bluuebunny/crossref_metadata_2025 huggingface dataset:
Extra‐pulmonary aspects of acquired pulmonary alveolar proteinosis as predicted by granulocyte‐macrophage colony‐stimulating factor‐deficient mice
Authors: SEYMOUR John F.
Published: January 2006

Abstract:  Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)–/– mice are an invaluable model for exploring the effects of systemic GM‐CSF deficiency. Their lung phenotype exactly reproduces the abnormalities seen in human pulmonary alveolar proteinosis (PAP). However, GM‐CSF–/– mice also have significant systemic functional abnormalities. These include immune defects which result in a reduced susceptibility to a range of experimentally induced autoimmune disorders. These immunological defects are also functionally manifest as an impaired ability to resolve a range of infections under certain conditions, usually implicating cellular effectors, including Listeria, Group B streptococcus, adenovirus, Pneumocystis carinii, and malaria. These observations are consistent with the known propensity for patients with PAP to develop a range of opportunistic infections. Conversely, the diminished immunological response to inflammatory stimuli may be beneficial in some settings by limiting inflammatory cell recruitment and pro‐inflammatory mediator‐release. GM‐CSF–/– mice also have distinct fertility defects, manifest as reduced litter size and an increased rate of early fetal loss. These observations may be clinically relevant for women affected by PAP and further support the evaluation of the role of GM‐CSF in human reproduction. These observations reinforce the importance of clinicians viewing PAP as a state of systemic functional GM‐CSF deficiency, albeit with prominent pulmonary manifestations, rather than purely a ‘lung disease’. These systemic manifestations of GM‐CSF deficiency should also be considered when deciding on the choice between pulmonary or systemic delivery of GM‐CSF as therapy for PAP, as only systemic drug delivery has the potential capcity to correct the systemic manifestations of GM‐CSF deficiency in these patients.
The role of genetics and cigarette smoking in the development of pulmonary fibrosis
Authors: STEELE Mark P. , SPEER Marcy C. , LOYD Jim C. , BROWN Kevin K. , HERRON Aretha , SLIFER Susan H. , BURCH Lauranell H. , WAHIDI Momen , PHILLIPS John A. , SPORN Thomas A. , MCADAMS Holman P. , SCHWARZ Marvin I. , SCHWARTZ David A.
Published: January 2006

Abstract:  Several lines of evidence suggest that genetic factors and environmental exposure play a role in the development of pulmonary fibrosis. The authors evaluated families with familial pulmonary fibrosis (FPF), defined as the presence of two or more cases of idiopathic interstitial pneumonia (IIP) in first degree family members. In total, 56 families with FPF were evaluated with 193 affected and 196 unaffected individuals. The presence of FPF was based on clinical history, DLCO, and CXR in 27 (14%); clinical history and HRCT scan in 102 (53%); clinical history and SLB in 55 (28%); and clinical history and autopsy in nine (5%). Older age (67.8 vs. 53.6; P < 0.001), male gender (48% vs. 34%; P = 0.004), and cigarette smoking (59% vs. 36%; P < 0.0001) were associated with the development of FPF. Of 237 subjects self‐reported as unaffected, 10 had probable or definite FPF, and 23 had possible FPF. Evidence for aggregation of disease was highly significant (P < 0.001) among sibling pairs. Several pedigrees demonstrated vertical transmission, consistent with autosomal dominant inheritance. More than 50% of pedigrees demonstrated phenotypic heterogeneity, with several subtypes of IIP occurring within families. These findings indicate that FPF is caused by an interaction between cigarette smoking and a gene (or genes) that predisposes to the development of pulmonary fibrosis.
Surfactant catabolism
Authors: IKEGAMI Machiko
Published: January 2006

Abstract:  Alveolar pulmonary surfactant is a complex of macromolecular aggregates composed of phospholipids and surfactant proteins (SP) that is essential for maintenance of normal lung function. The importance of surfactant homeostasis is recognized in the patients and the animal models with pulmonary disease, although the mechanisms of surfactant homeostasis are not fully understood. In this review the author will discuss: (i) the mechanisms of the surfactant catabolism by macrophage and type II cells; and (ii) the important role of SP‐D on ultrastructure of surfactant that affects uptake by type II cells.
Alveolar epithelial cells: differentiation and lung injury
Authors: SUGAHARA Kazuhiro , TOKUMINE Joho , TERUYA Koji , OSHIRO Tatsuo
Published: January 2006

Abstract:  Re‐epithelialization of alveolar epithelial cells is one of the important repair processes in many types of lung injury. The major functions of alveolar type II cells are synthesis and secretion of surfactant, hyperplasia in reaction to alveolar epithelial injury, and serving as progenitor cells for alveolar type I cells. The authors have examined the effects of several soluble factors on cultured alveolar type II cells in vitro, and also examined the histopathology and gene expression of surfactant proteins in the rat lungs with LPS, bleomycin and/or treated with keratinocyte growth factor. The authors next examined the effects of bone marrow stromal cells (BMSC) implanted transvenously into bleomycin‐induced lungs. The authors found that keratinocyte growth factor (KGF) is a strong growth factor for alveolar type II cells, and that KGF instillation prevents bleomycin‐induced lung injury. Furthermore, the authors showed the possibility of differentiation of implanted BMSC into alveolar epithelial cells. KGF and BMSC may play an important role in maintaining the alveolar epithelium and repairing the damaged epithelium after injury, and may well provide potential therapeutic alternatives.
Functional heterogeneity of colony‐stimulating factor‐induced human monocyte‐derived macrophages
Authors: AKAGAWA Kiyoko S. , KOMURO Iwao , KANAZAWA Hiroko , YAMAZAKI Toshio , MOCHIDA Keiko , KISHI Fumio
Published: January 2006

Objectives:  Macrophages (Mφs) have various functions and play a critical role in host defense and the maintenance of homeostasis. Mφs exist in every tissue in the body, but Mφs from different tissues exhibit a wide range of phenotypes with regard to their morphology, cell surface antigen expression and function, and are called by different names. However, the precise mechanism of the generation of macrophage heterogeneity is not known. In the present study, the authors examined the functional heterogeneity of Mφs generated from human monocytes under the influence of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and macrophage‐CSF (M‐CSF).

