Sustainable and equitable health programmes require a grounded understanding of the context in which they are being implemented. This socio-cultural understanding is pivotal for effective delivery of elimination programmes. Standardised valid methods are needed for gathering authentic socio-cultural insights. The currently recommended protocol for collecting Lymphatic Filariasis (LF) related socio-cultural data, while moving in the right direction, is inadequate. To collect data which provides an understanding of local health beliefs and practices, and communities' understanding of LF, techniques must be developed that are both valid and time efficient. An approach developed in the Pacific provides a basic snapshot of socio-cultural insights which are crucial to the development of relevant and sustainable health education and elimination programmes.The increasing interest in socio-cultural LF research presents a unique opportunity for coupling socio-cultural and bio-medical understandings of LF. To address the backlog in the socio-cultural sphere will require investment of time and effort to integrate valid qualitative approaches into current data collection methodologies. Lymphatic filariasis (LF) exacts an enormous infectious toll, affecting approximately 80 tropical and sub-tropical countries. Prevalence mapping is ongoing but a billion people are estimated to be at risk of infection, with 120 million already infected and 40 million seriously incapacitated or disfigured by the disease .In the second stage of our adaptation, we used the findings from our PNG experience to inform the redesign of the tool for use on the Federated States of Micronesia. Before data collection began, key theme areas were identified. On the basis of these themes, open-ended questions were designed to prompt discussion around these issues . Before On the islands of Satawal, Weno and Chuuk in FSM, the local chief, a local health worker, a religious leader, a women's group leader, and a teacher were interviewed. In addition to these specific individuals, six randomly selected  village members were consulted and asked to identify the figures in the community that they perceived to be key informants. Emphasising content over structure, the conversational style of the interview process proved very effective in eliciting insightful understandings.In gathering socio-cultural information, researchers must begin from the perspective of the people with whom they are trying to establish a meaningful dialogue. Attempts to administer qualitative-style questions in the manner of a quantitative structured study design will not yield valuable results. If we assume that the people we are interviewing share our biomedical interpretation of disease, we will engage in exchanges that do not improve our understanding of prevailing perceptions or the impact of LF on affected people's lives. Flawed information or understanding leads us to establish sub-optimal programmes .Valid qualitative research approaches can provide immensely useful data that allows us to design educational and interventional programmes in partnership with affected communities that will ensure high coverage, community support and sustainable control benefits ,13. EvenIn FSM, refined data collection techniques permitted more holistic understandings of LF and its affect on the health of the community. An in-depth snapshot of local understanding of basic health beliefs and health service provision in the three communities was established, while understandings and behaviours relating to the occurrence of LF were successfully probed. Although the majority of islanders knew or had heard of someone with elephantiasis or hydrocoele, there was very limited understanding of the cause or transmission cycle of LF. Confusion existed regarding the prevention and treatment of LF, and health staff themselves were insufficiently informed to educate people. Individuals from the outer islands generally appeared to delay until they were suffering from complications before seeking help from the health services on the larger island. Fever attacks and lymphatic tissue inflammation consistent with acute adenolymphangitis was widely reported, and these symptoms were frequently attributed to super-natural causes .These basic findings, although requiring more in-depth study, provide an important framework from which to begin to plan the information campaign necessary to assist the community in interpreting LF transmission and maximally benefiting from appropriate care-seeking.The increasing interest in socio-cultural LF research presents a unique opportunity for coupling socio-cultural and bio-medical understandings of LF, however, the limited tradition in the former is striking. Although, it would be preferable to conduct long-term ethnographic studies in populations affected by LF, the firm commitment to a time-bound elimination programme demands rapid appraisal approaches. The initial insights gleaned from in-depth interviews and focus group discussions with key informants regarding their beliefs and practices related to LF and its impact on local communities clearly indicates the immense value of applying this knowledge to further enhancing the efforts of communities and control programmes. The analysis of socio-cultural data, supported and triangulated with concurrent parasitological, epidemiological and entomological data provides a very valuable repository of information for adapting and refining control efforts that are both responsive to community needs and epidemiological realities.The author(s) declare that they have no competing interests.All authors contributed to the preparation of this manuscript, and have read and approved the final manuscript. SW coordinated the studies mentioned.SW and DD designed and analysed these studies; JC collected the data in the field and assisted in analysis; BS, JPC, PL and WM assisted in study design and logistical planning of the studies.


New terminology continuously enters the biomedical literature. How can curators identify new terms that can be added to existing nomenclatures? The most direct method, and one that has served well, involves reading the current literature. The scholarly curator adds new terms as they are encountered. Present-day scholars are severely challenged by the enormous volume of biomedical literature. Curators of medical nomenclatures need computational assistance if they hope to keep their terminologies current. The purpose of this paper is to describe a method of rapidly extracting new, candidate terms from huge volumes of biomedical text. The resulting lists of terms can be quickly reviewed by curators and added to nomenclatures, if appropriate. The candidate term extractor uses a variation of the previously described doublet coding method. The algorithm, which operates on virtually any nomenclature, derives from the observation that most terms within a knowledge domain are composed entirely of word combinations found in other terms from the same knowledge domain. Terms can be expressed as sequences of overlapping word doublets that have more specific meaning than the individual words that compose the term. The algorithm parses through text, finding contiguous sequences of word doublets that are known to occur somewhere in the reference nomenclature. When a sequence of matching word doublets is encountered, it is compared with whole terms already included in the nomenclature. If the doublet sequence is not already in the nomenclature, it is extracted as a candidate new term. Candidate new terms can be reviewed by a curator to determine if they should be added to the nomenclature. An implementation of the algorithm is demonstrated, using a corpus of published abstracts obtained through the National Library of Medicine's PubMed query service and using "The developmental lineage classification and taxonomy of neoplasms" as a reference nomenclature.A 31+ Megabyte corpus of pathology journal abstracts was parsed using the doublet extraction method. This corpus consisted of 4,289 records, each containing an abstract title. The total number of words included in the abstract titles was 50,547. New candidate terms for the nomenclature were automatically extracted from the titles of abstracts in the corpus. Total execution time on a desktop computer with CPU speed of 2.79 GHz was 2 seconds. The resulting output consisted of 313 new candidate terms, each consisting of concatenated doublets found in the reference nomenclature. Human review of the 313 candidate terms yielded a list of 285 terms approved by a curator. A final automatic extraction of duplicate terms yielded a final list of 222 new terms  that could be added to the reference nomenclature.The doublet method for automatically extracting candidate nomenclature terms can be used to quickly find new terms from vast amounts of text. The method can be immediately adapted for virtually any text and any nomenclature. An implementation of the algorithm, in the Perl programming language, is provided with this article. Samuel Johnson defines a lexicographer as a "harmless drudge" . The druMedical terminologies are replete with examples of minor term modification that can result in treatment error. One example is the "carcinoid tumor of appendix." Carcinoid tumors of the appendix are typically indolent. According to the U.S. National Cancer Institute, "Surgical resection is the standard curative modality. If the primary tumor is localized and resectable, 5-year survival rates are excellent" . There iBecause modern nomenclatures are used to annotate medical data so that clinical information can be merged with heterogeneous data sources , the duties of lexicographers have broadened to include a range of informatics activities. For this reason, the modern curator is involved in codifying terms , and mapping terms between different nomenclatures. In the past, nomenclatures were recorded on paper documents. Brevity was appreciated, and rare lesions may have been neglected. Modern nomenclatures are stored electronically. With no barriers to the size of nomenclatures, there is no reason to exclude any used terms .The purpose of this manuscript is to describe a simple method for extracting candidate new terms from any large corpus of text. The method uses the previously published doublet algorithm to compare connected word doublets in a medical text against a list of word doublets found in a nomenclature . Text phAs a sample implementation, the developmental lineage classification and taxonomy of neoplasms, hereinafter called "the neoplasm taxonomy," was used. The neoplasm taxonomy has several properties that make it particularly suitable:1. It is a free, open-access medical nomenclature.2. It has been described in two prior open access publications ,83. New versions of the nomenclature are made available for public download by the Association for Pathology Informatics .4. It is an easily parsed XML document, with every term appearing as a lower-case alphanumeric phrase.5. It is intended to be a comprehensive listing of all items in a knowledge domain The XML version of the neoplasm taxonomy file is neocl.xml see . In thisThe input file was created by a PubMed query on "am j surg pathol [jo]", at the U.S. government website . The queThe doublet method was described in a recent publication . Its utiAny multiword term can be constructed by a concatenation of overlapping doublets.For example:Serous borderline ovarian tumor -> The doublets composing the multiword terms from a nomenclature can be combined into a list . The list of nomenclature