Exploring the Basis of Disease
Pathobiology
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ISSN Print Edition: 1015–2008 ISSN Online Edition: 1423–0291 Journal Homepage: www.karger.com/pat Publication Data: Pathobiology is published 6 times a year. Volume 82 with 6 issues appears in 2015.
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Gazette Karger
Gazette Karger
No. 72 Published October 2012 Georg Wick The Aging Issue: Editorial Tamas Fulop Will We Ever Know What Causes Aging?
Michael R. Rose, Laurence D. Mueller Why Does Aging Stop?
Harald Hampel, Simone Lista Silent Alarm: The Quiet Epidemic of Alzheimer’s Disease David Paterson
The Digital World’s Silver Lining In conversation with:
Brian Kennedy CEO, Buck Institute for Research on Aging
Aging Issue
G . W i c k
Introduction Gerontology deals with an issue that af- fects every living organism. One may per- haps argue that bacteria and certain other single-cell organisms are not aging since they reproduce by division into equal halves with neither half being parent or descendant. One could also point to the fact that germline cells (i.e., eggs and sperm) that have been passed on from gen- eration to generation for billions of years have been maintained alive without aging [1]. Except for these special cases, the so- matic cells of all organisms undergo senes- cence, a process of age-dependent loss of function. Studying this phenomenon is both of theoretical and practical interest.
My personal interest in gerontological research was spawned when I was engaged in basic research focusing on the age- dependent decline of immune functions reflected by thymic involution. I was fasci- nated by the phenomenon of autoimmuni- ty, the loss of immunological self-recogni- tion leading to autoimmune diseases that begin early in life and become clinically manifest later [2]; my whole career as a ger- ontologist was motivated by the question of whether we can learn anything about the aging process by studying age-related dis- eases in animals and humans.
When we look at age-related diseases, it may be worthwhile to distinguish between those that are a primary manifestation of senescence, such as Werner’s disease or Hutchinson-Gilford syndrome, and those which represent secondary phenomena, suffered as a consequence of reaching old
The
From the above-mentioned rectangu- lar pattern of the human survival curve one can deduce that, based on an individ- ual fixed genetic background, modifica- tion of environmental factors is presently the only tool to achieve ‘healthy aging’.
The concept of pleiotropic antagonism is relevant when considering age-related diseases. It is based on the observation that genes that are beneficial early in life may play a detrimental role later on when they are expressed at sites other than their orig- inal position (pleiotropy). For instance, some genes allow for calcification of bones (osteocalcin and bone sialoprotein), mak- ing them stronger and improving fighting and fleeing capacity, but they acquire neg- ative, antagonistic effects later in life if they are expressed elsewhere, leading, for example, to calcified atherosclerotic le- sions. Therefore, the diseases of aging may be the price we pay for the vigor of youth.
It should also be reiterated that the natural rules underlying the development of age-related diseases are today skewed by the pace of change in human lifestyle (cul- tural evolution), which is far too fast for genetic adaptation to keep up with. Thus, we live under 21st century conditions with a pre-stone age genome. In the words of the evolutionary biologists Nesse and Wil- liams, ‘The price of not being eaten by a lion at the age of 30 may be a heart attack at 80’ [4].
Anti-Aging and Science Kitsch Often, gerontologists working in basic re- search at the single cell level, such as yeast, or with lower multicellular organisms, such as the worm C. elegans or the fruit fly Drosophila, are confronted with the risk of having their data overinterpreted, raising false hopes in lay people. Drum-beating by the scientists themselves in the media has tes, cancers, cardiovascular diseases, os-
teoporosis, arthrosis and dementia. It has, however, to be kept in mind that all these diseases start early in life – initially with- out clinical symptoms – and only become manifest in later years. Thus, diseases in older age are not the consequence of the body’s failure, but rather the result of its long survival. However, in this context we should remind ourselves that the design of the human body is both astoundingly pre- cise and surprisingly slipshod. Overall, it has been shaped by evolution to become an optimal compromise for its final destiny:
reproduction. Importantly, natural selec- tion is only effective during the reproduc- tive period and individuals living into postreproductive age, as is the case for the majority of people in developed societies, are no longer subjected to selective pres- sure. The question of whether having grandparents increases the survival chanc- es of an individual has still not been com- pletely settled [3].
age because our cultural evolution by far outpaces biological evolution. However, I think such a distinction between ‘pure’ se- nescence and pathological age-associated processes is a rather academic issue, rais- ing unnecessary barriers between basic and applied gerontological research that may impair the crucial and beneficial dia- logue between various disciplines. In addi- tion, we should not forget that gerontology in a broader sense encompasses many fields outside of biology, the aging society representing one of the most important socioeconomic problems facing not only the developed world, but increasingly also the less developed countries.
