bluuebunny/crossref_metadata_2025 huggingface dataset:
Muscarinic acetylcholine receptor activation increases transcellular transport of macromolecules across mouse and human intestinal epitheliumin vitro
Authors: Cameron H. L. , Perdue M. H.
Published: December 2006

Abstract The intestinal epithelium acts as a barrier restricting uptake of luminal macromolecules such as dietary antigens and microbes. Here, we examined the role of cholinergic signalling in the regulation of permeability to macromolecules. Mouse jejunum was mounted in Ussing chambers and permeability was determined by measuring the flux of the antigen‐sized protein, horseradish peroxidase (HRP), across the tissue. Baseline HRP permeability was significantly reduced by neural blockade with tetrodotoxin or cholinergic muscarinic antagonism with atropine, suggesting that ongoing release of endogenous acetylcholine from enteric nerves regulates barrier function. Exogenous addition of the muscarinic agonist bethanechol caused significant increases in both HRP flux and the area of HRP‐containing endosomes in enterocytes. Bethanechol‐enhanced HRP flux was abrogated by the M3 receptor antagonist, 4‐diphenylacetoxy‐N‐methylpiperidine methiodide (4‐DAMP), the phospholipase A2inhibitor quinacrine, and the cyclooxygenase inhibitor indomethacin. Complementary in vitro studies showed direct effects of bethanechol on T84 epithelial cells, where increased HRP uptake was associated with increased F‐actin, and increased cytosolic phospholipase A2(cPLA2) phosphorylation. Taken together, these results provide evidence for cholinergic regulation of transepithelial transport of macromolecules, mainly mediated by activation of M3 receptors with subsequent involvement of phospholipase A2and cyclooxygenase products.
Pharmacodynamic effects of a novel prokinetic 5‐HT4 receptor agonist, ATI‐7505, in humans
Authors: Camilleri M. , Vazquez‐roque M. I. , Burton D. , Ford T. , Mckinzie S. , Zinsmeister A. R. , Druzgala P.
Published: December 2006

Abstract  ATI‐7505, an investigational 5‐HT4 receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI‐7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI‐7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel‐group, double‐blind, placebo‐controlled study evaluated effects of 9‐day treatment with ATI‐7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric‐emptying (GE) T1/2, colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T1/2. Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T1/2 (P = 0.154); the 20 mg t.i.d. of ATI‐7505‐accelerated GE vs placebo (P = 0.038). ATI‐7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI‐7505 accelerated AC emptying T1/2 (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI‐7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.
Functional P2X7 Receptor Polymorphisms (His155Tyr, Arg307Gln, Glu496Ala) in Patients with Crohn's Disease
Authors: Haas S. L. , Ruether A. , Singer M. V. , Schreiber S. , Böcker U.
Published: December 2006

Genetic factors contribute to inflammatory bowel diseases. Recently, the P2X7 receptor was found to be a key player in caspase‐1‐mediated processing of the proinflammatory cytokines, interleukin‐1β and interleukin‐18. We therefore aimed to determine whether the gain‐of‐function single nucleotide polymorphism (SNP) His155Tyr and the loss‐of‐function SNP Arg307Gln and Glu496Ala were associated with susceptibility to Crohn's disease (CD). For association analysis, 681 unrelated CD patients and 736 healthy controls were enrolled. Furthermore, 490 CD trios were included for segregation analysis. Genotyping was performed by the application of the TaqMan® MGB biallelic discrimination system. The Arg307Gln polymorphism revealed a borderline significant difference in genotype frequencies between CD patients and controls (P = 0.06) without implying any pathological significance because of low case numbers. Case–control statistics for the variants His155Tyr and Glu496Ala showed no association with CD phenotype (P = 0.19 and 0.99). Subsequent family‐based transmission disequilibrium test did not prove an association of the investigated single‐nucleotide polymorphisms with CD. In conclusion, the analysed intragenetic variants of the P2X7 receptor may not be a susceptibility factor for CD.
Commonly Used Reference Genes are Actively Regulated in In vitro Stimulated Lymphocytes
Authors: Røge R. , Thorsen J. , Tørring C. , Øzbay A. , Møller B. K. , Carstens J.
Published: December 2006

Quantitative polymerase chain reaction (Q‐PCR) studies of urine sediments have demonstrated an increased expression of cytotoxin genes during episodes of acute rejection of renal allografts. To compensate for differences in initial sample size and cDNA preparation, standard Q‐PCR experiments involve normalization to a reference gene. Although stable expression of reference genes is a prerequisite for any Q‐PCR analysis, commonly used reference genes have demonstrated a varying expression across tissues and various stimuli. In this study, cellular expression of several reference genes was investigated in a mixed lymphocyte reaction as a model of gene expression during alloreactive T‐lymphocyte activation and acute rejection. Gene expression was quantified using Q‐PCR, normalized to cell counts obtained by DNA quantification and corrected for cell polyploidy using flow cytometry. Examined reference genes were 18S rRNA, β‐actin (ACTB), hydroxymethylbilane synthase (HMBS), hypoxanthine phosphoribosyltransferase (HPRT1) and peptidylprolyle isomerase B (PPIB). This study also examined two novel T‐lymphocyte‐specific reference genes: CD3E and CD8B. HMBS and HPRT were 18.8‐ and 7.4‐fold upregulated, respectively, ACTB was 5.3‐fold upregulated, PPIB was 3.2‐fold upregulated while 18S rRNA remained stably expressed. The T‐lymphocyte‐specific reference gene CD3E remained stable while CD8B was upregulated 2.3‐fold. In conclusion, several commonly used reference genes were actively regulated during alloreactive T‐lymphocyte activation. Additionally, we introduce two stable T‐lymphocyte‐specific reference genes that might be useful in a Q‐PCR analysis of T‐lymphocyte‐specific cytotoxin genes in urine sediments, as they overcome the contribution of reference gene mRNA from cells irrelevant for diagnosis.
Interferon‐βMediates Opposing Effects on Interferon‐γ‐dependent Interleukin‐12 p70 Secretion by Human Monocyte‐Derived Dendritic Cells
Authors: Nagai T. , Devergne O. , Van Seventer G. A. , Van Seventer J. M.
Published: December 2006

