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PubMed1980

alpha Thalassemia and the expression of hemoglobin G-Philadelphia.

The findings presented for these two families help to explain the inheritance of alpha thalassemia, alpha-chain variants, and the relative expression of alpha genes. An 18.0-kb EcoRI fragment contains only one functional alpha gene, whereas a 20.5-kb fragment contains two. Individuals homozygous for the 18.0-kb EcoRI fragment also lack the 4.1-kb HindIII fragment that normally connects the centers of the duplicated alpha genes. These findings are consistent with a deletion involving the 5' alpha-gene locus. Presence of alpha G-Philadelphia in both families was found in association with the 18.0-kb EcoRI fragment; this short fragment was also found in an individual with alpha A. Inheritance of alpha G-Philadelphia at one alpha-gene locus was therefore also linked to the inheritance of alpha thalassemia due to a deletion involving the second alpha gene. The high percentage (46% to 48%) of alpha G found in some family members was due to alpha-thalassemia trait, or deletion of two alpha genes (-alpha G/-alpha); others with levels of variant of 32% to 34% were shown to have three functional alpha genes (-alpha G/alpha alpha). The genetic expression of the four normal alpha genes therefore appears to be equal and furthermore implies the existence of separate independently functioning transcriptional units for each of these genes in humans. It would be interesting to analyze the alpha genes in Afro-Americans reported to have alpha G-Philadelphia in the 20% to 25% range to determine whether the inheritance of alpha G can be linked to a normal alpha gene.

Base Sequence↗

PubMed1985

Use of monoclonal antibodies in an epidemiological marker system: a retrospective study of lung specimens from the 1976 outbreak of Legionnaires disease in Philadelphia by indirect fluorescent-antibody and enzyme-linked immunosorbent assay methods.

Autopsy specimens of lung tissues from 15 patients that contracted legionellosis during the 1976 Philadelphia outbreak of Legionnaires disease were examined for the presence of Legionella organisms and soluble antigens by indirect fluorescent-antibody (IFA) testing and by an enzyme-linked immunosorbent assay (ELISA) with both polyclonal and monoclonal antibodies. In all 15 cases, at least one specimen was positive for Legionella pneumophila serogroup 1 (Lp-1) antigens by a polyclonal antibody ELISA system. Of the 15 cases tested for Lp-1, 9 were positive by a polyclonal antibody IFA test. Nine mouse monoclonal antibodies to Lp-1 gave essentially the same reactivity pattern with extracts from lung tissue homogenates as that obtained with a Philadelphia 1 culture extract by using a monoclonal antibody ELISA system. The same monoclonal antibody panel gave similar results when used in the IFA system with tissue homogenates. Monoclonal antibodies can be used as epidemiological marker systems with both IFA and ELISA testing. This study provides evidence that the 1976 common source outbreak in Philadelphia was probably caused by a single Lp-1 strain. ELISA testing of the soluble antigen of Lp-1 from lung tissue homogenate supernatants was more sensitive than IFA testing of the homogenates and should be extremely useful as either a primary test or as an adjunct to fluorescent antibody testing for legionellosis.

Antibodies, Bacterial↗

PubMed1993

Highly efficient elimination of Philadelphia leukemic cells by exposure to bcr/abl antisense oligodeoxynucleotides combined with mafosfamide.

Synthetic oligodeoxynucleotides complementary to the break-point junction of bcr-abl transcripts selectively inhibit the proliferation of Philadelphia-positive leukemic cells, but residual leukemic cells persist in antisense oligodeoxynucleotides-treated cultures. Cyclophosphamide derivatives such as mafosfamide and 4-hydroperoxycyclophosphamide are used at high doses for purging of Philadelphia leukemic cells from marrows but such treatment can be associated with delayed engraftment and prolonged cytopenias. To develop a more effective procedure that might optimize the killing of leukemia cells and the sparing of normal hematopoietic progenitor cells, a 1:1 mixture of Philadelphia leukemic cells and normal bone marrow cells was exposed to a combination of a low dose of mafosfamide and bcr-abl antisense oligodeoxynucleotides and assayed for growth ability in clonogenic assays and in immunodeficient mice. Bcr-abl transcripts were not detected in residual colonies, and cytogenetic analysis of individual colonies revealed a normal karyotype. Normal but not leukemic hematopoietic colonies of human origin were also detected in marrows of immunodeficient mice 1 mo after injection of the treated cells. Our results indicate that a combination of a conventional chemotherapeutic agent and a tumor-specific antisense oligodeoxynucleotide is highly effective in killing leukemic cells and in sparing a much higher number of normal progenitor cells as compared with high-dose mafosfamide treatment. This offers the prospect of a novel and more selective ex vivo treatment of chronic myelogenous leukemia.

