bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunohistochemical characterization of glomerular inflammatory cells and expression of adhesion molecules in anti‐glomerular basement membrane (anti‐GBM) glomerulonephritis induced in WKY rats with monoclonal anti‐GBM antibodies of different subclasses
Authors: Kado Tadashi , Kohda Takayuki , Okada Shinichi , Hayashi Atsushi , Utsunomiya Yasushi , Kanzaki Susumu , Sado Yoshikazu , Yamamoto Tadashi
Published: January 2006

According to previous report, adhesion of CD8‐positive cells and macrophages to glomerular endotherial cells through the lymphocyte function‐associated antigen‐1 (LFA‐1)/intercellular adhesion molecule‐1 (ICAM‐1) pathway is crucial for the initiation and subsequent progression of anti‐glomerular basement membrane (anti‐GBM) antibody‐induced glomerulonephritis (anti‐GBM nephritis) in WKY rats. In the present study glomerular inflammatory cell infiltration and LFA‐1/ICAM‐1 expression were examined in anti‐GBM nephritis induced in WKY rats with monoclonal anti‐GBM antibodies of different subclasses: IgG1, IgG2a, and IgG2b. The IgG2a and IgG2b subclasses induced significant proteinuria from day 3 as compared with the IgG1 subclass. Glomerular infiltration of macrophages and CD8‐positive cells after administration of IgG2a and IgG2b subclass antibodies was significantly elevated compared to that for the IgG1 subclass. The intensity of glomerular ICAM‐1 immunostaining by the IgG2a and IgG2b subclass antibodies tended to be stronger than that by the IgG1 subclass. Glomerular LFA‐1‐positive cell infiltration by the IgG2a and IgG2b subclasses was significantly higher than that of the IgG1 subclass. These results demonstrate that monoclonal antibodies belonging to the IgG2a and IgG2b subclasses strongly induce glomerular infiltration of inflammatory cells and expression of adhesion molecules in rat anti‐GBM nephritis.
Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms
Authors: Cho Eun Yoon , Choi YoonLa , Chae Seoung Wan , Sohn Jin Hee , Ahn Geung Hwan
Published: January 2006

To clarify possible roles of adhesion molecules including E‐cadherin, β‐ and γ‐catenin, CD44s, CD44v6, CD56, and CD99 in ovarian serous neoplasms, an immunohistochemical study was undertaken for 23 benign, 40 borderline, and 95 malignant ovarian serous neoplasms using tissue microarray (TMA). Significantly reduced expression of E‐cadherin, and overexpression of CD44s, CD56, and CD99 were more frequently observed in adenocarcinomas than in benign and borderline tumors. Expression of CD44v6 and nuclear β‐ and γ‐catenin were detected only in borderline tumors and adenocarcinomas. Reduced expression of E‐cadherin was also correlated with high tumor grade (P = 0.03), presence of peritoneal seeding (P = 0.03), and low overall survival rate (P = 0.02). Overexpression of CD44s was significantly associated with high tumor grade (P = 0.04), advanced stage (P = 0.03), and low overall survival rate (P = 0.02). CD56 was increasingly expressed in the case of advanced stage (P = 0.005) and peritoneal seeding (P = 0.001). Nuclear staining for γ‐catenin was correlated with tumor progression (P = 0.004) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.02). Only CD44s expression and stage were correlated with overall survival in multivariate study. These results suggest that although E‐cadherin, CD44s, CD56, and nuclear γ‐catenin immunoexpression seem to be useful prognostic markers for serous neoplasm of the ovary, CD44s expression and FIGO stage are independent prognostic factors.
Pancreatic, hepatic, splenic, and mesenteric mucinous cystic neoplasms (MCN) are lumped together as extraovarian MCN
Authors: Shiono Saori , Suda Koichi , Nobukawa Bunsei , Arakawa Atsushi , Yamasaki Shigetaka , Sasahara Noriko , Hosokawa Yoshinori , Suzuki Fujihiko
Published: January 2006

Mucinous cystic neoplasms (MCN) of the pancreas are mucin‐producing cystic tumors with an ovarian‐like stroma (OLS). In the present study MCN were obtained from 27 patients. These MCN were derived from 22 pancreas, three livers, spleen, and mesentery. MCN in various organs have common clinicopathological profiles, being unilocular or multilocular cystic tumors, with a fibrous capsule and lined by mucin‐secreting epithelium associated with an underlying subepithelial OLS. The OLS showed strong positivity for α‐smooth muscle actin (α‐SMA) and vimentin and weak, focal positivity for desmin. Both estrogen receptors and progesterone receptors were expressed in the nuclei of OLS cells. In addition, 20 ovarian MCN and 13 normal ovaries were studied with particular attention to the stroma. The stroma of ovarian MCN was strongly immunopositive for α‐SMA and vimentin and focally positive for desmin, whereas normal ovarian stroma was immunonegative for both α‐SMA and desmin. The OLS of MCN mentioned here was similar to the septa of ovarian MCN but not to ovarian stroma. In conclusion, MCN in various organs should be lumped together as ‘extraovarian’ MCN. The OLS was identified on the basis of myofibroblastic proliferation both in response to neoplastic development and dependent on hormones.
Mixed medullary and follicular cell carcinoma of the thyroid with lymph node metastasis in a 7‐year‐old child
Authors: Goyal Richa , Nada Ritambhra , Rao Katragadda L. N. , Radotra Bishan D.
Published: January 2006