Interferon‐β(IFN‐β) exposure during tumour necrosis factor‐α(TNF‐α)‐induced human monocyte‐derived dendritic cell (DC) maturation augments the capacity of DC to promote the generation of T helper 1 (Th1) cells, while IFN‐βexposure during naive Th cell stimulation inhibits Th1 cell generation (Nagai et al., J Immunol, 2003171:5233–43). Investigating these contradictory outcomes of IFN‐βexposure, we find that isolated DC matured with both TNF‐αand IFN‐βsecrete more IL‐12 p70 upon CD40L stimulation than DC matured with TNF‐αalone. mAb blocking studies indicate that the basis for this enhanced IL‐12 p70 production is augmentation of two successive CD40‐dependent autocrine pathways in the DC: (1) a pathway in which low levels of IL‐12 p70, IL‐27, IL‐18 and, possibly, IL‐23 act to mediate autocrine induction of DC IFN‐γsecretion; and (2) an IFN‐γ‐initiated autocrine pathway promoting optimal DC IL‐12 p70 secretion. In contrast to the IL‐12 p70 promoting effects of IFN‐βduring DC maturation, IFN‐βpre‐treatment before CD40L stimulation was found to inhibit IFN‐γ‐mediated enhancement of DC IL‐12 p70 secretion. Thus, IFN‐βexposure during TNF‐α‐mediated DC maturation may promote Th1 polarization by increasing DC IL‐12 p70 secretion, through enhancement of autocrine‐acting IFN‐γproduction by the DC. Moreover, IFN‐βexposure during naive Th cell stimulation may inhibit Th1 cell generation by blocking the IFN‐γ‐induced signals required for optimal CD40L‐induced DC IL‐12 p70 secretion. IFN‐βpre‐treatment was also observed to inhibit CD40L‐induced DC IL‐23 secretion. Our findings may account for some of the beneficial effects of IFN‐βtherapy in patients with relapsing remitting multiple sclerosis.
Airway Inflammation and Bronchial Remodelling in Toluene Diisocyanate‐exposed BALB/c Mouse Model
Authors: Sun L.‐Z. , Elsayed S. , Bronstad A. M. , Van Do T. , Irgens Å. , Aardal N. P. , Aasen T. B.
Published: December 2006

Toluene diisocyanate (TDI), a highly reactive industrial chemical, is one of the leading causes of occupation‐related asthma in industrialized countries. The pathogenesis of TDI‐induced asthma, however, remains not fully understood, in part due to lack of appropriate animal models. Twenty five female BALB/c mice (age: 8 weeks) were randomly divided into 5 groups: Ovabumin (OVA); OVA peptide amino acid residues No. 323–339 (Pep); TDI; alum and physiological saline. Mice were intraperitoneally injected with 25 μg OVA or pep absorbed on 300 μg alum, 300 μg alum or saline on days 0, 7 and 14. For the TDI group, mice were sensitized subcutaneously with 20 μl neat TDI on day 0; 20 μl of TDI in olive oil (1:10) on days 7 and 14; on days 21–23. Then each group was challenged intranasally with 20 μl of 1% OVA, 1% Pep, 1% TDI, 10% alum and saline respectively. On day 28, mice were killed under pentothal anesthesia. The results demonstrated that neutrophil‐dominant inflammation with a few eosinophil infiltration occurred in the peri‐bronchial and peri‐vascular regions of the lungs. This was accompanied by hyperplasia/hypertrophy of cells lining the airways and mucus production as shown by HE staining. Positive immunohistochemical MBP staining in parenchyma was also shown. Th2 cytokine IL‐4 and IgE production were significant increased 5 days after last challenge while IFN‐γ level was below the detection limit. Conclusion: the clear elevation of IL‐4 and IgE could allow to conclude a possible Th2‐like dominated allergic response in TDI‐exposed BALB/c mouse model.
The symbiotic ion channel homolog DMI1 is localized in the nuclear membrane of Medicago truncatula roots
Authors: Riely Brendan K. , Lougnon Géraldine , Ané Jean‐Michel , Cook Douglas R.
Published: December 2006

Legumes utilize a common signaling pathway to form symbiotic associations both with rhizobial bacteria and arbuscular mycorrhizal fungi. The perception of microbial signals is believed to take place at the plasma membrane, activating a cascade that converges on the nucleus where transcriptional reprogramming facilitates the symbioses. Forward genetic strategies have identified genes in this signaling pathway including Medicago truncatulaDMI1 (Doesn't Make Infections 1) that encodes a putative ion channel. Although the DMI1 homologs from Lotus japonicus, CASTOR and POLLUX, were recently reported to be localized in plastids, we report here that a functional DMI1::GFP fusion is localized to the nuclear envelope in M. truncatula roots when expressed both from a constitutive 35S promoter and from a native DMI1 promoter. Localization may be mediated in part by sequences located within the amino‐terminus of DMI1. This region of DMI1 is required for symbiotic signal transduction, and its replacement with a bona fide plastid transit peptide from the glutamine synthetase 2 gene does not restore DMI1 function. These new data place DMI1 in the nuclear envelope in close proximity to the origin of Nod‐factor‐induced calcium spiking.
Pimecrolimus 1% cream in the treatment of vulvar lichen sclerosus in postmenopausal women
Authors: Oskay Tugba , Kaya Sezer Halime , Genç Cüneyt , Kutluay Lale
Published: December 2006

Background  Vulvar lichen sclerosus (LS), a poorly recognized chronic inflammatory skin disease, may represent a therapeutic challenge. Pimecrolimus cream 1% is a nonsteroidal, selective inflammatory cytokine inhibitor that has recently been indicated for some inflammatory cutaneous diseases.