Animals↗

PubMed1985

The birth of American neurology and highlights from the first 100 years of the Philadelphia Neurological Society, 1884-1984.

The Philadelphia Neurological Society was founded 100 years ago by Charles K. Mills, together with Wharton Sinkler, J.T. Eskridge, and Francis X. Dercum. S. Weir Mitchell was the first president and served for 5 additional years. American neurology was born in Philadelphia at the Orthopedic Hospital and the Infirmary for Nervous Diseases. The growth in neurology in this country is reflected in the activities of the Philadelphia Neurological Society.

History, 19th Century↗

PubMed1999

Laboratory recognition of a rare hemoglobinopathy: hemoglobins SS and SG(Philadelphia) associated with alpha-thalassemia-2.

This article describes the laboratory investigation of an unusual hemoglobinopathy involving hemoglobin (Hb) S, HbSG(Philadelphia), and alpha-thalassemia-2 in a patient whose phenotype was HbSC by alkaline electrophoresis. Findings of a mean corpuscular volume of 62 fL and microcytes on the blood smear were inconsistent with HbSC disease. The patient's clinical course over several years had been mildly symptomatic. Testing in our hospital laboratory using isoelectric focusing and cation-exchange high-performance liquid chromatography to separate hemoglobins showed an unknown variant. Additional studies, including globin chain electrophoresis, reverse-phase high-performance liquid chromatography, and polymerase chain reaction-based DNA analysis were performed at reference laboratories, which reported the following findings: HbG(Philadelphia) associated with alpha-thalassemia-2, HbS and HbG(Philadelphia), and the alpha-globin deletions defining the -alpha3.7/-alpha3.7 genotype. The hemoglobin molecular defects, alpha-thalassemia-2, and the pattern of inheritance are discussed.

Adult↗

PubMed1992

Antibody recognition of the tumor-specific b3-a2 junction of bcr-abl chimeric proteins in Philadelphia-chromosome-positive leukemias.

The reciprocal translocation between chromosome 9 and chromosome 22, as observed in chronic myeloid leukemia (CML) as well as in acute lymphoblastic leukemia (ALL), results in a 22q- chromosome, the so-called Philadelphia chromosome. The translocation event creates on the Philadelphia chromosome a fusion between two genes: bcr and abl. Depending on the localization of the breakpoint in the bcr gene different chimeric bcr-abl genes are generated, each encoding their own tumor-specific protein: e1-a2P190bcr-abl, b2-a2p210bcr-abl, or b3-a2P210bcr-abl. Especially in ALL, the presence of such a tumor-specific protein is highly associated with a poor prognosis. Detection of these proteins therefore has a strong clinical significance. In this study a polyclonal antiserum, termed BP-2, was raised against a synthetic peptide, corresponding to the tumor-specific 'fusion-point' epitope of the b3-a2P210bcr-abl protein. The specificity of BP-2 for the bcr-abl joining region in b3-a2P210bcr-abl is demonstrated by means of peptide inhibition studies in combination with immunoprecipitation. In addition we show the reactivity of BP-2 with bcr-abl proteins in leukemic cells of a Philadelphia-chromosome-positive ALL patient.

Amino Acid Sequence↗

PubMed2005

[STI571 used in treating acute myeloid leukemia with Philadelphia chromosome].

The objective was to use STI571, a kind of tyrosine kinase inhibitor, to treat acute myeloid leukemia (AML) with Philadelphia chromosome. 2 AML cases with Philadelphia chromosome, were collected to observe effect of STI571. One of them was given STI571 after routine chemotherapy failed to respond to treatment, other case received routine chemotherapy only. Both of them underwent HLA-matched/mismatched sibling hematopoietic stem cell transplantation (HSCT). The results showed that cytogenetic and hematologic CR was acquired in case 1 with STI571 while another one gained hematologic CR by accepting routine chemotherapy. Recovery of hemopoiesis was found at 18 and 11 days after HSCT respectively without serious graft-versus-host-disease. The case 1 has been surviving in disease-free state for 5 months since HSCT. The case 2 died from interstitial pneumonia at 8 months after HSCT. In conclusion, STI571 is one of choice for the treatment of Philadelphia chromosome positive AML.