A 7‐year‐old boy presented with midline swelling in the neck. On fine‐needle aspiration cytology it was diagnosed as papillary carcinoma of the thyroid. The patient underwent total thyroidectomy. Histopathological examination, immunohistochemistry and electron microscopy revealed the presence of two intermingled components: medullary carcinoma and papillary carcinoma. One of the submandibular lymph nodes had metastasis of both the components. The case was diagnosed as ‘mixed medullary and follicular cell carcinoma’ with papillary carcinoma pattern and lymph node metastasis. Mixed medullary and follicular cell carcinoma with intermingling of medullary and papillary carcinoma components is a rare tumor. In adults, only eight such cases with lymph node metastasis have been published. To the best of the authors’ knowledge no pediatric case has previously been reported in the English‐language literature.
Female adnexal tumor of probable wolffian origin: Morphological, immunohistochemical, and ultrastructural study with c‐kit gene analysis
Authors: Harada Oi , Ota Hiroyoshi , Takagi Kimiyo , Matsuura Hiroyuki , Hidaka Eiko , Nakayama Jun
Published: January 2006

Female adnexal tumors of probable wolffian origin (FATWO) are rare neoplasms believed to originate from mesonephric (wolffian) remnants. Rarity and variable location of FATWO make the diagnosis difficult. Although most cases follow a benign clinical course, approximately 10% of them either recur or metastasize and are thought to be resistant to chemoradiation therapy. In 2004, imatinib therapy, a tyrosine kinase inhibitor known to be effective against gastrointestinal stromal tumors, was reported to be effective also in a case of KIT‐positive FATWO. However, c‐kit gene mutations in FATWO have never been studied. Herein is reported the case of a 50‐year‐old Japanese woman with FATWO arising in the right paratubal site. The tumor had typical characteristics of FATWO in both morphology and immunohistochemistry. KIT protein was diffusely and weakly expressed, but DNA analysis revealed no mutational change in exon 9 or 11 of the c‐kit gene. It is believed that accumulation of such genetic data of FATWO are essential from a therapeutic standpoint, although the present case had no mutation. In addition, the cytological features of this rare tumor are presented, which have not been described previously.
Early recurrence of dense deposit disease with marked endocapillary proliferation after renal transplantation
Authors: Aita Kumi , Ito Shinichi , Tanabe Kazunari , Toma Hiroshi , Yamaguchi Yutaka , Nagata Michio
Published: January 2006

Dense deposit disease (DDD), also known as type II membranoproliferative glomerulonephritis (MPGN), is characterized by the presence of continuous intramembranous dense deposits. At present, the histogenesis of DDD is not well known. Reported herein are two cases of early recurrence of DDD in renal allografts, with marked endocapillary proliferation. In case 1 the first allograft biopsy revealed electron‐dense deposits mainly in the subendothelial and mesangial areas along with subepithelial humps, but a continuous intramembranous deposition was not obvious. In the sequential biopsy, the deposits were more often seen in the intramembranous area and finally formed a continuous osmiophilic substance, which is a characteristic feature of DDD. In case 2, continuous intramembranous deposition already coexisted with endocapillary proliferation at the first biopsy. In both cases, endocapillary proliferation was alleviated slightly as time progressed. The present report suggests that endocapillary proliferative glomerulonephritis is the earliest lesion in some cases of DDD. Detailed review of a clinical history and a subsequent follow‐up biopsy should be done to distinguish these lesions from other types of endocapillary proliferative glomerulonephritis.
Possible role of excitotoxicity in the pathogenesis of glaucoma
Authors: Casson Robert J
Published: February 2006

Abstract

Excitotoxicity describes the process of neuronal injury by excess stimulation of amino acid receptors. This form of insult was first described in the retina, and subsequently has been shown to be an important component of the pathogenesis of ischaemic and traumatic injury in the central nervous system. Furthermore, there is increasing evidence that excitotoxicity is involved in several chronic neurological conditions, and anti‐excitotoxic treatment has already been approved for some of these conditions. A large‐scale trial is currently underway that will determine the efficacy of an anti‐excitotoxic drug (memantine) in the management of glaucoma. This review provides an overview of neurotransmission and the mechanisms of excitotoxicity. The evidence for excitotoxicity as a component of certain neurological diseases, including glaucoma, is discussed.
Use of packaged entrees as part of a weight‐loss diet in overweight men: an 8‐week randomized clinical trial
Authors: Hannum S. M. , Carson L. A. , Evans E. M. , Petr E. L. , Wharton C. M. , Bui L. , Erdman J. W.
Published: February 2006

Aim:  This study assessed the efficacy of a weight‐loss diet by using packaged portion‐controlled entrees vs. a self‐selected diet based on the United States Department of Agriculture Food Guide Pyramid (FGP).

Methods:  Sixty healthy overweight men (body mass index (BMI) 26–42 kg/m2; aged 24–60 years) were randomized into two groups for an 8‐week intervention. Group E consumed two portion‐controlled entrees daily, plus recommended servings from the FGP. Group P consumed a self‐selected diet consisting of a recommended number of servings from the FGP. Diets were designed to be isocaloric (1700 kcal) and identical in macronutrient composition (55% carbohydrate, 25% protein and 20% fat). Participants were instructed to make no changes in physical activity levels. Each group was blinded to the protocol of the other group, and received separate diet instructions, but no behavioural or diet counselling. Outcomes included weight, BMI, body composition by dual energy X‐ray absorptiometry, waist and hip circumference, blood pressure (BP), fasting blood lipids, glucose, insulin and C‐reactive protein.