Objective  To investigate the efficacy, tolerability, and safety of 1% pimecrolimus cream therapy in postmenopausal women with LS.

Methods  A total of 16 patients applied pimecrolimus cream 1% twice a day over the first 3 months and then as required. All the patients completed this study and were then followed up over the next 12 months. The symptoms and clinical appearance of the lesions in every subject were recorded before and after treatment using a severity scale.

Results  Using pimecrolimus, most of the patients exhibited a significant improvement with respect to symptoms and the clinical appearance of the disease. After 3 months of treatment, complete remission was seen in 11 patients, partial remission in four, whereas one patient experienced no response at all. Over the subsequent 12 months of follow‐up, 10 patients exhibited complete remission while five had partial remission. Four cases with complete remission experienced a few relapses during the follow‐up period. Older patients and those with an advanced stage of the disease responded poorly. No significant side effects were observed.

Conclusions  Pimecrolimus cream 1% appears to be an effective and well‐tolerated therapeutic alternative option in the treatment of early stage of vulvar LS. Pimecrolimus may reduce the incidence of flare ups, improve long‐term disease control, and enhance the patients’ quality of life, especially in postmenopausal women.
A novel HLA‐DQB1*06 allele, DQB1*0628†, found through routine sequence‐based HLA typing and confirmation of DQB1*060302
Authors: Witter K. , Albert T. , Zahn R. , Kauke T.
Published: December 2006

In this paper we report the identification of human leukocyte antigen (HLA)‐DQB1*0628 and the confirmation of HLA‐DQB1*060302.
Haplotype association of IL‐8 gene with Behcet’s disease
Authors: Lee E. B. , Kim J. Y. , Zhao J. , Park M. H. , Song Y. W.
Published: December 2006

Interleukin‐8 (IL‐8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of Behcet’s disease (BD). To investigate the association of the genetic polymorphism of IL‐8 and BD, we genotyped IL‐8 −845 T/C, −738 T/A, −353 A/T, −251 A/T, +293 G/T, +678 T/C and receptors CXCR‐1 +2607 G/C and CXCR‐2 +785 C/T polymorphisms in 119 Korean patients with BD and 119 age‐ and sex‐matched healthy blood donors. Then, single nucleotide polymorphisms (SNPs) and haplotypes were analyzed between patients and controls. There were no SNPs associated with BD. However, the frequency of haplotype TAT inferred from SNPs, IL‐8 −353 A/T, −251 A/T and +678 T/C, was significantly higher in patients with BD than controls (5.9 vs 0.0%, P = 0.0001), as was haplotype ATC (6.7 vs 0.0%, P < 0.0001). The haplotype difference was still valid in human leukocyte antigen‐B51‐negative subjects. In conclusion, we found a significant difference in the distribution of IL‐8 gene haplotypes between patients with BD and healthy controls. These results suggest that the genetic polymorphisms of proinflammatory chemokine IL‐8 can contribute to the pathogenesis of BD.
Immune regulation by mesenchymal stem cells: two sides to the coin
Authors: Stagg J.
Published: December 2006

Mesenchymal stem cells (MSCs) constitute a rare population of adult stem cells that can be isolated from a simple bone marrow aspirate in the absence of prior mobilization. For this reason, MSCs are particularly attractive for cell‐based medicine. Ex‐vivo‐expanded MSCs isolated from different species, including human MSCs, have been shown to suppress the activity of a broad range of immune cells, including T cells, antigen‐presenting cells, natural killer (NK) cells and B cells. New studies have further shown that MSCs interact with NK cells, express NK cell receptor ligands, express Toll‐like receptors (TLRs), respond to TLR ligands and act as antigen‐presenting cells upon interferon‐γ stimulation. Taken together, these studies suggest that MSCs may constitute a previously unrecognized player of the immune system with dichotomy of function reminiscent of other antigen‐presenting cells. An important question that remains unanswered is whether resident MSCs actually play a role in endogenous immune responses? I here review the mechanisms of MSC‐mediated immune regulation and discuss the major roles of resident MSCs in health and disease.
Leaf age‐related changes in respiratory pathways are dependent on complex I activity in Nicotiana sylvestris
Authors: Priault Pierrick , Vidal Guillaume , De Paepe Rosine , Ribas‐Carbo Miquel
Published: December 2006

