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B Childs

Publications and source records attributed to B Childs.

At least 19 recordsLinked to original sources
PubMed2001

Human disease genes.

The complete human genome sequence will facilitate the identification of all genes that contribute to disease. We propose that the functional classification of disease genes and their products will reveal general principles of human disease. We have determined functional categories for nearly 1,000 documented disease genes, and found striking correlations between the function of the gene product and features of disease, such as age of onset and mode of inheritance. As knowledge of disease genes grows, including those contributing to complex traits, more sophisticated analyses will be possible; their results will yield a deeper understanding of disease and an enhanced integration of medicine with biology.

Disease↗
PubMed1999

Ifosfamide, carboplatin, and etoposide: a highly effective cytoreduction and peripheral-blood progenitor-cell mobilization regimen for transplant-eligible patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate a chemotherapy regimen that consisted of ifosfamide administered as an infusion with bolus carboplatin, and etoposide (ICE) supported by granulocyte colony-stimulating factor (G-CSF) for cytoreduction and stem-cell mobilization in transplant-eligible patients with primary refractory or relapsed non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: One hundred sixty-three transplant-eligible patients with relapsed or primary refractory NHL were treated from October 1993 to December 1997 with ICE chemotherapy at Memorial Sloan-Kettering Cancer Center. Administration of three cycles of ICE chemotherapy was planned at 2-week intervals. Peripheral-blood progenitor cells were collected after cycle 3, and all patients who achieved a partial response (PR) or complete response (CR) to ICE chemotherapy were eligible to proceed to transplantation. Event-free and overall survival, ICE-related toxicity, and the number of CD34(+) cells collected after treatment with ICE and G-CSF were evaluated. RESULTS: All 163 patients were assessable for response, and there was no treatment-related mortality. A major response (CR/PR) was evident in 108 patients (66.3%); 89% of the responding patients underwent successful transplantation. Patient who underwent transplantation and achieved a CR to ICE had a superior overall survival to that of patients who achieved a PR (65% v 30%; P =.003). The median number of CD34(+) cells/kg collected was 8.4 x 10(6). The dose-limiting toxicity of ICE was hematologic, with 29.4% of patients developing grade 3/4 thrombocytopenia. There were minimal nonhematologic side effects. CONCLUSION: ICE chemotherapy, with ifosfamide administered as a 24-hour infusion to decrease CNS side effects, and the substitution of carboplatin for cisplatin to minimize nephrotoxicity, is a very effective cytoreduction and mobilization regimen in patients with NHL. Furthermore, the quality of the clinical response to ICE predicts for posttransplant outcome.

Adolescent↗
PubMed1998

Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21.

Schizophrenia is a common disorder characterized by psychotic symptoms; diagnostic criteria have been established. Family, twin and adoption studies suggest that both genetic and environmental factors influence susceptibility (heritability is approximately 71%; ref. 2), however, little is known about the aetiology of schizophrenia. Clinical and family studies suggest aetiological heterogeneity. Previously, we reported that regions on chromosomes 22, 3 and 8 may be associated with susceptibility to schizophrenia, and collaborations provided some support for regions on chromosomes 8 and 22 (refs 9-13). We present here a genome-wide scan for schizophrenia susceptibility loci (SSL) using 452 microsatellite markers on 54 multiplex pedigrees. Non-parametric linkage (NPL) analysis provided significant evidence for an SSL on chromosome 13q32 (NPL score=4.18; P=0.00002), and suggestive evidence for another SSL on chromosome 8p21-22 (NPL=3.64; P=0.0001). Parametric linkage analysis provided additional support for these SSL. Linkage evidence at chromosome 8 is weaker than that at chromosome 13, so it is more probable that chromosome 8 may be a false positive linkage. Additional putative SSL were noted on chromosomes 14q13 (NPL=2.57; P=0.005), 7q11 (NPL=2.50, P=0.007) and 22q11 (NPL=2.42, P=0.009). Verification of suggestive SSL on chromosomes 13q and 8p was attempted in a follow-up sample of 51 multiplex pedigrees. This analysis confirmed the SSL in 13q14-q33 (NPL=2.36, P=0.007) and supported the SSL in 8p22-p21 (NPL=1.95, P=0.023).

Adult↗
PubMed1998

Differential growth patterns in SCID mice of patient-derived chronic myelogenous leukemias.

The development of an in vivo model for the study of CML would be of significant importance in studying its biological behavior and developing novel therapeutic strategies. We examined the ability of human leukemic cells derived from patients in either chronic (CP), accelerated (AP) or blast phase (BP) CML to grow and disseminate in CB17-SCID mice by subcutaneous (s.c.) inoculation without conditioning treatment or administration of cytokines. Additionally, samples derived from patients with CP-CML were injected s.c. into CB17-SCID mice treated with anti-Asialo GM1 (an anti-NK cell antibody) and NOD-SCID mice (absent NK cell activity) to study the potential role of NK cell-mediated anti-leukemic activity in preventing the propagation of CP-CML cells. We observed a significant differential growth pattern of CML cells in the mice such that BP-CML grew rapidly as s.c. tumors and disseminated, while AP-CML or CP-CML cells grew temporarily as small nodules that spontaneously regressed and did not disseminate. This differential growth pattern suggests possible important biological differences. Furthermore, no significant difference in s.c. growth or dissemination of CP-CML samples derived from newly diagnosed patients in untreated CB17-SCID mice and CB-17 SCID mice treated with Anti-Asialo GM1 and NOD-SCID mice occurred, suggesting that factors other than NK cell anti-leukemic activity may be important.

Adolescent↗
PubMed1996

Preliminary evidence for genetic anticipation in Crohn's disease.