Results:  Fifty‐one men completed the study. The portion‐control group E (n = 25) experienced greater decreases in weight (−7.4 ± 3.1 vs. −5.1 ± 4.0 kg), BMI (−2.4 ± 1.0 vs. −1.6 ± 1.3 kg/m2), fat mass (−3.6 ± 1.8 vs. −2.5 ± 1.8 kg), waist circumference (−6.6 ± 3.3 vs. −4.3 ± 2.9 cm) and diastolic BP (−6.0 ± 7.2 vs. + 0.2 ± 10.1 mmHg) than group P (n = 26) (p < 0.05). Consumption of a packaged entree diet resulted in greater losses of weight and fat mass, and reduced BP.

Conclusions:  Use of packaged entrees as part of a weight‐loss diet is an effective means of achieving portion control and enhancing losses of weight and fat mass in overweight men.
Reactive species and early manifestation of insulin resistance in type 2 diabetes
Authors: Fridlyand L. E. , Philipson L. H.
Published: February 2006

The early stages of type 2 diabetes mellitus are characterized by the development of insulin resistance (IRe) in muscle cells and adipocytes with the concomitant loss of β‐cell compensation. We have extensively reviewed the literature related to metabolic and signalling pathways of reactive oxygen species (ROS) in regard to the coordinated development of oxidative stress and IRe. We considered the hypothesis that oxidative stress leads to IRe in muscle cells and adipocytes, but found that the data are more consistent with the hypothesis that the cellular mechanisms that protect against oxidative stress per se are capable of creating an ROS‐dependent insulin‐resistant state. Furthermore, ROS‐induced mitochondrial dysfunction can lead to disruptions of lipid metabolism, increasing the intracellular lipid content, and, in addition, contribute to lipid‐dependent IRe in myocytes. Together, these two ROS‐activated pathways to IRe can contribute to a global state of profound resistance to insulin action. Therapeutic strategies should, therefore, be directed towards reducing insulin resistance without an increase in ROS production or concentration. Pharmacological or other approaches to IRe that result in the activation of mitochondrial biogenesis in particular could be highly beneficial in the prevention or treatment of both insulin resistance and type 2 diabetes.
Consistency of the Semi‐parametric MLE in Linear Regression Models with Interval‐censored Data
Authors: YU QIQING , WONG GEORGE Y. C. , KONG FANHUI
Published: January 2006

Abstract.  Consider the model Y=β′X+ε. Let F0 be the unknown cumulative distribution function of the random variable ε. Consistency of the semi‐parametric Maximum likelihood estimator of (β,F0), denoted by , has not been established under any interval censorship (IC) model. We prove in this paper that is consistent under the mixed case IC model and some mild assumptions.
Power and Democracy in Norway: The Transformation of Norwegian Politics1
Authors: Østerud Øyvind , Selle Per
Published: February 2006

The Norwegian Power and Democracy Project concluded that the parliamentary chain of government is weakened in every link; parties and election are less mobilizing; minority governments imply that the connection between election results and policy formation is broken; and elected assemblies have been suffering a notable loss of domain. Popular participation has moved from long‐term organisations and political parties to short‐term action groups and associations with immediate concerns. The judicialisation of politics has strengthen the legal system and weakened the autonomy of local democracy, while the expansion of market forces further affects the span of parliamentary rule. The mass media has become politically more independent, while adapting more closely to economic forces and the quest for return of investment. There has, accordingly, been centralisation of economic power through mergers and acquisitions following the globalisation of the Norwegian economy. The so‐called ‘Scandinavian’ (or ‘Nordic’) model is increasingly strained, while corporatism is partly weakened and partly restructured. After the end of the Cold War, there has also been a consistent strategy in foreign policy for the branding of Norway as a champion for peace and human rights. There is a cluster of corporate bureaucratic agencies around the high‐profile peace mediation and humanitarian engagement.
Social Security Reform and Investment in Education: Is There Scope for a Pareto Improvement?
Authors: KÖTHENBÜRGER MARKO , POUTVAARA PANU
Published: February 2006

We propose a Pareto‐improving policy which reduces the overall wage tax burden in an economy with intergenerational trade in a fixed factor of production, here labelled as land. We analyse a second‐best environment in which the government cannot resort to non‐distortionary land taxes. Reducing the social security contribution rate encourages investment in human capital. Future efficiency gains accruing to complementary land are capitalized in its value. The capital gains may compensate land‐owning pensioners for reduced benefits. We also explain why the unfunded pension system may have lost its appeal even for pensioners after its introduction.
A role for mixed lineage kinases in granule cell apoptosis induced by cytoskeletal disruption
Authors: Müller Georg Johannes , Geist Marie Aavang , Veng Lone Merete , Willesen Mette Georgi , Johansen Flemming Fryd , Leist Marcel , Vaudano Elisabetta
Published: January 2006

Microtubule disruption by colchicine induces apoptosis in selected neuronal populations. However, little is known about the upstream death signalling events mediating the neurotoxicity. We investigated first whether colchicine‐induced granule cell apoptosis activates the c‐Jun N‐terminal kinase (JNK) pathway. Cultured murine cerebellar granule cells were exposed to 1 µmcolchicine for 24 h. Activation of the JNK pathway was detected by western blotting as well as immunocytochemistry using antibodies against phospho‐c‐Jun (p‐c‐Jun). Next, adult male rats were injected intracerebroventricularly with colchicine (10 µg), and JNK pathway activation in dentate granule cells (DGCs) was detected by antibodies against p‐c‐Jun. The second part of the study tested the involvement of mixed lineage kinases (MLK) as upstream activators of the JNK pathway in colchicine toxicity, using CEP‐1347, a potent MLK inhibitor.In vitro, significant inhibition of the JNK pathway, activated by colchicine, was achieved by 100–300 nmCEP‐1347, which blocked both activation of cell death proteases and apoptosis. Moreover, CEP‐1347 markedly delayed neurite fragmentation and cell degeneration.In vivo, CEP‐1347 (1 mg/kg) significantly prevented p‐c‐jun increase following injection of colchicine, and enhanced survival of DGCs. We conclude that colchicine‐induced neuronal apoptosis involves the JNK/MLK pathway, and that protection of granule cells can be achieved by MLK inhibition.
Histamine protects against NMDA‐induced necrosis in cultured cortical neurons through H2 receptor/cyclic AMP/protein kinase A and H3 receptor/GABA release pathways
Authors: Dai Haibin , Zhang Zhongmiao , Zhu Yongpin , Shen Yao , Hu Weiwei , Huang Yuwen , Luo Jianhong , Timmerman Henk , Leurs Rob , Chen Zhong
Published: January 2006