doublets can be used to determine whether a fragment of text is composed from doublets included in the list.The following algorithm determines those terms present in a nomenclature that are composed of doublets found in other terms within the nomenclature.1. Collect all the doublets that occur in the entire nomenclature .2. Number the occurrences of these doublets 3. Advance through the nomenclature, term by term, decomposing the term into its doublets.4. For each of the doublets that compose a term, retrieve the total number of occurrences of the doublet in the nomenclature.5. Each doublet occurring in a term that has an occurrence number of 1 is unique to that term and indicates that the term is not composed entirely of doublets found in other terms in the nomenclature.The following algorithm parses through text, extracting candidate term phrases:1. Collect all the doublets that occur in the entire nomenclature .2. Parse text  into an ordered array of overlapping doublets .3. Compare each consecutive text doublet against the array of doublets from the nomenclature to determine whether the doublet exists somewhere in the nomenclature.4. If the doublet from the text does not exist in the nomenclature, it can be deleted. If it exists in the nomenclature, it is concatenated with the following doublet if the following doublet exists in the nomenclature. Otherwise, it is deleted. This process continues, concatenating doublets that exist somewhere in the nomenclature. Extraneous leading words  and trailer words,  are automatically deleted from the final concatenated sequence. Final concatenated sequences of two or greater consecutive doublets that match to doublets from the nomenclature are saved as candidate terms.All code was written in Perl. Perl is an open source language that is bundled with the Unix and Linux operating systems. In the past decade, Perl has become very popular in the bioinformatics community. Perl interpreters are available at no cost and in versions suitable for virtually all operating systems. Perl can be obtained from the Comprehensive Perl Archives Network  or from 2. The Perl script doubuniq.pl implements algorithm 1 to locate terms in the nomenclature that contain any uniquely occurring doublets  see . Only th3. The Perl script getdoub.pl implements algorithm 2 to extract phrases from the text corpora composed of sequences of doublets included in the original nomenclature and exceeding 4 words in length see . The outThe current version of the neoplasm nomenclature contains 149,192 unique terms. Of these terms 126,756 terms are classified terms and are composed of at least two words . Of these 126,756 terms, all but 6,308 (4.97%) are composed entirely of doublets extracted from other terms in the reference nomenclature. This means that 95% of the classified terms from the nomenclature are formed entirely of doublet terms found in other terms from the same nomenclature. The Perl script and the output text are included as supplemental files see  see Add.The Perl script, getdoub.pl was run on a CPU with a processor speed of 2.79 GHz. The parsed corpus was a PubMed file in XML format that exceeded 31 Megabytes in length and contained 4,289 PubMed records. Each record contained an abstract title enclosed by a tag, <ArticleTitle>. The parser extracted the abstract titles demarcated by the XML tag, dropped all characters to lower-case, deleted all characters other than alphanumerics, spaces and hyphens, deleted the possessive suffix characterized by "'s" and converted plural words to singular words if the word ended in the suffix "oma" or consisted of the word "tumors" or "tumours". The total number of words contained in the 4,289 abstract titles was 50,547, and the total number of characters contained in the 4,289 abstract titles was 395,396. The total execution time to extract a list of candidate terms from the corpus was 2 seconds.The output file produced by getdoub.pl is tumoram.out. It contains 313 candidate phrases each phrase followed by a copy of the original text from which the candidate term was extracted. The output is included as a supplemental file see . Each exIn some cases, terms consisting of concatenated doublets were obviously not names of neoplasms, and a human expert in the knowledge domain would be needed to distinguish a real name of a neoplasm from a series of words that have no particular significance.The curator read through all 313 phrases, looking for phrases that suggest a new concept. In this case, the curator looked for names of neoplasms. This step can only be performed by a domain expert. Because the exact candidate phrases are found in PubMed abstract titles, curators can obtain additional information on any candidate phrase by inserting the phrase into the PubMed query box . In someAs example, consider line 100 from the output file see . The canThe output file, tumoram.out contained 313 candidate terms see . Of thes"acinic cell carcinoma of the lung, adenocarcinoma and large cell carcinoma of lung, adenomatous hyperplasia of the rete testis, adenosarcoma of the renal pelvis with heterologous elements, adenosarcoma of the uterus with sarcomatous overgrowth, adrenal cortical adenoma in the spinal canal, aggressive digital papillary adenoma and adenocarcinoma, anaplastic carcinoma of the lung, atypical burkitt lymphoma arising from follicular lymphoma, atypical duct hyperplasia of the breast, atypical fibrous histiocytoma of the skin, atypical polypoid adenomyoma of the uterus, b-cell lymphoma of mucosa-associated lymphoid tissue, benign cystic mesothelioma of the liver, benign epithelioid peripheral nerve sheath tumor of the soft tissues, benign mesenchymal tumor of lymph node, benign mesenchymal tumor of the uterus, benign schwannoma of the digestive tract, bile duct adenoma clear cell type, bizarre parosteal osteochondromatous proliferation of bone, borderline epithelial lesions of the breast, borderline papillary serous tumour of the fallopian tube, botryoid rhabdomyosarcoma of the biliary tract, breast tumor resembling the tall cell variant of papillary thyroid carcinoma, carcinoid tumor of the extrahepatic bile ducts, carcinosarcoma of the female genital tract, clear cell carcinoma of the gallbladder, clear cell carcinoma of the ovary, clear cell carcinoma of the skin, clear cell myomelanocytic tumor of the thigh, clear cell myomelanocytic tumor of the urinary bladder, clear cell sarcoma of soft tissues, clear cell sarcoma of the ileum, clear cell sugar tumor of the pancreas, clear cell tumor in the liver, clear cell tumor of the kidney, clear cell tumor of the lung, combined small cell and spindle cell carcinoma of the lung, composite follicular variant of papillary carcinoma and mucoepidermoid carcinoma of the thyroid, condylomata acuminata of the urinary bladder, congenital cystic adenomatoid malformation of the lung, cutaneous epidermotropic alveolar rhabdomyosarcoma, cutaneous follicle center b-cell lymphoma, cystadenofibroma of the ovary with epithelial atypia, cystic hamartoma of the renal pelvis, desmoplastic small cell tumor in the pancreas, desmoplastic small cell tumor of soft tissues, desmoplastic small round cell tumor of the pleura, diffuse mesothelioma of the genital tract and peritoneum, ductal adenoma of the breast, ductal carcinoma in situ in breast, ductal carcinoma in situ in salivary duct carcinoma, ductal carcinoma in situ of the female breast, dysplasia of the epididymis, endometrial stromal and smooth muscle tumor of the uterus, epithelial mesothelioma of the pleura, epithelial-stromal tumor of the seminal vesicle, epithelioid hemangioendothelioma of skin and soft tissues, epithelioid leiomyosarcoma of the skin and subcutaneous tissue, epithelioid mesothelioma of the pleura, ewing family of tumor, extragastrointestinal stromal tumor gastrointestinal stromal tumor of the soft tissue, extramammary paget disease of the oral mucosa, familial adenomatous polyposis associated with multiple endocrine neoplasia, foamy gland high-grade prostatic intraepithelial neoplasia, follicle center lymphoma of the ampulla of vater, follicular center-cell lymphoma with plasmacytic differentiation, follicular dendritic cell tumor of the liver, follicular dendritic cell tumor of the oral cavity, follicular thyroid carcinoma with clear cell change, gastric mucosa-associated lymphoid tissue, gastric neuroendocrine tumor in multiple endocrine neoplasia, gastrointestinal autonomic nerve tumor in the colon, germ cell neoplasms of the testis, giant cell tumor of soft tissues, glycogen-rich clear cell carcinoma of the breast, granular cell tumor of the lung, granulocytic sarcoma of the female genital tract, hematopoietic tumor in chronic myeloproliferative disorders, high-grade dysplasia in a colonic adenoma, histiocytic lymphoma of the central nervous system, histiocytic sarcoma involving the central nervous system, hyalinizing trabecular adenoma and papillary carcinoma of the thyroid gland, hyalinizing trabecular tumor of the thyroid gland, hyperplasia of interstitial cells of cajal, infiltrating colloid carcinoma of the pancreas, inflammatory fibroid polyp of the stomach, intestinal metaplasia of the distal esophagus, intraductal carcinoma of the oral cavity, juvenile granulosa cell tumor of the ovary, keratinizing squamous cell cancer of the cervix, langerhans cell granulomatosis of the thymus, large cell lymphoma of the mediastinum, lobular carcinoma in situ of the female breast, low grade b-cell lymphoma of mucosa associated lymphoid tissue, low malignant potential tumor of the ovary, low-grade b-cell lymphoma of mucosa-associated lymphoid tissue, low-grade endometrial stromal sarcoma, lymphoid hyperplasia of the gastrointestinal tract, lymphoma of the gastrointestinal tract, malignant epithelioid hemangioendothelioma of the liver, malignant epithelioid schwannoma, malignant fibrous histiocytoma of the extremities, malignant fibrous tumor of the pleura, malignant giant cell tumor of the tendon sheaths, malignant lymphoma of the mucosa-associated lymphoid tissue, malignant lymphoma of the small bowel, malignant lymphoma of the upper aerodigestive tract, malignant melanoma of the esophagus, malignant melanoma of the urethra, malignant mesonephric tumor of the female genital tract, malignant mesothelioma of the tunica vaginalis, malignant neuroendocrine tumor of the jejunum with osteoclast-like giant cells, malignant ovarian tumor with osteoclast-like giant cells, malignant peripheral nerve sheath tumor of infancy, malignant small cell tumor of thoracopulmonary region, marginal zone b-cell lymphoma in children and young adults, marginal zone b-cell lymphoma of the salivary gland arising in chronic sclerosing sialadenitis, melanocytic neoplasms of the central nervous, metaplasia of the renal collecting ducts, microinvasive squamous carcinoma of the esophagus, micropapillary variant of transitional cell carcinoma of the urinary bladder, mixed endometrial stromal and smooth muscle tumor of the uterus, mucin-secreting adenocarcinoma of the prostate with neuroendocrine differentiation, mucinous adenocarcinoma of the prostate gland, mucinous borderline tumor of the ovary mucinous cystic tumor of the ovary, multiple lymphomatous polyposis of the gastrointestinal tract, myoepithelial carcinoma of the salivary glands, neuroendocrine merkel cell carcinoma, nonsmall cell carcinoma of the lung, oat cell carcinoma of the kidney, oncocytic mucoepidermoid carcinoma of the salivary glands, ovarian sertoli cell tumor with retiform and heterologous elements, papillary carcinoma of the bladder, papillary cystic tumor of