The observed decrease in respiration during rosette leaf maturation of Nicotiana sylvestris wild‐type (WT) plants was shown to be because of a decline in the cytochrome oxidase (COX) pathway activity, measured by 18O/16O oxygen discrimination, while the alternative oxidase pathway (AOX) remained stable. This suggests a higher contribution of the COX pathway to growth respiration than to maintenance respiration. Mitochondrial superoxide dismutase (MnSOD) activity paralleled the decrease in COX activity with leaf age, whereas chloroplastic FeSOD activity increased. Age‐dependent respiratory changes were much less apparent in the Cytoplasmic Male Sterile II (CMSII) mitochondrial mutant devoid of respiratory complex I and previously shown to possess increased AOX content and enhanced respiration but lower photosynthesis in mature leaves. Respiration declined less rapidly with leaf age in CMSII than in the WT, and was significantly higher in the mutant when compared with the WT in mature leaves only. In contrast, photosynthesis was lower in the mutant than in the WT at all leaf stages. The higher respiration of mature CMSII leaves was supported exclusively by enhanced COX activity, in association with an increased mitochondrial MnSOD activity. Steady‐state levels of AOX1 transcripts increased in maturing WT leaves, and the CMSII mutant had higher amounts of coxI, AOX1 and MnSOD transcripts than the WT. Enhanced activity of the proton‐pumping COX route in the mutant can be viewed as a compensation for the lack of the first coupling site of the respiratory chain. However, this is not quite sufficient to ensure normal growth rates in the mutant.
Lidocaine exerts its effect on induced bronchospasm by mitigating reflexes, rather than by attenuation of smooth muscle contraction
Authors: Groeben H. , Peters J.
Published: December 2006

Background:  Lidocaine inhalation attenuates histamine‐induced bronchoconstriction, as well as bronchoconstriction elicited by mechanical irritation. This effect could be mediated by direct effects on smooth muscle or by reflex attenuation. Therefore, we evaluated whether lidocaine attenuated the bronchial response of direct smooth muscle stimulation with methacholine.

Methods:  In 15 volunteers with bronchial hyperreactivity, a methacholine challenge was performed following the inhalation of lidocaine, dyclonine (which does not attenuate bronchial reactivity) or saline on three different days in a randomized, double‐blind fashion. Lung function, response to methacholine, and lidocaine and dyclonine plasma concentrations were measured.

Results:  The inhaled methacholine concentration (PC20) necessary for a 20% decrease in the forced expiratory volume in 1 s (FEV1) was 8.8 ± 6.1 mg/ml at the screening evaluation. The sensitivity to methacholine challenge (PC20) remained unchanged regardless of which solution was inhaled (9.1 ± 7.5 mg/ml for lidocaine, 10.2 ± 9.0 mg/ml for dyclonine and 9.8 ± 8.3 mg/ml for saline; P= 0.58, means ± standard deviation). Furthermore, the inhalation of all three solutions caused a significant decrease in FEV1 from baseline (P= 0.0007), with a significantly larger effect for dyclonine than lidocaine (P= 0.0153).

Conclusions:  Although both inhaled and intravenous lidocaine attenuates histamine‐evoked bronchoconstriction, it does not alter the response to methacholine. Therefore, the attenuation of bronchial reactivity by lidocaine appears to be related solely to neurally mediated reflex attenuation, rather than to the attenuation of direct constriction of airway smooth muscle.
Propofol causes more hypotension than etomidate in patients with severe aortic stenosis: a double‐blind, randomized study comparing propofol and etomidate
Authors: Bendel S. , Ruokonen E. , Pölönen P. , Uusaro A.
Published: December 2006

Background:  Vasodilatation and hypotension are thought to be harmful in patients with severe aortic stenosis. Etomidate is preferred to propofol for anaesthesia induction in haemodynamically unstable patients, but may disturb cortisol synthesis. We assessed the haemodynamic effects of etomidate vs. propofol as anaesthesia induction agents, and the effects of these drugs on cortisol concentrations, in patients with severe aortic stenosis. The main end‐point of the study was the incidence of hypotension.

Methods:  Sixty‐six patients with severe aortic stenosis scheduled for elective aortic valve replacement were enrolled in the study. The patients were randomized to receive either propofol or etomidate for induction of anaesthesia. Haemodynamic parameters, i.e. mean arterial pressure (MAP), pulmonary capillary wedge pressure (PCWP) and cardiac index (CI), were measured. If MAP decreased below 70 mmHg for more than 30 s, phenylephedrine was administered. Serum cortisol concentrations were also measured.

Results:  MAP decreased in all patients (P < 0.001). MAP decreased to a greater extent in patients receiving propofol than in those receiving etomidate (P= 0.006). Patients receiving propofol needed phenylephedrine more often than those receiving etomidate (20/30 vs. 8/30, P= 0.002). CI and PCWP decreased in both groups (P < 0.001), with no difference between the groups. Patients receiving etomidate had a lower serum cortisol concentration immediately after the operation than those receiving propofol (P < 0.001), but no differences between the groups were observed on the first post‐operative morning.

Conclusion:  Propofol is twice as likely as etomidate to evoke hypotension in anaesthesia induction of patients with severe aortic stenosis; however, etomidate transiently decreases post‐operative serum cortisol concentrations.
Can the Cerebral State Monitor replace the Bispectral Index in monitoring hypnotic effect during propofol/remifentanil anaesthesia?
Authors: Hoymork S. C. , Hval K. , Jensen E. W. , Raeder J.
Published: December 2006

Background:  In 2004, the cerebral state monitor, CSM, was launched as a low‐cost alternative to the bispectral index, BIS, for monitoring depth of sleep during anaesthesia. We tested whether the two monitors would reflect hypnosis equally during propofol/remifentanil anaesthesia.

Methods:  During laparoscopy or breast/surface surgery, 55 non‐paralyzed patients were monitored simultaneously with the BIS and the CSM. Trend curves for the indexes [BIS and cerebral state index (CSI)] were compared for congruence. The difference between the two indexes for the entire course was quantified, and the ability of the two monitors to separate awake from asleep during induction was described.

Results:  In the majority of the patients, 87%, there was a good fit between the indexes. There were major deviations in seven patients, in whom CSI indicated that the patients were awake during parts of the course despite clinical sleep, correctly identified with the BIS. Both indexes separated awake from asleep during induction in the individual patient, but the overlap in values between patients was more pronounced for CSI.