Methodology:  CD14 positive human monocytes (Mos) were incubated with M‐CSF and GM‐CSF for 6–7 days to stimulate the generation of M‐CSF‐induced monocyte‐derived Mφs (M‐Mφs) and GM‐CSF‐induced monocyte‐derived Mφs (GM‐Mφs), respectively. The expression of cell surface antigens and several functions such as antigen presenting cell activity, susceptibility to oxidant stress, and the susceptibility to HIV‐1 and mycobacterium tuberculosis infection were examined.

Results:  GM‐Mφs and M‐Mφs are distinct in their morphology, cell surface antigen expression, and functions examined. The phenotype of GM‐Mφs closely resembles that of human Alveolar‐Mφs (A‐Mφs), indicating that CSF‐induced human monocyte‐derived Mφs are useful to clarify the molecular mechanism of heterogeneity of human Mφs, and GM‐Mφs will become a model of human A‐Mφs.
Alveolar macrophages and emphysema in surfactant protein‐D‐deficient mice
Authors: YOSHIDA Mitsuhiro , WHITSETT Jeffrey A.
Published: January 2006

Abstract:  Surfactant protein‐D (SP‐D) is a member of the collectin family of collagenous proteins with lectin activity. SP‐D is expressed in numerous tissues, primarily in type II alveolar cells in the periphery of the lung. SP‐D plays an important role in host defense of the lung. To evaluate the importance of SP‐D in vivo, transgenic mice lacking SP‐D (SP‐D‐/‐ mice) have been generated. Lipid accumulation and airspace enlargement were observed in the lungs of SP‐D‐/‐ mice within 3 weeks after birth, and progressed with advancing age. Airspace enlargement and abnormalities in elastin fibers supported the concept that SP‐D was required to inhibit destruction of the alveoli. Alveolar macrophages from SP‐D‐/‐ mice produced more H2O2 and matrix metalloproteinases (MMP)‐2, ‐9, and ‐12 compared with wild‐type mice. In vitro studies demonstrated that oxidants derived in part from NADPH oxidase enhanced NF‐κB activation and MMP production in alveolar macrophages from SP‐D‐/‐ mice. A specific inhibitor of NF‐κB reduced MMP production by alveolar macrophages from SP‐D‐/‐ mice. Taken together, these data demonstrated oxidant‐dependent activation of NF‐κB and enhanced MMP expression by alveolar macrophages from SP‐D‐/‐ mice, a process likely to mediate airspace remodeling caused by SP‐D deficiency. SP‐D plays a critical role in regulating alveolar macrophage activation, oxidant production, and MMP activity that may influence the pathogenesis of various pulmonary disorders.
Clinical features and genetic analysis of surfactant protein C in adult‐onset familial interstitial pneumonia
Authors: SETOGUCHI Yasuhiro , IKEDA Tomomi , FUKUCHI Yoshinosuke
Published: January 2006

Abstract:  Familial cases of interstitial pneumonia (FIP) have been reported to be linked to mutations of the surfactant protein C (SP‐C) gene. Based on this knowledge, we evaluated the characteristics of patients with adult‐onset FIP in the Tokyo area using clinical and radiopathological findings, and further evaluated the genetic background of patients with FIP compared with sporadic IP patients using genetic sequencing of the SP‐C gene. A total of 22 patients with FIP from 13 families were identified, and the mean age at first diagnosis of these patients was 50 ± 2.7 years (range: 20–66 years). Based on the specimen histology, UIP and non‐specific interstitial pneumonia accounted for 64 and 36%, respectively. Distribution of the interstitial pattern in HRCT imaging resulted in 36% upper lung dominant, 5% whole lung and 59% lower lung dominant. Two missense mutations in exon 4 (N138T) and exon 5 (N186S) were identified in the SP‐C gene from 11 cases with FIP. Each exonic mutation consisted of DNA polymorphism. The frequencies of these DNA polymorphisms were evaluated among 11 subjects with FIP, 30 subjects with sporadic IP, and 43 healthy volunteers as controls. Interestingly, the genotype and allele frequencies in exon 5 were statistically different among these groups. In particular, the N186S substitution of exon 5 in the SP‐C gene was shown in patients with FIP or sporadic IP, with a statistically higher frequency. While pathophysiological mechanisms remain to be elucidated, the N186S missense variant may have potential susceptibility in the development of IP. The gene or genes that prove to be important in the development of FIP may provide insights into the pathogenesis of other forms of interstitial lung diseases.
Regulation of inflammation and bacterial clearance by lung collectins
Authors: SANO Hitomi , KURONUMA Koji , KUDO Kazumi , MITSUZAWA Hiroaki , SATO Morihito , MURAKAMI Seiji , KUROKI Yoshio
Published: January 2006

