test/test_base.rb in mesh-medical-subject-headings-2.3.0 vs test/test_base.rb in mesh-medical-subject-headings-3.0.0

@@ -3,12 +3,186 @@
 module MESH
   class TestBase < Minitest::Test
 
     def initialize arg
       super
-      @@mesh_tree ||= MESH::Tree.new
-      @@mesh_tree.load_translation(:en_gb)
-      @@mesh_tree.load_wikipedia
+      @@mesh_tree ||= begin
+        tree = MESH::Tree.new
+        tree.load_translation(:en_gb)
+        tree.load_wikipedia
+        tree
+      end
+      @mesh_tree = @@mesh_tree
+      @example_text ||= 'Leukaemia in Downs Syndrome
+Overview
+Downs Syndrome Leukaemia The link between Downs Syndrome and Leukaemia
+Epidemiology
+Aetiology
+Future research Implications for other leukaemias Treatment
+Downs Syndrome
+Originally described in 1866
+Associated with Trisomy 21 in 1959
+Prevalence 1/1000 births
+95% due to chromosomal non-disjunction; 5% due to translocations Risk factors:
+increased maternal age
+1/1000 maternal age 30 years
+9/1000 maternal age 40 years
+infertility treatment
+Clinical Features
+physical appearance
+intellectual disability
+developmental delay
+sensory abnormalities congenital heart disease
+Alzheimers Disease
+GI malformations
+thyroid disorders
+poor immune system
+LEUKAEMIA
+Downs Syndrome
+Leukaemia
+cancer
+WBC proliferation in the bone marrow
+Classification:
+acute/chronic
+type of WBC
+Current leukaemia model:
+2 co-operating mutations
+1 leading to impaired differentiation
+1 leading to increased proliferation/cell survival
+Picture: Hitzler & Zipursky, 2005
+Leukaemia
+Acute lymphoblastic leukaemia (ALL)
+derived from B lymphocyte or T lymphocyte precursors
+80% childhood leukaemia
+Acute myeloid leukaemia (AML)
+e.g. myeloid, monocytic, megakaryocytic, erythroid
+20% childhood leukaemia
+Acute megakaryoblastic leukaemia (AMKL)
+AML subtype: leukaemic cells have platelet precursor phenotype
+6% childhood AML cases
+Leukaemia in Downs Syndrome
+10-20 fold increased risk of leukaemia
+ALL
+80% childhood leukaemia; 60% Downs Syndrome leukaemia
+20 times higher incidence children with Downs Syndrome compared to children without Downs Syndrome AML
+20% childhood leukaemia; 40% Downs Syndrome leukaemia AMKL
+6% childhood AML; 62% Downs Syndrome AML
+500 times higher incidence children with Downs Syndrome compared to children without Downs Syndrome
+Leukaemia in Downs Syndrome
+AML in Downs Syndrome
+AMKL in most cases
+younger median age of onset
+2 in Downs Syndrome
+8 in non-Downs Syndrome
+myelodysplastic syndrome more common prior to leukaemia
+Transient Leukaemia
+Transient Leukaemia
+Also termed: Transient Abnormal Myelopoiesis and Transient Myeloproliferative Disorder
+10% newborn infants with Downs Syndrome
+peripheral blood contains clonal population of megakaryoblasts
+cannot be distinguished from AMKL blasts by routine methods
+usually clinically silent
+usually disappear within 3 months
+majority of cases totally resolve
+However
+can be fatal
+20% develop MDS and AMKL by the age of 4 yearsTransient Leukaemia
+Leukaemic cells in Transient Leukaemia and AMKL can:
+show variable megakaryocytic differentiation
+show features of multiple haematopoietic lineages Evidence that Transient Leukaemia is a precursor for AMKL
+near identical morphology, immunophenotype, ultrastructure
+clone-specific GATA1 mutations
+GATA1: X chromosome, zinc-finger transcription factor, essential for differentiation of megakaryocytic, erythroid and basophillic lineages
+therefore have common cell of originLeukaemic cells in Transient Leukaemia and AMKL in Downs Syndrome can form megakaryocytic, erythroid or basophillic lineages
+GATA1
+all Transient Leukaemia and AMKL cases have GATA1 mutations
+most abrogate splicing of exon 2 or produce stop codon prior to alternative start codon at position 84
+lack N-terminal domain
+mutations disappear upon remission
+disease specific mutations
+leukemogenisis model: transcription factor mutation blocks differentiation
+GATA1 mutation determines haematopoietic lineage
