Phase II Trial of Fludarabine Phosphate in Multiple Myeloma Using a Loading Dose and Continuous Infusion Schedule

A phase II trial of fludarabine phosphate using a bolus and continuous infusion regimen in previously treated multiple myeloma was performed. No responses were observed in eleven patients. There was no significant non-hematologic toxicity noted. Fludarabine phosphate is inactive in multiple myeloma using this schedule.     

Kienb?ck's disease

Kienb?ck's disease is an isolated disorder of the lunate resulting from vascular compromise to the bone. The symptoms include wrist pain, limited range of motion, and decreased grip strength. The diagnosis is made from characteristic changes seen in the lunate on radiograms of the wrist. The severity of the disease can be categorized by staging the degree of involvement. This is helpful in guiding the practitioner through the maze of treatment options. Initial treatment of Kienb?ck's disease is conservative and includes immobilization, analgesics, and/or anti-inflammatory medication. If symptoms are not relieved, then based on the degree of involvement, several surgical options exist that will provide a successful result. These include autogenous tendon replacement arthroplasty, revascularization, radial shortening, ulnar lengthening, limited intercarpal arthrodesis, and silicone replacement arthroplasty. Salvage procedures for Kienb?ck's disease include wrist denervation, wrist arthrodesis, and proximal-row carpectomy. Currently, we prefer immobilization for treatment of stage I Kienb?ck's disease. For stage II, a revascularization procedure may be attempted or ulnar lengthening/radial shortening done, particularly if there is significant negative ulnar variance. In stage III, replacement arthroplasty and/or limited intercarpal arthrodesis is our treatment of choice, and for stage IV, one of the salvage procedures is indicated.     

Entry-Level Degrees for Midwifery Practice

The Governing Board of the ACNM Division of Accreditation (DOA) has been charged by the ACNM Board of Directors to consider requiring an entry-level degree for nurse-midwifery practice. This decision has far-reaching implications and must be considered with utmost care. The decision will not be based on the issue of clinical competence but rather, the political statement to be made through the imposition of a degree requirement. The author urges the DOA's Governing Board to consider the implications of its action on a variety of audiences, including potential students, potential consumers, other health professionals, current and future employers, our international colleagues, health insurers and managed care organizations, and policymakers and lawmakers.     

Bioavailability of Soil-Bound TCDD: Dermal Bioavailability in the Rat

Bioavailability of Soil-Bound TCDD: Dermal Bioavailability inthe Rat. SHU, H., TEITELBAUM, T., WEBB, A. S., MARPLE, L., BRUNCK,B. DEI ROSSI, D., MURRAY, J., AND PAUSTENBACH, D. (1988). Fundam.Appl. Toxicol. 10, 335-343. 2,3,7,8-Tetrachlorodibenzo-p-dioxin(TCDD), an unwanted by-product formed during the manufactureof hexachlorophene and phenoxyherbicides, has been found asan environmental contaminant in many U.S. and Western Europeansites. This study examines in the rat the degree of dermal absorptionof TCDD bound to soil. Such information would assist regulatoryagencies in evaluating the degree of exposure of humans whocome in contact with TCDD-contaminated soil. Several parameterswhich may influence dermal absorption were studied, includingTCDD dose, duration of contact, presence of crankcase oil asa co-contaminant, and environmentally contaminated vs laboratory-preparedsoil. The dermal penetration of TCDD following 4 hr of contactwith skin was approximately 60% of that following 24 hr of contact(P 0.05). Following 24 hr of contact with the skin, the degreeof dermal uptake of TCDD contaminated soil was approximately1% of the administered dose. Under the conditions of the presentstudy, the degree of uptake does not appear to be influencedto any significant extent by the concentration of TCDD on soil,the presence of crankcase oil as co-contaminants, or by environmentallyvs laboratory-contaminated soil. Although a number of parametersexamined in this study did not significantly influence the degreeof dermal absorption of TCDD in the rat following 24 hr of contactwith the contaminated soil, the unqualified use of the 1% valueto estimate human exposure would overestimate human exposure,since there is general agreement among researchers that ratskin tends to be more permeable than human skin to highly lipid-solublecompounds such as TCDD.     

Intergenerational instability of the CAG repeat of the gene for Machado- Joseph disease (MJD1) is affected by the genotype of the normal chromosome: implications for the molecular mechanisms of the instability of the CAG repeat

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder caused by unstable expansion of a CAG repeat in the MJD1 gene at 14q32.1. To identify elements affecting the intergenerational instability of the CAG repeat, we investigated whether the CGG/GGG polymorphism at the 3' end of the CAG repeat affects intergenerational instability of the CAG repeat. The [expanded (CAG)n-CGG]/[normal (CAG)n- GGG] haplotypes were found to result in significantly greater instability of the CAG repeat compared to the [expanded (CAG)n- CGG]/[normal (CAG)n-CGG] or [expanded (CAG)nGGG]/[normal (CAG)n-GGG] haplotypes. Multiple stepwise logistic regression analysis revealed that the relative risk for a large intergenerational change in the number of CAG repeat units (< -2 or > 2) is 7.7-fold (95% CI: 2.5-23.9) higher in the case of paternal transmission than in that of maternal transmission and 7.4-fold (95% CI: 2.4-23.3) higher in the case of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes than in that of transmission from a parent with the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n- GGG]/[normal (CAG)n-GGG] haplotypes. The combination of paternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-GGG] haplotypes resulted in a 75.2-fold (95% CI: 9.0-625.0) increase in the relative risk compared with that of maternal transmission and the [expanded (CAG)n-CGG]/[normal (CAG)n-CGG] or [expanded (CAG)n- GGG]/[normal (CAG)n-GGG] haplotypes. The results suggest that an inter- allelic interaction is involved in the intergenerational instability of the expanded CAG repeat.      