Abstract:  Pulmonary surfactant proteins (SP) A and D play important roles in the innate immune system of the lung. These proteins belong to the collectin subgroup in which lectin domains are associated with collagenous structures. To obtain a better understanding of how lung collectins modulate cellular responses, the authors investigated whether SP‐A interacts with the toll‐like receptor 2 (TLR2). SP‐A bound to TLR2 and inhibited interactions between TLR2 and TLR2‐ligands such as peptidoglycan (PGN) and zymosan. NF‐κB activation and tumour necrosis factor‐α expression induced by PGN or zymosan were significantly inhibited in the presence of SP‐A. Lung collectins may act as inhibitors of lung inflammation in respiratory infections. The authors also examined the effects of lung collectins on the phagocytosis of bacteria by alveolar macrophages. Lung collectins enhanced the uptake of S. pneumoniae or M. avium by alveolar macrophages. It was demonstrated that the direct interaction of lung collectins with macrophages resulted in increased cell surface expression of scavenger receptor A or mannose receptor, which are responsible for phagocytosis. This study has emphasized the biological relevance of SP‐A and SP‐D against various respiratory infections, however, a more complete understanding of the molecular mechanism is required.
Monitoring markers of disease activity for interstitial lung diseases with serum surfactant proteins A and D
Authors: TAKAHASHI Hiroki , SHIRATORI Masanori , KANAI Akiko , CHIBA Hirofumi , KUROKI Yoshio , ABE Shosaku
Published: January 2006

Objectives:  Surfactant protein (SP) A and D are specific serum markers for interstitial lung diseases including idiopathic pulmonary fibrosis (IPF). The authors evaluated the critical roles of these markers on the prognoses of patients with IPF and the mechanisms of their elevation in sera.

Methodology:  The authors evaluated the relationship between prognosis and the serum markers in 82 IPF patients. The protein content and mRNA expression of the markers were evaluated using rats with interstitial pneumonia induced by bleomycin administration.

Results:  Higher levels of serum SP‐D at the time of the initial visit to the Sapporo Medical University Hospital were associated with poorer prognoses, while SP‐A showed no significant affect on survival. Causes of the elevation in sera were due to the acceleration of, not only production in the lungs, leakage into the circulation. The elevation was associated with alveolitis but not fibrosis.

Conclusions:  SP‐D is a good predictor of the prognosis in patients with IPF.
Epidemiological and clinical features of idiopathic pulmonary alveolar proteinosis in Japan
Authors: INOUE Yoshikazu , NAKATA Koh , ARAI Toru , TAZAWA Ryushi , HAMANO Emi , NUKIWA Toshihiro , KUDO Koichiro , KEICHO Naoto , HIZAWA Nobuyuki , YAMAGUCHI Etsuro , EDA Ryosuke , OISHI Kazunori , MAEDA Yuuka , KOREEDA Yukiko , KODO Naohiko , SAKATANI Mitsunori
Published: January 2006

Abstract:  Idiopathic pulmonary alveolar proteinosis (IPAP) is a rare disease characterized by excessive amounts of lipoproteinaceous material in the alveolus. This report presents an interim analysis of nationwide epidemiological data from Japanese patients with pulmonary alveolar proteinosis, and the roles of serum markers for IPAP. (i) The nationwide demographic data from 166 Japanese patients with IPAP are shown. The female to male ratio was 1:2, and the average age was 51 ± 14 years old (age range: 15–79 years) at registration or diagnosis. A total of 30% of patients with IPAP have a poor clinical course. In total, 30% of patients were treated with whole lung lavage therapy (WLL). Under WLL, the patients significantly improved in the short term, but 40% of the patients who underwent WLL worsened again. A new strategy such as granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) therapy for intractable PAP is required. (ii) The correlation of serum KL‐6, carcinoembryonic antigen, surfactant proteins D and A, and LDH with disease severity suggests their potential as disease markers. In contrast, serum anti‐GM‐CSF antibody did not correlate with disease severity, but is a specific marker for the diagnosis of IPAP. The combined measurements of the serum markers may well prove very useful for both the diagnosis and the management of IPAP patients.
Granulocyte‐macrophage colony‐stimulating factor inhalation therapy for patients with idiopathic pulmonary alveolar proteinosis: a pilot study; and long‐term treatment with aerosolized granulocyte‐macrophage colony‐stimulating factor: a case report
Authors: TAZAWA Ryushi , NAKATA Koh , INOUE Yoshikazu , NUKIWA Toshihiro
Published: January 2006

Abstract:  Idiopathic pulmonary alveolar proteinosis (IPAP) is considered to be caused by an autoantibody to the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), which neutralizes GM‐CSF and therefore impairs the differentiation of alveolar macrophages. The authors have previously characterized the BAL fluid and alveolar macrophages obtained from three IPAP patients who were successfully treated with aerosolized GM‐CSF and demonstrated restoration of the cell number, expression of surface marker, and phagocytic ability of the alveolar macrophages as well as a decrease in the autoantibody levels in the BAL fluid. The condition recurred in one of the patients after 20 months. This patient underwent a second and third course of GM‐CSF inhalation therapy with the same dose and schedule as the first one. Since the second therapeutic intervention did not succeed in producing any improvement in the symptoms and disease markers, the authors used a new nebulizer and a liquid preparation of the drug instead of the lyophilized preparation for the third therapeutic session and this restored the respiratory function considerably. A 6‐month maintenance therapeutic regimen with a lower GM‐CSF inhalation frequency brought about a further improvement in the disease markers. The results suggest that the efficacy of GM‐CSF inhalation therapy might be related to the drug preparation mode, choice of nebulizer, and duration of treatment.
Why does the autoantibody against granulocyte‐macrophage colony‐stimulating factor cause lesions only in the lung?
Authors: NAKATA Koh , KANAZAWA Hiroko , WATANABE Masato
Published: January 2006

Objectives:  During the course of investigating the etiology of idiopathic pulmonary alveolar proteinosis (IPAP), the authors found that the autoantibody against granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was consistently present in both sera and the lung tissue. The autoantibody completely blocked bioactivity by direct binding with high specificity and avidity. Because of the existence of patients with congenital PAP who lack GM‐CSF receptors and the development of PAP in GM‐CSF and GM‐CSF receptor knock‐out mice, the autoantibody is likely to be the causative agent for IPAP. However, this finding posed the question as to why the autoantibody against GM‐CSF caused lesions only in the lung.