the pancreas, papillary transitional cell carcinoma of the renal pelvis, papillary urothelial neoplasms of low malignant potential, pediatric soft tissue tumor, peripheral nerve sheath tumor of the adrenal, peritoneal serous micropapillomatosis of low malignant potential serous borderline tumor of the peritoneum, perivascular epithelioid clear cell family of tumor, peutz-jeghers syndrome with adenoma and adenocarcinoma, plasma cell granuloma of the lung, plasmablastic lymphoma of the oral cavity, pleomorphic adenoma mixed tumor of the major salivary glands, pleomorphic hyalinizing angiectatic tumor of soft parts, pleomorphic large cell lymphoma of the mediastinum, pleomorphic soft tissue myogenic sarcoma of adulthood, polycystic adenosis of major salivary glands, precursor of uterine papillary serous carcinoma, primary embryonal rhabdomyosarcoma of long bone, primary hepatic non-hodgkin lymphoma in childhood, primary lung carcinoma with signet-ring cell carcinoma, primary lymphoma of the small intestine, primary malignant lymphoma of the cauda equina, primary malignant melanoma of the anterior mediastinum, primary mixed adenocarcinoma and small cell carcinoma of the appendix, primary mucinous carcinoma of the skin, primary mucinous tumor of the ovary, primary neuroendocrine merkel cell carcinoma of the skin, primary ovarian small cell carcinoma, primary ovarian squamous cell carcinoma, primary squamous cell carcinoma of the ovary, primary synovial sarcoma of the kidney, primary tumor of the exocrine pancreas, pulmonary carcinoma with pleomorphic sarcomatoid or sarcomatous elements, pulmonary malignant lymphoma of mucosa-associated lymphoid tissue, reactive lymphoid hyperplasia of the spleen, renal angiomyolipoma with epithelioid sarcomatous transformation, renal cell carcinoma in children and young adults, renal cell carcinoma in tuberous sclerosis, reticulum cell neoplasms of lymph nodes, rhabdoid tumor of the gastrointestinal tract, round cell tumor of the tibia, sclerosing mucoepidermoid thyroid carcinoma with eosinophilia, serous borderline tumor of the peritoneum, serous borderline tumor of the peritoneum, signet-ring cell lymphoma of t-cell origin, small cell anaplastic carcinoma of the lung, small cell sweat gland carcinoma, small cell sweat gland carcinoma in childhood, small cell tumor of the lung, small cleaved cell lymphoma in bone marrow, small lymphocytic lymphoma leukemia, smooth muscle tumor of the gastrointestinal tract, smooth muscle tumor of the liver, smooth muscle tumor of the ovary, soft tissue lymphoma of the extremities, solid and cystic papillary epithelial neoplasm of the pancreas, solitary fibrous tumor of soft tissue, solitary fibrous tumor of the kidney, solitary fibrous tumor of the liver, solitary fibrous tumor of the mediastinum, solitary fibrous tumor of the nasal cavity, solitary fibrous tumor of the orbit, solitary fibrous tumor of the spinal cord, solitary fibrous tumor of the thyroid gland, solitary fibrous tumor of the upper respiratory tract, spindle cell and epithelioid cell nevi with atypia, spindle cell neoplasms of lymph nodes, spindle cell tumor of the pleura, spindle-cell carcinoid tumor of the lung, spindle-cell carcinoma of the upper aerodigestive tract, squamous cell carcinoma of the palatine tonsil, squamous cell carcinoma of the upper aerodigestive tract, stromal neoplasms of the gastrointestinal tract, systemic mast cell disease involving the bone marrow, t-cell histiocyte-rich large b-cell lymphoma of the spleen, t-cell lymphoma in the small intestine, t-cell-rich b-cell lymphoma of the spleen, thymic squamous cell carcinoma associated with mixed type thymoma, transitional cell carcinoma with rhabdoid features, transitional cell metaplasia of the uterine cervix, transitional cell tumor of the pituitary, urothelial carcinoma of the renal pelvis, urothelial transitional cell neoplasms of the urinary bladder, variant of malignant peripheral nerve sheath tumor, vascular hamartoma of the small bowel, well-differentiated neuroendocrine tumor, well-differentiated papillary mesothelioma of the pleura, yolk sac tumor of the anterior mediastinum."Examination of the terms indicates that the majority of terms are either very rare and obscure tumors, unusual variants of common tumors, or just unusual terms for common and uncommon tumors. Pathologists reading this list may agree that the tumors from this list include clinically distinct and significant subclasses of tumors and would be welcome additions to a truly comprehensive nomenclature of neoplastic entities.Adding terms to an existing vocabulary is best done by reading the current literature in the knowledge domain of the nomenclature, and transcribing new terms when they are encountered. It is difficult to imagine any automatic process that can replace this scholarly pursuit. Terms encountered while reading a scientific text appear in a structured context that often defines the term, clarifies the relationship of the new term to related terms, and sometimes provides sufficient information to classify the new term within a structured taxonomic hierarchy.Sadly, it is impossible for curators to read all of the biomedical literature pertaining to a nomenclature's domain. The purpose of the doublet phrase extractor is to parse through any corpus of text, extracting phrases that may contain new nomenclature terms. The phrases are chosen to meet two criteria: 1) they are composed of word doublets that are contained in an existing nomenclature, and 2) the matched phrases do not already occur in the nomenclature. The doublet extractor works fast to produce a neat list of candidate phrases that can be conveniently reviewed by a curator. In the case described herein, a 31+ MByte corpus was extracted in 2 seconds, to produce 313 candidate phrases. From the candidate phrases, the curator found 222 phrases that could be added to the reference nomenclature (30 minutes of human effort).Because the final term list was extracted from PubMed abstract titles, the contained terms have two important properties:1. The terms have whatever legitimacy publication confers. Nobody can say that the extracted terms are confabulated or never actually used.2. The terms can be searched and found through a PubMed search. The articles that contain the terms are likely to describe or define the terms.New terms that are not composed of doublets found in pre-existing nomenclature terms will be missed by the doublet extraction method. This would certainly apply to most new eponymous terms, new terms extracted from a foreign language, new terms using variant orthography, or newly invented words . In the realm of neoplasms, it would be difficult to create a new term that is not partially composed of older terms.If the extraction software used a vocabulary that already contained every term in the knowledge domain, then there would be very few candidate terms extracted . In addition, any candidate terms extracted from the corpus would always be rejected by the human curator (0% precision). This is because the nomenclature would be complete, and any candidate terms must be false terms.If the extraction software used a text corpus that consisted exclusively of valid, new nomenclature terms that should be added to an incomplete vocabulary, then all of the extracted candidate terms would be valid new terms (100% precision). If the extraction used a text that contained no valid terms from the knowledge domain, then every extracted candidate term would be an invalid term (0% precision).This is a problem: the effectiveness of the software is dependent on the completeness of the source vocabulary and on the presence of valid new terms existing in the text corpus. In addition, the suitability of candidate terms for inclusion in the vocabulary will ultimately depend on subjective decisions reached by the human curator.For this manuscript, the author chose to include the extractor's output as a supplemental file see , so thatRecently, Krauthammer and Nenadic reviewed methods for identifying nomenclature terms within text . In all It is the perception of the author that the field of medical informatics suffers from a lack of simple and generalized methods that can be easily tested in various use cases or compared with alternate or new methods using shared corpora. In their review of methods for automatically identifying medical terms contained in text, Krauthammer and Nenadic commented that few terminologically tagged biomedical corpora are available , and thiThis manuscript describes a method for extracting candidate terms from a corpus of text. It uses the doublet method previously described . The dou1. The method will work with any nomenclature and with any plain-text file2. The implementation is provided with the details of operation, allowing others to repeat the study.3. The source code is platform-independent and is made freely available to the public. This permits other laboratories to modify the program and publish an improved version of this documented prototype.4. The output files are provided, permitting others to review the results from this study or to compare the results with the results obtained with other methods.Almost all terms in medical nomenclatures can be formed by combining word doublets derived from other terms in the same nomenclature. By collecting all the word doublets found in a nomenclature, it is possible to quickly parse through enormous tracts of text, extracting phrases composed of sequences of these doublets. From these extracted candidate terms, a curator can select new terms. The doublet method is a novel approach to term extraction that curators can use to augment medical nomenclatures.The provided supplementary scripts are short programs written in Perl. Perl is a freely available open source programming language. Perl interpreters for virtually any operating system are available from several sites on the web ,12. ThesThe Perl scripts provided with this manuscript will work without modification using the current version of the neoplasm taxonomy see . New verThe author(s) declare that they have no competing interests.The work expresses the opinion of the author and does not represent policy of the U.S. government.The pre-publication history for this paper can be accessed here:Neoclxml.gz is the compressed version of neocl.xml, the XML-format for the developmental lineage classification and taxonomy of neoplasms. This version of neocl.xml supercedes prior published versions ,7. BecauClick here for fileDoubuniq.pl is a Perl script that parses the reference nomenclature (neocl.xml) and ouputs a list of terms that contain one or more unique doublets .Click here for fileDoubuniq.txt is the output file of doubuniq.pl, and consists of 6,305 terms from the reference nomenclature (neocl.xml) that contain one or more unique doublets .Click here for fileGetdoub.pl is a Perl script that implements the doublet method for automatic extraction of candidate nomenclature terms. It requires an external plain-text corpus and a reference nomenclature.Click here for fileTumoram.out is a plain-text file containing the output of the getdoub.pl, the Perl script that extracts terms consisting of concatenated doublets found in the reference nomenclature.Click here for file