Acute Disease↗

PubMed1978

Variability in the interaction of beta-thalassemia with the alpha-chain variants Hb G-Philadelphia and Hb Rampa.

Two unrelated families are reported in which beta-thalassemia trait occurred with a heterozygosity of Hb G-Philadelphia (alpha2 68(E17)Asn leads to Lys beta2) in one family and with Hb Rampa (alpha2 95(G2)Pro leads to Ser beta2) in the other. The percentage of Hb G-Philadelphia was not influenced by the simultaneous presence of a beta-thalassemai determinant, but that of Hb Rampa was descreased from 20% in the simple heterozygote to about 6% in persons with the Hb Rampa-beta-thalassemia combination. Data from in vitro recombination experiments with isolated alpha X, alpha A, and beta A chains, with heme attached, indicated a preferential formation of Hb A over Hb Rampa but not over Hb G-Philadelphia in conditions of relative beta-chain deficiency. This suggests that the rate of assembly of monomers to form dimers or tetramers can be an important mechanism of controlling the quantity of certain hemoglobin variants with critical substitutions in heterozygotes.

Adolescent↗

PubMed1988

Philadelphia-positive acute myelomonocytic leukemia with inversion of chromosome 16 and eosinobasophils.

Cytogenetic studies in a case of acute nonlymphocytic leukemia, type M4-FAB with eosinophilia, showed an acquired abnormal karyotype characterized by both a t(9;22) Philadelphia translocation and a pericentric inversion of chromosome 16, inv(16)(p13q22). This unique case shows that the previously described association between inversion of chromosome 16 and myelomonocytic leukemia with bone marrow eosinophilia is true also in Philadelphia-positive disorders. The present findings are consistent with the existence of a group of chromosome anomalies, namely t(15;17) and inv(16), which are specifically associated with one single stage of morphological differentiation of myeloid leukemic cells.

Basophils↗

PubMed2001

Cohort mortality study of Philadelphia firefighters.

BACKGROUND: Fire fighters are exposed to a wide variety of toxic chemicals. Previous studies have reported excess risk of some cancers but have been limited by small numbers or little information on employment characteristics. METHODS: We conducted a retrospective cohort mortality study among 7,789 Philadelphia firefighters employed between 1925 and 1986. For each cause of death, the standardized mortality ratios (SMRs) and 95% confidence intervals were estimated. We also compared mortality among groups of firefighters defined by the estimated number of career runs and potential for diesel exposure. RESULTS: In comparison with U.S. white men, the firefighters had similar mortality from all causes of death combined (SMR = 0.96) and all cancers (SMR = 1.10). There were statistically significant deficits of deaths from nervous system diseases (SMR = 0.47), cerebrovascular diseases (SMR = 0.83), respiratory diseases (SMR = 0.67), genitourinary diseases (SMR = 0.54), all accidents (SMR = 0.72), and suicide (SMR = 0.66). Statistically significant excess risks were observed for colon cancer (SMR = 1.51) and ischemic heart disease (SMR = 1.09). The risks of mortality from colon cancer (SMR = 1.68), kidney cancer (SMR = 2.20), non-Hodgkin's lymphoma (SMR = 1.72), multiple myeloma (SMR = 2.31), and benign neoplasms (SMR = 2.54) were increased among firefighters with at least 20 years of service. CONCLUSIONS: Our study found no significant increase in overall mortality among Philadelphia firefighters. However, we observed increased mortality for cancers of the colon and kidney, non-Hodgkin's lymphoma and multiple myeloma. There was insufficient follow-up since the introduction of diesel equipment to adequately assess risk.

Adult↗

PubMed2001

Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13.