Methodology:  To answer this question, the authors investigated, using immunohistochemistry, confocal laser microscopy, and immunoblotting, the expression of PU.1 in tissue macrophages. PU.1 is a critical transcription factor for terminal differentiation of alveolar macrophage (AM), as reported previously in the lung, liver, spleen, kidney, intestine and brain.

Results:  PU.1 was consistently expressed in the nuclei of normal AM, but faintly or not at all in IPAP‐AM. Moreover, it was not expressed in the nuclei of any other normal tissue macrophages tested. Blood monocytes expressed PU.1 in the cytosol but not in the nuclei. These results suggested that the differentiation pathway is different between AM and other tissue macrophages. PU.1 was not expressed in the nuclei of newborn rat lung AM but was gradually expressed during the first 10 days.

Conclusions:  The authors demonstrated that GM‐CSF is crucial for terminal differentiation of AM, but not for that of other tissue macrophages.
Pulmonary surfactant transport in alveolar type II cells
Authors: OSANAI Kazuhiro , TSUCHIHARA Chiharu , HATTA Rieko , OIKAWA Taku , TSUCHIHARA Katsuma , IGUCHI Masaharu , SEKI Toshimitsu , TAKAHASHI Masakatsu , HUANG Jyongsu , TOGA Hirohisa
Published: January 2006

Abstract:  Pulmonary surfactant (PS) is a mixture of several lipids (mainly phosphatidylcholine; PC) and four apoproteins (A, B, C and D). The classical hypothesis of PS transport suggests that PS is synthesized in the endoplasmic reticulum and transported to the lamellar body (LB) via the Golgi apparatus. However, recent studies have raised questions regarding this single route. This study examined, independently, the intracellular trafficking route of three different components of PS, that is, PC, SP‐A and SP‐B. Alveolar type II cells were isolated from Sprague–Dawley rats or Japanese white rabbits. The cells were cultured with either [3H]choline or [35S]methionine/cysteine with or without brefeldin A, which disassembles the Golgi apparatus. LB was purified from disintegrated cells with sucrose density gradient centrifugation. [3H]PC was extracted from radiolabeled media, cells, and the LB fraction with Bligh–Dyer's method. [35S]SP‐A or [35S]SP‐B was immunoprecipitated from each sample with a specific antibody. [3H]PC was transported and stored to the LB via a Golgi‐independent pathway. [35S]SP‐A was transported to the Golgi apparatus, underwent glycosylation, and was then constitutively secreted. The secreted [35S]SP‐A was re‐uptaken into the LB. [35S]SP‐B was transported and stored to the LB via the Golgi‐dependent pathway. These results indicate that, rather than a single route, surfactant components take different pathways to reside in the LB. These different pathways may reflect the different nature and role of each surfactant component such as surface tension‐lowering activity and innate host defense.
Successful treatment of congenital pulmonary alveolar proteinosis with intravenous immunoglobulin G administration
Authors: CHO Kazutoshi , NAKATA Koh , ARIGA Tadashi , OKAJIMA Satoru , MATSUDA Tadashi , UEDA Keiko , FURUTA Itsuko , KOBAYASHI Kunihiko , MINAKAMI Hisanori
Published: January 2006

Abstract:  The authors report a female patient with congenital pulmonary alveolar proteinosis (PAP). She had two brothers who died from the same disease. BAL did not improve her progressive respiratory failure. After intravenous immunoglobulin G (IVIG) administration for complicated hypogammaglobulinemia, she recovered from respiratory failure. The efficacy of IVIG was confirmed by recovery from deterioration in respiratory status and improvement in chest CT findings on two separate occasions. Subsequently, the patient remains free from respiratory symptoms for more than 3 years on an ongoing regimen of monthly IVIG. She had no surfactant protein (SP) B deficiency. Alveolar macrophages (AM) obtained from her BAL fluid were small and showed decreased phagocytotic activity. Immunostaining revealed weak expression of PU.1 in her AM, a key protein in AM maturation. All nucleotide sequences of granulocyte‐macrophage colony stimulating factor (GM‐CSF), GM‐CSF‐receptor and PU.1 were normal. Endotoxin‐induced GM‐CSF release from peripheral mononuclear cells (PMNC), and proliferation of PMNC in response to GM‐CSF were normal. In addition, an antibody against GM‐CSF, as seen in adult patients with idiopathic PAP, was not detected in the serum or BAL fluid. Although the patient's PMNC secreted only small amounts of IgG and IgM, an EB virus‐derived cell line of her B cells secreted IgM as much as normal control cells. In a flow cytometric study, IgM was expressed on the cell surface. In conclusion, an abnormality in a single gene may have decreased secretion of immunoglobulin from the B cells and the AM phagocytotic activity in the patient.
Chemoprevention of colorectal cancer with nonsteroidal anti‐inflammatory drugs
Authors: HILMI I. , GOH KL
Published: January 2006

