternally inherited antigens on the fetal neutrophils. While human neutrophil antigens (HNA) antibodies are found in half of ANN cases, specific antibodies have not been defined in the remaining cases.Study Design and Methods: Reported here is a neonate with omphalitis due to neutropenia. To elucidate the cause of ANN, flow cytometric and PCR analyses were used. Reactions of the patient's and mother's sera with neutrophils, lymphocytes, and platelets were examined by lymphocytotoxicity test (LCT), anti-human immunoglobulin-LCT, and mixed passive hemagglutination test.Results: The maternal sera reacted with neutrophils, lymphocytes, and platelets of the patient and father. The platelet adsorption eliminated the reaction of the maternal serum with the patient's neutrophils. The HLA typing of the family and an LCT using a panel of lymphocytes of 20 HLA-typed donors showed HLA-A2 antigen as a target of antibodies in the maternal serum. According to anti-human immunoglobulin-LCT, the anti-HLA-A2 was present in the neonatal serum. On the other hand, HNA antibodies were not detectable in the patient's or the mother's serum.Conclusion: These results suggest that the transplacental passage of the maternal HLA antibody caused neutropenia in this patient. [ABSTRACT FROM AUTHOR]

Desmoplastic ameloblastoma is a rare variant of ameloblastoma and only 54 cases have been previously reported in the English literature. We report ten cases of desmoplastic ameloblastoma of the jaw observed between 1972 and 1998 and discuss the pathogenesis of the tumor. Eight of the ten tumors were located in the anterior region of the jaw. Radiographically, six cases showed mixed radiolucent/radiopaque appearance with ill-defined margins and the other four cases lacked typical findings of ameloblastomas. The tumors were located mainly in the alveolar region and occupied the tooth-bearing area, without tooth resorption or impacted teeth. Histologically, the desmoplastic ameloblastomas were characterized by extensive stromal desmoplasia, and small tumor nests of odontogenic epithelium were scattered in the stroma. Oxytalan fibers stained by potassium monopersulfate-aldehyde fuchsin were demonstrated in the stroma of all desmoplastic ameloblastomas. From these findings, we presumed that the desmoplastic ameloblastomas might have developed in the periodontal membrane. [ABSTRACT FROM AUTHOR]

A 8-month-old, female miniature Dachshund dog was presented for the complaint of pruritic, generalized, multiple nodules and plaques. Two months previously, a nodule on the left pinna was excised and diagnosed as a cutaneous histiocytoma. One month post-excision, a nodule reappeared at the same site and, shortly thereafter, additional nodules developed. Histopathological examination revealed a diffuse proliferation of histiocytic cells, which reacted strongly to antibodies for vimentin and lysozyme. Immunophenotypic analysis showed that most of the cells expressed CD1a, CD1c, CD11c, CD18, CD45 and MHC class II markers. Electron microscopic examination revealed cytoplasmic filopodia and paracrystalline structures. These findings indicated that the cells originated from Langerhans’ cell. The disease progressed despite glucocorticoid therapy and griseofulvin was administered as an immunomodulating drug. All lesions resolved completely after 7 weeks of griseofulvin treatment. The dog, however, died three months later after discontinuation of griseofulvin therapy and a necropsy was not performed. It is considered that the present canine dermatosis corresponds with a severe form of Langerhans’ cell histiocytosis in humans rather than canine cutaneous histiocytoma. [ABSTRACT FROM AUTHOR]

Her screening gastroduodenoscopy showed a 1-cm semi-pedunculated polyp in the second part of the duodenum which was removed via hot snare polypectomy and another large pedunculated polyp measuring 4 × 5 cm in the fourth part of the duodenum (D4) (Fig. Gastrointestinal: Underwater selective ligation of a large duodenal Peutz-Jeghers polyp using a detachable snare On follow-up endoscopy, the initial plan of endoscopic resection was aborted due to the benign biopsy findings, the large polyp size, and difficult location of the duodenal polyp. [Extracted from the article]