Using histamine and the H3 receptor antagonist thioperamide, the roles of histamine receptors in NMDA‐induced necrosis were investigated in rat cultured cortical neurons. Within 3 h of intense NMDA insult, most neurons died by necrosis. Histamine reversed the neurotoxicity in a concentration‐dependent manner and showed peak protection at a concentration of 10−7 m. This protection was antagonized by the H2 receptor antagonists cimetidine and zolantidine but not by the H1 receptor antagonists pyrilamine and diphenhydramine. In addition, the selective H2 receptor agonist amthamine mimicked the protection by histamine. This action was prevented by cimetidine but not by pyrilamine. 8‐Bromo‐cAMP also mimicked the effect of histamine. In contrast, both the adenylyl cyclase inhibitor 9‐(tetrahydro‐2‐furanyl)‐9H‐purine‐6‐amine and the cAMP‐dependent protein kinase inhibitor N‐[2‐(p‐bromocinnamylamino) ethyl]‐5‐isoquinolinesulfonamide reversed the protection by histamine. Thioperamide also attenuated NMDA‐induced excitotoxicity, which was reversed by the H3 receptor agonist (R)‐α‐methylhistamine but not by pyrilamine and cimetidine. In addition, the protection by thioperamide was inhibited by the GABAA receptor antagonists picrotoxin and bicuculline. Further study demonstrated that the protection by thioperamide was due to increased GABA release in NMDA‐stimulated samples. These results indicate that not only the H2 receptor/cAMP/cAMP‐dependent protein kinase pathway but also the H3 receptor/GABA release pathway can attenuate NMDA‐induced neurotoxicity.
Shift in the ratio of three‐repeat tau and four‐repeat tau mRNAs in individual cholinergic basal forebrain neurons in mild cognitive impairment and Alzheimer's disease
Authors: Ginsberg Stephen D. , Che Shaoli , Counts Scott E. , Mufson Elliott J.
Published: January 2006

Molecular mechanisms underlying tauopathy remain undetermined. In the current study, single cell gene expression profiling was coupled with custom‐designed cDNA array analysis to evaluate tau expression and other cytoskeletal elements within individual neuronal populations in patients with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer's disease (AD). Results revealed a shift in the ratio of three‐repeat tau (3Rtau) to four‐repeat tau (4Rtau) mRNAs within individual human cholinergic basal forebrain (CBF) neurons within nucleus basalis (NB) and CA1 hippocampal neurons during the progression of AD, but not during normal aging. A shift in 3Rtau to 4Rtau may precipitate a cascade of events in the selective vulnerability of neurons, ultimately leading to frank neurofibrillary tangle (NFT) formation in tauopathies including AD.
The BH3‐only protein Puma is both necessary and sufficient for neuronal apoptosis induced by DNA damage in sympathetic neurons
Authors: Wyttenbach Andreas , Tolkovsky Aviva M.
Published: January 2006

DNA damage activates apoptosis in several neuronal populations and is an important component of neuropathological conditions. While it is well established that neuronal apoptosis, induced by DNA damage, is dependent on the key cell death regulators p53 and Bax, it is unknown which proteins link the p53 signal to Bax. Using rat sympathetic neurons as an in vitro model of neuronal apoptosis, we show that cytosine arabinoside is a DNA damaging drug that induces the expression of the BH3‐only pro‐apoptotic genes Noxa, Puma and Bim. Increased expression occurred after p53 activation, measured by its phosphorylation at serine 15, but prior to the conformational change of Bax at the mitochondria, cytochrome c (cyt c) release and apoptosis. Hence Noxa, Puma and Bim could potentially link p53 to Bax. We directly tested this hypothesis by the use of nullizygous mice. We show that Puma, but not Bim or Noxa, is a crucial mediator of DNA damage‐induced neuronal apoptosis. Despite the powerful pro‐apoptotic effects of overexpressed Puma in Bax‐expressing neurons, Bax nullizygous neurons were resistant to Puma‐induced death. Therefore, Puma provides the critical link between p53 and Bax, and is both necessary and sufficient to mediate DNA damage‐induced apoptosis of sympathetic neurons.
Ethanol inhibits L1 cell adhesion molecule activation of mitogen‐activated protein kinases
Authors: Tang Ningfeng , He Min , O'Riordan Mary Ann , Farkas Chloe , Buck Kevin , Lemmon Vance , Bearer Cynthia F.
Published: January 2006