The 9th International Conference on Salt Lake Research was held 26–30 September 2005 in Western Australia at the Curtin University of Technology, Perth, Australia. One hundred scientists from 10 countries presented research on a diverse array of topics highlighting research findings and opportunities, and management challenges associated with inland saline waters. Major emergent themes of the conference included modeling of ecosystem processes, microbial communities, and features of Western Australian inland saline environments, including current threats, conservation and management. Since 1979 the International Society for Salt Lake Research has organized triennial conferences in various salt lake regions of the world including the USA, Canada, China, Russia, Kenya, Bolivia, Spain, and South Australia [-1, and other inland saline habitats encompass a diverse array of ecosystems and the 3-day scientific program was equally wide-ranging. While this brief commentary cannot do justice to all the topics presented as part of the scientific program , I consin situ instrumentation for designing process-oriented limnological experiments.Permanent salt lakes lie along a continuum of salinity and all but those at the highest salinities share many common features and processes with their freshwater counterparts. They also share common threats and anthropogenic stressors with eutrophication, toxic contamination, exotic species invasions, and over-fishing among the most important. Of the widespread stressors on freshwater lakes, changing hydrological and salinity regimes caused by water diversions and climate change are major concerns, threatening permanent salt lakes throughout the world . By contDeveloping complex ecological models is a large task and Imberger has been central to the development, implementation, and maintenance of a suite of hydrodynamic and ecological models at the Centre for Water Research, UWA (CWR) . CWR's lArtemia juvenile bottlenecks and alternative stable states of shallow saline lakes. However, modeling of simpler saline lake ecosystems will likely provide insights into the challenges of modeling more complex freshwater lakes.It has often been hypothesized that the lower biodiversity in moderately saline and hypersaline lakes should make them more amenable to modeling than their more biotically complex freshwater counterparts. This has not yet been tested and even simple systems may display complex behaviors as shown by presentations on The advent of new molecular tools and recognition of the predominant role of microbes in biogeochemical fluxes and cycling, which control or effect nearly all ecosystem processes, have led to an increasing interest in the microbes of saline environments. The unique species and high metabolic diversity of microbes associated with the chemically diverse array of saline environments presents excellent opportunities for basic research. In the US, the National Science Foundation's Microbial Observatories research initiative includes many saline environments . New species with unique metabolic abilities are routinely described and the conference included a good sampling of these activities from around the world.A plenary talk by Juergen Wiegel  entitled "Life at extreme limits: halophilic alkalithermophiles, a novel group of extremophiles" began the second day of presentations. These "triple" extremophiles form a unique group of organisms growing in physiochemical conditions beyond those currently described for microbial growth. Microbial research from the Great Salt Lake, Mongolian soda lakes, gypsum crusts in salterns, meromictic Shira Lake, and microbial mats of Rottnest Island  salt lakes was presented.Jacob John , the conference host and chief organizer, presented an overview of saline environments in Western Australia with associated threats and conservation issues in the third plenary session. Western Australia is rich in saline environments including coastal and island salt lakes, hypersaline lagoons containing stromatolites and thrombolites, large inland salt lakes, and thousands of small seasonally filled and episodic ephemeral salt lakes. John and colleagues presented papers on the diatom flora of microbial mats, acid lakes, the Canning River, and a regional study of rivers and lakes which developed a novel diatom transfer function for detecting secondary salinisation.Parartemia! One was discovered only a couple of weeks before during scouting for the field trip. The other three have been known for a few years, but their specific habitat requirements are just being learnt. It is a race against time to describe their diversity and environmental adaptations before their habitats are lost to secondary salinisation. Descriptive research on many aspects of Western Australia's inland saline environments provided conference participants with an appreciation of the regional natural diversity. Groundwater estuaries, regions of inland subterranean salinity gradients, containing diverse and ancient fauna represented one of the more unusual ones. Other regions of Australia were also discussed, including descriptions of lakes and their fauna on the Eyre Peninsula  and the middle Paroo  by Brian Timms.Despite their widespread occurrence, inland saline environments have historically received much less attention than their freshwater counterparts and there is much work yet to be done to adequately describe those of Western Australia. This was aptly illustrated during the post-conference field trip, when we visited lakes containing four undescribed species of Secondary salinisation is one of the chief threats facing inland rivers and lakes in large agricultural regions of Australia and, although less well-documented elsewhere, it also occurs in other parts of the world ,6. This Further inland, salt loads are increased by large-scale mining operations that discharge hypersaline groundwater into surface lakes and drainages. Several researchers addressed monitoring, which is made more difficult by the episodic nature of these systems, and the actual and potential impacts of these discharges.As economic forces are driving the destruction of many ecosystems on which human well-being depends, a broad and rapidly growing field of eco-economics has arisen with the goal of building a worldwide sustainable economy . ProponeWhile many permanent salt lakes have significant economic value , in many, if not most cases, the economic value of water diverted for agriculture or industrial and human consumption may be much greater. Cultural, wildlife, especially avian, biodiversity, aesthetic, and other non-economic values are often defining features of salt lakes. Any economic assessment of these values is difficult and dependent on cultural and human conditions. Where salt lake conservation has occurred it is often because of increased awareness and valuation brought about by nongovernmental organizations and advocacy groups.Since 1971, the International Treaty on Wetlands (Ramsar Treaty) has been instrumental in raising the public awareness of the ecological value of all types of wetlands including inland saline lakes . Of 1,47The most widely recognized ecological value of salt lakes is as habitat for migratory and nesting populations of birds. While the critical dependence of flamingo populations throughout the world on salt lakes is widely publicized, many other waterbirds are equally dependent on salt lakes, including many species of phalaropes, grebes, gulls, pelicans, swans, and plovers. All 26 of the Australian Ramsar sites are listed as important to birds. Hindle and colleagues combined bird monitoring and habitat mapping to develop a model of Black Swan feeding habitat for monitoring and management. Others presented papers on avian use at saline wetlands in eastern Australia, and San Francisco estuaries and Salton Sea of California.Aquaculture is playing an increasing role in feeding the world as demand increases and natural fishery stocks are depleted. In China, fish farm output is about 30% of the oceanic fish catch . A suiteFinally, other presentations addressing a wide range of topics illustrative of the diverse topics presented at the meeting, including, the roles of calcium and iron in Northern Great Plains lakes (USA), sulfide irruption and gypsum blooms in the Salton Sea, and hydrochemical characteristics of salt lakes in the Qinhai-Tibet region.ISSLR was founded to enhance communication and interaction among scientists interested in inland saline waters, to encourage these interests, and to educate the public in the scientific management and conservation of salt lakes. Organizing a triennial salt lake conference and editing volumes of selected papers are primary activities of the society. Conference sites are purposefully selected to highlight various salt lake regions of the world, engage regional scientists and managers, and enable field trips to the diverse array of aquatic habitats represented by inland saline lakes.The Perth conference was well-organized and the venue well-suited to a small scientific meeting. Following brief welcoming remarks by Prof. Lance Twomey, Vice-Chancellor and President of Curtin University and Hon. Dr. Judy Edwards, Minister for the Environment and Science , the Wadumbah Aboriginal Dance Group treated participants to traditional music and dances. Mid and post-conference field trips enabled participants to visit local and regional saline habitats. ISSLR's president and fairy shrimp enthusiast, Brian Timms  led an unforgettable 7-day post-conference field trip inland through a vast array of inland salt lakes and back along the southwest coast.The late W. D. Williams was a driving force in Australian limnology and passionately interested in salt lake research and conservation. In his honor, the first Williams' awards for superior student presentations were awarded at the Perth conference. As a member of the award committee, I was particularly pleased with the quality and number of student presentations. Recipients included Michelle Hindle , Lien Sim  and Courtney Salm  presenting research on Black Swan feeding habitat, submerged plants in salinised wetlands, and primary production in prairie saline lakes of the USA, respectively (see conference abstracts for further information).Inland saline ecosystems present unique research opportunities and pressing conservation and management issues. The research spans much of modern limnology and progress requires integration and interaction with the larger limnological community represented by ASLO, SIL, national limnological societies, and the various subdisciplines. Saline Systems, whose primary aim is to enhance communication between and among scientists concerned with saline environments, is strongly supported by many ISSLR members as evidenced by the editorial board  and manuscript submissions. The open access format should facilitate sharing knowledge among scientists, managers, and policy-makers throughout the world to aid conservation and sustainable management.ISSLR has maintained a policy of holding each of their triennial conferences within a different salt lake region, sometimes at remote locations away from major transportation hubs. As a result, these conferences have engaged scientists from diverse backgrounds and participants gain new perspectives on regional management challenges and research opportunities. They are usually held in intimate and often spectacular settings, and have resulted in memorable experiences of both high scientific merit and personal value. Extended post-conference field trips provide participants with first-person experiences and knowledge of saline environments that cannot be gained by other means. The Perth conference fulfilled all these expectations and having attended this and previous conferences, it is clear to me they occupy a special niche that many scientists find rewarding. I look forward to the next and many more.