BACKGROUND: The term genetic anticipation is used to describe earlier onset of disease, increased severity, or both, in succeeding generations of families affected by a particular disease. This process has been linked with expanded genomic trinucleotide repeat regions in some neurological disorders. Crohn's disease, an inflammatory bowel disorder, has genetic influences, which remain undefined. We studied pairs of two-generation first-degree relatives with Crohn's disease to seek evidence for genetic anticipation in this disorder. METHODS: Through retrospective review of the records of 552 patients treated for Crohn's disease at Johns Hopkins Hospital, we identified 27 pairs of two-generation first-degree relatives. We also studied 32 such pairs identified through a multicentre survey. After exploratory analyses by t tests, a generalised estimating equations approach was used to fit a marginal regression model. FINDINGS: The age at diagnosis was earlier in the younger member of the pair both in the Johns Hopkins Hospital dataset (18.9 [SE 6.9] vs 31.4 [12.0] years) and in the multicentre survey dataset (16.9 [7.4] vs 33.1 [11.9] years). The regression model confirmed the findings: the best-fitting model for the Johns Hopkins Hospital data showed an average 10.8 (SE 4.2) year difference in age at diagnosis between parent and child; that for the multicentre data showed an average difference of 15.1 (1.5) years. There was evidence of a further difference between the second and third generations. Disease was more extensive in the offspring than in the parent for 15 of the 27 pairs at Johns Hopkins Hospital; in 13 of these pairs the affected parent was the father. INTERPRETATION: The evidence of a lower age at diagnosis and a greater extent of disease in the younger member of two-generation pairs affected by Crohn's disease, as well as the association with paternal transmission, suggest that genetic anticipation does occur in Crohn's disease. A search for triplet repeat regions is warranted.

Adolescent↗
PubMed1996

Crohn's disease: influence of age at diagnosis on site and clinical type of disease.

BACKGROUND & AIMS: Crohn's disease has a bimodal age distribution of disease onset diagnosis. The peaks (20 and 50 years) may represent different phenotypes or different genetic and/or environmental influences between younger- and older-onset individuals. The aim of this study was to examine the influences of age at diagnosis of Crohn's disease on disease site, type, and course. METHODS: Records of 552 consecutive patients with Crohn's disease were reviewed retrospectively. RESULTS: Younger age at diagnosis (younger than 20 years), compared with an older age (40 years or older), was associated with a greater prevalence of a family history of Crohn's disease (29.9% vs. 13.6%), greater small bowel involvement (88.7% vs. 57.5%), more stricturing disease (45.8% vs. 28.8%), and a higher frequency of surgery (70.6% vs. 55.3%). Older age at diagnosis was associated with a greater prevalence of colonic disease (84.8% vs. 71.2%) and the inflammatory subtype (54.5% vs. 34.4%). A conditional logistic regression analysis confirmed an independent effect of age at diagnosis on ileal disease and surgery for intractable disease. CONCLUSIONS: In Crohn's disease, early age at diagnosis is associated with more complicated disease and a greater likelihood of having affected relatives. Stratification of Crohn's disease by age at diagnosis provides support for the concept of genetic heterogeneity.

Adult↗
PubMed1995

Nephrogenic diabetes insipidus. A personal perspective.

To summarize these ideas that all center around time and variations, we might think of the genes as constituting a biological memory that serves at once to connect individuals with other people and with the past. The genes also provide a plan to construct and maintain an individual homeostatic memory that mediates experiences in the context of an ontogenetic memory that preserves individuality through time and change to set on health and disease a personal stamp. It is the mission of medicine to understand the individuality of these memories and of the elements that constitute them and, where necessary, to adjust the environment to homeostatic limitation. It is my hope that this account of this often colorful but hapless and stricken family might give substance to these thoughts.

Diabetes Insipidus, Nephrogenic↗
PubMed1995

Response to treatment in hereditary metabolic disease: 1993 survey and 10-year comparison.

Knowledge about cause, pathogenesis, and manifestations of hereditary metabolic diseases puts them among the best known of all human diseases. On the other hand, outcomes of treatment are cause for uncertainty and concern. In 1985, Hayes et al. analyzed efficacy of treatment up to 1983 in 65 of these diseases selected randomly from the McKusick catalogs. Disease scores were calculated for seven parameters: longevity; reproductive capability; somatic and cognitive development; and handicaps affecting schooling, work, and cosmetic appearance. Scores of the untreated and treated phenotypes were then compared. We have now measured progress over the past decade by calculating scores on the same 65 diseases from data in several hundred new reports published since 1983. All seven parameters in the 1993 survey reflect improved efficacy of treatment in the 10-year interval. However, the percent of diseases for which all manifestations of the disease were removed by treatment has not changed (12% in 1983; 12% in 1993). The group in which manifestations were untouched by treatment has become smaller (48% in 1983; 31% in 1993), and the group partially ameliorated by treatment had increased reciprocally (40% in 1983; 57% in 1993). Progress in the treatment of hereditary metabolic disease is thus better than it was, but it is still only a partial success. The advances are attributable to greater success with organ and tissue transplantation, better pharmacotherapy, and better support systems. Restoration of normal homeostasis, the key to successful treatment, remains an elusive challenge and is a logical, major focus for research in human genetics.

Data Collection↗
PubMed1995

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Adult↗
PubMed1994

Hyperfractionated total lymphoid irradiation and cyclophosphamide for preparation of previously transfused patients undergoing HLA-identical marrow transplantation for severe aplastic anemia.

PURPOSE: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients. METHODS AND MATERIALS: From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32). RESULTS: One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series. CONCLUSION: Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.

Adolescent↗