Conclusion:  CSM and BIS show some important differences in measuring hypnotic state during clinical propofol/remifentanil anaesthesia.
The functional status and perceived quality of life in long‐term survivors of out‐of‐hospital cardiac arrest
Authors: Harve H. , Tiainen M. , Poutiainen E. , Maunu M. , Kajaste S. , Roine R. O , Silfvast T.
Published: December 2006

Background:  Limited data exist on how long‐term survivors after pre‐hospital cardiac arrest lead their lives. This study assessed functional status and perceived quality of life in patients surviving for 15 years after successful resuscitation from witnessed out‐of‐hospital cardiac arrest as a result of ventricular fibrillation.

Methods:  A 15‐year follow‐up study of 59 1‐year survivors after successful pre‐hospital resuscitation who were thoroughly evaluated at 3 and 12 months after out‐of‐hospital cardiac arrest. Eleven patients were still alive 15 years later. Ten of them were reached and underwent a comprehensive neuropsychological and neurological examination. Cognitive performance was evaluated and compared with individual results 15 years earlier and with an age‐matched control group. The cause and time of death of the non‐survivors were established.

Results:  All 10 evaluated long‐term survivors lived at home and were independent in their activities of daily living. Their mean age was 72 years. In nine patients there was no change in the present neurological status compared with the status at 1 year after resuscitation, and in one patient it had improved. Five patients were cognitively intact. In four patients mild cognitive problems had emerged or slightly progressed. All but one were satisfied with their perceived quality of life. By the time of examination, the mean survival time for the 1‐year survivors was 7 years, and the mean age at the time of death was 70 years.

Conclusion:  Once good outcome after cardiac arrest is achieved, it can be maintained for more than 10 years.
Roles of the ribosomal protein S19 dimer and the C5a receptor in pathophysiological functions of phagocytic leukocytes
Authors: Yamamoto Tetsuro
Published: December 2006

Monocytes and neutrophils, the major phagocytic leukocytes, migrate to inflammatory sites by sensing chemoattractants such as anaphylatoxin C5a with membrane receptors such as C5a receptor. Upon stimulation, the leukocytes increase cytoplasmic Ca2+ concentration and generate radical oxygen species. These leukocytes have different functions in inflammation. Neutrophils migrate more rapidly and induce vascular plasma leakage upon infiltration. Monocytes infiltrate tissue more slowly but have superior capacities of phagocytosis and antigen presentation. There must be mechanisms to separately recruit the leukocyte species at an inflammatory site. Ribosomal protein S19 (RP S19) is a component of ribosome. During apoptosis, RP S19 is dimerized and obtains a ligand capacity to C5a receptor. The RP S19 dimer attracts monocytes to phagocytically clear the apoptotic cells that released the dimer molecules. The phagocytic monocytes/macrophages then translocate to regional lymph nodes and present apoptotic cell‐derived antigens. Oppositely, the RP S19 dimer inhibits C5a‐induced neutrophil migration and promotes apoptosis of neutrophils via the C5a receptor. The RP S19 dimer seems to prevent excessive tissue destruction induced by neutrophils. Skp is a molecular chaperon of Gram‐negative bacteria. Skp also attracts monocytes and neutrophils as a ligand of C5a receptor. However, it promotes neither cytoplasmic Ca2+ enhancement nor radical oxygen generation.
Lack of association between BRAF V600E mutation and mitogen‐activated protein kinase activation in papillary thyroid carcinoma
Authors: Zuo Hui , Nakamura Yasushi , Yasuoka Hironao , Zhang Ping , Nakamura Misa , Mori Ichiro , Miyauchi Akira , Kakudo Kennichi
Published: December 2006

The BRAF V600E mutation has been identified in a high proportion of papillary thyroid carcinoma (PTC). In cell lines and a transgenic mouse model it has been demonstrated that the mutation constitutively activates the mitogen‐activated protein kinase (MAPK) pathway but in human PTC samples its effects remain unexamined. Herein the correlation of BRAF mutation and MAPK activation was examined in 42 human PTC samples. Activating mutations of the BRAF gene and all three RAS genes were detected by polymerase chain reaction‐direct sequencing, and RET/PTC1 rearrangements were screened by nested reverse transcription–polymerase chain reaction. MAPK activation was assessed by immunohistochemistry and western blot analysis. Twenty‐eight cases (66.7%) of BRAF V600E mutation, three cases (7.1%) of RET/PTC1 rearrangement but no cases of RAS genes mutation were identified. Activated MAPK was found in six cases (14.3%) with only two cases of mutant BRAF. In total 7.1% of PTC with BRAF mutation had activated MAPK. Furthermore, BRAF mutations were more prevalent in patients 0e;45 years, but did not correlate with aggressive clinical behaviors. Absence of association between BRAF mutation and activation of MAPK pathway in PTC suggests the presence of mechanisms that downregulate MAPK activation.
Angiomatous spindle cell lipoma: Report of three cases with immunohistochemical and ultrastructural study and reappraisal of former ‘pseudoangiomatous’ variant
Authors: Zamecnik Michal , Michal Michal
Published: December 2006

