Ethical issues in pain management

Dr Albert Schweitzer is reported to have stated, "We must all die. But that I can save ... [someone] from days of torture, that is what I feel is my great and ever new privilege". If, in spite of their anecdotal texture, the reflections in this article challenge my clinical colleagues to further hard reflection, comparison, or contrast with their own professional experience, they will have been worthwhile. If our collective experiences view pain management as a clinical-ethical issue, then no patient should ever have to bear pain due to the ignorance or apathy of well-intentioned but misinformed caregivers. I conclude with the words of Judith Spross, an oncology nurse: Pain is an emergency for the person who experiences it regardless of the urgency of the underlying pathology. I believe we must apply the science and art of pain relief as though life depended upon it. Certainly the quality of life does.     

Phase I study of 4′-deoxydoxorubicin (esorubicin) in children with malignant solid tumors

Summary 4 -Deoxydoxorubicin was given to 15 patients with drug-resistant pediatric malignant solid tumors with the objectives of determining the maximum tolerated dosage and dose-limiting toxicity. Maximum tolerated dosage was 36 mg/m₂ given IV once every 3 weeks. Dose limiting toxicity was myelosuppression, which was severe and prolonged. Therapeutic benefits were not observed for these patients.     

Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks,chromosomal instability,and reduced life span in mice

The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(lex1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51.     

Hemolytic uremic syndrome after bone marrow transplantation: clinical characteristics and outcome in children.

Hemolytic uremic syndrome (HUS) is an uncommon but potentially life-threatening complication of hematopoietic stem cell transplantation. We retrospectively studied the medical records of 293 children who underwent allogeneic bone marrow transplantation at St. Jude Children's Research Hospital between 1992 and 1999 to describe the clinical course of and to identify risk factors for transplant-associated HUS. Conditioning regimens included cyclophosphamide, cytarabine, and total body irradiation for patients with hematologic malignancies (n = 244); patients with nonmalignant diseases (n = 49) received disease-specific regimens. Grafts from unrelated or mismatched related donors were depleted of T lymphocytes, whereas matched sibling grafts were unmanipulated. All patients received cyclosporine as prophylaxis for graft-versus-host disease. Recipients of grafts from matched siblings also received pentoxifylline or short-course methotrexate. HUS developed in 28 (9.6%) patients at a median of 171 days after transplantation. We identified older donor age (P = .029), use of antithymocyte globulin in the conditioning regimen (P = .008), and recipient CMV seronegativity (P = .011) as being associated with an increased risk of HUS. With a multiple regression analysis, the use of antithymocyte globulin (beta = .86; P = .04) and recipient cytomegalovirus seronegativity (beta = .93; P = .035) remained significant risk factors for the development of HUS.     

Highly diverse heparan sulfate analogue libraries: a novel resource for bioactivity screening of proteins

Introduction Fibroblast growth factors (FGFs) are a multipotent family of growth factors that are important for many biological processes, including development and wound healing. Normal, protease sensitive, prion protein (PrPC) can be converted to the protease resistant, infectious, form (PrPSc) believed to be associated with the pathogenesis of transmissible spongiform encephalopathies. FGFs signal through a family of tyrosine kinase receptors, the FGF receptors (FGFR) with the aid of heparan sulfate (HS), while the role of HS in the biology of PrPC is currently unknown, although depleting cells of HS can prevent production of PrPSc. HS, or its more highly sulfated relation heparin, can exert both positive and negative regulatory activities on a particular FGF‐FGFR combination. The nature of this regulation is determined by the structure of the HS that binds to the proteins. This structure is at least partially determined by the presence of particular sulfate groups along the sugar backbone. Identification of specific sulfate groups that can regulate the activity of proteins has been a long‐term goal in the field. Previously, heparins that had been completely lacking sulfates at specific positions were used to determine the binding and activity requirements for a particular protein. However, this may not necessarily allow for a full examination of the regulatory properties of HS. Here, we present a heparan sulfate analogue library produced by the partial, combinatorial desulfation of heparin. This library was the used to examine the structural properties of heparin required for FGF‐1 signalling through FGFR2c as well as the interactions of HS with PrPC. Materials and methods Porcine intestinal mucosal heparin was subjected to chemical desulfation and enzymatic cleavage. Polysaccharides and oligosaccharides derived from gel filtration chromatography and ion exchange chromatography were tested for their ability to activate FGF signalling through FGF receptors using a BaF3 assay system. Optical biosensors and cell assays were used to study the interaction of PrPC with chemically modified heparin. Results This library possessed vastly more heterogeneity than tissue heparan sulfates, allowing for more systematic screening to help identify those minimal structural features associated with activity. This library was used to examine the different structural features in heparin that support FGF‐1 signalling through FGFR2, showing that HS activity was not strictly dependant on size or charge. In addition, small, low‐sulfated heparins were found to interfere with the PrPC–heparin interaction. Discussion This supports the idea that overall structural features of the HS, rather than just the presence or absence of specific sulfate groups is important for the regulation of protein activity. Future efforts will be focused on further subfractionating the library and identifying specific structural features in HS that support FGF‐1 activity through FGFR2 and other FGFRs as well as the role of HS in the normal function of prion diseases, which may allow for the generation of novel, heparin‐based, therapeutics.     

I Get by with a Little Help from my Family and Friends: Adolescents' Support for Diabetes Care

Evaluated and compared the support provided by family membersand friends for adolescents' diabetes care. Family and friendsupport also were examined in relation to other measures ofsocial support, to demographic variables (age, gender, durationof diabetes) and to adherence. Using a structured interview,74 adolescents with diabetes described the ways that familymembers and friends provided support for diabetes management(insulin shots, blood glucose monitoring, eating proper meals,exercise), and for helping them to "feel good about their diabetes."Families provided more support than friends for three managementtasks (insulin injections, blood glucose monitoring, meals);this support was largely instrumental. In contrast, friendsprovided more emotional support for diabetes than families.Greater family support was related to younger age, shorter diseaseduration, and better treatment adherence. Implications of thefindings include encouraging parents to remain involved in adolescents'treatment management, and involving peers as supportive companionsfor meals and exercise.