Inhibition of the functions of L1 cell adhesion molecule (L1) by ethanol has been implicated in the pathogenesis of the neurodevelopmental aspects of the fetal alcohol syndrome (FAS). Ethanol at pharmacological concentrations has been shown to inhibit L1‐mediated neurite outgrowth of rat post‐natal day 6 cerebellar granule cells (CGN). Extracellular signal‐related kinases (ERK) 1/2 activation occurs following L1 clustering. Reduction in phosphoERK1/2 by inhibition of mitogen‐activated protein kinase kinase (MEK) reduces neurite outgrowth of cerebellar neurons. Here, we examine the effects of ethanol on L1 activation of ERK1/2, and whether this activation occurs via activation of fibroblast growth factor receptor 1 (FGFR1). Ethanol at 25 mm markedly inhibited ERK1/2 activation by both clustering L1 with cross‐linked monoclonal antibodies, or by L1‐Fc chimeric proteins. Clustering L1 with subsequent ERK1/2 activation did not result in tyrosine phosphorylation of the FGFR1. In addition, inhibition of FGFR1 tyrosine kinase blocked basic fibroblast growth factor (bFGF) activation of ERK1/2, but did not affect activation of ERK1/2 by clustered L1. We conclude that ethanol disrupts the signaling pathway between L1 clustering and ERK1/2 activation, and that this occurs independently of the FGFR1 pathway in cerebellar granule cells.
Semax, an analogue of adrenocorticotropin (4–10), binds specifically and increases levels of brain‐derived neurotrophic factor protein in rat basal forebrain
Authors: Dolotov Oleg V. , Karpenko Ekaterina A. , Seredenina Tamara S. , Inozemtseva Lyudmila S. , Levitskaya Natalia G. , Zolotarev Yuriy A. , Kamensky Andrey A. , Grivennikov Igor A. , Engele Juergen , Myasoedov Nikolay F.
Published: January 2006

The heptapeptide Semax (Met‐Glu‐His‐Phe‐Pro‐Gly‐Pro) is an analogue of the N‐terminal fragment (4–10) of adrenocorticotropic hormone which, after intranasal application, has profound effects on learning and memory formation in rodents and humans, and also exerts marked neuroprotective effects. A clue to the molecular mechanism underlying this neurotropic action was recently given by the observation that Semax stimulates the synthesis of brain‐derived neurotrophic factor (BDNF), a potent modulator of synaptic plasticity, in astrocytes cultured from rat basal forebrain. In the present study, we investigated whether Semax affects BDNF levels in rat basal forebrain upon intranasal application of the peptide. In addition, we examined whether cell membranes isolated from this brain region contained binding sites for Semax. The binding of tritium‐labelled Semax was found to be time dependent, specific and reversible. Specific Semax binding required calcium ions and was characterized by a mean± SEM dissociation constant (KD) of 2.4 ± 1.0 nm and a BMAX value of 33.5 ± 7.9 fmol/mg protein. Sandwich immunoenzymatic analysis revealed that Semax applied intranasally at 50 and 250 µg/kg bodyweight resulted in a rapid increase in BDNF levels after 3 h in the basal forebrain, but not in the cerebellum. These results point to the presence of specific binding sites for Semax in the rat basal forebrain. In addition, these findings indicate that the cognitive effects exerted by Semax might be associated, at least in part, with increased BDNF protein levels in this brain region.
Use of microarray biomarkers to identify longevity therapeutics
Authors: Spindler Stephen R.
Published: January 2006

A number of lines of evidence, including nonhuman primate and human studies, suggest that regulatory pathways similar to those invoked by caloric restriction (CR) may be involved in determining human longevity. Thus, pharmaceuticals capable of mimicking the molecular mechanisms of life‐ and health‐span extension by CR (CR mimetics) may have application to human health. CR acts rapidly, even in late adulthood, to begin to extend life‐ and health‐span in mice. We have linked these effects with rapid changes in the levels of specific gene transcripts in the liver and the heart. Our results are consistent with the rapid effects of caloric intake on the lifespan and/or biochemistry and physiology of Drosophila, rodents, rhesus macaques and humans. To test the hypothesis that existing pharmaceuticals can mimic the physiologic effects of CR, we evaluated the effectiveness of glucoregulatory drugs and putative cancer chemopreventatives in reproducing the hepatic gene‐expression profiles produced by long‐term CR (LTCR). We found that 8 weeks of metformin treatment was superior to 8 weeks of CR at reproducing the specific changes in transcript levels produced by LTCR. Consistent with these results, metformin reduces cancer incidence in diabetic humans and ameliorates the onset and severity of metabolic syndrome. Metformin extends the mean and maximum lifespans of female transgenic HER‐2/neu mice by 8% and 13.1% in comparison with control mice. Phenformin, a close chemical relative of metformin, extends lifespan and reduces tumor incidence in C3H mice. These results indicate that gene‐expression biomarkers can be used to identify promising candidate CR mimetics.
Rules for the use of model organisms in antiaging pharmacology
Authors: Jafari Mahtab , Rose Michael R.
Published: January 2006

The use of animal models for initially screening antiaging drugs is a promising approach for drug discovery. However, there a number of potential artifacts, confounds and errors that can arise in such research programs. The following rules are intended to minimize such problems: (1) since aging occupies an increasing proportion of human adulthood, data that conflate aging and late life should not be extrapolated to human aging; (2) the response to candidate medications should show a normal dose‐response pattern, although not necessarily a linear response; (3) medicated animal models should not be hypometabolic; (4) medicated animal models should not show pronounced reductions in fertility; (5) medicated animal models should not exhibit general nervous system depression; (6) the effect of the medication should not be highly sensitive to the culture environment; (7) the effect of the medication should not be highly dependent on the genetic ancestry of the stock employed, leaving aside inbreeding, which should be avoided because humans are not generally inbred. While these rules do not guarantee successful extrapolation of successful drug results from the animal model to humans in a clinical setting, the failure to adhere to these rules should raise doubts about such extrapolation.
Predicting Interfacial Loads between the Prosthetic Socket and the Residual Limb for Below‐Knee Amputees – A Case Study
Authors: Amali R. , Noroozi S. , Vinney J. , Sewell P. , Andrews S.
Published: January 2006