Pseudoangiomatous spindle cell lipoma (PASCL) is a rare variant of spindle cell lipoma that is composed of spindle fibroblast‐like cells and mature adipose cells, and that is further characterized by intratumoral branching spaces regarded originally to be non‐vascular (hence the adjective ‘pseudoangiomatous’). Reported herein are three cases of this tumor, with literature review of all six cases described previously. PASCL appears to have clinical features (age, sex, location, prognosis) similar to those of conventional spindle cell lipoma (SCL). Immunohistochemically, the spindle cells in all of the present cases were positive for CD34, as in conventional SCL. All lesions had at least mild positivity for sex steroid hormone receptors. The cells lining intratumoral dilated and branching spaces typical of this variant were strongly positive for lymphatic endothelial marker D2‐40 in all cases, and for vascular markers CD31 and F‐VIII in one case. Ultrastructural study confirmed the endothelial nature of these cells. The results indicate that pseudoangiomatous SCL is truly angiomatous and should be termed as such. It could represent a sex steroid hormone‐dependent lesion.
Autopsy case of desminopathy involving skeletal and cardiac muscle
Authors: Yuri Takashi , Miki Katsuaki , Tsukamoto Reiko , Shinde Akiyo , Kusaka Hirofumi , Tsubura Airo
Published: December 2006

Desminopathy is a familial or sporadic skeletal and cardiac muscular dystrophy caused by mutation in the desmin gene. Desmin‐reactive deposits in the affected muscles are the morphological hallmarks of this disease. Herein is reported an autopsy case of a 57‐year‐old Japanese man with adult‐onset skeletal muscle weakness and atrioventricular (A‐V) conducting block, with a missense A337P mutation in exon 5 of the desmin gene. Disease onset occurred when the patient was 45 years old. The initial presentation was lower limb weakness, and the weakness progressed to the upper limbs. When the patient was 51 years old, a cardiac pacemaker was implanted due to complete A‐V block. When the patient was 53 years old, respiratory insufficiency occurred due to weakness of respiratory muscles, and the patient died at the age of 57 years. On autopsy, intrasarcoplasmic desmin‐immunoreactive deposits were identified in the skeletal and cardiac muscle, and abnormal accumulations of granulofilamentous material were identified at the ultrastructural level. In the cardiac conducting system, calcification was observed at the bundle of His, and sporadic calcium deposits were observed at the left and right bundle branches.
Pure acinic cell carcinoma of the breast in an 80‐year‐old Japanese woman
Authors: Tanahashi Chisato , Yabuki Suguru , Akamine Noriko , Yatabe Yasushi , Ichihara Shu
Published: December 2006

Acinic cell carcinoma of the breast is an uncommon neoplasm. Since the first case of this rare variant of breast carcinoma was reported in 1996, only 10 cases have been reported in the English‐language literature. Reported herein is the first case of primary acinic cell carcinoma of the breast in a Japanese woman. To the naked eye, the tumor appeared well circumscribed and the cut surface was grayish‐pink and hemorrhaging. Microscopically, the tumor was predominantly made up of a monotonous proliferation of cells with a finely granular cytoplasm, resembling acinic cells of the parotid gland. Some neoplastic cells had a clear cytoplasm. In spite of extensive sampling, no common histological patterns of breast carcinoma such as in situ and invasive ductal carcinoma were recognized in the present case, indicating that the present case was pure acinic cell carcinoma. In addition, the immunohistochemical profile of this tumor was identical to that of the acinic cell carcinoma of the salivary gland: estrogen receptor, progesterone receptor, HER2 and cytokeratin (CK)20 were negative and amylase and CK7 were positive. The patient has been well for 22 months since the wide local excision of the tumor and no signs of salivary neoplasm are evident to date.
Estrogens and aspects of prostate disease
Authors: Prezioso Domenico , Denis Louis J , Klocker Helmut , Sciarra Alexandria , Reis Mario , Naber Kurt , Lobel Bernard , Pacik Dalibor , Griffiths Keith
Published: December 2006

Abstract:  Estrogens have long been associated with the processes involved in prostate carcinogenesis, particularly in cancer suppression. However, the synergistic influence of low concentrations of estrogens, together with androgens, in promoting aberrant growth of the gland has also been recognized. As new insights into the complex molecular events implicated in growth regulation of the prostate are revealed, the role of the estrogens has become clearer. The present review considers this role in relation to the pathogenesis of prostate cancer and the potential cancer‐repressive influence of the dietary estrogens.
Testicular seminoma occurring 8 years after treatment of a metastatic extragonadal germ cell tumor
Authors: Ando Ryosuke , Yasui Takahiro , Tozawa Keiichi , Sasaki Shoichi , Hayashi Yutaro , Kohri Kenjiro
Published: December 2006

Abstract:  A 30‐year‐old man was admitted with a chief complaint of left‐sided scrotal enlargement, and was diagnosed as having testicular seminoma after orchiectomy. Eight years earlier, he had been treated with chemotherapy for an extragonadal germ cell tumor, without orchiectomy, leading to complete remission. His histological diagnosis at that time was a germ cell tumor, composed of choriocarcinoma and embryonal carcinoma. He was followed up without testicular biopsy. Routine pretreatment testicular biopsy in patients with extragonadal germ cell tumor is controversial, but regular long‐term follow up and information on the risk of developing a metachronous testicular tumor are needed after treatment of extragonadal germ cell tumors, even when there seems to be a partial or complete clinical response.
Case of carcinosarcoma of urinary bladder obtained a pathologically complete response by neoadjuvant chemoradiotherapy
Authors: Hoshi Senji , Sasaki Mituharu , Muto Akinori , Suzuki Kenichi , Kobayashi Takashi , Tukigi Masaaki , Ono Kunio , Sugano Osamu , Saso Shunichi
Published: December 2006

