Treatment of malignant esophageal obstructions with covered metallic Z stents: long-term results in 52 patients

PURPOSE: To prospectively evaluate the clinical efficacy of silicone-covered Gianturco-R?sch self-expandable Z (GRZ) stents in the treatment of malignant esophageal obstruction. PATIENTS AND METHODS: GRZ stents were placed in 52 patients (39 men, 13 women) with severe dysphagia due to high-grade malignant esophageal obstruction. RESULTS: Stent placement was technically successful, and immediate relief of dysphagia was achieved in 50 of 52 patients (96%), with long-term relief in 47 patients (90%). Fifty-one patients (98%) died during follow-up (range, 1 week to 33 months; mean, 4.3 months). Late complications were most prevalent and included stent migration (n = 5), food impaction (n = 2), chest pain (n = 2), membrane disruption with tumor ingrowth (n = 1), granulomatous reaction above the stent (n = 1), esophageal perforation with mediastinitis (n = 1), and upper gastrointestinal hemorrhage (n = 4). Twelve complications were easily managed with medical, endoscopic, or radiologic intervention. Four deaths may have been related to stent placement (early mortality rate, 7.7%). CONCLUSION: GRZ stents provide relatively safe and effective long-term palliation in patients with severe, malignant esophageal obstruction.     

Deletion and editing of B cells that express antibodies to DNA

We previously demonstrated that in mice transgenic for genes coding for an anti-ssDNA autoantibody B cells were functionally inactivated but not physically deleted. We have now extended this model by introducing an arginine into the CDR2 of the heavy chain transgene. This change alters the specificity of the Ab from anti-ssDNA to anti-dsDNA and increases the affinity for ssDNA. Mice carrying this transgene displayed a significant reduction of peripheral B cells and anti-dsDNA B cells were not recovered from the spleens. The remaining B cells escape deletion by revising their Ag receptors in several ways: 1) elimination of the transgenic heavy chain gene via intrachromosomal recombination, followed by rearrangement and expression of endogenous VH genes; 2) ongoing rearrangement of endogenous kappa light chain genes to generate a non-dsDNA-binding Ab; and 3) expression of a rare V lambda gene, V lambda x, to generate a non-DNA-binding Ab.     

Minimum attack rate for measuring measles vaccine efficacy

BACKGROUND: For evaluating measles vaccine efficacy (VE) in the field, some investigators have suggested that an overall attack rate level of 5% or more in a randomly mixing population is sufficient to provide equal exposure to the viral agent in both vaccinated and unvaccinated groups. It is not clear, however, if this assumption is valid given the effect of herd immunity. METHODS: We created a computer simulation model based on the stochastic extension of the Reed-Frost model and tested for variation in bias in VE estimation due to herd immunity, based on runs of 200 trials. RESULTS: At higher levels of attack rate, the degree of herd immunity decreases, as does the percentage of trials with bias in VE estimation. The two main factors that affect the level of attack rate are the probability of adequate contact and the number of susceptibles. At a given level of attack rate, the number of susceptibles is positively associated with the percentage of biased trials in VE estimation. Since vaccination reduces the number of susceptibles, we also observe that when controlling for attack rate, higher vaccination coverage results in lower bias in VE estimation. CONCLUSION: The results show that the assumption of no bias when the attack rate is 5% or more becomes increasingly true when a large percentage of a randomly mixing population is immune.     

Endoscopic Lothrop procedure: the University of Miami experience

The aim of this study was to assess whether percentage of body fat (BF) can be predicted adequately from skinfold measurements in comparative studies of children with spastic cerebral palsy (CP) and healthy control children. The deuterium dilution technique (D2O) was used as a reference method. In contrast with what was expected, %BF predicted from skinfold measurements was considerably lower than that determined by the D2O method in children with CP, whereas in the controls this was not seen. A proportionally large internal fat deposit and a different distribution of subcutaneous fat in children with CP may be responsible for this. It was concluded that skinfold measurements are not suitable for predicting %BF in comparative studies of children with CP and control children. For evaluation of diet- or exercise-related interventions in children with CP, the use of skinfold measurements seems to be justified. However, it may be more appropriate to use skinfold thicknesses without converting them to BF.     