Abstract:  In this study, an artificial neural network (ANN) was deployed as a tool to determine the internal loads between the residual limb and prosthetic socket for below‐knee amputees. This was achieved by using simulated load data to validate the ANN and captured clinical load data to predict the internal loads at the residual limb–socket interface. Load/pressure was applied to 16 regions of the socket, using loading pads in conjunction with a load applicator, and surface strains were collected using 15 strain gauge rosettes. A super‐position program was utilised to generate training and testing patterns from the original load/strain data collected. Using this data, a back‐propagation ANN, developed at the University of the West of England, was trained. The input to the trained network was the surface strains and the output the internal loads/pressure. The system was validated and the mean square error (MSE) of the system was found to be 8.8% for 1000 training patterns and 8.9% for 50 testing patterns, which was deemed an acceptable error. Finally, the validated system was used to predict pressure‐sensitive/‐tolerant regions at the limb–socket interface with great success.
An Operational Model for Implementing Conservation Action
Authors: KNIGHT ANDREW T. , COWLING RICHARD M. , CAMPBELL BRUCE M.
Published: January 2006

Abstract:  The preoccupation of many conservation planners with the refinement of systematic assessment techniques has manifested an “implementation crisis” in conservation planning. This preoccupation has provided systematic assessments with well‐tested tools (e.g., area selection algorithms) and principles (e.g., representation, complementarity), but our understanding of these techniques currently far exceeds our ability to apply them effectively to pragmatic conservation problems. The science is informative about where one needs to do conservation, but silent on how to achieve it. Operational models, defined as simplified conceptualizations of processes for implementing conservation action at priority conservation areas, are essential for guiding conservation planning initiatives because they assist understanding of how these processes function. Operational models developed to date have largely been linear, simplistic, and focused on the systematic assessment of biological entities. Experience in the real world indicates that operational models for conducting conservation planning initiatives should explicitly complement a systematic conservation assessment with activities that empower individuals and institutions (enabling) and explicitly aim to secure conservation action (implementation). Specifically, implementing effective conservation action requires that systematic assessments be integrated functionally with a process for developing an implementation strategy and processes for stakeholder collaboration while maintaining a broad focus on the implementation of conservation action. A suite of hallmarks define effective operational models (e.g., stakeholder collaboration, links with land‐use planning, social learning, and action research). Greater development and testing of the practical application of operational models should lead to higher levels of effective implementation and alleviate the implementation crisis. Social learning institutions are essential for ensuring ongoing improvement in the development and application of operational models that deliver effective conservation action.
The Role of Roadsides in Plant Invasions: a Demographic Approach
Authors: CHRISTEN DOUGLAS , MATLACK GLENN
Published: January 2006

Abstract:  Non‐native plant species are common along roadsides, but presence does not necessarily indicate spread along the road axis. Roadsides may serve merely as habitat for a species spreading independently of roads. The potential conduit function of roads depends on the habitat specificity of the spreading species, its dispersal range relative to the spacing of roads in the landscape, and the relative importance of long‐ and short‐range dispersal. We describe a demographic model of the road×species interaction and suggest methods of assessing conduit function in the field based on the model results. A species limited to roadside habitat will be constrained to spread along the road axis unless its long‐range dispersal is sufficient to carry it across the intervening unfavorable area to another road. It will propagate along a road corridor at a rate determined by the scale of short‐range dispersal. Effective management of an invasion requires distinguishing between the habitat and conduit functions, a distinction difficult to make with only snapshot data. Invasions can be reconstructed by several methods, but none is totally satisfactory. We suggest comparing stem distributions on transects parallel and perpendicular to the road axis, and beside the road, and away from it, with an idealized Gaussian curve. Such comparisons would allow discrimination between pattern determined by habitat suitability and pattern reflecting random and facilitated dispersal.
ACQUIRING SCANNING ELECTRON MICROSCOPICAL, LIGHT MICROSCOPICAL AND MULTIPLE GENE SEQUENCE DATA FROM A SINGLE DINOFLAGELLATE CELL1
Authors: Takano Yoshihito , Horiguchi Takeo
Published: February 2006

We have developed a useful method to obtain light and scanning electron micrographs of a single dinoflagellate cell, prior to applying the cell to the single cell PCR technique. This method allows us to record detailed morphological information on any cell used for sequencing, which can be extremely important for the future identification of the organism, because cells used for single cell PCR usually cannot be retained. Furthermore, by applying multiple sets of PCR primers at the same time, we have successfully amplified and sequenced multiple genes (and DNA regions) simultaneously, even from a single cell. In this note, we demonstrate the methods of this technique by using two different types of dinoflagellates, i.e. an armored freshwater species, Peridinium willei Huitfeld‐Kaas, and an unarmored marine species, Akashiwo sanguinea (Hirasaka) Hansen and Moestrup. By rotating the cell, photographs of all aspects of a single cell can be taken even using the SEM. The genes and DNA regions sequenced in these examples include a region of the ribosomal DNA (SSU, ITS1, 5.8S, ITS2, and part of the LSU) as well as part of the mitochondrial DNA‐encoded gene, cox1. This technique can be applied to both photosynthetic and heterotrophic dinoflagellates and will accelerate biodiversity studies.
Are Patient Preferences for Life‐Sustaining Treatment Really a Barrier to Hospice Enrollment for Older Adults with Serious Illness?
Authors: Casarett David , Van Ness Peter H. , O'Leary John R. , Fried Terri R.
Published: February 2006

OBJECTIVES: To determine whether patient preferences are a barrier to hospice enrollment.

DESIGN: Prospective cohort study.