Age-Related Diseases:
The Price for the Vigor of Youth In 1900, the mean life expectancy in Cen- tral Europe and the USA was about 49 years. Since that time, life expectancy has increased more than in the 10,000 years before. This has been due to advances in medicine and hygiene, as well as improve- ments in socioeconomic conditions.
Although the mean life expectancy has increased, this has been associated with a rather constant value for maximally attain- able age. When plotted on a graph, this leads to a ‘rectangularization’ of the hu- man survival curve (Fig. 1, page 2). This observation is one of many indications that the aging process is governed by both ge- netic and environmental factors. Discuss- ing this issue in depth is beyond the scope of this article. Suffice it to mention that dif- ferent species exhibit different maximal lifespans that show a significant correla- tion with their capacity to repair DNA damage.
Increasing age is fraught with increas- ing morbidity. The list of diseases associ- ated with aging is long and includes diabe-
Stimulating reading
in and around the world of medicine
matic cells of all organisms undergo senes- cence, a process of age-dependent loss of function. Studying this phenomenon is both of theoretical and practical interest.
My personal interest in gerontological research was spawned when I was engaged in basic research focusing on the age- dependent decline of immune functions reflected by thymic involution. I was fasci- nated by the phenomenon of autoimmuni- ty, the loss of immunological self-recogni- tion leading to autoimmune diseases that begin early in life and become clinically manifest later [2]; my whole career as a ger- ontologist was motivated by the question of whether we can learn anything about the aging process by studying age-related dis- eases in animals and humans.
When we look at age-related diseases, it may be worthwhile to distinguish between those that are a primary manifestation of senescence, such as Werner’s disease or Hutchinson-Gilford syndrome, and those which represent secondary phenomena, suffered as a consequence of reaching old
herosclerotic le- example, to calcified ath
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eing eaten by a liams, ‘The price of not be lion at the age of 30 may be a heart attack
li h f 30 b
at 80’ [4].
Antnti-Aging and Science Kitsch Often, gerontologists working in basic re- search at the single cell level, such as yeast, or with lower multicellular organisms, such as the worm C. elegans or the fruit fly Drosophila, are confronted with the risk of having their data overinterpreted, raising false hopes in lay people. Drum-beating by the scientists themselves in the media has tess, cancers, cardiovascular diseases, os-
teooporosis, arthrosis and dementia. It has, hoowever, to be kept in mind that all these disseases start early in life – initially with- ouut clinical symptoms – and only become maanifest in later years. Thus, diseases in oldder age are not the consequence of the boody’s failure, but rather the result of its lonng survival. However, in this context we should remind ourselves that the design of thee human body is both astoundingly pre- cisse and surprisingly slipshod. Overall, it has been shhaped by evolution to become anbh d b l i b optimal coompromise for its final destiny:
reproductiion. Importantly, natural selec- tion is onlly effective during the reproduc- tive periood and individuals living into postreprodductive age, as is the case for the majority of people in developed societies, f ld ld are no longer subjected to selective pres- sure. The question of whether having grandparents increases the survival chanc- es of an individual has still not been com- pletely settled [3].
In 1900, thee mean life expectancy in Cen- tral Europee and the USA was about 49 years. Sincee that time, life expectancy has increased mmore than in the 10,000 years before. Thiss has been due to advances in medicine annd hygiene, as well as improve- ments in socioeconomic conditions.
Althoughh the mean life expectancy has increased, tthis has been associated with a rather consttant value for maximally attain- able age. WWhen plotted on a graph, this leads to a ‘‘rectangularization’ of the hu- man survivval curve (Fig. 1, page 2). This observationn is one of many indications that the aging pprocess is governed by both ge- netic and ennvironmental factors. Discuss- ing this issuue in depth is beyond the scope of this articlle. Suffice it to mention that dif- ferent speciies exhibit different maximal lifespans that show a significant correla-hh f l tion with their capacity to repair DNA damage.