Research has suggested that organized violence and torture have long-term psychological effects that persist throughout the lifespan. The present survey aimed at examining the prevalence of posttraumatic stress disorder (PTSD), and other disorders and symptoms, all present in old age, as long-term consequences of politically motivated violence in a comparison design.A group of former political detainees  who had been arrested by the Romanian communist regime were compared to an age- and gender-matched control group (N = 39). PTSD was assessed using a structured clinical interview (CIDI). The investigation of the clinical profile was further accomplished by self-rating measures for anxiety, depression, and health-related functioning, as well as by clinician-administrated interviews for substance abuse, dissociation, and somatization symptoms.Lifetime prevalence of PTSD was 54%. In the case of participants left untreated, PTSD persisted, often over four decades, such that current PTSD was diagnosed still in a third of the survivors. Other clinical conditions such as somatization, substance abuse, dissociative disorders, and major depression were also common among the former political detainees and often associated with current PTSD.Our findings suggest that political detention may have long-term psychological consequences that outlast the changes in the political system. Research on victims of organized violence and torture has suggested that prolonged severe traumata produce long-term psychological effects that persist even into old age. Many comparative epidemiological studies have been conducted to investigate the long-term consequences of organized violence, but there is still a lack of information regarding psychological and physical status of the survivors in their late life. In particular, there is little information about the consequences of subjection to political persecution in the formerly communist countries of Eastern Europe. The extensive review of empirical support for the co-occurrence of complex symptoms led to the conclusion that this was mainly the consequence of prolonged, repeated trauma that usually occurred during captivity, such as in prisons, concentration camps, or labor camps . It has Information about the persistence of posttraumatic sequelae into old age comes mostly from investigations on Holocaust survivors and on POW-s in World War II. Irrespective of the particular type of assessment used to determine mental health consequences, most studies have found that survivors suffered from long-lasting impairment even later in life . In addiHowever, these results may be influenced by the participants' selection procedures. Earlier clinical investigations of Holocaust consequences late in life have also underlined an increase in the severity of depressive and somatic symptoms as an outcome of the unsuccessful emotional processing of the trauma . These dResearch concerning posttraumatic consequences of organized violence has lately focused mainly on refugees. In addition to the very relevant studies on refugees, the importance of research on victims of organized violence who continued to live in their countries of origin has been emphasized , as the In countries with a history of dictatorship, terror, and institutionalized violence, both political opponents and arbitrary victims fell prey to severe abuse. In Romania, political imprisonment and deportation procedures, commonly used under King Carol's dictatorship and during the Nazi era, were reinforced beginning with August 23, 1944, when Romania started the war against Germany and the Communists came to power under the supervision of the Soviet state which had administrative control over Romania at that time. Whereas the earlier political coercion had been directed against Jews and individual political opponents, under the Communist regime it extended to the whole Romanian society, becoming part of everyday life and generating pervasive fear and terror, which affected social structures as well as individual behaviour . BetweenThe present study documents a clinical psychological investigation that was conducted in Romania on a sample of Romanian former political detainees now in their late sixties and seventies. A control group of elderly people that have not undergone political persecution served to explore the cause of the symptoms. Our aims were the following: (1) to explore the severity of traumatic conditions during detention; (2) to investigate the range of PTSD, the health-related functioning, anxiety, depression, substance abuse, somatization, and dissociation within this population in a controlled comparison; (3) to analyze the interrelationships between PTSD diagnosis and the clinical profile of the participants; (4) to compare clinical conditions between the former political prisoners who received psychological support and those who did not.The study design included two groups: a political detainee group and a control group. The group of political detainees consisted of N = 59  Romanian survivors of the Communist political imprisonment practice and persecution, who had been political activists or just arbitrary victims. Regardless of their political affiliation, time of imprisonment, or actual need for help, participants in this group were Romanian citizens arrested after 1948, according to the decision of the Military Court, some arrest warrant, the administrative order given by the Ministry of Internal Affairs or even without any written order, simply by means of the abuse of the police state organs. All possessed a legal status as former political prisoners, according to documents that prove their imprisonment. Study announcements were made at the Romanian Association of Former Political Detainees (AFDPR) in Iasi, Suceava, Botosani, and Brasov, an anti-Communist organization militating for the rights of the former political prisoners, and at the Medical Rehabilitation Clinic (MRCT) in Iasi, a branch of the IRCT  in Moldavia, which offers medical and psychological support for victims of political persecution and torture. The psychological support sessions were conducted by a psychiatrist at the clinic headquarters, and consisted of a regular group treatment procedure in which the participants were able to share their stressful experiences and to discuss their problems. From the 83 former political detainees  who were approached and invited to participate, after informed consent, 58 (82%) of the men and 1 (8%) of the women agreed to enter the study. We have no explicit information on the reasons for non-participation. According to the employees of the two institutions, many women had been sexually abused during prison and they might not be willing to report such experiences, which is consistent with the analysis of written testimonies on this topic . Twenty-The control group  was a general population sample recruited from a city clinic where mostly old age pensioners from Moldavia were under treatment for rheumatoid and arthritic problems. These persons had responded to the hospital's employees' announcements for participants in the research study. From the control group, one participant reported a history of torture and four and a half years of political imprisonment between 1980–1985, because of his origins , another reported ordinary conviction to two-and-a-half- month imprisonment due to his refusal to become a member of the Communist party, and a third one reported having been persecuted because he had studied abroad. With these few exceptions, in the other cases of control subjects, their life during the Communist era had had a normal course, without interferences of the state authorities. For matching purposes, exclusion criteria were age and gender.informed consent containing a detailed description of the research purposes. The study was approved by the Konstanz University Ethical Review. The interviews were carried out in July–October 2001 and in August–November 2002 at the subsidiaries of the institutions participants had been recruited from.Overall, the two groups were comparable in terms of institutional social contacts, most socidemographic characteristics, WWII veterans, psychiatric history of the family, former psychiatric illness, and traumatic experiences other than those related to political imprisonment and persecution Table . The meaAn extensive evaluation of the psychological status for all participants was conducted by self-report and diagnostic clinical interview measures. A clinical psychologist and two master-degree students in psychology who had been specifically trained in the use of diagnostic interviews carried out assessments. A translation/back-translation technique concerning contents, criteria, semantic, notional and procedural correspondence was used to develop Romanian versions of the instruments , except Every subject completed a series of self-report surveys with the assistance of an interviewer. The next sequence for the completion of these items was the following:Demographic characteristics of the participants were recorded by the interviewer.(1) Mini Mental State Inventory  y . Based Short Form-12 Health Survey   . This qState-Trait-Anxiety Inventory  y . In thiBeck Depression Inventory  ry . We useAn adjusted version of the Persecution and Maltreatment Checklist.Within the group of survivors, the PTSD score correlated positively with STAI-anxiety , with BDI-depression , and negatively with SF-12-physical health . Also, the depression score (BDI) was positively correlated with STAI-anxiety  and negatively correlated with SF-12-mental health . Current PTSD associated with dissociative disorders  = 8.3, p < 0.001).Although there was no significant difference regarding lifetime PTSD between these two groups, a significantly higher prevalence of current PTSD was noted among former political detainees who did not receive psychological support Table . DissociThe present study is based on the clinical assessment of a sample of 59 survivors of the political detention regime in Romania in their late life, and it aimed at exploring long-term psychological consequences of traumatic conditions during detention within this group. Participants in our sample were young or very young at the time of arrest. As compared to other studies on political victims of former communist regimes ,17, our The investigation of posttraumatic symptoms in our study was related to the experience of political imprisonment. Our results add evidence to the qualification of political detention among traumatic consequences with complex long-term consequences . The ratSomatization symptoms 48%) were frequently diagnosed among former political detainees. The prevalence of other disorders such as substance abuse (37%), dissociative disorders (34%) and major depression 27%) was also high. High associations between the current PTSD diagnosis and the prevalence of dissociative disorders confirm their co-morbidity with PTSD, which has previously been found in aged survivors as well ,35. Also% were fr7% was alSome of our participants received psychological support within a clinical context. This group had the same life-time prevalence of PTSD as those left untreated (54%), but exhibited a significant lower rate of current PTSD, substance abuse, and dissociative disorders. Further analyses showed that a lack of psychological support was associated with current PTSD, dissociative disorders and substance abuse. As the assignment to these two groups was not done at random, we cannot ascertain a causal relationship. Nevertheless, as compared to recovery from PTSD in the treated group, which reached a worth-mentioning 70%, spontaneous remission in the untreated sample was very low (less than 15%), suggesting that, once it has developed, PTSD is likely to persist over the whole lifespan. However, treatment seemed not to produce a reduction on the level of intrusion, somatization, and major depression. Possibly, psychological support was efficient only in the reduction of posttraumatic hyperarousal and avoidance, substance abuse, and dissociation. Alternatively, it might be that those who recovered from PTSD sought treatment for their remaining mental health problems, i.e., intrusions, somatization and the collateral depressive symptoms. Given that intrusions and somatization both result from implicit memories that are not sufficiently integrated with explicit autobiographical recollection , a traumRecruitment strategies may not have allowed for the estimation of the epidemiological prevalence. First, the participants recruited from one institution did not look for treatment, whereas the other ones had already been offered psychological assistance. However, other recruitment strategies without an institutional frame would have not allowed for the selection of a sufficient number of participants, since most victims are still extremely suspicious when asked to report their experiences . SecondlThe educational level of control subjects was lower than that of survivors. This difference was predictable, since a remarkably high educational level was a distinctive feature of the political detainees population, given that the bourgeoisie and the intelligentsia were the favorite target groups for political persecutions during the former Communist regimes . The covWe also acknowledge that the long period of time of 43.9 years on the average, which had passed since the trauma until the moment of the interview, may have affected the validity of the data collected retrospectively with the Persecution and Maltreatment Checklist. On the other hand, the traumatic experiences, reported by the respondents involve "hot" memory, i.e., episodes with strong emotional and sensory components that seem to be highly consistent and long-lasting ,40.The present study shows that PTSD and other mental disorders developed significantly in former political detainees of the Romanian communist regime as a consequence of trauma, maltreatment and other stress factors that acted during the political imprisonment. Across four decades, the disorder persisted in severe forms, particularly in the former political detainees who did not receive psychological assistance. Thus, political detention and post-detention life conditions are likely to have negative long-term effects on the mental health status of former political detainees that may last even into the latest stages of life when left untreated. A high prevalence of co-morbid disorders and symptoms, including somatic complaints, add to the suffering of these survivors. Obviously, these victims need psychotherapeutic help and care that includes rigorous research concerning political persecution. However, in view of a highest efficiency, public recognition and political rehabilitation would also be necessary requirements. Further research on survivors of political persecution in the former Communist countries of Eastern Europe may add helpful data in understanding the psychological effects of this phenomenon.The author(s) declare that they have no competing interests.DB conducted the study in Romania, performed the statistical analysis, and drafted the manuscript. MS designed the study and coordinated the studies activities in Romania. ES participated in the analyses. AN participated in the design of the study and its coordination. TE designed the study and revised the manuscript. FN designed the study and revised the manuscript. All authors read and approved the final version.