SETTING: Fifteen ambulatory primary care and specialty clinics and three general medicine inpatient units.

PARTICIPANTS: Two hundred three seriously ill patients with cancer (n=65, 32%), congestive heart failure (n=77, 38%), and chronic obstructive pulmonary disease (n=61, 30%) completed multiple interviews over a period of up to 24 months.

MEASUREMENTS: Preferences for high‐ and low‐burden life‐sustaining treatment and site of death and concern about being kept alive by machines.

RESULTS: Patients were more likely to enroll in hospice after interviews at which they said that they did not want low‐burden treatment (3 patients enrolled/16 interviews at which patients did not want low‐burden treatment vs 47 patients enrolled/841 interviews at which patients wanted low‐burden treatment; relative risk (RR)=3.36, 95% confidence interval (CI)=1.17–9.66), as were interviews at which patients said they would not want high‐burden treatment (5/28 vs 45/826; RR=3.28, 95% CI=1.14–7.62), although most patients whose preferences were consistent with hospice did not enroll before the next interview. In multivariable Cox regression models, patients with noncancer diagnoses who desired low‐burden treatment (hazard ratio (HR)=0.46, 95% CI=0.33–0.68) were less likely to enroll in hospice, and those who were concerned that they would be kept alive by machines were more likely to enroll (HR=5.46, 95% CI=1.86–15.88), although in patients with cancer, neither preferences nor concerns about receiving excessive treatment were associated with hospice enrollment. Preference for site of death was not associated with hospice enrollment.

CONCLUSION: Overall, few patients had treatment preferences that would make them eligible for hospice, although even in patients whose preferences were consistent with hospice, few enrolled. Efforts to improve end‐of‐life care should offer alternatives to hospice that do not require patients to give up life‐sustaining treatment, as well as interventions to improve communication about patients' preferences.
T‐Wave Oversensing in Implantable Cardiac Defibrillators Is Due to Technical Failure of Device Sensing
Authors: GILLIAM F. ROOSEVELT
Published: January 2006

The expanded indications for the use of implantable cardioverter defibrillators (ICDs) for primary prevention of sudden cardiac death have increased concerns about inappropriate delivery of therapies. Dual‐chamber systems have improved the capacity of ICDs to differentiate ventricular arrhythmias from supraventricular arrhythmias. Still, T‐wave oversensing is a major source of inappropriate therapy. It is likely the true incidence of T‐wave oversensing is greater than reported as documented events reflect only those stored in a device memory. Reviewing cases of T‐wave oversensing that failed noninvasive correction; we found successful resolution resulted from generator replacement. We conclude that T‐wave oversensing is due to inadequate signal processing by some ICD generators.
Anatomic Proximity of the Esophagus to the Coronary Sinus: Implication for Catheter Ablation Within the Coronary Sinus
Authors: TSAO HSUAN‐MING , WU MEI‐HAN , CHERN MING‐SHENG , TAI CHING‐TAI , LIN YENN‐JIANG , CHANG SHIH‐LIN , CHIANG SHUO‐JU , ONG MARY GERTRUDE , WONGCHAROEN WANWARANG , HSU NAI‐WEI , CHANG CHENG‐YEN , CHEN SHIH‐ANN
Published: January 2006

Introduction: The anatomic proximity between the esophagus and the coronary sinus (CS) might render the esophagus vulnerable to thermal injury during ablation. Therefore, we investigated the anatomic relationship between the esophagus and the CS in patients with atrial fibrillation (AF).

Methods and Results: Thirty patients (25 males, mean age = 54 ± 11 years) with drug‐refractory paroxysmal AF were included. Sixteen‐slice multidetector computed tomography was performed to depict the course of the esophagus and relationship to the CS. The esophagus was in direct contact with the CS in 57% (17/30) of patients (group 1). The mean length of the contact was 6.1 ± 3.4 mm. In the remaining 13 patients, the esophagus did not come in direct contact with the CS (group 2). The shortest distance between the esophagus and the CS was 4.0 ± 2.6 mm. The CS diameter (9.4 ± 1.8 vs 8.5 ± 2.4 mm, P = 0.15), esophagus width (18.6 ± 1.6 vs 18.6 ± 1.7 mm, P = 0.87), anteroposterior diameter of the left atrium (35.9 ± 3.8 vs 35.0 ± 3.3 mm, P = 0.58), thickness of the anterior wall of the esophagus (2.9 ± 0.6 vs 2.9 ± 0.6 mm, P = 0.97), and shortest distance from the esophagus to the CS ostium (19.3 ± 5.4 vs 25.0 ± 6.2 mm, P = 0.02) and to the great cardiac vein (8.5 ± 5.3 vs 12.1 ± 6.9 mm, P = 0.10) were compared between the two groups.

Conclusions: In 57% of our patients, the esophagus was in direct contact with the CS, and a significantly shorter distance between the esophagus and the CS ostium was noted in these patients. It is important to prevent esophageal damage when applying energy within the CS.
Do Intramural Virtual Electrodes Facilitate Successful Defibrillation? Model‐Based Analysis of Experimental Evidence
Authors: HOOKS DARREN A. , TREW MARK L. , SMAILL BRUCE H. , PULLAN ANDREW J.
Published: January 2006

Introduction: Recent computer model and experimental studies have suggested that microscopic intramural collagenous planes may facilitate successful defibrillation through the generation of shock‐induced virtual electrodes deep within the ventricular wall. Evidence supporting the existence of intramural virtual electrodes has been drawn from several recent studies, which map shock‐induced membrane potential (Vm) over the cut transmural surface of dissected segments of porcine left ventricle (LV). The artificially created transmural boundary in these experiments is impermeable to intracellular current. It is not known how this constraint limits the interpretation of these experiments in terms of the shock response of the intact ventricle.