Increasing age is fraught with increas- ing morbidity. The list of diseases associ- ated with aging is long and includes diabe-
Anatomy
through & the Ages Art
Daniel H. Garrison Vesalius and the Achievement of the Fabrica
Hubert Steinke Why History of Medicine Matters Martin Kemp Art and the Science of Appearance
Minds Wide Open: Art Meets Science Interview with Pascale Pollier No. 73 Published October 2013
Daniel H. Garrison Vesalililiusususandndndthe Achievememement of theFabrica
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Gazette Karger
When we were first approached by the trans- lators of Andreas Vesalius’ ground-breaking atlas of anatomy De humani corporis fabrica, I was not aware of how much the publication of this English translation from the original Lat- in would influence our publishing house and me personally. I have always been fascinated by the Renaissance and its art and architec- ture, but I now fully appreciate the enormous impact the Renaissance invention of the print- ing press had on the rise of modern science and medicine – and how much this resembles the profound effect that the dawn of the digital age has had on our own times.
Now, after two years of intensive and challeng- ing work, the first comprehensive and anno- tated translation into English of both editions of the original Fabrica has just been published by Karger – a modern and user-friendly edi- tion with a total of over 1,400 pages in A3 for- mat, with greatly enhanced illustrations, and an impressive weight of 14 kg.
The articles in this issue of the Karger Gazette introduce you to Vesalius as a pioneer of modern anatomy and also go beyond to look at the role of art and illustration in a medical and historical context. I also invite you to visit our special website www.vesalius-fabrica.com where you will find some more interesting sto- ries about Vesalius, his times and his work as well as background information on the pro- duction of the New Fabrica.
With this excursion into the beginnings of modern medicine and printing, I wish you en- joyable reading. Gabriella Karger Publisher’s Note
Noow, after two yearars ingng work,the firstt comprehensivee a
t d t slation i toEngli h ofboth editio tatated translation innto English of booth editions of tf the original Fabbrica has just beeen publishn ed byy Karger– a mododern and user-frfriendly edi- byy Karger – a moddern and user frfriendly edi tioon witha total off over 1,400 pagees in A3 for- ma
mat, withgreatly eenhanced illustrrations, and impres ive weight of 14 kg ann impressive weigght of 14 kg.
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modern anatomy aand also go beyoyond to look at tthe role of art anand illustration inin a medical annd historical contntext. I also invitee you to visit ouur special websitete www.vesalius-f-fabrica.com whhere youwill findd some more inteerestingsto whhere youwill findd some more inteeresting sto- riees about Vesaliusus, his times and hd his work as we
well as backgrounndinformation oon the pro- well as backgroundinformation on the pro duuction of the Neww Fabrica.
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With thisexcursision into the begeginnings of With thexcu n into e ggin mo
modern medicine ae and printing, I wwish you en- joyoyable reading. GabrriellaGabrriella KargerKarger Kent R. Anderson The Medical Publisher in the Information Age The People behind Our Publications Meet the Editors of Karger’s Journals Passion, Persistence, Progress Interviews with Marcel Tanner, Michael Hall
, and Susan Gasser No. 74 Published April 2015
Dear Reader, 125 years – how do we celebrate such an anniversary, focusing on our present achievements while not losing sight of our history and origins? How do we judge our impact as a medical and scientific publish- er over the last 25 years? And in 2040, how will we look back at the preceding 25 years?
Questions like these have been on my mind for some time.
Visiting Berlin a little while ago, I took inspiration from this city whose history touches me on so many levels. Berlin, which bears its marks and scars of the past, is where my great-grandfather Samuel Karger founded the publishing house on April 1, 1890, and where the family lived and the business thrived until the political situation forced his son Heinz in 1937 to relocate his family and company to Basel, Switzerland. Thankful that my generation never had to live through the hardships the generations before us experienced, I have great respect for those who did. This issue of the Karger Gazette focuses on the present, which is the foundation on which we can and will build the future. In the first article, Kent R. Anderson, Pub- lisher of the renowned journal Science, de- scribes why STM publishers are still need- ed even in the Digital Age – and will con- tinue to be needed. I couldn’t agree more:
there will always be a demand for publish- ers who efficiently collect, screen, and se- lect medical and scientific information in order for it to be condensed, disseminated, archived, and protected for the scientific community.