Binding specificity of a class II-restricted hepatitis B epitope by DR molecules from responder and nonresponder vaccine recipients

A small but significant proportion of people who receive the hepatitis B vaccine do not produce anti-hepatitis B antibodies, a phenomenon associated with certain human leukocyte antigen (HLA) class II haplotypes. We were interested in determining whether natural allelic differences between two HLA-DR4 molecules associated with responder versus nonresponder subtypes differed with respect to binding of an immunodominant hepatitis B surface antigen (HBsAg) peptide as measured using a resonant mirror biosensor. In contrast to our original hypothesis, we found a ten-fold difference in the affinity in favor of the nonresponder DRB1*0401 allele, with a KD of 6.89 x 10(-8) M versus a KD of 6.71 x 10(-7) M for the responder DRB1*0404 allele. Half-times of dissociation were 1.3 min and 7.7 min, respectively, although association rate constants for both HLA class II molecules were similar (approximately 10(4) M(-1)s(-1)). Of particular interest was the observation of different on-rates during the association phase, suggesting that stoichiometry of binding was not 1:1 or that different structural forms of the HLA-peptide complex exist. Our observations indicate that whereas HBsAg peptide binding to HLA class II molecules is influenced by HLA polymorphism, the nonresponse to hepatitis B vaccine associated with this HLA-DR4 subtype is not a result of failure of processed HBsAg to bind HLA class II molecules.     

Detecting and correcting hyperlipidemia

The dangers of elevated serum cholesterol levels--and in particular, of increased concentrations of small, dense lipoproteins--have been fully delineated. Although effective therapies are available, too many physicians fail to look for hypercholesterolemia, or fail to treat it effectively. Adhering to therapeutic guidelines and encouraging patient compliance can be lifesaving.     

Prognostic implications of p53 overexpression in cutaneous melanoma from sun-exposed and nonexposed sites

Reduced energy expenditure may predispose children to the development of obesity, but there are limited longitudinal studies to support this theory. We studied 75 white, preadolescent children over 4 y by taking annual measures of body composition and resting energy expenditure (by indirect calorimetry) and two annual measures of total energy expenditure and physical-activity-related energy expenditure (by doubly labeled water). Body composition of parents was assessed at the onset of the study with use of underwater weighing. The major outcome variable was the individual rate of change in fat mass (FM) adjusted for fat-free mass (FFM). The influence of sex, energy expenditure components, initial FM, and parental FM on the rate of change in FM was analyzed by hierarchical linear modeling and analysis of variance. The rate of change in absolute FM was 0.89 +/- 1.08 kg/y (range: -0.44 to 5.6 kg/y). The rate of change in FM adjusted for FFM was 0.08 +/- 0.64 kg/y (range: -1.45 to 2.22 kg/y) and was similar among children of two nonobese parents and children with one nonobese or one obese parent, but was significantly higher in children with two obese parents (0.61 +/- 0.87 kg/y). The major determinants of change in FM adjusted for FFM were sex (greater fat gain in girls), initial fatness, and parental fatness. None of the components of energy expenditure were inversely related to change in FM. The main predictors of change in FM relative to FFM during preadolescent growth are sex, initial fatness, and parental fatness, but not reduced energy expenditure.     

Effect of modulators of protein tyrosine kinase activity on gender-related differences in vascular reactivity at reduced temperature

We used the isolated-muscle-bath technique to examine the effect of protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) inhibitors on the response of rings of tail artery from male and female rats to cooling and reduced temperature in the absence and presence of two PTK-dependent (clonidine and serotonin) and one PTK-independent (phenylephrine, PE) agonists. At 37 degrees C, reactivity to clonidine, serotonin, and PE was the same in tail artery from female and male rats. At 25 degrees C, reactivity to clonidine and serotonin, but not PE, was greater in tail artery from female rats compared with those from male rats. Sodium orthovanadate (SOV) eliminated the gender-related difference in the contractile effect of clonidine and serotonin at 25 degrees C. The sensitivity to relaxation by genistein was considerably greater for clonidine and serotonin at both temperatures as compared with PE. At 25 degrees C the sensitivity to genistein was greater for the clonidine and serotonin-contracted rings from female rats. In the presence of SOV, temperature reduction led to contraction of rat-tail artery. This effect was greater in rings from female rats. Our results strongly implicate differences in the activity of the PTK transduction pathway as the cause of the observed gender-related differences in agonist-mediated contraction at 25 degrees C and in cold-induced vasoconstriction.     