Abstract: A structural feature of aureobasidins, cyclic depsipeptide antibiotics produced by Aureobasidium pullulans R106, is the N‐methylation of four out of seven amide bonds. In order to investigate possible relationship between the molecular conformation and the amide N‐methylation, aureobasidin A (AbA), which exhibits the potent antifungal activity, was subjected to X‐ray crystal analysis. The crystal, recrystallized from ether (orthorhombic, space group P2[sub 1]2[sub 1]2[sub 1], a = 21.643 (3) Å, b = 49.865(10) Å, c = 12.427 (1) Å, Z = 8), contained two independent conformers per asymmetric unit and they took on a similar arrowhead‐like conformation. The conformation consisted of three secondary structures of antiparallel β‐sheet, and β‐ and γ‐turns, and was stabilized by three intramolecular and transannular N‐H[sup ...]O=C hydrogen bonds. The β‐hydroxy‐N‐methyl‐l‐valine residue, which is indispensable for its bioactivity, was located at the tip of the corner. Since a nearly identical conformation has been observed for aureobasidin E, a related cyclic depsipeptide, this arrowhead‐like conformation may be energetically stable and important for biological activity. The contribution of the amide N‐methylation to the conformation was investigated by model building and energy calculations. The energy‐minimizations of AbA analogs, in which some (one to four) of four N‐methylated amide bonds were replaced with usual amide bond, led to some conformers which are fairly different from the arrowhead form of AbA, although they are stabilized by three intramolecular N‐H[sup ...]O=C hydrogen bonds. This result explains the reason why four out of the seven amide bonds have to be methylated to manifest biological activity, i.e. the high N‐methylation of aureobasidin is necessary to form only one well‐defined conformation. [ABSTRACT FROM AUTHOR]

gTwenty cases of malignant lymphomas (ML) of the oral cavity were reviewed in the light of recent histologic classification. They occurred in 12 male and 8 female patients, with the age range of 11-80 years (median 51 years of age). Eighty percent of patients were stages IE and IIE. Histologically, 15 cases (75%) were ordinary non-Hodgkin's lymphoma (NHL) with diffuse large cell type being the most common. The remaining 5 cases, undefinable by classification scheme for ordinary NHL, were designated as malignant histocytosis of the oral cavity (3 cases) and peripheral T-cell lymphoma (2 cases), respectively. There were no cases of follicular lymphoma. The present cases comprised 45%, of high grade. 40% of intermediate grade, and 15% of low grade malignancy. A follow-up study showed that the stage of diseage, histologic classification, and frequency of mitosis correlated well with survival. [ABSTRACT FROM AUTHOR]

The new monoclonal antibodies (MoAbs) E401, E811, E907 and E919 were prepared and characterized. These recognized an extracellular domain (amino acids No. 292-370) on the human c-erbB-2 gene product. Utilizing MoAb E811 and MoAb E919, a double determinant immunoassay (DDIA) was established to detect the soluble and the shed forms of the c-erbB-2 molecule. The levels of circulating erbB-2 antigen in the sera of patients with benign diseases and healthy controls were very low. The incidence of positivity for shed c-erbB-2 antigen in gastric cancer, colonic cancer, gall-bladder cancer, pancreatic cancer and other cancers were 7.4%, 4.2%, 0%, 6.7% and 0%, respectively. Four of 54 patients with gastric carcinoma showed high levels of serum c-erbB-2 antigen. They belonged to clinical stage IV and their histological types were all well differentiated adenocarcinomas (two papillary and two tubular adenocarcinomas). Furthermore, the incidence of positive staining in gastric cancer was 34.6%; higher than that for shedding erbB-2 antigen. Most of the cases which showed erbB-2 expression on cells were well-differentiated adenocarcinomas. Meanwhile, the distribution of erbB-2 antigen was limited in normal tissues. The results suggest that the expression of erbB-2 antigen is largely restricted to adenocarcinoma cells. It may not shed easily from these cells, and therefore it may be a very useful target molecule for passive immunotherapy. [ABSTRACT FROM AUTHOR]