+GATA1 mutations present in Transient Leukaemia at birth
+mutations in utero
+proportion of Downs Syndrome fetuses acquire GATA1 mutation
+large clone = Transient Leukaemia
+small clone = no clinical signs
+Aetiology
+Three distinct steps:
+fetal heamatopoietic cell with trisomy 21
+rare Transient Leukaemia cases in people without Downs syndrome
+acquired trisomy 21 only in haematopoietic cells
+mutation of GATA1
+expression of shortened
+GATA1 (GATA1s) extra, as of yet unknown event
+not all cases of Transient
+Leukaemia progress to AMKL
+Picture: Hitzler & Zipursky, 2005
+Aetiology
+Transient Leukaemia with clinical signs of disease
+Transient Leukaemia with no clinical signs of diseasePicture: Ahmed et al, 2004
+Future Research
+Loss of GATA1 function in people without Downs Syndrome results in:
+accumulation of abnormally differentiated megakaryocytes
+thrombocytopenia
+NO LEUKAEMIC TRANSFORMATION
+discovered by Shivdasani et al, 1997
+What is the effect of Trisomy 21
+What advantage does GATA1 mutation provide to people with Downs SyndromeWhat is the second-hitImplications for other leukaemias
+current acute leukaemia model:
+2 co-operating mutations
+1 leading to impaired differentiation
+1 leading to increased proliferation/cell survival
+This means that that the sequence of Transient Leukaemia to AMKL as seen in Downs Syndrome is a chance to investigate this model of leukaemia and discover the timing and nature of the 2 necessary events.
+Treatment of Leukaemia in Downs Syndrome
+AML (AMKL)
+increased sensitivity to cytarabine
+80% 5 year survival
+failure usually due to toxicity (mucositis and infection)ALL
+similar treatment as in AML
+60-70% cure rate (75-85% in population without Downs Syndrome)
+no increased sensitivity, but increased toxicity
+dose reduction would increase risk of relapse
+supportive care
+References
+Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., OMarcaigh, A., Wynn, R., Stevens, R., Addison, M., King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. (2004). Natural History of GATA1 mutations in Down syndrome, Blood, 103(7):2480-2489.
+Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W., Zipursky, A. (2003). GATA1 mutations in transient leukaemia and acute megakaryoblastic leukaemia of Down syndrome, Blood, 101(11):4301-4304.
+Hitzler, J.K., Zipursky, A. (2005). Origins of leukaemia in children with down syndrome, Cancer, 5:11-20.
+Puumala, S.E., Ross, J.A., Olshan, A.F., Robison, L.L., Smith, F.O., Spector, L.G. (2007). Reproductive history, infertility treatment, and the risk of acute leukaemia in children with down syndrome, Cancer, [Epub ahead of print].
+Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A., Orkin, S.H. (1997). A loneage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development, Embo J., 16:3965-3973.
+Slordahl, S.H. et al. (1993). Leukaemic blasts with markers of four cell lineages in Down\'s syndrome (megakaryoblastic leukaemia), Med. Pediatr. Oncol., 21:254-258.
+Vyas, P., Crispino, J.D. (2007). Molecular insights into Down syndrome-associated leukemia, Current Opinion in Pediatrics, 19:9-14.
+Webb, D., Roberts, I., Vyas, P. (2007). Haematology of Down syndrome, Arch. Dis. Child. Fetal Neonatal Ed., [published online 5 Sep 2007].
+http://www.intellectualdisability.info/home.htm
+http://news.bbc.co.uk/nol/shared/spl/hi/pop_ups/05/health_shifting_perspectives/img/1.jpg
+Originally described by John Langdon Down
+Associated with Trisomy 21 by Professor Jerome Lejeune
+Overall incidence is 1/1000, so 600 babies with Downs syndrome are born in the UK each year
+It is estimated that there are 60,000 people living with Downs syndrome in the UK
+80% of children with Downs Syndrome are born to mothers under 35 years of age
+Research suggests that infertility treatment increases risk of chromosomal abnormalitiesFacial appearance: flat profile, flat nasal bridge, small nose, eyes that slant upwards and outwards often with an epicanthic fold a fold of skin that runs vertically between the lids at the inner corner of the eye), small mouth.