Membrane potential mediates H(+)-ATPase dependence of "degradative pathway" endosomal fusion

BACKGROUND: In recent years Tpot (potential doubling time) has been measured before treatment in human tumors in an attempt to estimate the proliferation taking place during a course of irradiation. Tpot is defined as Ts/LI, where Ts is the duration of DNA synthesis and LI is the labeling index (proportion of cells synthesizing DNA). Ts is more difficult to measure than LI, so the question arises whether variation introduced during the determination of Ts is compensated by the theoretically better relevance of the quotient Tpot than of LI alone. It is not clear from comparisons with clinical outcome whether Tpot is a useful indicator of proliferation or whether LI is more prognostic, as suggested by a currently ongoing multicenter analysis elsewhere. Therefore, we investigated intercomparisons between Tpot and its components LI and Ts in two in their proliferation rates contrasting types of tumor where multiple biopsies were taken from each tumor. MATERIALS AND METHODS: Sixty patients with esophageal carcinoma and 57 patients with breast cancer were included in this study. All patients were injected with IUdR 6-8 h before surgery. From each tumor three to five biopsies were taken at surgery. Using flow cytometry, LI and Ts were measured on all biopsies in order to calculate Tpot. Logarithmic transformations of the distributions were used to examine correlations. Kappa-tests were used to assess how reliable an LI value could be in predicting the corresponding Tpot. RESULTS: Ts and LI were not completely independent, based on the within-tumor coefficients of variation (CVw). The ratio of between-tumor coefficient of variation (CVb) to the CVw suggested that the discriminative power of Tpot was higher than LI for esophagus, but the reverse in breast tumors, which had a larger range. Pearson correlation coefficients were high for log Tpot versus log LI in both types of tumor, but the predictive power was low, as shown by kappa-values of only 0.3-0.41 starting with LI and trying to predict the corresponding value of Tpot. Increasing widths of a central 'gray zone' were investigated for improved discrimination between fast and slow proliferation. Multiples of the within-tumor standard deviation, equally on each side of the median, were used to vary the width of the gray zone. Without a gray zone no more than 70% successful matching was obtained in esophagus tumors, compared with 80% in breast tumors. However, by excluding about half of the esophageal tumors an 80% success rate was achieved. In breast tumors over 90% matching was obtained more easily, keeping 80% of the tumors classifiable. For both tumor types correlations between Ts and Tpot were weak, with a trend towards short Ts associated with short Tpot and also with low LI. The latter correlation was significant for esophageal tumors and resulted in Tpot values having a smaller range than the LIs. CONCLUSION: Although there were good correlation coefficients between Tpot and LI, the predictive power of either from the other was not reliable, except by excluding a significant number of tumors close to the medians. The predictive value of LI for Tpot was higher for breast tumors because the spread in cell kinetic measurements was wide. Until more clinical data become available on outcome in comparison with LI or Tpot, it is still worthwhile to measure Tpot and to assess the prognostic value of both LI and Tpot in relation to outcome.     

Three-dimensional low dose gadolinium-enhanced peripheral MR venography

Cases with absolute immotile sperm syndrome are rare, and include the genetic defect of immotile cilia syndrome with the absence of dynein arms in the flagellum. We attempted to increase the percentage of viable spermatozoa to improve the outcome of intracytoplasmic sperm injection (ICSI). Three couples in whom repeated analysis of the male partners indicated 100% sperm immotility underwent an in-vitro fertilization (IVF) procedure in which ICSI was performed. On their first ICSI cycle the males produced a single ejaculation while in their successive ICSI cycles they were requested to repeatedly ejaculate (two to four times) and only the last ejaculation was used. The eosin-Y test was performed on each used sample. Following their first treatment, one couple had one repeated treatment cycle, another had two and the third couple had three repeated treatment cycles. The mean percentages of viable spermatozoa were 41+/-7.4 and 71+/-6.9% in the first and repeated cycles respectively (P < 0.01; t-test). Of the 39 oocytes injected in the first ICSI cycles only one (3%) was normally fertilized (2PN) compared with 41 (48%) of the 85 oocytes injected in the repeated ICSI cycles. One (3%) embryo in the first and 35 (41%) embryos in the repeated ICSI cycles respectively were obtained (P < 0.001), enabling their replacement into the uterine cavity in all the repeated cycles. One woman (in a repeated cycle) conceived a twin pregnancy and delivered two healthy babies. The use of spermatozoa from repeated ejaculation is recommended in men with absolutely immotile spermatozoa so as to obtain significantly better viability and fertilizing capacity.