Chromosomal aberrations and micronucleus frequency in nurses occupationally exposed to cytotoxic drugs

In this study, we evaluated the effect of low level occupationalexposure of nurses in a medical oncology unit in Cairo, Egypt,to anticancer drugs. Twenty nurses who constantly handled thesedrugs and 20 controls, matched according to age and sex, wereexamined. Metaphase chromosomes were studied. Percentages ofmetaphases with chromosomal aberrations were significantly higher(P < 0.001) in the exposed group (6.1 ± 2.7) versusthe controls (2.6 ± 1.6). The detected chromosomal aberrationswere in the form of chromatid gaps, chromatid breaks and acentricfragments. Micronucleated peripheral blood lymphocytes werealso analyzed in cytochalasin B treated binucleated lymphocytes.There was significant increase in cells with micronuclei (P< 0.001) in nurses (10.05 ± 4.71) in comparison tothe matched control (5.42 ± 2.22) (P < 0.001). Nursesexposed to the cytotoxic drugs for     

The mouse Mid1 gene: implications for the pathogenesis of Opitz syndrome and the evolution of the mammalian pseudoautosomal region

We have recently reported isolation of the gene responsible for X- linked Opitz G/BBB syndrome, a defect of midline development. MID1 is located on the distal short arm of the human X chromosome (Xp22. 3) and encodes a novel member of the B box family of zinc finger proteins. We have now cloned the murine homolog of MID1 and performed preliminary expression studies during development. Mid1 expression in undifferentiated cells in the central nervous, gastrointestinal and urogenital systems suggests that abnormal cell proliferation may underlie the defect in midline development characteristic of Opitz syndrome. We have also found that Mid1 is located within the mouse pseudoautosomal region (PAR) in Mus musculus , while it seems to be X- specific in Mus spretus. Therefore, Mid1 is likely to be a recent acquisition of the M. musculus PAR. Genetic and FISH analyses also demonstrated a high frequency of unequal crossovers in the murine PAR, creating spontaneous deletion/duplication events involving Mid1. These data provide evidence for the first time that genetic instability of the PAR may affect functionally important genes. In addition, we show that MID1 is the first example of a gene subject to X-inactivation in man while escaping it in mouse. These data contribute to a better understanding of the molecular content and evolution of the rodent PAR.      

Stability of Th1 and Th2 populations

Using an in vitro model for the development of IFN-y-producIng(Th1) and IL-4-produclng (Th1) cells from CD4 T lymphocytesexpressing a transgenlc TCR, we show that IL-12 and IL-4 arethe most potent stimuli for the differentiation of naive T cellsto effector populations. When combinations of cytokines arepresent during T cell priming, the effect of IL-4 Is dominant.Furthermore, differentiated Th1 cells can be converted intoIL-4 producers by exposure to IL-4, but the Th2 phenotype Isnot reversible. The stability of Th2 populations may limit theability to regulate Th2-domlnant responses In pathologic situations.     

Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats

The purpose of the present study was to investigate the disruptive effects of cannabinoids on working memory as assessed in the eight-arm radial-maze. Systemic administration of ⁹-THC, WIN-55,212-2, and CP-55,940 increased the number of errors committed in the radial-maze. CP-55,940 was the most potent cannabinoid in impairing memory (ED₅₀=0.13 mg/kg). ⁹-THC and WIN-55,212-2 disrupted mazechoice accuracy at equipotent doses (ED₅₀ values =2.1 and 2.2 mg/kg, respectively). In addition, systemic administration of each of these agents retarded completion time. Whereas the doses of ⁹-THC and CP-55,940 required to retard maze performance were higher than those needed to increase error numbers, WIN-55,212-2 was equipotent in both of these measures. On the other hand, neither anandamide, the putative endogenous cannabinoid ligand, nor cannabidiol, an inactive naturally occurring cannabinoid, had any apparent effects on memory. A second aim of this study was to elucidate the neuroanatomical substrates mediating the disruptive effects of cannabinoids on memory. Intrahippocampal injections of CP-55,940 impaired maze performance in a dose-dependent manner (ED₅₀=8 µg/rat), but did not retard the amount of time required to complete the maze. The effects of intrahippocampal CP-55,940 were apparently specific to cognition because no other cannabinoid pharmacological effects (e.g., antinociception, hypothermia, and catalepsy) were detected. This dissociation between choice accuracy in the radial-maze and other cannabinoid pharmacological effects suggests that the working memory deficits produced by cannabinoids may be mediated by cannabinoid receptors in the hippocampus.