Colorectal carcinoma is one of the commonest solid organ tumors in the world and its prevalence appears to be increasing in Asia. Recently, there has been much interest in various chemotherapeutic agents for the management of this condition, in particular nonsteroidal anti‐inflammatory drugs (NSAIDs). There is a large amount of data that suggest traditional NSAIDs, as well as the new cyclooxygenase (COX)‐2 selective inhibitors such as rofecoxib and celecoxib, have a role in the setting of primary and secondary prevention, and adjuvant therapy of both sporadic colorectal carcinoma and familial adenomatous polyposis. This review examines some of this data, as well as the potential problems and limitations of using these agents, particularly in light of the recent withdrawal of rofecoxib.
Pathogenesis of nonalcoholic steatohepatitis (NASH)
Authors: MA Xiong , LI Zhiping
Published: January 2006

Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver diseases that range from hepatic steatosis at the most clinically benign end of the spectrum, through an intermediate lesion, nonalcoholic steatohepatitis (NASH), to cirrhosis at the opposite extreme. Epidemiology studies have estimated that about 20–30% of adults in the United States and other Western countries have NAFLD, and of these about 10% (2–3% of adults) meet the diagnostic criteria of NASH. Studies of animals and humans with obesity‐related fatty liver disease have revealed much about the mechanisms that mediate this common pathology. The pathogenesis of NASH is multifactorial and includes insulin resistance, excessive intracellular fatty acids, oxidant stress, mitochondrial dysfunction and the role of innate immunity. This review will briefly discuss the epidemiology of NAFLD and focus on current understanding of the pathogenesis of NASH.
Serous cystic neoplasms of the pancreas: a clinicopathologic and immunohistochemical analysis [This article has been retracted]
Authors: JI Yuan , WANG Xiu Nan , LOU Wen Hui , SUJIE Akesu , TAN Yun Shan , JIN Da Yong
Published: January 2006

OBJECTIVE:  To clarify whether the various subtypes of serous cystic neoplasms (SCNs) of the pancreas can be distinguished from each other by marker profiles.

METHODS:  The immunoprofiles of 13 SCNs were defined by using antibodies against cytoskeletal, neuroendocrine, hormone receptor, and mucin markers. In addition, we examined the expression of calrentinin and alpha‐inhibin.

RESULTS:  SCN included 7 cases of serous microcystic adenomas (SMA), 3 cases of serous oligocystic ill‐defined adenomas (SOIA), 1 case of solid serous adenoma (SSA), 1 case of von Hippel‐Lindau‐associated cystic neoplasm (VHL‐CN), and 1 case of serous cystadenocarcinoma (SCC). These neoplasms are histologically similar, but differ in their localization, gross appearance, gender distribution, and biological behavior. The various types of SCNs showed a very similar immunoprofile, characterized by positivity for cytokeratins (100%) and negativity for vimentin and synaptophysin. Other markers that were commonly expressed in the SCNs were alpha‐inhibin (85%), MUC1 (69%) and MUC6 (77%).

CONCLUSION:  The results suggest that, despite their biologic differences, the various types of SCNs have the same (or a very similar) cell type and may therefore have a common direction of differentiation. A centroacinar origin is supported by the finding that a number of SCNs share MUC1 and MUC6 expression with pancreatic centroacinar cells. Alpha‐inhibin, and MUC6 may be regarded as new markers for this type of pancreatic tumor.
Prospective randomized clinical trial of two drug delivery pathway in the treatment of inoperable advanced pancreatic carcinoma
Authors: HAN Guo Hong , YIN Zhan Xin , MENG Xiang Jie , HE Chuang Ye , ZHANG Hong Bo , SUN An Hua , WU Kai Chun , DING Jie , FAN Dai Ming
Published: January 2006

OBJECTIVES:  Evaluate the effect of an implanted percutaneous left subclavian artery port‐catheter drug delivery system for regional chemotherapy of inoperable pancreatic carcinoma.

METHODS:  One hundred and forty patients with inoperable pancreatic carcinoma were enrolled and randomized into two groups to receive the FAM regimen on a 6‐day cycle at 1‐month intervals: 70 patients in the regional interventional chemotherapy group in which treatment was infused directly into the common hepatic artery, and 70 patients who received the same chemotherapy regimen via the peripheral vein.

RESULT:  In the interventional chemotherapy group, there were 5 cases of complete remission (CR) and 49 cases of partial remission (PR), giving a response rate (CR+PR) of 77.1%; pain control was effective in 95.7% cases; survival time was 3–34 months (median 13.5). There was no case of CR in the systemic chemotherapy group, and 25 cases of PR, giving a response rate of 35.7%; pain control was effective in 35.7%, and survival time was 1–13 months (median 6.2). The differences between the two groups in response rate and survival were statistically significant (P < 0.005). Nausea and vomiting occurred in 48.6% of the interventional chemotherapy group and 41.3% of the systemic chemotherapy group (NS). There were three cases of serious myelosuppression in the systemic chemotherapy group and one case died. There was a significant difference between the two groups in white blood cell count after the chemotherapy, indicating that the myelosuppressive effect was serious in the systemic chemotherapy group.

CONCLUSION:  Interventional arterial infusion chemotherapy could significantly improve quality of life and prolong the survival of patients with inoperable pancreatic carcinoma.
Meta‐analysis of inoperable pancreatic cancer: gemcitabine combined with cisplatin versus gemcitabine alone
Authors: XIE De Rong , LIANG Han Lin , WANG Yu , GUO Shuang Shuang
Published: January 2006

OBJECTIVES:  To compare the therapeutic effects of gemcitabine (GEM) monotherapy with GEM‐cisplatin (DDP) combination chemotherapy in patients with advanced stage pancreatic cancer (APCa) through meta‐analysis.

METHODS:  MEDLINE and EMBASE searches were supplemented by information from trial registers of randomized controlled trials (RCTs) for GEM‐DDP combination chemotherapy and GEM alone in APCa. A quantitative meta‐analysis using updated information based on inclusion criteria from all available RCTs was carried out by two reviewers. The primary meta‐analysis involved the overall survival (OS), objective remission rate (ORR) and toxicity.