Without the editors of our publica- tions, our print and digital publishing
program would not be what it is. As a tribute we have dedicated a section of this Gazette to feature their portraits. My father Thomas Karger and I gladly take this opportunity to extend our heartfelt gratitude to all of our editors, and also to the numerous editorial board members, peer reviewers, and everybody else in- volved in the success of our publications – including, of course, all of our staff in Basel and around the world – for their loyal sup- port and commitment. To maintain direct and personal relationships with all our partners has been and always will be a priority for us.
To provide you with a perspective on current research, science journalist Patrik Tschudin interviewed three world-re- nowned scientists based in Basel – Susan Gasser (Director of the Friedrich Miescher Institute), Michael Hall (Professor of Bio- chemistry at the University of Basel), and Marcel Tanner (Director of the Swiss
Gazette
Tropical and Public Health Institute). They talk about their most important research accomplishments and explain what they feel to be crucial for future progress in their field and science in general.We know where we come from and are proud of where we are – dare I predict where we are going? The future will bring more technological challenges as the im- pact of digital media on publishing and the dissemination of our content increases.
Furthermore, we’ll have to keep an eye on the turbulent financial markets and what effect the rising number of mergers among STM publishers will have on the publish- ing industry. However, we at Karger are ready to meet these challenges. Continuity, hand in hand with innovation, is and will remain the hallmark of Karger Publishers as summed up by the motto for our 125- year anniversary, ‘Inheriting the Future’.
And as an independent family-owned company, we feel privileged to continue to serve and connect the world of biomedical science.
Yours sincerely, 2015
1892
1990 1980
1977 1946
Karger
Karger Publishers
P.S. The richly illustrated Karger Fest- schrift by Harold V. Schmeck for our centenary in 1990 has been brought up to date for this year’s 125th anniversary. It chronicles the company’s development and contributions in the service of medicine and science since 1890. Please see page 12 for details on how to get your free copy.
Breast translational research has markedly evolved over the past few decades and the emerging knowl- edge has revolutionized our understanding of breast neoplasms. Novel techniques and concepts in study- ing breast cancer have been developed. These have contributed to the understanding and recognition of this complex disease.
This special topic issue on Breast Translational Re- search provides pertinent and succinct reviews on tumor microenvironment, metabolomics, the role of the calpain family of enzymes, the molecular mecha- nisms of lymphovascular invasion, and predictors of response to neoadjuvant therapy. It proposes and illustrates a new terminology for the practising pa- thologist who needs to describe a diagnostically challenging group of breast neoplasms showing dermal analogue differentiation. It also evaluates the role of p40 immunohistochemistry in diagnostic breast pathology.
This publication is of special interest to pathologists as well as scientists and members of the breast mul- tidisciplinary team, since it provides a useful overview of pertinent markers and techniques in the field of breast cancer translational research and diagnostic histopathology.
Contents Editorial
• Breast Translational Research: Past, Present and Future: Shaaban, A.M.
Invited Review
• Molecular Mechanisms Underlying Lymphovascular Invasion in Invasive Breast Cancer: Aleskandarany, M.A.; Sonbul, S.N.;
Mukherjee, A.; Rakha, E.A.
• Radiological and Pathological Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: A Brief Literature Review: Parekh, T.;
Dodwell, D.; Sharma, N.; Shaaban, A.
• Calpain in Breast Cancer: Role in Disease Progression and Treatment Response: Storr, S.J.;
Thompson, N.; Pu, X.; Zhang, Y.; Martin, S.G.
• Role of the Tumor Microenvironment in Breast Cancer: Soysal, S.D.; Tzankov, A.; Muenst, S.E.
• Metabolomic Biomarkers for Breast Cancer:
Guenther, U.L.
Original Paper
• Evaluation of p40 as a Myoepithelial Marker in Different Breast Lesions: Kővári, B.; Szász, A.M.;
Kulka, J.; Marušić, Z.; Šarčević, B.; Tiszlavicz, L.; Cserni, G.
Novel Insights from Research Practice
• Breast Neoplasms with Dermal Analogue Differentiation (Mammary Cylindroma): Report of 3 Cases and a Proposal for a New Terminology:
Rakha, E.A.; Lee, A.H.S.; Sheeran, R.; Abbosh, C.; Hodi, Z.;
Merchant, W.; Ellis, I.O.; Shaaban, A.M.