Methods and Results: This study uses a realistic 3D computer model of LV myocardium to aid experimental interpretation. The model incorporates a microstructural description of intramural cleavage plane discontinuities measured by confocal microscopy of rat LV. Electrical shocks are applied across the model tissue, with and without introduced transmural boundaries. Shocks of varying strength (4–40 V/cm) are also applied to the model and the response analyzed. Results show that shock‐induced Vm changes (ΔVm) on a transmural tissue boundary are significantly different to ΔVm of the intact ventricle, and the extent of difference depends on boundary orientation. However, the presence and qualitative behavior of intramural virtual electrodes is preserved irrespective of boundary placement. The model also confirms experimental observations that most rapid transmural activation occurs for shocks of strength 5–10 V/cm. Two distinct mechanisms suppress virtual electrode propagation, and hence slow tissue activation, outside of this optimal shock strength range.

Conclusions: This study supports the hypothesis that distributed microscopic intramural virtual electrodes contribute to rapid activation of the ventricular wall during defibrillation.
Comparison of the Effects of VVI Versus DDD Pacing on Cardiac Baroreflex Function
Authors: OGINOSAWA YASUSHI , ABE HARUHIKO , YASUMASU TOMIYA , TSURUGI TAKUO , KOHNO RITSUKO
Published: January 2006

Introduction: Conventional baroreceptor‐heart rate (HR) reflex sensitivity cannot be examined in chronotropically incompetent patients or in pacemaker recipients. However, cardiac baroreceptor reflex sensitivity (BRS)‐stroke volume (SV), which is closely and linearly correlated with BRS‐HR, may be an alternative in that population. The aim of this study was to compare the BRS‐SV in pacemaker recipients with a fixed HR paced in VVI versus DDD modes in the supine and upright positions.

Methods: The pacing mode was set randomly to DDD or VVI with complete atrial and/or ventricular capture, then crossed over to the alternate mode in 9 recipients of dual‐chamber pacemakers with atrioventricular (AV) block. Beat‐to‐beat mean blood pressure and SV were measured in the supine and upright positions, using a tilt table. The BRS‐SV, expressed in %/mmHg, was the ratio of low‐frequency (LF) power to total power (TP) of SV variability, measured by spectral analysis of spontaneous variations in mean blood pressure and SV.

Results: BRS‐SV was significantly lower in the VVI than in the DDD mode in the supine (37.2 ± 26.7 vs 14.5 ± 7.7%/mmHg) and upright (22.9 ± 16.9 vs 10.6 ± 6.6%/mmHg) positions (P < 0.05 for both comparisons).

Conclusions: VVI pacing is adverse from the standpoint of cardiac autonomic baroreflex function. A decreased BRS‐SV may be one of the factors involved in the hemodynamic intolerance associated with VVI pacing.
Atypische klinische Manifestation einer Pigmentpurpura
Authors: Zalaudek Iris , Ferrara Gerardo , Brongo Sergio , Giorgio Caterina M. , Argenziano Giuseppe
Published: January 2006

Der Name “Pigmentpurpura” umfasst ein Spektrum verschiedener Krankheitsbilder, die mit petechialen Blutungen einhergehen und zu umschriebenen, fleckartigen gelbbraunen Verfärbungen der Haut führen.Traditionsgemäß können 5 verschiedene Typen unterschieden werden, jedoch können auch atypische klinische Manifestationen auftreten. Aufgrund der verschiedenen klinischen Erscheinungsformen und eines häufig nicht genau unterscheidbaren histologischen Bildes, ist eine exakte Unterscheidung der verschiedenen Typen oftmals schwer oder sogar unmöglich. Wir berichten über einen Fall einer atypischen klinischen Manifestation einer Pigmentpurpura, der die Schwierigkeiten einer genauen klinischen Unterscheidung widerspiegelt.
Farbstofflaser‐Behandlung eines periungualen Granuloma pyogenicum
Authors: Tscharner Gion G. , Hunziker Thomas
Published: January 2006

Die Behandlung eines Granuloma pyogenicum in Lokalisationen wie Gesicht oder Fingerkuppen gestaltet sich nicht immer einfach. Wir berichten über die erfolgreiche Therapie eines 1 cm messenden solchen Tumors periungual an einer Fingerkuppe mit dem Farbstofflaser.
Behandlung aktinischer Keratosen mit Birkenkorkextrakt: Eine Pilotstudie
Authors: Huyke Constance , Laszczyk Melanie , Scheffler Armin , Ernst Reinhard , Schempp Christoph M.
Published: January 2006

Background: Birch bark contains a variety of apoptosis‐inducing and anti‐inflammatory substances such as betulinic acid, betulin, oleanolic acid and lupeol. Therefore, birch bark extract may be effective in the treatment of actinic keratoses. To address this issue, a pilot study using a standardized birch bark ointment was performed.

Methods: Twenty‐eight patients with actinic keratoses were enrolled in this prospective, non‐randomized pilot study. Fourteen patients were treated with birch bark ointment only; fourteen patients received a combination therapy with cryotherapy and birch bark ointment. Treatment response was assessed clinically after two months.

Results: Clearing of more than 75 % of the lesions was seen in 79 % of the patients treated with birch bark ointment monotherapy. The response rate of the combined treatment modality was 93 %. Therapy with birch bark ointment was well tolerated.

Conclusion: In this pilot study, a standardized birch bark extract was effective in the treatment of actinic keratoses. This therapy is easy to perform and it has no side effects. Birch bark ointment may be a new therapeutic option for actinic keratoses.