Biomedical subjects
Publications and source records attributed to W Robinson.
The tumors can progress rapidly from superficial lesions of the epidermis, which are nearly all curable by excision, to invasive cancers unresponsive to current therapy. New strategies for regional and systemic spread include multiagent chemotherapy combined with biologic response modifiers, such as alpha-interferon or interleukin-2. On the early evidence, some of these approaches are promising.
The disease is perhaps the clearest instance of a cancer for which early treatment is crucial. Increasing knowledge of risk factors (including brief, intense sun exposure and sunburn damage early in life) aids the identification of persons at highest risk--one reason for physicians not to be pessimistic about the value of urging patients to limit their sun exposure.
BACKGROUND: Based on prior experience with dacarbazine (DTIC) and an outpatient interleukin-2 (IL-2) regimen, the current study was conducted to improve the antitumor efficacy and assess the immunologic interactions between chemotherapy and IL-2. METHODS: Thirty-two patients were registered onto a treatment program, which included DTIC 750 mg/m2 with cisplatin 100 mg/m2, each by intravenous bolus on day 1. Recombinant IL-2 was administered on an outpatient basis intravenously by 15-30-minute infusion (24.0 x 10(6) IU/m2) daily on days 12-16 and 19-23 of a 28-day cycle for three cycles and then every 42 days for responding patients. RESULTS: There were responses in 13 of the 32 registered patients (41% response rate), including five complete and eight partial remissions. Responses in the liver, lung, spleen, lymph nodes, and soft tissue sites were noted. The median duration of response was 8.0 months (range, 3.0-20.0+ months), and the overall median survival duration was 10.2 months. Three patients (9%) are alive, free of disease, without any treatment at 32.0+, 36.0+, and 42.0+ months after initiation of treatment. Only minor nephrotoxicity was observed, and treatment delays were rare. CONCLUSIONS: Additional chemotherapeutic, hormonal, or biologic agents may be added to enhance efficacy further if they have toxicities that do not overlap.
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The polymerase chain reaction method (PCR) was used to detect feline immunodeficiency virus proviral DNA in peripheral blood mononuclear cells (PBMC) of a group of 8 experimentally infected cats. The proportion of PBMC containing provirus was determined from 6 to 32 weeks post inoculation (p.i.) by performing PCR on serially diluted samples of PBMC. Primers from the p15 and p24 regions of the gag gene were used and Southern hybridization using an end-labelled probe was required to confirm primer-specific products. Provirus was detected in 5 of 8 cats by 6 weeks p.i. in 50000 PBMC, and in all 8 infected cats by 8 weeks p.i. Provirus was not detected in PBMC from any of 3 FIV negative cats. The proportion of PBMC containing provirus in individual cats ranged from 1 in 70 to 1 in 99600 PBMC. There was no significant decline over time in the proportion of PBMC containing provirus. Sequencing of a segment (287 bases) of the gag region of a West Australian FIV isolate (T90) revealed only slight nucleotide divergence from the North American Petaluma and PPR isolates and wider divergence from the Japanese TM2 clone.
The Prader-Willi syndrome and the Angelman syndrome are caused by the loss of function of distinct but closely linked genes on human chromosome 15. Based on a yeast artificial chromosome restriction map and two key patients we have determined that the shortest region of deletion overlap in the Prader-Willi syndrome comprises 320 kb. The region includes the anonymous DNA marker PW71 (D15S63) and the gene for the small nuclear ribonucleoprotein N (SNRPN). The SNRPN gene maps 130 kb distal to PW71 and is transcribed from centromere to telomere.
Twenty patients with previously untreated hairy cell leukemia were randomized to undergo either splenectomy or to receive interferon alfa-N1, a highly purified natural alpha interferon, as primary therapy. A response in the peripheral blood elements to a hemoglobin greater than 110 gm/l, a granulocyte count greater than 1 x 10(9)/l, and a platelet count greater than 100 x 10(9)/l (Catovsky criteria) was noted in all ten patients receiving alpha interferon but in only three of the patients undergoing splenectomy (P = less than .01). Median time to response was longer in the ten interferon patients (153 days) than in the three splenectomy responders (20 days). Median time to treatment failure was significantly greater in the alpha interferon patients (greater than 18 months) than in the splenectomy patients (less than 1 month). Survival was no different since patients relapsing following splenectomy subsequently responded to alpha interferon. A significant decrease in leukemic bone marrow infiltration was observed in seven of ten patients receiving alpha interferon and in none of the patients undergoing splenectomy. Side effects, primarily infections, were more frequent in patients receiving interferon. Alpha interferon is preferable to splenectomy as initial treatment for hairy cell leukemia.