RESULTS:  The meta‐analysis included six RCTs. There was no significant advantage for the GEM‐DDP combination group in 6‐month survival rate (P = 0.24) or clinical benefit rate (P = 0.58). There was a marginal significant improvement for the GEM‐DDP combination group in ORR (RD = 6%, P = 0.05; RD, risk difference = risk in the GEM‐DDP combination group – risk in the GEM alone group). Moreover, there was a significant improvement for the combination group in 6‐month TTP/TTF (RD = 9%, P = 0.02). WHO grade 3–4 toxicity was higher for the GEM‐DDP combination group in terms of neutropenia (RD = 6%, P = 0.08), thrombocytopenia (RD = 8%, P = 0.17) and vomiting/nausea (RD = 11%, P = 0.07); none reached significant difference.

CONCLUSION:  GEM‐DDP combination should not be recommended and GEM monotherapy remains the standard treatment for patients with APCa.
Prevalence and risk factors of Helicobacter pylori infection in healthy schoolchildren
Authors: BANI‐HANI Kamal E , SHATNAWI Nawaf J , EL QADERI Saleh , KHADER Yousef S , BANI‐HANI Bayan K
Published: January 2006

OBJECTIVE:  Data regarding the prevalence of Helicobacter pylori infection and its potential risk factors among schoolchildren from the Middle East is scarce.

METHODS:  An enzyme‐linked immunosorbent assay was used to investigate H. pylori status in four groups of children: The first and second groups, 50 children each (25 boys, 25 girls) included children from high socioeconomic class (group 1 = 6 years old; group 2 = 9 years old). The third and fourth groups were sex‐ and age‐matched, but from low socioeconomic class. To evaluate the association between the seroprevalence of H. pylori and selected risk factors, odds ratios (crude and adjusted) were calculated using multiple regression analysis.

RESULTS:  Overall seroprevalence rate was 55.5%. Seropositivity was 42%, 52%, 60%, and 68% for groups 1, 2, 3, and 4, respectively. Age and sex were not significantly associated with H. pylori seropositivity. In the final logistic regression model, which was adjusted for age and sex, the following risk factors were found to be significantly associated with seropositivity: living in rural areas (P = 0.015), poor sanitation (P < 0.001), overcrowding (P = 0.014), low maternal educational level (P = 0.010) and low socioeconomic status (P = 0.011).

CONCLUSIONS:  The prevalence of H. pylori infection in Jordanian schoolchildren is high, suggesting that most acquisition occurs before the age of 6 years. The seroprevalence for H. pylori increases with social deprivation.
Association of peptic ulcer with increased expression of Lewis antigens, but not vacuolating cytotoxin activity or babA2 gene status, in Helicobacter pylori strains from China
Authors: ZHENG Peng Yuan , TANG Fu Ai , QI Yuan Ming , LI Jian
Published: January 2006

OBJECTIVE:  Controversies exist regarding the virulence factors, such as vacA, babA2 and Lewis blood group antigens, of Western and Asian strains of Helicobacter pylori. The aim of the present study was to determine the significance of these potential virulence factors in the Chinese population.

METHODS:  Seventy‐two strains of H. pylori isolated from patients in Zhengzhou, China, including 43 cases of peptic ulcer (PU) and 29 cases of chronic gastritis, were determined. Vacuolating cytotoxin assay was performed by HeLa cells. The expression of Le blood group antigens (Lea, Leb, Lex and Ley) was performed by enzyme‐linked immunosorbent assay (ELISA). babA2 gene was identified by polymerase chain reaction. Frequencies were compared using two‐tailed Fisher's exact test. Cytotoxin activities were compared using Spearman's rank correction test.

RESULTS:  Vacuolating cytotoxin activity was detected in 61 of the 72 strains (84.7%), but there was no significant difference in vacuolating cytotoxin activity (83.7% vs 86.2%, P = 0.821) or titer (4.4 ± 3.8 vs 4.2 ± 4.1, P = 0.876) between the PU and gastritis strains. Significantly more PU strains expressed two or more Lewis antigens (Lex, Ley, Lea or Leb) than strains from the chronic gastritis patients (90.7% vs 65.5%, P = 0.029). Of the 43 strains from PU patients, 17 (39.5%) were positive for babA2, compared with 11 (38.5%) of the 29 strains from gastritis patients (P = 0.924). There was no significant difference in the vacuolating cytotoxin activity or titer between strains expressing two or more Lewis antigens and less than two antigens (84.5% vs 85.7%, P = 1.000; 4.4 ± 4.2 vs 4.3 ± 3.2, P = 0.965). Of the 72 H. pylori strains, 28 were babA2 positive, of which 24 were cytotoxic, compared with 37 of 44 babA2‐negative strains (P = 1.000).

CONCLUSION:  The present study suggests that PU is associated with increased Lewis antigen expression, but not vacuolating cytotoxin production or the presence of babA2, in the H. pylori strains in the Chinese population.
Anp32e/Cpd1 regulates protein phosphatase 2A activity at synapses during synaptogenesis
Authors: Costanzo Roxana V. , Vilá‐Ortíz Guillermo J. , Perandones Claudia , Carminatti Héctor , Matilla Antoni , Radrizzani Martín
Published: January 2006