BACKGROUND: The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor and reports from large studies are scarce. We evaluated the efficacy of allogeneic bone marrow transplantation (allo-BMT) for children with this type of leukemia. PROCEDURE: The chemotherapy regimens consisted of an induction phase and very intensive consolidation followed by a reinduction phase and late intensification treatment. The selection of treatment modalities such as chemotherapy, allo-BMT, or autologous transplantation was made by each institute. The principal endpoint was the outcome of children with Ph(+) ALL according to the treatment options. RESULTS: Thirty-two patients (4.3%) were diagnosed as Ph(+) ALL out of the 741 cases of ALL consecutively enrolled in two protocols of the Tokyo Children's Cancer Study Group (TCCSG) from 1989 to 1994. Thirty patients (93.8%) were induced into complete remission (CR). Of these 30 patients, eight children electively received allo-BMT in the first CR. Six of these patients are in continuous remission at a median follow-up of 58 (range 48-105) months after the diagnosis. One patient died following recurrence and another patient died of graft vs. host disease. Three patients treated with autologous BMT or peripheral blood stem cell transplantation in the first CR experienced a subsequent relapse. In the remaining 19 patients, 13 patients were treated with very high-risk chemotherapy alone and all relapsed within 28 months. One patient was excluded from the analysis because he was treated with standard-risk chemotherapy until relapse. The other five patients were also excluded from the analysis because Philadelphia chromosome was not detected until they relapsed. None of the relapsed patients survived in spite of treatment including allo-BMT. In multivariate analysis, only allo-BMT remained as an independent factor for good prognosis. CONCLUSIONS: The only way to cure children with Ph(+) ALL was allo-BMT in this study and its outcome seemed promising.

Adolescent↗

PubMed1995

Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation.

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also might provide insight into the validity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions include the alternative ABL first exons 1b and 1a, a new gene 5' to the first ABL exon, and an open reading frame with homology to an EST within the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chromosome translocation breakpoints from chronic myelogenous leukemia patients also were sequenced, and the positions of these and several other previously sequenced breakpoints now have been mapped precisely, although no consistent breakpoint features immediately were apparent. Comparative analysis of genomic sequences encompassing the murine homologues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these regions.

Animals↗

PubMed1986

Breakpoints in variant Philadelphia translocations in chronic myeloid leukemia.

To date, 327 cases of variant Philadelphia translocations found in chronic myeloid leukemia have been described. A statistical analysis using the Monte Carlo simulation was performed to determine which chromosomal bands were preferentially involved in variant Philadelphia translocations. The results showed that twenty-eight bands were significantly rearranged (P less than 0.05).

Chromosome Banding↗

PubMed1989

Opportunities and risks in Philadelphia's capitation financing of public psychiatric services.

The city of Philadelphia was one of nine sites selected by the Robert Wood Johnson (RWJ) Foundation and the U.S. Department of Housing and Urban Development (HUD) to receive five-year funding to improve the delivery, quality and cost efficiency of public mental health services to its chronically mentally ill population. As part of the RWJ project, the city plans to restructure its delivery and reimbursement system, creating a not-for-profit central authority which will function as a health insurance organization (HIO) responsible for coordinating and managing psychiatric care to Medicaid clients. Operating under a model of capitation, the central authority will employ diverse funding mechanisms to finance and manage service delivery. This paper examines the benefits and risks inherent in the reorganization of Philadelphia's mental health service system under a capitation financing model. Issues considered include cost and utilization patterns, treatment outcomes, providers and their staffing patterns, service mix and the overall impact of capitation on clients.

Capitation Fee↗

PubMed1991

The relationship between the site of breakpoints within the bcr gene and thrombopoiesis of Philadelphia-positive chronic myelocytic leukemia.

We determined the position of the breakpoint within the bcr gene in 22 patients with Philadelphia-positive chronic myelocytic leukemia using conventional Southern-blots and analyzed its relationship to thrombopoiesis. After DNA digestion with restriction endonucleases (Hind III, Bam HI and Bgl II), we localized the breakpoint in bcr using two genomic probes. The location of the breakpoint within the bcr was assigned to one of five zones. Breakpoints in zones 1 and 2 were grouped as "5"', and those in zones 3, 4 and 5 as "3'". Thus we subdivided patients with bcr rearrangements into those with genomic breaks at either 5' or 3' of the Bam HI site, just upstream of exon 3. Nine patients had 5' breakpoints and 13 patients had 3' breakpoints. The platelet counts of 3' patients were significantly higher than those of 5' patients (1395 vs 274 x 10(9)/l; p less than 0.03). The megakaryocyte counts from bone marrow histological sections in 3' patients (n = 12) and 5' patients (n = 7) were 63.4/mm2 and 19.5/mm2, respectively, with a significant difference of p less than 0.006. The mean number of megakaryocyte progenitor cells assayed by in vitro cloning was 128.3/2 x 10(5) bone marrow cells for 3' patients (n = 7) compared with 46.3 for 5' patients (n = 4). These results suggest that Philadelphia-positive CML patients with 3' breakpoints have higher thrombopoietic activity than patients with 5' breakpoints.