Author Index/Subject Index
An update on
breast cancer diagnosis and translational research
The easiest way to order: w w w.karger.com/pat
Breast Translational Research
Editor
Abeer M. Shaaban
Y Jou rnal P u b li ca ti on
Breast Translational Research
Editor Dr. Abeer M., Shaaban
Exploring the Basis of Disease
S. Karger Medical and Scientific Publishers Basel . Freiburg . Paris . London . New York . Chennai . New Delhi . Bangkok . Beijing . Shanghai . Tokyo . Kuala Lumpur . Singapore . Sydney
Pathobiology
82(3–4) 107–180 (2015) 82 | 3–4 | 15printISSN 1015–2008 online e-ISSN 1423–0291
www.karger.com/pat ISBN 978–3–318–05587–0
Karger – Medical and Scientific Publishers CH–4009 Basel, Switzerland
orders@karger.com, f: +41 61 306 12 34 www.karger.com
KI15427
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Breast Translational Research Editor: Shaaban, A.M. (Birmingham) 74 p., 10 fig., 9 in color, 7 tab., 2015 CHF 29.00 / EUR 27.00 / USD 34.00 (soft cover)
CHF 35.00 / EUR 32.00 / USD 41.00 (online) CHF 44.00 / EUR 41.00 / USD 51.00 (combined print/online)
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ISBN 978–3–318–05587–0 (soft cover)
e-ISBN 978–3–318–05588–7
Special Topic Issue
Pathobiology
Vol. 82, No. 3–4 (2015)
Included in subscription
Listed in MEDLINE/PubMed
Medical Statistics has never been easier!
The easiest way to order: w w w.karger.com/medical_ statistics
The fifth revised edition of this highly successful book presents the most extensive enhancement since Using and Understanding Medical Statistics was first published 30 years ago. Without question, the single greatest change has been the inclusion of source code, together with selected output, for the award- winning, open-source, statistical package known as R. This innovation has enabled the authors to de- emphasize formulae and calculations, and let soft- ware do all of the ‘heavy lifting’.
This edition also introduces readers to several graph- ical statistical tools, such as Q-Q plots to check nor- mality, residual plots for multiple regression models, funnel plots to detect publication bias in a meta- analysis and Bland-Altman plots for assessing agree- ment in clinical measurements. New examples that better serve the expository goals have been added to a half-dozen chapters. In addition, there are new sections describing exact confidence bands for the Kaplan-Meier estimator, as well as negative binomial and zero-inflated Poisson regression models for over- dispersed count data.
The end result is not only an excellent introduction to medical statistics, but also an invaluable reference for every discerning reader of medical research lit- erature.
Contents
Preface to the Fifth Edition Prefaces to the Previous Editions
• Basic Concepts
• Tests of Significance
• Fisher’s Test for 2 × 2 Contingency Tables
• Approximate Significance Tests for Contingency Tables
• Some Warnings concerning 2 × 2 Tables
• Kaplan-Meier or ‘Actuarial’ Survival Curves
• The Log-Rank or Mantel-Haenszel Test for Comparing Survival Curves
• An Introduction to the Normal Distribution
• Analyzing Normally Distributed Data
• Linear Regression Models for Medical Data
• Binary Logistic Regression
• Regression Models for Count Data
• Proportional Hazards Regression
• The Analysis of Longitudinal Data
• Analysis of Variance
• Data Analysis
• The Question of Sample Size
• The Design of Clinical Trials
• Further Comments regarding Clinical Trials
• Meta-Analysis
• Epidemiological Applications
• Diagnostic Tests
• Agreement and Reliability References
Subject Index
David E. Matthews Vernon T. Farewell
Using and Understanding Medical Statistics
5th, revised and extended edition
D.E. Matthews . V.T. Farewell
Using and Understanding Medical
Statistics
5th, revised and extended edition
∑
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E1 +(O2−E2)2
E2
Karger – Medical and Scientific Publishers CH–4009 Basel, Switzerland
orders@karger.com, f: +41 61 306 12 34 www.karger.com
Dear Librarian
I have reviewed this publication and would like to recommend it for our library.
Recommended by:
Department:
Date:
Signature:
Orders may be placed with any bookshop, subscription agency, directly with the publisher or through a Karger distributor.
