Maternal serum alpha-fetoprotein levels as an index of fetal risk.

In a prospective study on an obstetric population (1,059 cases) an association was found between elevated levels of maternal serum AFP at weeks 16 to 22 and the occurrence of premature labor or the need for emergency cesarean section in the third trimester. There was no association with other late fetal complications including perinatal death, perinatal asphyxia, and intrauterine growth retardation. The sensitivity of the test in respect of premature labor was 14 per cent but the high incidence of false-positive results reduces the practical value of the test.     

Prognostic significance of immunohistochemical micrometastases in node negative gastric cancer patients

BACKGROUND AND OBJECTIVES: The purpose of this study is to examine the prognostic significance of immunohistochemical (IHC) evidence of lymph node (LN) metastases in histologic node negative gastric cancer patients. METHODS: Retrospective review from 1981 to 1998 revealed 25 patients resected for T1-4N0M0 gastric and gastroesophageal (GE) junction adenocarcinoma. All cases were reviewed and histopathologic parameters were defined for each primary tumor. All LNs underwent IHC analysis with the epithelial marker CAM 5.2. Data are reported as median (range). RESULTS: The median number of LN resected was 7 (range 1-33). The median follow-up time was 25 months (range 4-195) with an overall 5-year survival rate of 55%. For patients with IHC evidence of LN micrometastasis (n = 9), the 5-year survival rate was significantly decreased (35%) compared to a 66% 5-year survival rate for IHC negative patients (n = 16, P = 0.05). CONCLUSIONS: The presence of IHC-detected LN micrometastases correlates with worse prognosis for patients with histologic node negative gastric cancer. IHC may be a useful additional staging modality in this subset of patients.     

Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism

BACKGROUND: P-glycoprotein (P-gp) pumps a wide range of cytotoxic drugs out of cells. Inhibiting maturation of P-gp would be a novel method for circumventing P-gp-mediated multidrug resistance, which complicates cancer chemotherapy and treatment of patients infected with human immunodeficiency virus. We examined the effect of disulfiram (Antabuse(TM)) on the maturation and activity of P-gp. METHODS: Embryonic kidney cells were transfected with a complementary DNA for the P-pg gene, and the effects of disulfiram on the sensitivity of the transfected cells to cytotoxic agents were determined. Enzyme assays were used to determine the effects of disulfiram on the verapamil-stimulated adenosine triphosphatase (ATPase) activity of P-gp. Disulfiram modifies cysteine residues, and mutant forms of P-gp that lack individual cysteines were used to determine whether particular cysteine residues mediate disulfiram's effects on P-gp activity. Maturation of recombinant P-gp was followed on immunoblots. RESULTS: Disulfiram increased the sensitivity of P-gp-transfected cells to vinblastine and colchicine and inhibited P-gp's verapamil-stimulated ATPase activity. Half-maximal inhibition of ATPase activity occurred at 13.5 microM disulfiram. Disulfiram (at 100 microM) inhibited a P-gp mutant by 43% (95% confidence interval [CI] = 37%-48%) when cysteine was present at position 431 only and by 72% (95% CI = 66%-77%) when cysteine was present at position 1074 only. Treatment of P-gp-transfected cells with 50 nM disulfiram blocked maturation of recombinant P-gp. CONCLUSIONS: Disulfiram can potentially reduce P-gp-mediated drug resistance by inhibiting P-gp activity (possibly via cysteine modification) and/or by blocking its maturation. These results suggest that disulfiram has the potential to increase the efficacy of drug therapies for cancer and acquired immunodeficiency syndrome.     

Epithelial stem cells in the mammary gland: casting light into dark corners

The epithelial structures of the human breast or the mouse mammary gland are derived from a relatively small number of multipotent, tissue-specific stem cells, of which we are surprisingly ignorant. We do not know how many are required to produce a complete mammary gland, how many times they divide during the process, where they are situated in the gland, or even what they look like. We want to know the answers to these questions, not just to satisfy intellectual curiosity, but also because the answers may shed light on the evolution of breast cancer. Now, studies carried out by Kordon and Smith at the National Cancer Institute have pointed the way toward a new understanding of mammary stem cells and their progeny.     