Epithelioid sarcomas of the hand are rare, high-grade tumors with a propensity for regional lymphatic spread approaching 40%.A 54-year-old male with an epithelioid sarcoma of the palm was treated with neoadjuvant radiation, wide excision, and two-stage reconstruction. Sentinel lymph node biopsy was used to stage the patient's axilla. Sentinel node biopsy results were negative. The patient has remained free of local, regional and distant disease for the follow-up time of 16 months.The rarity of this tumor makes definitive conclusions difficult but SLN biopsy appears to be a useful adjunct in the treatment of these sarcomas. Epithelioid sarcoma is a rare, high-grade, soft tissue sarcoma. These tumors typically present on the extremities, in males who are 20 to 30 years of age. Overall 5 and 10-year survival rates are 70% and 42% respectively [The success of SLN biopsy is based on the principle that the primary tumor drains to one or a few lymph nodes in the regional basin. Histopathological analysis of these sentinel nodes has been shown to reflect the histology of the entire lymphatic basin ,9. This We report a case of SLN biopsy in conjunction with limb salvage surgery and complex soft tissue, neurovascular, and staged tendon reconstruction for the management of an epithelioid sarcoma of the hand.th web space. An epithelioid sarcoma was identified upon histological analysis. Review of surgical pathology at our institution confirmed this diagnosis  of the chest was negative. The axilla was reported as having benign appearing lymph nodes, fatty in nature with no evidence of necrosis.The patient received preoperative radiation of 50 Gy in 25 fractions. CT simulation was used for planning the gross tumor volume (GTV) to ascertain the depth to be treated using electrons. A customized lead cutout was designed to avoid treating the full width of the hand and to avoid normal tissues ulnarly, radially and at depth. Bolus was placed over the palm to ensure adequate superficial skin and scar dose whilst ensuring the dose at depth covered the tumor and previous operative bed. A daily dose of 2 Gy was delivered to a total of 50 Gy over a five week period. Moderate erythema of the palm occurred which healed well post-treatment. There was no significant edema post-irradiation. Dysethesias were reported on the radial aspect of the small finger; however, two point discrimination remained normal.Surgery was performed 6 weeks following completion of radiotherapy. Preoperative lymphoscintography figure  identifien bloc excision was carried out including palmar skin, subcutaneous fat, palmar fascia, flexor digitorum superficialis and profundus tendons  to the small and ring finger, and the neurovascular bundles to the 3rd and 4th web space. The excision plane was carried down to the level of the fascia of the interossei, along the volar shafts of the metacarpals .Surgical pathology of the rd and 4th toes for restoration of active finger flexion.At six months post-procedure, the radial forearm flap and donor site were well healed Figure . The secAt 16 months post treatment, the patient remains free of local, regional and distant disease. He has regained acceptable hand function, with small and ring finger individual joint range of motion of 90 degrees at the metacarpal-phalangeal joints, 30 degrees at the proximal interphalyngeal joints, and 30 degrees at the distal interphalangeal joints   and regiTreatment of sarcomas of the hand is particularly challenging due to the concentrated and intricate anatomy, which makes sparing of critical structures difficult. Furthermore, the majority of these tumors are extra-compartmental, violating multiple tissue planes. Microsurgical skill for complex vascular and neural repair is an integral part of the overall planning of these cases, since without sophisticated reconstruction, limb salvage for hand sarcomas is unlikely to be useful. Free flaps are commonly required to restore function as well as to facilitate primary healing. -18The propensity of epithelioid sarcoma for regional spread supports the role of minimally invasive regional node staging procedures for prognosis and treatment. SLN biopsy has dramatically changed the management of melanoma and breast cancer. It has been investigated in the mapping of other tumors including penile , lung 22, colon Given the success of the technique in other malignancies, it seems reasonable to apply SLN biopsy to soft tissue sarcomas of the extremity . The rolIdentification of the sentinel node in sarcomas is more challenging than in breast and melanoma patients. Although successful identification of sentinel nodes exceeds 95% when using both a vital blue dye and a nuclear tracer ,33, we aWe report a case of epithelioid sarcoma of the hand successfully managed with a multi-disciplinary approach including neoadjuvant radiation, sentinel node biopsy and wide surgical excision. The rarity of this tumor makes definitive conclusions difficult but SLN biopsy appears to be a useful adjunct in the treatment of these sarcomas.In the past five years we have not received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future. No such an organization financed this manuscript (including the article-processing charge).• We do not hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future.• We do not hold nor are applying for any patents relating to the content of the manuscript. We have not received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript.• We have no other financial competing interests.We do not have any non-financial competing interests  to declare in relation to this manuscript.CT: Primary surgeon; report conception, writing, preparation and revision of manuscript, response to reviewers' questions, submission of manuscript, photographsRT: First assistant surgeon; literature review, chart review, data collection, writing and preparation of manuscriptAS: Second assistant surgeon; literature review, chart review, data collection, writing and preparation of manuscriptAH: Radiation oncologist; chart review, writing and preparation of manuscriptBW: Pathologist; writing, preparation and revision of manuscript, histologic slide review, photographs


The continuous cell line UCRU BL 17CL was derived from a human invasive bladder cancer and expresses elements of transitional, squamous and glandular differentiation. Nine clones of this line were established by limit dilution and have been extensively characterised. Only six of these clones grew subcutaneously in nude mice. Of these, three have exhibited local invasion, each in one of five implanted mice. Although all xenografts expressed transitional, squamous and glandular elements, different histological subtypes predominated within each clone. Only clones which grew in nude mice formed colonies in semi-solid medium, and each responded differently to the influence of medium that had been conditioned by the growth of UCRU BL 17CL, suggesting the possible secretion of a growth factor by these cells. The DNA content and lectin binding profiles of the clones also reflected the heterogeneity of the line. UCRU BL 17CL and the nine clones provide a unique model for the study of tumour heterogeneity, progression and differentiation, and the potential autocrine regulation of growth of bladder cancer.