Abstract:  Carcinosarcoma of the bladder is an unusual malignancy characterized by an intimate admixture of malignant epithelial elements (carcinoma) and malignant soft tissue elements (sarcoma). To our knowledge, almost 80 cases have been reported, usually as case reports or small series. Patient with carcinosarcoma usually present with a high stage malignancy. Cystectomy or transurethral resection is the preferred treatment, often followed by radiation therapy, although prognosis is very bad. We herein report a case of carcinosarcoma of bladder obtained pathologically complete response by neoadjuvant chemoradiotherapy. She now shows no evidence of disease 30 months after the operation. To our knowledge, it is the first case where urinary bladder carcinosarcoma obtained a pathologically complete response by chemoradiotherapy.
Intrascrotal involvement of sarcoidosis presenting like testicular appendices
Authors: Obinata Daisuke , Yamaguchi Kenya , Hirano Daisaku , Fuchinoue Aya , Nemoto Norimichi , Takahashi Satoru
Published: December 2006

Abstract:  A 31‐year‐old male visited our clinic with a complaint of painless intrascrotal mass in the left side. He had been diagnosed with pulmonary sarcoidosis 6 years prior. Scrotal ultrasound revealed a distinct mass measuring 18 mm × 16 mm at the left epididymal tail. An epididymectomy was performed for treatment and pathological diagnosis. Four nodules shaped like testicular appendices were also found on the testicular surface and subsequently removed. Histopathological examination established that both the epididymal and appendix‐like lesions consisted of non‐caseating epithelioid granulomas with giant cells, and were diagnosed as sarcoidosis. The patient has no recurrence of intrascrotal lesions after 6‐month follow up. This is the first report of intrascrotal involvement of sarcoidosis presenting like testicular appendices.
Chronic acid ingestion promotes renal stone formation in rats treated with vitamin D3
Authors: Okamoto Naohiko , Aruga Seiji , Tomita Kyoichi , Takeuchi Takumi , Kitamura Tadaichi
Published: December 2006

Objective:  Although hypercalciuria, a well‐established adverse effect of vitamin D3, can be a risk factor of renal stone formation, the risk of nephrolithiasis has not been well defined. The consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium‐based kidney stones. In the present study, we investigated the effect of chronic acid ingestion on kidney stone formation in rats treated with calcitriol (1–25[OH]2 D3).

Methods:  Control rats (C‐C), calcitriol‐treated rats (C‐V; three treatments of 0.5 µg of calcitriol per week) and acid‐ingested (water containing 0.21 mol/L NH4Cl), calcitriol‐treated (three treatments of 0.5 µg of calcitriol per week) rats (A‐V) were fed in metabolic cages. After 1 month, urine, blood, kidney and bone samples were analyzed.

Results:  The A‐V rats exhibited elevated serum calcium concentrations, urinary calcium and phosphate excretion, urinary type I collagen cross‐linked N‐peptide (NTx)/creatinine values, mRNA expression of osteopontin in the kidney, and renal calcium contents as well as decreased bone mineral densities, compared with the C‐C and C‐V rats. Urinary citrate excretion was lower and NaDC‐1 mRNA expression in the kidney was higher in the A‐V rats than in the C‐C and C‐V rats. Calcium phosphate kidney stones were found in the A‐V rats.

Conclusions:  The ingestion of NH4Cl, an acid precursor, promotes calcium phosphate kidney stone formation in calcitriol‐treated rats. The chronic intake of a diet rich in acid precursors may be a risk factor for the development of kidney stones in subjects who are being treated with calcitriol.
Severity of erectile dysfunction in married impotent patients: Interrelationship with anthropometry, hormones, metabolic profiles and lifestyle
Authors: Paick Jae‐Seung , Yang Ji Hyun , Kim Soo Woong , Ku Ja Hyeon
Published: December 2006

Objective:  This study was designed to evaluate the effects of risk factors for erectile dysfunction (ED) or cardiovascular disease on the disease severity in impotent men.

Methods:  A total of 87 men, 25–75 years old (mean age, 53.4) were included in the study. Patients were evaluated with anthropometry, hormones, metabolic profiles and lifestyle. Baseline erectile function (EF) was evaluated using the International Index of Erectile Function (IIEF). The severity of ED was classified into the following four grades based on the six‐item EF domain of the IIEF: severe (6–10); moderate (11–16); mild to moderate (17–21); and mild (22–25). Patients were deemed to have metabolic syndrome (MS) if they had three or more of five criteria according to National Cholesterol Education Program, with some modification.

Results:  Of 87 patients, 15 patients (17.2%) had mild, 11 (12.6%) had mild to moderate, 33 (37.9%) had moderate and 28 (32.3%) had severe ED. There was no correlation between scores of IIEF or EF domain and continuous parameters. On the multivariate model used, hypertensive patients had 26‐fold higher risk (odds ratio, 26.195; 95% confidence interval, 1.463–46.072; P = 0.027) of severe ED than those without hypertension. Other factors were not significant.

Conclusion:  The results of the study indicate that MS might not influence the severity of ED in impotent men. However, our findings suggest that hypertension plays a role in the disease severity in these patients.
The efficacy and safety of laparoscopic nephrectomy in patients with three or more comorbidities
Authors: Naya Yukio , Tobe Toyofusa , Suyama Takahito , Araki Kazuhiro , Komiya Akira , Suzuki Hiroyoshi , Igarashi Tatsuo , Ichikawa Tomohiko
Published: December 2006

Objectives:  Laparoscopic surgery for kidney treatment is a common procedure. However, the efficacy of this procedure in patients with several comorbidities has not been well investigated. We conducted a retrospective comparison of results of laparoscopic surgery between patients with several comorbidities and patients with no comorbidity to access the efficacy and safety of this procedure.

Methods:  The subjects were 20 patients with three or more comorbidities (group A) and 46 patients with less than three comorbidities (group B). These 66 patients were 48 men and 18 women with a mean age of 62.3 years (age range, 24–83 years). The data from these two groups were compared for American Society of Anesthesiology (ASA) physical status score, previous surgical history, duration of surgery, estimated blood loss, tumor size, complications during and after surgery, conversion rates, time to oral intake, and length of hospital stay.