+Body appearance: reduced muscle tone, big space between first and second toe, broad hands with short fingers and a little finger that curves inwards, often a single palmar crease.
+Sensory abnormalities: visual and hearing
+Congenital Heart Disease is present in 50% of people with Downs SyndromeThere are two methods of classifying leukaemias: acute/chronic or according to the type of WBC that is proliferating abnormally ALL describes leukaemia where the cancerous cell is derived from precursors of B or less commonly T lymphocytes.  ALL makes up 80% of all childhood leukaemias.
+AML describes leukaemia where the cancerous cell is not B or T cell derived and the subtype is determined by the phenotype of the leukaemic cells.  AML makes up 20% of childhood leukaemias.
+AMKL is a subtype of AML where the leukaemic cell looks like platelet precursors.  AMKL makes up 6% of childhood AML cases.ALL makes up 80% of childhood leukaemia, but 60% of leukaemia in children with DS.  Children with DS have a 20 fold increased risk of developing ALL when compared to children without DS.
+AML makes up 20% of childhood leukaemia, but 40% of leukaemia in children with DS.
+AMKL makes up 6% of childhood AML, but in children with Downs Syndrome makes up 62% of AML cases.  Children with DS have a 500 fold increased risk of developing AMKL when compared to children without DS.The rest of this talk is going to focus on AMKL in DS.  The majority of AML cases in DS are AMKL and have a younger age of onset than in the population without DS.  AMKL in DS much more commonly begins as a MDS.  This is a process of abnormal megakaryocytic differentiation.  Furthermore, children with DS are at risk of Transient Leukaemia  a condition that is almost exclusive to children with DS.Tranisent leukaemia is only found in infants with DS and is found in about 10% of newborns with DS.  These children are born with a clonal population of megakaryoblasts in their blood.  These megakaryoblasts cannot be distinguished from the blasts of AMKL by routine methods and usually spontaneously disappear within the first 3 months of life.
+TL begins in utero and usually does not cause any symptoms.  The majority of cases resolve and the children do not have any lasting haematological problems.  There is no evidence as to how TL spontaneously resolves.  However, it can also be fatal due liver damage or complications in the lungs or heart and 20% of children with TL proceed to develop MDS and AMKL by the age of 4 years.mutations of GATA1 are present in the cells of TL and AMKL in Downs Syndrome and these cells can become megakaryocytes, erythroid cells or basophils!  The megakaryoctic lineage is particularly dependant on the level of expression of GATA1.
+MULTIPLE HAEMATOPOIETIC LINEAGES: for example precursor cells of erythrocytes and basophils.  Ferritin is found in the cytoplasm of DS-AMKL cells.
+This slide equates the aeitology to the model of leukaemia I mentioned earlier, with points 2 and 3 being the 2 mutations.
+2) It is currently not known if it is the absence of normal GATA1 or the presence of GATA1s that causes leukaemic proliferation of megakaryocytes.  It could be both, because GATA1s fails to suppress some pro-proliferative genes such as GATA2 and MYC)  although these are pro-proliferative for erythrocytes.The previous slide shows us how a child with DS can progress to developing AMKL.  Of course we know that not all children with DS or indeed all children with DS and Transient Leukaemia proceed to develop AMKL.  This slide shows us all the possible routes children with DS can take.
+Normal
+GATA1s  small clone or large clone
+clonal extinction  normal
+clonal expansion plus additional genetic event  AMKL
+AMKL  death or remission (normal)Although our understanding of leukaemia in DS have progressed a long way over recent years, there still remain unknowns in the aetiology.
+Loss of GATA1 function has different effect on people without DS and people with DS  therefore what is the effect of Trisomy 21
+why are GATA1 mutations so relatively common in children with DS  It has been postulated that there may be some selective advantage, but it is only a hypothesis.
+thirdly, what is the second-hit  We know that there must be a second genetic event, with GATA1 mutation being the first, but we do not know what this is yet.NB: GATA1 mutation is the first mutation for DS-AMKL.AML  failure of treatment usually due to toxicity due to mucositis and infection.  Resistant disease and relapse are rare.
+ALL  there is no increased sensitivity to treatment, but there is increased risk of toxicity.  Cannot reduce the dose because of the high risk of relapse and so the emphasis is now on improving supportive care.
+'
+
     end
 
   end
 end