Population genetics studies based on the analysis of mtDNA and mitochondrial disease studies have produced a huge quantity of sequence data and related information. These data are at present worldwide distributed in differently organised databases and web sites not well integrated among them. Moreover it is not generally possible for the user to submit and contemporarily analyse its own data comparing them with the content of a given database, both for population genetics and mitochondrial disease data..HmtDB is a well-integrated web-based human mitochondrial bioinformatic resource aimed at supporting population genetics and mitochondrial disease studies, thanks to a new approach based on site-specific nucleotide and aminoacid variability estimation. HmtDB consists of a database of Human Mitochondrial Genomes, annotated with population data, and a set of bioinformatic tools, able to produce site-specific variability data and to automatically characterize newly sequenced human mitochondrial genomes. A query system for the retrieval of genomes and a web submission tool for the annotation of new genomes have been designed and will soon be implemented. The first release contains 1255 fully annotated human mitochondrial genomes. Nucleotide site-specific variability data and multialigned genomes can be downloaded. Intra-human and inter-species aminoacid variability data estimated on the 13 coding for proteins genes of the 1255 human genomes and 60 mammalian species are also available. HmtDB is freely available, upon registration, at The HmtDB project will contribute towards completing and/or refining haplogroup classification and revealing the real pathogenic potential of mitochondrial mutations, on the basis of variability estimation. Thanks to its outstanding features, mitochondrial DNA (mtDNA) has been widely exploited both in population genetics and mitochondrial disease studies. In particular, the high mutation rate, absence of recombination, and maternal transmission make this molecule suitable for evolutionary studies aimed at tracing the migrations which led to the colonization of the various geographic areas of the world. Nevertheless, mitochondrial DNA also plays an important role in the oxidative metabolism of the cell, as it encodes for different subunits of the proteins involved in the respiratory chain. Hence, mutations occurring in mitochondrial DNA can alter the oxidative phosphorylation which seriously damages cells and tissues.Mitochondrial DNA is a haploid molecule, and the number of identical copies of mitochondrial DNA per human cell ranges from 10000 to 100000 molecules. However, due to an inefficient repair system, mitochondrial DNA mutations are more easily fixed with respect to nuclear DNA, thus making mtDNA transitorily heteroplasmic . Indeed the mtDNA population rapidly becomes homoplasmic being the mutation fixed in one individual. If this mutation is not apparently deleterious and is transmitted to the following generations, then this mutation can be considered fixed in the lineage.The mtDNA genome of two unrelated individuals may differ by about 50 nucleotides ,2. HowevMitochondrial disorders – associated with dysfunctions of the Oxidative Phosphorylation (OXPHOS) system – are caused by genetic defects both in the mitochondrial and nuclear genome, leading to energy metabolism errors, and have an estimated frequency of 1 out of 10000 live births. Due to the important role played by the OXPHOS system in ATP production, the causes and effects of mitochondrial disorders are extremely heterogeneous and complex. This explains the pressing need for further research on this topic, despite the many studies on mitochondrial disorders published in the last 20 years.). The two last databases report frequency data associated with mitochondrial SNPs, whereas MITOMAP simply associates mtSNP with the different phenotypes and to literature data.Population genetics studies based on analysis of mtDNA and mitochondrial disease studies have produced a huge quantity of sequence data and related information. Classified as RFLPs, mtDNA SNPs, pathogenic mutations, HVS1 and HVS2 sequences, and complete mtDNA sequences, these data are now distributed worldwide in variously organized databases and web sites, not all well integrated. Several specialized mitochondrial databases for human and primates have been designed and implemented, providing good quantity and quality of human mitochondrial data: MITOMAP , HVRBASEHmtDB, the resource presented here, is aimed at filling the gap, gathering all the complete human mitochondrial genomes worldwide distributed and enriching sequence information with statistically validated variability data estimated through the application of specific algorithms implemented in an automatically running Variability Generation Work Flow (VGWF). A second work flow, called Classification Work Flow (CWF) is implemented in the resource to perform automatic classification of newly sequenced genomes. Here we describe in detail HmtDB aims and design as well as its potential applications and future developments.The aims of HmtDB are (1) to collect and integrate all human mitochondrial genomes publicly available, (2) to produce and provide the scientific community with site-specific nucleotide and aminoacid variability data estimated on all available human mitochondrial genome sequences through the automatic application of VGWF, (3) to allow researchers to analyse their own human mitochondrial sequences  in order to detect automatically any nucleotide variants according to the revised Cambridge Reference Sequence (rCRS) and to predict their haplogroup paternity. This is automatically performed thanks to the application of the CWF.VGWF is applied both to the entire HmtDB genome collection and to continent-specific subgroups. The resulting site-specific variability values highlight functional constraints in both control and coding regions and, thus, distinguish polymorphic sites from constrained ones. From a population genetics point of view, this allows complete and/or refined mitochondrial haplogroup classification, providing a more precise interpretation of population sequence data and thus a refinement of phylogenetic models. From a clinical point of view, it contributes towards shedding light on the real pathogenic potential of certain mitochondrial mutations, not yet clearly associated with any mitochondrial pathology. through a log-in procedure, after free registration.HmtDB is a bioinformatic platform which allows storage, query and analysis of human mitochondrial sequences. It is available at the web address This web-based application is organized as a relational database, storing complete human mitochondrial genomes, data related to the sample and the subject from which the mtDNA was extracted, and the results of variability analyses performed through the automatically running VGWF implemented in the resource itself. A web-service interface to the PubMed public database also allows automatic retrieval of reference information during sequence annotation.Five macro-functions have been designed for HmtDB and are available to users after they have completed the log-in procedure. From the first page, users can (1) browse through the contents of the database, in order to view and download multialigned sequence data and site-specific nucleotide variability data, both regarding the entire database and continent-specific subsets; (2) analyse their own mitochondrial sequences in order to classify them automatically according to the latest mitochondrial haplogroup classification; (3) view the history of previously performed analyses and, if necessary, recover them, thanks to the existence of a personal session for each user (this is why users must register their access to HmtDB); (4) query the database through (a) a simple text search form or (b) a multicriterion form made up of pop-up menus and free text retrieval windows; (5) submit a new human mitochondrial genome through an easy-to-fill-in web interface. Functions 4 and 5 have been designed but are not yet implemented. Figures The HmtDB database is of relational type, designed and implemented using the DB2 IBM Database Management System. Currently, it is composed of 24 tables  and data produced by the application of nucleotide and aminoacid site variability software ("HmtDB WORKFLOWS"). In the first category, the associated information is: geographic origin of the subject from whom the mtDNA comes, sex, age, disease acronym , biological source of mtDNA, bibliographic references, haplogroup and haplotype code as reported from the authors, and the sequencing protocol adopted. These are subdivided into several tables, e.g., GENOME, REFERENCES, INDIVIDUAL DATA, COUNTRY, ETHNIC GROUPS, etc.. Missing information are left empty.Data in the second category are mtSNPs, deletions and/or insertions determined by comparing each genome with the revised Cambridge Reference Sequence ,9. NucleMoreover information about mtSNPs with phenotypic effect, derived from MITOMAP database annotations . JSPs are more efficient, easier to use, more powerful and more portable than traditional CGI. They have been extensively linked to each other, so that users can easily access data independently from the navigation starting point. A complete set of "help" information, widely distributed throughout each web page, supports users during navigation and interpretation of data derived from the application of the HmtDB VGWF to human mitochondrial genomes.The "Welcome" page is the first page of HmtDB. It gives some general information about the resource, and offers the possibility of registering (through an appropriate form) or of logging in directly to HmtDB (provided that a previously successful registration has been completed).After log-in, users access a main menu page, from which HmtDB macro-functions are available.The HmtDB browsing function allows the selection of a specific genome through a menu reporting the list of the database source Accession Numbers, displaying the Genome Card of the selected genome. This is the page on which most of the results available through HmtDB are shown: both CWF and VGWF analytical results are displayed, together with information from MITOMAP and mtREV mitochondrial substitution indices  associatThe "Analysis" page offers the possibility of inserting a human mitochondrial sequence and analysing it according to the CWF procedure. Results are shown through the generation of a new Genome Card on which the relative haplogroup classification is displayed, as well as the VGWF results on mitochondrial nucleotide variants detected for that sequence.The "Query" and "Submission" pages have not yet been implemented, and the words "work in progress" highlight this condition. However, it is worth mentioning that, if a new human mitochondrial sequence is submitted, HmtDB automatically checks that it is not already present in the database, and in any case the new sequence is analysed according to the CWF procedure.Lastly, the "My HmtDB Sessions" page displays the list of analyses performed by each user, together with the date and completion status (marked by different colours)., EMBL , MITOMAP , GOBASE , Mitokor  and mtDB . The total resulting dataset is composed of 2291 genomes analysed with the CleanUP program [The first bulk of data stored in the database consists of 1255 human mitochondrial sequences, of which 560 are coding region sequences only, and the rest are complete genomes. They were retrieved from GenBank  program  in order.Information on the annotation of genomes in HmtDB is derived from the entry of the database from which the sequences were retrieved. Further data such as geographic origin, age, sex, haplogroup, disease acronym, tissue, and sequencing method were extracted from the relative literature. Ethnic information was annotated following the Ethnologue database Quality of the sequences stored in HmtDB is under the responsibility of the sequence producers and of the source databases. Anyway in case of personal submissions, a check for possible errors will be made before the submission procedure is complete.Inter-species aminoacid site variability was estimated on the multialignment of the 13 mtCDS of 60 complete mitochondrial genomes from various mammal species. These were retrieved from the AMmtDB database .Information about polymorphic and pathological mutations was retrieved from MITOMAP and is organized in tables describing the phenotypic effect of each mutation.The execution of both CWF and VGWF procedures requires the application of a set of bioinformatics methods described below. Figure CWF procedure is performed on a single human mitochondrial sequence (Query), and aims at predicting its haplogroup paternity. It consists essentially of an automatic comparison between Query and rCRS sequences, with the aim of detecting the pattern of Query mtSNPs. Matching an obtained pattern against the haplogroup classification stored in HmtDB can predict the Query sequence haplogroup paternity. A Genome Card of the analysed genome is generated and displayed, on which haplogroup paternity is expressed as a list of haplogroups for which a match was found, and a percentage value of the detected variations with respect to the total number of variations defining the haplogroup. Also in this case, a complete set of links, supported by help information, allows users to navigate through the data and to retrieve information about haplogroups.VGWF is performed both on the entire contents of the database, and on continent-specific subsets. It aims at estimating nucleotide and aminoacid site-specific variability through the application of appropriate software to multialigned data. Also in this case, the procedure is completely automatic (including division of the entire dataset into continent-specific subsets) and is repeated each time the contents of the database is significantly updated, as the site-specific variability software performs statistical estimates whose results change significantly only in cases of considerable changes in the starting data (number of sequences). In order to make these results statistically more significant, bootstrap values are also estimated. This is done by an automatic simulated sampling procedure which, starting from real data stored in the database, estimates a number M of sequences equal to the number of the less numerous continent-specific dataset. Then M sequences from each continent-specific dataset and from the entire database are chosen at random 100 times, and 100 site-specific nucleotide variability values are estimated for each subset on these simulated samples. The final result, consisting of the mean site-specific variability value plus its standard deviation, estimated for each dataset on the 100 simulated values, is then displayed in appropriately formatted tables, and can also be downloaded. The simulated variability values statistically support real ones, as they provide an idea of the statistical significance of the dimension of the real samples: the closer the simulated value is to the real value, the more "ideal" is the dimension of the real sample stored in the database.Progress in sequencing techniques is making the sequencing of complete genomes increasingly easy, in terms of human resources, so that since 2000 the number of complete genomes has significantly increased ,15-26, pThe HmtDB project is intended to store and analyse human mitochondrial genomes in a well-integrated web-based bioinformatic resource, in order to support population genetics and mitochondrial disease studies, thanks to a new approach based on site-specific nucleotide and aminoacid variability estimation. This will contribute towards completing and/or refining haplogroup classification on the basis of variability values obtained from HmtDB, in order to detect new haplogroups and/or modifying existing classifications. In addition, site-specific variability may reveal the real pathogenic potential of mitochondrial mutations, excluding those which present too high inter-and intra-species nucleotide and aminoacid variability values , and focusing attention on those mutations presenting more intriguing variability values.In this way, HmtDB may contribute in a more rigorous way to quantitative estimation of the pathogenetic proneness of mutated sites and to the detection of ethnic-specific sites, and consequently to refining haplogroups.