Anp32e/Cpd1, a member of the acidic nuclear phosphoprotein (Anp)32 family, is characterized by the presence of an amino terminal domain containing four leucine‐rich repeats and a carboxyl‐terminal low‐compositional complexity acidic region. In previous studies performed to understand the biological role of Anp32e/Cpd1, we showed a predominant presence of Anp32e/Cpd1 in the nucleus. However, when Anp32e/Cpd1 is in the cytoplasm, it co‐localizes spatially with protein phosphatase 2A (PP2A) near cell membranes, far from the synapses. In the present work, we show that Anp32e/Cpd1 is also present as a membrane‐bound 74/76‐kDa protein with a widespread distribution in the brain. We reveal that the expression, synthesis and half‐life of this high‐molecular‐weight form of Anp32e/Cpd1 are spatially and temporally correlated with the cerebellar synaptogenesis period. We demonstrate that synaptic Anp32e/Cpd1 co‐localizes, interacts and inhibits PP2A activity, and that phosphorylation of Anp32/Cpd1 is required for the Anp32e–PP2A interaction. Also, subcellular localization was shown with electronic microscopy. Finally, we examine Anp32e/Cpd1 and PP2A distribution in two ataxic mutant models, weaver and staggerer, and show that their co‐localization in Purkinje cell dendrites depends on parallel fibre/Purkinje cell contacts. Based on these observations, we propose that Anp32e/Cpd1 mediates synaptogenesis process by modulating PP2A activity.
Reduced ethanol response in the alcohol‐preferring RHA rats and neuropeptide mRNAs in relevant structures
Authors: Guitart‐Masip Marc , Giménez‐Llort Lydia , Fernández‐Teruel Albert , Cañete Toni , Tobeña Adolf , Ögren Sven Ove , Terenius Lars , Johansson Björn
Published: January 2006

Roman rat strains, genetically selected for high (RHA) or low (RLA) active avoidance acquisition in the two‐way shuttle box, differ in dopaminergic activity. These two strains appear to be a valid laboratory model of divergent sensation/novelty and substance‐seeking profiles. RHA rats show higher ethanol intake and preference than do RLA rats, and it was suggested that RHA rats are more tolerant than RLA to the effects of alcohol. In the hole‐board test, we found that the non‐alcohol‐preferring RLA rats showed enhanced responsiveness to the stimulatory effects of intraperitoneal administration of 0.25 g/kg ethanol when compared with RHA rats. In situ hybridization analysis showed higher levels of preprodynorphin in the accumbens shell and higher levels of preproenkephalin in the cingulate cortex in RHA rats. RLA rats showed higher levels of enkephalin gene transcripts in restricted areas of the dorsal striatum. Finally, differences in cholecystokinin gene transcript, suggestive of a different arrangement of certain interneurons, were found in different cortical areas. The differences in peptide gene expression found between the two strains might reflect the differences in alcohol preference and sensitivity. RHA rats may have more predictive value than other rodent alcoholism models, as high initial tolerance to ethanol is a risk factor for alcoholism in humans.
Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex
Authors: Resstel L. B. M. , Corrêa F. M. A.
Published: January 2006

The ventral portion of the medial prefrontal cortex (vMPFC) is involved in the modulation of the parasympathetic component of the baroreflex. In the present study, we verified the effect of blockade of vMPFC glutamatergic receptors and nitric oxide synthases (NOS) on the parasympathetic component of baroreflex in awake rats. Bilateral microinjection of the non‐selective ionotropic glutamate antagonist kynurenic acid (KYN) into the vMPFC caused a shift of the threshold of reflex bradycardia toward higher pressures in response to increases in mean arterial pressure (MAP) caused by intravenous infusion of phenylephrine, thus indicating a tonic facilitatory influence action of vMPFC glutamate receptors on the parasympathetic component of the baroreflex. The effect of blockade of vMPFC‐NMDA receptors by AP7 was similar to that observed after KYN, suggesting mediation via NMDA receptors. Pretreatment with the NOS inhibitor L‐NAME or the specific neural NOS (nNOS)Nω‐propyl‐l‐arginine microinjected in the vMPFC caused a shift of the reflex threshold toward higher pressures that was similar to that observed after blockade of NMDA receptors, thus indicating participation of the NO/NMDA‐receptor pathway in the vMPFC modulation of the parasympathetic component of the baroreflex. In conclusion, our data indicate that glutamatergic neurotransmission in the vMPFC has a tonic facilitatory influence on the parasympathetic component of the baroreflex. Because local treatment with either the nNOS inhibitorNω‐propyl‐l‐arginine or the specific NMDA antagonist AP7 had similar effects on the baroreflex, it is also suggested that this modulation involves an NMDA–NO interaction within the vMPFC.
Evidence for a functional role of GABACreceptors in the rat mature hippocampus
Authors: Alakuijala Anniina , Alakuijala Jyrki , Pasternack Michael
Published: January 2006

Both γ‐aminobutyric acid (GABA)Creceptor subunit mRNA and protein are expressed in the stratum pyramidale in the CA1 area of the adult rat hippocampus, but so far no conclusive evidence about functional hippocampal GABACreceptors has been presented. Here, the contribution of GABACreceptors to stimulus‐evoked postsynaptic potentials was studied in the hippocampal CA1 area with extracellular and intracellular recordings at the age range of 21–47 postnatal days. Activation of GABACreceptors with the specific agonistcis‐4‐aminocrotonic acid (CACA) suppressed postsynaptic excitability and increased the membrane conductance. The GABACreceptor antagonist 1,2,5,6‐tetrahydropyridine‐4‐ylmethylphosphinic acid (TPMPA), but not the GABAAreceptor antagonist bicuculline, inhibited the effects of CACA. GABA‐mediated long‐lasting depolarizing responses evoked by high‐frequency stimulation of local inhibitory interneurons in the CA1 area in the presence of ionotropic glutamate receptor and GABABreceptor blockers were prolonged by TPMPA, indicating that GABACreceptors are activated under these conditions. For weaker stimulation, the effect of TPMPA was enhanced after GABA uptake was inhibited. Our data demonstrate that GABACreceptors can be activated by endogenous synaptic transmitter release following strong stimulation or under conditions of reduced GABA uptake. The lack of GABACreceptor activation by less intensive stimulation under control conditions suggests that these receptors are extrasynaptic and activated via spillover of synaptically released GABA.
Visuospatial reorienting signals in the human temporo‐parietal junction are independent of response selection
Authors: Astafiev Serguei V. , Shulman Gordon L. , Corbetta Maurizio
Published: January 2006