Prader-Willi syndrome (PWS) is associated with paternally derived chromosomal deletions in region 15q11-13 or with maternal disomy for chromosome 15. Therefore, loss of the expressed paternal alleles of maternally imprinted genes must be responsible for the PWS phenotype. We have mapped the gene encoding the small nuclear RNA associated polypeptide SmN (SNRPN) to human chromosome 15q12 and a processed pseudogene SNRPNP1 to chromosome region 6pter-p21. Furthermore, SNRPN was mapped to the minimal deletion interval that is critical for PWS. The fact that the mouse Snrpn gene is maternally imprinted in brain suggests that loss of the paternally derived SNRPN allele may be involved in the PWS phenotype.
Optimal management of cervical cord injury in the presence of documented instability and/or compression of neural elements remains a controversial topic. Surgery and internal stabilization of cervical spine fracture/dislocations are effective and well accepted, but controversy exists on the relative merits of the anterior versus the posterior approach as well as the optimal timing of surgical intervention. We report our experience with the Caspar technique and instrumentation for anterior stabilization in 54 patients for acute cervical spine injury. Our series consists of 38 male and 16 female patients whose ages ranged from 16 to 68 years, with a mean age of 29.2 years. Thirty-two of these patients had complete neurological sensory/motor deficits at the time of presentation, eight were neurologically intact, and 14 had preservation of some motor and sensory function. All 54 patients had radiographic evidence of posterior instability as well as anterior disruption of either a vertebral body or intervertebral disk. We found that "early" intervention (less than 24 hours after injury) was performed frequently in the neurologically compromised patients. Twelve of the 22 patients undergoing surgery less than 24 hours after admission regained significant neurological function, with 13 of 22 developing postoperative complications. In the "delayed" group (surgery more than 24 hours after injury, mean 14.3 days), 14 patients experienced postoperative complications, with 15 of 24 demonstrating neurological improvement. The eight patients who were intact did uniformly well. There was no mortality during the follow-up. All 54 patients showed a solid fusion (clinically and radiologically) within 6 months of surgery. In two cases the plates had to be removed, without risking the fusion. Our experience suggests that although anterior cervical fusion and Caspar plating remain appropriate for patients with documented anterior compromise of the canal, it should not substitute for more traditional posterior stabilization procedures. Because this route has the potential for more serious complications, it should be reserved for the cases in which anterior decompression is deemed necessary or posterior fusion was unsuccessful. With appropriate selection of patients, no adverse effect of early surgery was demonstrated. In fact, neurologically compromised patients had the benefits of increased ease of patient care and early transfer to rehabilitation.
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A degree of conservation of the genes located between class II and class I [central major histocompatibility complex (MHC) genes] is apparent among mammalian species including primates and the mouse. Few others have been analyzed. The caprine MHC is of particular interest, since it has recently been observed that susceptibility to a lentivirus-induced polyarthritis (caprine arthritis) segregates with serologically defined MHC class I antigens. This arthritis resembles, in a number of respects, rheumatoid arthritis in man. Human cDNA probes were used to examine the caprine central MHC and class I and II genes by restriction fragment length polymorphism (RFLP) and by pulsed field gel electrophoresis (PFGE) in order to define the polymorphism and linkage of central MHC genes to class I and class II genes. An outbred population of dairy goats (Saanen, British Alpine, Anglo Nubian, and Toggenberg) was examined for class I and class II RFLPs. Both regions were found to be highly polymorphic. The number of fragments hybridizing to an HLA-B7 probe after Eco RI, Bam HI, Bgl II, or Hind III digestion suggests there may be 10-13 class I genes. The degree of polymorphism was comparable to that reported in the mouse. Limited polymorphism was found in the central MHC genes. The caprine C4 and CYP21 genes were duplicated and demonstrated RFLP with Bam HI, Hind III, Eco RV, and Taq I. An infrequent Taq I C2 polymorphism was found. PFGE revealed substantial conservation of both the order and linkage of the central MHC genes when compared with mouse and man. C4, C2, CYP21, HSP70, and tumor necrosis factor (TNF) genes are all located within 800 kilobase (kb) of the class I loci. Distant from the class I region, the C4, C2, and CYP21 genes are linked on a short genomic segment (180 kb Not I and 190 kb Pvu I fragments). HSP70 cohybridizes with the complement genes on a 380 kb Mlu I fragment. Linkage of HSP70, TNF, and class I genes was found on a single Not I fragment (610 kb). TNF and class I cohybridize on Pvu I (730 kb) and Not I (610 kb) fragments. Conservation of a similar central MHC genomic structure across species argues for functional interaction between the central MHC genes. We postulate selection for these central MHC genes through their role as non antigen-specific regulators of immune response.