Samples of vitrified and unvitrified Eocene woody plant tissues collected from the Fossil Forest site, Geodetic Hills, Axel Heiberg Island, have been characterized by TMAH thermochemolysis. All samples are gymnosperm-derived, are of very low maturity and all share the same post-depositional geologic history. Differences in the distributions of products observed from vitrified and unvitrified samples suggest that vitrification of woody tissue is associated with modification of the lignin C3 side chain, following loss of all or most of the carbohydrate present in the precursor woody tissues. The key driver of vitrification appears to be physical compression of the tissue following biological removal of cellulosic materials. Vitrinite is the geologic product resulting from diagenetic alteration of lignocellulosic (woody) plant tissues. It is a major component of most coals and accounts for a significant fraction of sedimentary organic matter (SOM) on a global scale, especially SOM derived from terrestrial biomass. Vitrification, used in this context to refer to the conversion of lignocellulosic tissues to vitrinite, is a key process affecting the long-term burial of woody plant tissues. In general, both hemi-cellulose and cellulose are greatly reduced or completely lost, and lignin-derived structures are selectively enriched ,2 duringNumerous authors have investigated the structural characteristics of vitrinite, especially in relation to understanding the overall structural characteristics of coals, and to some extent much of the voluminous work that has been reported on coal maturation is relevant to the structural changes that occur in vitrinite as it progresses through the geologic column. The structural changes that occur during the initial stages of vitrification; that is, the earliest conversion of recognizably woody tissue into glassy vitrified material are, however, much less thoroughly investigated. This step is critical in that it converts relatively labile, bio-available carbon into relatively resistant, largely bio-unavailable carbon, Hence this process is a key step in the long-term burial and sequestration of terrestrial organic carbon.In the present study, woody and vitrified plant tissues collected from Eocene deposits in the Canadian Arctic have been characterized by thermochemolysis with tetramethylammonium hydroxide (TMAH) to investigate structural changes associated with the initial vitrification of woody plant tissues. Samples were collected from the Fossil Forest site, located in the Geodetic Hills region of Axel Hieberg Island . This deTMAH Thermochemolysis is a thermally assisted hydrolysis technique that is widely used for analysis of humic and other macromolecular materials ,5 includThis technique has major advantages over conventional pyrolysis for analysis of lignin-related/lignin-derived materials ,13,15,16o = 0.11,  reported by Goodarzi and coworkers  yieldedAll of the major products observed in these data have been previously reported by other workers in TMAH thermochemolysis products derived from lignin or lignin-related and derived samples ,14-16,19Py-GC-MS data from vitrified (root and branch) and unvitrified (branch) tissues are illustrated in Figure Differences in the data derived from the two vitrified samples are subtle and are generally within the range of intra-sample variation, as described above, indicating that the structural characteristics of these samples are at least grossly similar. Differences between the data derived from vitrified and unvitrified tissues, however, are more significant. The pyrolysate of the unvitrified wood is dominated by compounds 12,13,17,18,25 and 26. Studies by Kuroda and coworkers ,16,19, aIn their report , Obst anVarious authors have attempted to apply parameters such as acid: aldehyde ratio (13:12) and other proxies in TMAH studies of lignin and lignin degradation, as a measure of the degree of degradation or modification of the initial lignin structure. However, in the opinion of the present authors, the usefulness of these parameters in TMAH thermochemolysis studies of lignin is open to question. It is well known that treatment of aldehydes and even alcohols with hydroxide bases at elevated temperatures results in Cannizarro-type reactions -27 whichConsideration of the data illustrated in Figure It is a widely accepted belief that vitrification occurs gradually over time as part of the overall coalification process and that it is largely temperature-driven. Previous studies discussing this process have generally compared samples collected from different sites and covering a range of maturities [e.g. ] and in Samples characterized are all gymnosperm-derived, were collected from the same site, share the same very mild thermal history and were recovered in close proximity to each other. In all cases, cellulosic and hemi-cellulosic materials have been largely removed, suggesting similar degrees of biological diagenesis and further indicating that residual product, (vitrified or unvitrified) is derived largely or exclusively from lignin. Therefore, observed differences between vitrified and unvitrified samples are not the result of differences in the age, thermal maturity or initial composition of the samples. The key difference between the samples is the degree of physical compression experienced. The vitrified samples were all recovered from coaly layers that have undergone significant compaction and compression due to the weight of the overlying sediments. Unvitrified materials were recovered from unconsolidated sands adjacent to the coaly layers. Sands are much less compressible than peats and hence, materials deposited in these layers were protected from compaction. Therefore, it is the view of the present authors that physical compression is a key driver of the geochemical changes that are associated with the initial vitrification of buried lignin-rich plant tissues.Comparison of thermochemolysis results from vitrified and unvitrified samples suggests that vitrification is associated with significant changes in the lignin structure. The data suggest that these changes occur primarily by reactions involving and altering the nature of the C3 side-chain unit, reducing the number of β-O-4 linked lignin units. This is consistent with previously reported observations ,11,29, eSupporting interactive supplemental data for Figure Click here for fileSupporting interactive supplemental data for Figure Click here for file


Premature labour (PTL) is the single most significant factor contributing to neonatal morbidity in Europe with enormous attendant healthcare and social costs. Consequently, it remains a major challenge to alleviate the cause and impact of this condition. Our ability to improve the diagnosis and treatment of women most at risk of PTL is, however, actually hampered by an incomplete understanding of the ways in which the functions of the uterine myocyte are integrated to effect an appropriate biological response at the multicellular whole organ system. The level of organization required to co-ordinate labouring uterine contractile effort in time and space can be considered immense. There is a multitude of what might be considered mini-systems involved, each with their own regulatory feedback cycles, yet they each, in turn, will influence the behaviour of a related system. These include, but are not exclusive to, gestational-dependent regulation of transcription, translation, post-translational modifications, intracellular signaling dynamics, cell morphology, intercellular communication and tissue level morphology.in silico clinical diagnosis and treatment of PTL.We propose that in order to comprehend how these mini-systems integrate to facilitate uterine contraction during labour (preterm or term) we must, in concert with biological experimentation, construct detailed mathematical descriptions of our findings. This serves three purposes: firstly, providing a quantitative description of series of complex observations; secondly, proferring a database platform that informs further testable experimentation; thirdly, advancing towards the establishment of a virtual physiological uterus and  PTL accounts for 6–8% of all births across Europe (~6% in the UK) . Of evenintegrated uterine function that is encapsulated by the term 'myometrial physiome'.Perhaps our greatest challenge ahead, as evoked in the quotation above, is to consider how we can assimilate the vast arrays of molecular and cellular information currently generated into a proper physiological context: biological systems are often dynamic, non-linear, non-homogeneous and operate at various mesmerising levels of organisation and hierarchy. Still yet more complexity is introduced with the remodelling of physiological events during pregnancy and labour. Figure in utero stimuli, be they endocrine, nutritional or metabolic for example, that impact upon gene expression without a change in nucleotide sequence of the genome [Underpinning this goal is our quest to answer the questions of (i) what are the cellular mechanisms regulating myometrial contractility? and (ii) what factors control the timing of onset of labour? Much of the research in the former field has been led by reductionist principles, if inadvertently. We have very focussed research questions that often allow us to assess the expression of a gene(s), the encoded protein(s) and, hopefully, make an assessment of its location and function in the myometrial cell. Determining the answer to these strictly defined questions then informs our development of further hypothesis-driven research aims. As just one example, such strategies have been employed to investigate the possible roles of proteins associated with specialised structures of the myometrial cell membrane – caveolae – in the signal processing of contractile stimuli -8 and Fi; this, te genome . Thus we2+ . Eventuin silico tools for predicting the physiological impact of any new treatment regimens for women at the risk of preterm labour. In other words, the creation of a virtual physiological uterus. Similar approaches have been exceptionally successful in the last 15 years at informing us of the function (and dysfunction) of isolated cardiac cells, specialised cardiac regions or the heart as a whole [There is an overall goal underpinning our wish to combine theoretical and empirical approaches to understanding uterine physiology and pathophysiology. That is, to eventually establish a comprehensive and rigorous model of integrated gravid uterine function that enables the application of non-invasive  a whole .A final consideration concerns establishing meaningful access to the divergent datasets related to PTL for computational modelling purposes by the academic community of biologists, chemists, mathematicians and clinicians. Certainly this requires a web-based forum for the storage, and continued supplementation, of datasets in a standardized, well-defined and cross-referenced manner with open access to software tools allowing for model developments and data analysis ,19.The authors declare that they have no competing interests.MJT and HZ conceived of the study, and participated in its design and coordination and helped to draft the manuscript. AB participated in the design of the study and co-ordination and, together with MJT, performed the experiments of Figure