This study contrasts visuospatial reorienting and response selection signals in the right temporo‐parietal junction (TPJ) with functional magnetic resonance imaging. The overall goal was to investigate whether spatial orienting signals and motor signals interacted or were independent in TPJ. The right TPJ showed a greater response to targets at invalidly rather than validly cued locations, but no significant modulation from the effector used to respond. We suggest that TPJ may work as a modality‐independent ‘circuit breaker’ for the dorsal fronto‐parietal attention system, directing attention to salient events and enabling a variety of responses to those events.
Propofol block ofIhcontributes to the suppression of neuronal excitability and rhythmic burst firing in thalamocortical neurons
Authors: Ying Shui‐Wang , Abbas Syed Y. , Harrison Neil L. , Goldstein Peter A.
Published: January 2006

Although the depressant effects of the general anesthetic propofol on thalamocortical relay neurons clearly involve γ‐aminobutyric acid (GABA)Areceptors, other mechanisms may be involved. The hyperpolarization‐activated cation current (Ih) regulates excitability and rhythmic firing in thalamocortical relay neurons in the ventrobasal (VB) complex of the thalamus. Here we investigated the effects of propofol onIh‐related functionin vitroandin vivo. In whole‐cell current‐clamp recordings from VB neurons in mouse (P23–35) brain slices, propofol markedly reduced the voltage sag and low‐threshold rebound excitation that are characteristic of the activation ofIh. In whole‐cell voltage‐clamp recordings, propofol suppressed theIhconductance and slowed the kinetics of activation. The block ofIhby propofol was associated with decreased regularity and frequency of δ‐oscillations in VB neurons. The principal source of theIhcurrent in these neurons is the hyperpolarization‐activated cyclic nucleotide‐gated (HCN) type 2 channel. In human embryonic kidney (HEK)293 cells expressing recombinant mouse HCN2 channels, propofol decreasedIhand slowed the rate of channel activation. We also investigated whether propofol might have persistent effects on thalamic excitability in the mouse. Three hours following an injection of propofol sufficient to produce loss‐of‐righting reflex in mice (P35),Ihwas decreased, and this was accompanied by a corresponding decrease in HCN2 and HCN4 immunoreactivity in thalamocortical neuronsin vivo. These results suggest that suppression ofIhmay contribute to the inhibition of thalamocortical activity during propofol anesthesia. Longer‐term effects represent a novel form of propofol‐mediated regulation ofIh.
A null model of exotic plant diversity tested with exotic and native species–area relationships
Authors: Stark Scott C. , Bunker Daniel E. , Carson Walter P.
Published: January 2006

At large spatial scales, exotic and native plant diversity exhibit a strong positive relationship. This may occur because exotic and native species respond similarly to processes that influence diversity over large geographical areas. To test this hypothesis, we compared exotic and native species–area relationships within six North American ecoregions. We predicted and found that within ecoregions the ratio of exotic to native species richness remains constant with increasing area. Furthermore, we predicted that areas with more native species than predicted by the species–area relationship would have proportionally more exotics as well. We did find that these exotic and native deviations were highly correlated, but areas that were good (or bad) for native plants were even better (or worse) for exotics. Similar processes appear to influence exotic and native plant diversity but the degree of this influence may differ with site quality.
Niche breadth, competitive strength and range size of tree species: a trade‐off based framework to understand species distribution
Authors: Morin Xavier , Chuine Isabelle
Published: January 2006

Understanding the mechanisms causing latitudinal gradients in species richness and species range size is a central issue in ecology, particularly in the current context of global climate change. Different hypotheses have been put forward to explain these patterns, emphasizing climatic variability, energy availability and competition. Here we show, using a comparative analysis controlling for phylogeny on 234 temperate/boreal tree species, that these hypotheses can be included into a single framework in an attempt to explain latitudinal gradients in species range size. We find that species tend to have larger ranges when (i) closer to the poles, (ii) successionally seral, (iii) having small and light seeds, and (iv) having short generations. The patterns can simply be explained by energy constraints associated with different life‐history strategies. Overall, these findings shed a new light on our understanding of species distribution and biodiversity patterns, bringing new insights into underlying large‐scale evolutionary processes.
Local and regional scale recovery of Diadema promotes recruitment of scleractinian corals
Authors: Carpenter Robert C. , Edmunds Peter J.
Published: January 2006

The phase change from coral to macroalgal dominance on many Caribbean reefs was exacerbated by the mortality of the echinoid Diadema antillarum in 1983–1984, and until recently, this sea urchin has remained rare on reefs throughout the western Atlantic. By the late 1990s, Diadema started to reappear in large numbers on some Jamaican reefs, and by 2000, the high densities were correlated with significantly greater abundances of juvenile corals. Here, we show that dense populations of Diadema now occur over a multi‐kilometre‐wide scale at six locations scattered along a 4100 km arc across the entire Caribbean. In all cases, these dense populations are found in shallow water (< 6 m depth) on outer reef communities and are associated with reduced macroalgal cover and enhanced coral recruitment. We conclude that population recovery of Diadema is occurring at both local and regional scales, and that grazing by this echinoid is creating conditions favouring the recruitment of corals.