Results:  The initial ASA score and age were significantly higher for the patients with comorbidities (P < 0.0001, P = 0.0008, respectively). All other variables before, during, and after surgery were similar for both laparoscopic groups. However, the incidence of atelectasis of laparoscopy was higher than that of open surgery.

Conclusions:  Laparoscopic nephrectomy for patients with comorbidities is safe and minimally invasive. Further investigation to prevent atelectasis is necessary.
Evaluation of regional lymph node dissection in patients with upper urinary tract urothelial cancer
Authors: Secin Fernando P , Koppie Theresa M , Salamanca Juan I Martinez , Bokhari Shahid , Raj Ganesh V , Olgac Semra , Serio Angel , Vickers Andrew , Bochner Bernard H
Published: December 2006

Objective:  The role of the lymph node dissection (LND) in conjunction with nephroureterectomy (NU) in upper tract urothelial cell carcinoma (UT‐UCC) remains undefined. We evaluated the manner in which the LND was applied at NU, the patterns of lymph node (LN) involvement and the preoperative variables that could identify patients at high risk for lymph node metastasis (LNM).

Methods:  We examined clinical, radiological and pathological records of patients who underwent NU for UT‐UCC between 1985 and 2004. The central pathology laboratory reviewed all specimens and graded tumors using the 2002 World Health Organization/International Society of Urologic Pathologists grading system.

Results:  Of the NU performed in 252 patients for UT‐UCC, 105 (42%) were N0, 28 (11%) N+ and 119 (47%) Nx. Some form of LN resection was performed with NU in 53% of patients, with a median of four LN sampled (interquartile range, 2–10). After adjustment for tumor and patient characteristics, surgeon remained a significant predictor of LN resection (P < 0.0005). Of the evaluated variables, suspicious LN on preoperative computed tomography, present in 60% of N+ patients, was the only preoperative variable associated with the pathological finding of LNM (P < 0.0005).

Conclusions:  LND in patients with UT‐UCC is surgeon‐dependent. Given the prognostic importance of LN status and the limited accuracy of preoperative staging of the regional LN, surgeons should perform a regional LND at the time of NU.
Location of spina bifida occulta and ultrasonographic bladder abnormalities predict the outcome of treatment for primary nocturnal enuresis in children
Authors: Miyazato Minoru , Sugaya Kimio , Nishijima Saori , Owan Tomoko , Ogawa Yoshihide
Published: December 2006

Objective:  We examined whether the existence of spina bifida occulta or ultrasonographic bladder abnormalities was related to the outcome of treatment for primary nocturnal enuresis in children.

Methods:  Between April 1996 and September 2005, a total of 77 subjects (53 boys and 24 girls, aged 5–18 years; mean age, 9.9 years) with primary nocturnal enuresis were studied. Plain X‐ray films of the spine and ultrasonographic bladder measurements (bladder wall thickness, bladder neck descent and bladder neck opening) were obtained and the correlations with the outcome of treatment using imipramine hydrochloride were assessed.

Results:  On plain X‐ray films of the spine, spina bifida occulta (lumbar vertebrae in three, lumbosacral vertebrae in 19 and sacral vertebrae in 31) was recognized in 53 children (69%). Ultrasonographic bladder abnormalities were recognized in 40 children (52%). Children with lumbar and lumbosacral spina bifida occulta showed a higher rate of concomitant ultrasonographic bladder abnormalities (P = 0.006) and had a poorer response to treatment (P = 0.041) compared with the children who had sacral spina bifida occulta. Children with ultrasonographic bladder abnormalities had a worse response to treatment (P = 0.005) compared to the children without bladder abnormalities.

Conclusions:  The presence of lumbar spina bifida occulta and ultrasonographic bladder abnormalities was related to the outcome of treatment for primary nocturnal enuresis in children, suggesting that spinal radiography and vesical ultrasonography may be useful predictive tests.
Plasma and dietary vitamin E in relation to insulin secretion and sensitivity
Authors: Costacou T. , Ma B. , King I. B. , Mayer‐Davis E. J.
Published: December 2006

Aim:  In the Insulin Resistance and Atherosclerosis Study (IRAS), we have previously shown a protective effect of plasma α‐tocopherol concentration against diabetes incidence among persons not taking vitamin E supplements. The biologic mechanism for such a protective effect could involve improvement in either insulin sensitivity (SI), insulin secretion or both. Thus, we examined vitamin E in relation to insulin secretion and SI among persons not taking vitamin E supplements.

Methods:  This analysis included 457 adults aged 40–69 years without a previous diabetes diagnosis or vitamin E supplement use at baseline and seen at the 5‐year follow‐up examination. Baseline nutrient intake was estimated from a validated 1‐year food frequency questionnaire; plasma levels of α‐tocopherol were also assessed. At follow up, a frequently sampled intravenous glucose tolerance test determined SI, acute insulin response to glucose (AIR), and the disposition index (DI) was calculated as the sum of the log‐transformed AIR and SI to reflect pancreatic compensation for insulin resistance.

Results:  In multivariable regression analyses, no relationship was observed for vitamin E intake and either SI, AIR or DI. However, plasma α‐tocopherol concentration was positively associated with log‐transformed SI (β= 0.27 ± 0.09, p < 0.01) and DI (β= 0.41 ± 0.14, p < 0.01), but not with log‐transformed AIR.

Conclusions:  Plasma concentration of α‐tocopherol may improve SI and pancreatic compensation for insulin resistance, although it does not seem to be related to acute insulin response.