Matthews, D.E. (Waterloo, Ont.);
Farewell, V.T. (Cambridge)
Using and Understanding Medical Statistics 5th, revised and extended edition
XX + 338 p., 48 fig., 103 tab., 2015 CHF 49.00 / EUR 46.00 / USD 54.00 (hard cover + online supplementary material) Online version for institutional purchase Prices subject to change, VAT not included EUR price for eurozone countries, USD price for USA and Latin America only
ISBN 978–3–318–05458–3
(hard cover + online supplementary material) e-ISBN 978–3–318–05459–0
eBook available on:
KI15406
Highlighting new opportunities
for the development of effective therapies
The easiest way to order: w w w.karger.com/cto
Functional recovery after peripheral nerve injury is poor, and it has become clear that surgical recon- struction should be combined with novel therapies which address the problems of the limited rate and quantity of axonal regeneration, neuronal cell death and target organ atrophy. There is significant scope for the application of cellular and biological ap- proaches towards peripheral nerve repair. This special topics issue begins with an introduction to the im- portance of Schwann cell-axon interactions which is followed by a series of papers highlighting the excit- ing therapeutic potential of various cell types includ- ing skin, adipose, bone marrow and hair follicle-de- rived adult stem cells, induced pluripotent stem cells and olfactory ensheathing cells. Another biological approach, the use of chondroitinase to overcome nerve scarring, is also described. Finally, noninvasive imaging methods, which will be necessary to deter- mine the efficacy of these novel treatments, are re- viewed.
The publication will be of interest to a large number of interdisciplinary scientists including cell biologists, biomaterials scientists and chemists as well as sur- geons who are involved in translational research aimed at improving the treatment of peripheral nerve injury.
Contents
· Preface: Kingham, P.J.; Wiberg, M.; English, A.W.
Reviews
The Role of Schwann Cell-Axon Interaction in Peripheral Nerve Regeneration: Namgung, U.
· Recent Advances in Stem Cell-Mediated Peripheral Nerve Repair: Grochmal, J.; Midha, R.
· Adipose-Derived Stem Cells for Nerve Repair:
Hype or Reality?: Kingham, P.J.; Reid, A.J.; Wiberg, M.
· Mesenchymal Stem Cells as a Source of Schwann Cells: Their Anticipated Use in Peripheral Nerve Regeneration: Wakao, S.; Matsuse, D.; Dezawa, M.
· Nestin-Expressing Hair Follicle-Accessible Pluripotent Stem Cells for Nerve and Spinal Cord Repair: Hoffman, R.M.
· Olfactory-Ensheathing Cell Transplantation for Peripheral Nerve Repair: Update on Recent Developments: Radtke, C; Kocsis, J.D.
· The Role of Chondroitinase as an Adjuvant to Peripheral Nerve Repair: Gause II, T.M.; Sivak, W.N.;
Marra, K.G.
· Noninvasive Imaging of Peripheral Nerves:
Rangavajla, G.; Mokarram, N.; Masoodzadehgan, N.;
Pai, S.B.; Bellamkonda, R.V.
Original Paper
· Long-Term Efficacy and Safety Outcomes of Transplantation of Induced Pluripotent Stem Cell-Derived Neurospheres with Bioabsorbable Nerve Conduits for Peripheral Nerve Regeneration in Mice: Uemura, T.; Ikeda, M.; Takamatsu, K.; Yokoi, T.;
Okada, M.; Nakamura, H.
Author and Subject Index
Cellular Biological
Approaches to Treating Peripheral Nerve Injuries
Editors
Arthur W. English Paul J. Kingham Mikael Wiberg
Y Jou rnal P u b li ca ti on
Cells Tissues Organs200(1) 1–92 (2014) 200 | 1 | 14 printISSN 1422–6405online e-ISSN 1422–6421www.karger.com/cto ISBN 978–3–318–05432–3
Cellular Biological Approaches to Treating Peripheral Nerve Injuries Guest Editors
Paul J. Kingham (Umeå) Mikael Wiberg (Umeå) Arthur W. English (Atlanta, Ga.)
Cells Tissues Organs
S. Karger Medical and Scientific Publishers Basel . Freiburg . Paris . London . New York . Chennai . New Delhi . Bangkok . Beijing . Shanghai . Tokyo . Kuala Lumpur . Singapore . Sydney