Physicochemical factors governing the performance of nedocromil sodium as a dry powder aerosol

Previous investigations have found that the in vitro aerosol performance of nedocromil sodium is poor. A study has been undertaken to gain a better understanding of the physicochemical properties of the drug particles together with the factors governing the aerosol performance of inhalation systems containing this drug. Material previously passed through a hammer mill only and particles subsequently passed through a micronizer were characterized, and the information gathered was correlated with the in vitro aerosol performance of the pure drug systems. Optimization of particle sizing procedures revealed that both sets of materials were ultrafine powders with a volume median diameter of approximately 1 microm. It is concluded that the processing stages, employed in the manufacture of these batches of fine particle nedocromil sodium trihydrate, may not in fact be primary particle size reduction stages but instead deaggregation stages and that these govern the aerosol performance. The in vitro aerosol performance of samples of the "micronized" nedocromil sodium stored over a range of relative humidities (RHs) was characterized. Storage RHs in the range 12-76% (where nedocromil sodium is stable as the trihydrate) did not have a dramatic effect on the in vitro aerosol performance of the drug. However, conversion to the heptahemihydrate (following storage of the drug at 86% RH) significantly decreased the deaggregation performance in an in vitro model.     

Effects of nicotine and chlorisondamine on cerebral glucose utilization in immobilized and freely-moving rats

Chlorisondamine blocks central nicotinic receptors for many weeks via an unknown mechanism. Intracerebroventricular administration of [(3)H]-chlorisondamine in rats results in an anatomically restricted and persistent intracellular accumulation of radioactivity. The initial aim of the present study was to test whether nicotinic receptor antagonism by chlorisondamine is also anatomically restricted. Male adult rats were pretreated several times with nicotine to avoid the disruptive effects of the drug seen in drug-na?ve animals. They then received chlorisondamine (10 microg i. c.v.) or saline, and local cerebral glucose utilization (LCGU) was measured 4 weeks later after acute nicotine (0.4 mg kg(-1) s.c.) or saline administration. During testing, rats were partially immobilized. Nicotine significantly increased LCGU in the anteroventral thalamus and in superior colliculus. Chlorisondamine completely blocked the first of these effects. Chlorisondamine significantly reduced LCGU in the lateral habenula, substantia nigra pars compacta, ventral tegmental area, and cerebellar granular layer. The second experiment was of similar design, but the rats were not pre-exposed to nicotine, and were tested whilst freely-moving. Acute nicotine significantly increased LCGU in anteroventral thalamus, superior colliculus, medial habenula and dorsal lateral geniculate. Overall, however, nicotine significantly decreased LCGU. Most or all of the central effects of nicotine on LCGU were reversed by chlorisondamine given 4 weeks beforehand. These findings suggest that chlorisondamine blocks nicotinic effects widely within the brain. They also indicate that in freely-moving rats, nicotine can reduce or stimulate cerebral glucose utilization, depending on the brain area. British Journal of Pharmacology (2000) 129, 147 - 155     

Sulfasalazine metabolite pharmacokinetics in pediatric patients with inflammatory bowel disease: effects of disease activity, acetylator phenotype, and age

The pharmacokinetics and protein binding of sulfapyridine (SP) and its major metabolite, acetylsulfapyridine (ACSP) were examined in 17 prepubertal children and 4 postpubertal adolescents receiving sulfasalazine (SASP) for treatment of inflammatory bowel disease (IBD). Five patients were studied in both active disease and remission. Comparisons were made with a group of 24 outpatients (9-62 years) with IBD controlled on SASP and in remission. Acetylator phenotype was calculated from plasma metabolite ratios. Slow acetylators had increased plasma concentrations of SP and ACSP + SP (P less than 0.05). Apparent SP clearance (clearance/availability) was increased in active disease (P less than 0.05) and AUCSP + ACSP and AUCSP were decreased (P less than 0.05). There were no age-related alterations in apparent SP clearance. Side effects were frequent but were unrelated to SASP dose, SP concentrations, or acetylator phenotype. Disease activity did not significantly alter the serum protein binding of SP or ACSP. The decreased SP and ACSP concentrations seen in active disease may be due to a combination of disease related alterations in either cleavage of SASP or absorption and clearance of SP.