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The authors performed this retrospective study to further investigate the relationship between non-Hodgkin's lymphoma (NHL) and the Acquired Immunodeficiency Syndrome (AIDS). From January 1984 through December 1987 all cases of AIDS and NHL diagnosed at the University of Colorado affiliated hospitals were identified and submitted to chart review. Twenty-five patients fulfilled criteria for the diagnosis of AIDS and 24 had biopsy-proven NHL, an additional patient met criteria for the diagnosis of primary central nervous system lymphoma and was included in the analysis. All patients had known risk factors for the development of AIDS. Of the biopsy proven tumors, 23 were categorized as high grade. Most patients (68%) presented with stage IV disease and 92% with extra nodal involvement. Median survival was 5 months and the cause of death was most often progressive lymphoma and/or opportunistic infections. These data are similar to previously published series. Clinical trials to evaluate effective treatment are warranted.
A brother and two sisters of remotely consanguineous parents had congenital laryngeal abductor paralysis and moderate mental retardation. In the two older sibs, mental deficiency could have resulted from birth asphyxia, but the youngest girl was already microcephalic at birth and had no apparent asphyxia. The mother, who was healthy and of normal intelligence, was found on laryngoscopy to have unilateral laryngeal abductor paralysis. This is the first family with both mentally retarded and nonretarded affected members with congenital laryngeal abductor paralysis. Inheritance is most likely autosomal dominant with variable expression, but autosomal recessive inheritance, with both parents carriers and the mother an affected homozygote, and X linked inheritance are also possible.
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A scheme is outlined for analyzing the genotypic contributions of two unlinked loci in producing a disease, using DR and the 5' insulin locus (INS) in insulin-dependent diabetes mellitus (IDDM) as examples. Although genotypes of both DR and INS play roles in IDDM susceptibility, both the relatively small size of the Genetic Analysis Workshop 5 (GAW5) data set and the apparently limited magnitudes of the contributory effects prevent the identification of the exact nature of the association of these two loci in disease causation. The Gm allotypes showed no association with IDDM, either alone or in combination with other variables. Association of reactivity among the six strains of Coxsackie B virus is described, with no evidence of associations with DR type and IDDM found. The unaffected offspring segregated DR alleles according to expectations, while the segregation of affected alleles revealed the various contributions of DR alleles to IDDM pathogenesis, with the suggestion that DR4 from fathers is more diabetogenic than that from mothers. Lastly, a method is described for revealing the accuracy of typing in family data, and applied to RFLP variants subdividing DR3.
This study investigated the effects of recombinant human interleukin-1 (rhIL-1 alpha) on granulocyte recovery following treatment of mice with cyclophosphamide (CPM). CF1 mice were injected with 0.5 microgram rhIL-1 alpha or heat-inactivated rhIL-1 alpha according to five different regimens, before and/or following 200 mg/kg CPM. Significant neutrophilia initially developed in treatment mice of all five regimens and accelerated granulocyte recovery occurred in treatment mice of four IL-1 regimens. Significant elevations in serum colony stimulating activity (CSA) occurred in treatment mice at a number of time points studied. In addition, marked increases in the percentage of maturing granulocyte precursors and in the proportion of cells cycling in S and G2/M were observed in treatment marrow throughout the IL-1 regimen. Before granulocyte recovery, premature nuclear segmentation was noted in metamyelocytes of treatment marrow. Concomitant with granulocyte recovery, treatment marrow was significantly more cellular and contained more total CFU-GM, more CFU-GM in S phase, more cells in S and G2/M, and more mitotic figures than control marrow. Splenic myelopoiesis was also enhanced in treatment mice. These data suggest that IL-1 significantly hastens granulocyte recovery following treatment with CPM by enhancing both proliferation and maturation of myeloid precursors.
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