Adult↗

PubMed1993

Isodicentric Philadelphia chromosome in accelerated phase of chronic myeloid leukemia.

We describe a case of chronic myeloid leukemia (CML) associated with the finding of an isodicentric Philadelphia chromosome [idic(Ph)] during the accelerated phase of the disease. Chromosome study was carried out on bone marrow aspirate cells, obtained and cultured 5 months after the clinical diagnosis. The presence of an isodicentric Philadelphia chromosome was found in 90% of the analyzed metaphases; among the remaining observed metaphases, 6% showed two idic(Ph) chromosomes, 2% a t(9;22), and 2% a normal karyotype. The patient died 7 months after the clinical diagnosis, and 2 months after our chromosome study. The observation of idic(Ph) during CML has seldom been reported and the few cases studied have been inconsistently correlated with the course of the disease. In the present case, the finding of an idic(Ph) and the short patient survival from the time of clinical diagnosis may suggest the observed chromosome aberration as a factor associated with a poor prognosis.

Aged↗

PubMedDate not supplied

How complete are immunization registries? The Philadelphia story.

OBJECTIVE: To assess accuracy and completeness of Philadelphia, Pa, registry data among children served by providers in areas at risk for underimmunization. METHODS: Philadelphia's Department of Public Health selected a simple random sample of 45 children age 19-35 months (or all children age 19-35 months if there were <45 children in the practice) from each of 30 private practices receiving government-funded vaccine and located in zip codes where children are at risk for underimmunization. Chart and registry data were compared with determine the proportion of children missing from the registry and assess differences in immunization coverage. RESULTS: Of 620 children reviewed, 567 (92%) were in the registry. Significant differences (P < .05) were observed in immunization coverage for 4 diphtheria-tetanus-acellular pertussis vaccinations, 3 polio vaccinations, 1 measles-mumps-rubella vaccination, and 3 Haemophilus influenzae type b vaccinations between the chart (80% coverage) and registry (62% coverage). Providers submitting electronic medical records or directly transferring electronic data to the registry had significantly more children in the registry and higher registry-reported immunization coverage than those whose data were entered from billing records or log forms. All practice types experienced difficulties in transferring complete data to the registry. CONCLUSIONS: Although 92% of study children were in the registry, immunization coverage was significantly lower when registry data were compared with chart data. Because electronic medical records and direct electronic data transfer resulted in more complete registry data, these methods should be encouraged in linking providers with immunization registries.

Child↗

PubMed2005

Additional clonal abnormalities in Philadelphia-positive ALL and CML demonstrate a different cytogenetic pattern at diagnosis and follow different pathways at progression.

The cytogenetic patterns in addition to the Philadelphia translocation in Philadelphia-positive (Ph+) ALL and chronic myeloid leukemia (CML) is heterogenous. We investigated 154 patients with Ph+ ALL at diagnosis or at relapse and 174 patients with different phases of CML. Ph+ ALL at diagnosis demonstrated a heterogenous pattern with a high frequency of numerical and structural chromosomal aberrations. CML at diagnosis presented with rare additional chromosomal changes. In Ph+ ALL, the pathway from diagnosis to relapse was characterized by the acquisition of a higher number of chromosomal aberrations, but the pattern of frequent aberrations at relapse did not differ from that observed at diagnosis. In contrast, in CML the pathway from chronic to the advanced phases was characterized by the acquisition of new chromosomal changes and by the development of karyotype complexity. In addition, the investigation of 10 cases of lymphoid blast crisis of CML showed significant differences in the karyotype in comparison to Ph+ ALL at diagnosis. Therefore, the karyotype can be helpful in discriminate de novo lymphoid blast crisis of CML from de novo Ph+ ALL. In conclusion, we were able to demonstrate that the cytogenetic patterns of Ph+ ALL and of CML are different at diagnosis and furthermore follow different pathways during progression or relapse.

Blast Crisis↗