Growth inhibition of human colon carcinoma cells by combinations of anti-epidermal growth factor-related growth factor antisense oligonucleotides

To gain insight into the factors controlling the maintenance or loss of T cell self tolerance we produced beef insulin (BI)-transgenic BALB/c mice. Transgenic mice express BI under control of the human insulin promoter and secrete physiological amounts of beef insulin. Although these mice are tolerant to BI, as evidenced by the lack of insulin-specific IgG antibody production following intraperitoneal immunization, tolerance is not complete. Footpad immunization results in a weak antigen-specific T cell proliferative response, indicating the presence of self-reactive BI-specific T cell in the periphery. These T cells are functional in vivo, providing support for IgG1, IgG2a, and IgG2b BI-specific antibody production, but require higher higher concentrations of antigen than nontransgenic T cells (both in vivo and following recall responses in vitro) to become activated. In vitro, BI-specific T cell proliferation in BI-transgenic mice can be largely restored by addition of interleukin-2, indicating that a significant component of T cell tolerance is mediated by anergy. To characterize the autoreactive T cells that become activated when tolerance is broken, BI-specific T cell hybridomas were generated from transgenic mice and compared to a panel of hybridomas previously derived from nontransgenic BALB/c mice. The majority of BI-transgenic hybridomas recognized the immunodominant A1-14 beef insulin peptide but with lower avidity than BALB/c hybridomas. Consistent with this, none of the dominant T cell receptor rearrangements found in the BALB/c BI-specific T cell receptor repertoire were found in the transgenic hybridomas. These results indicate that, despite evidence for clonal inactivation of many BI-specific T cells in BI-transgenic mice, loss of tolerance results from activation of low-affinity antigen-specific T cells that appear to have escaped this process.     

Does palpability of primary cutaneous melanoma predict dermal invasion?

BACKGROUND: Relatively few studies have addressed the question of whether clinical estimation of melanoma thickness by palpation can accurately predict its histologic thickness. If palpability was a reliable predictor of dermal invasion, it could be used to define the surgical margin. OBJECTIVE: We sought to determine whether clinical elevation of melanoma could be used to predict the presence or absence and the degree of dermal invasion in patients with stage 1 cutaneous melanoma. METHODS: Melanomas in 165 patients were categorized by one observer as flat, just palpable, palpable, or nodular. This was compared with histologic measurements of tumor thickness. RESULTS: Overall there was significant correlation between the degree of palpability of melanoma and the presence or absence of dermal invasion (p<0.001), Breslow thickness (p<0.0001), and Clark level (p<0.001). However, the relation between palpability and Breslow thickness for invasive melanomas less than 1 mm thick was weaker (n=62, p=0.053), and the correlation between elevation and Clark level was not significant for invasive melanomas less than 4 mm thick (n=111, p>0.999). CONCLUSION: We conclude that palpability of melanoma is an inadequate guide to the presence or absence and degree of dermal invasion in melanomas less than 1 mm thick and cannot be used to determine the surgical margin.     

Analysis of the association of a heat shock protein70-1 gene promoter polymorphism with myocardial infarction and coronary risk traits

In 12 depressed inpatients referred for bilateral electroconvulsive therapy (ECT), each patient was titrated at the first treatment session by using an ascending method-of-limits procedure with a step-wise increase in pulse frequency (frequency titration) or train duration (duration titration). At the second treatment session, seizure threshold was redetermined by using the method (frequency or duration titration) not used at the first treatment. Frequency or duration was maintained at the lowest level when the other parameter was titrated. Seizure threshold was significantly lower with duration titration (mean, 90 mC; SD, 27.3) than frequency titration (mean, 114 mC; SD, 35.6; p = 0.03). On average, patients in the duration-titration group required 1.2 (SD, 0.6) subconvulsive stimulations before a seizure was elicited, and patients in the frequency-titration group required 1.7 (SD, 0.9) subconvulsive stimulations before a seizure was elicited, a nonsignificant difference. These findings suggest that to elicit a seizure during ECT, increasing train duration may be slightly more efficient than increasing frequency. Basic and other clinical research findings indicate that increasing pulse width may be an inefficient way to elicit a seizure. Therefore the following sequence in the determination of seizure threshold is worth considering when using dose-titration or related techniques: the train duration should be increased first before increasing pulse frequency, and the decision to increase pulse width should be reserved for patients who do not seize at the maximal duration and frequency settings. Further empiric research is needed to establish the utility of this approach.     

Psychiatric illness and family support in children and adolescents with diabetic ketoacidosis: a controlled study

BACKGROUND: In the adult respiratory distress syndrome, nitric oxide (NO) inhalation improves oxygenation through reducing ventilation-perfusion mismatching, but detailed information on the pulmonary effects of NO inhalation in septic shock is scarce. The present study investigated the effects of inhaled NO on alveolar dead space (Vdalv) and venous admixture as well as on respiratory system compliance (Crs) and respiratory system resistance (Rrs) in a porcine model of septic shock. Protective effects of NO are discussed. METHODS: Thirteen anaesthetised and ventilated pigs were given an infusion of endotoxin for an observation time of 220 min to induce acute lung injury (ALI). In the NO-early group (n=6), an inhalation of 60 ppm NO was started simultaneously with the endotoxin infusion and continued for 190 min. In 7 control/NO-late animals, 60 ppm NO was administered for 30 min following 190 min of endotoxin infusion. Haemodynamics, single-breath CO2-, pressure-, and flow signals were recorded. RESULTS: Endotoxin induced haemoconcentration, pulmonary vasoconstriction, and a decrease in Crs, while venous admixture, Vdalv, and Rrs increased. In the NO-early group, the pulmonary vasoconstriction was attenuated, no increase in pulmonary venous admixture or in Vdalv was seen before cessation of NO, and the improvements in oxygenation outlasted the NO inhalation. In the control/NO-late group, the NO inhalation reversed the changes in dead space and venous admixture. NO had no effect on the changes in respiratory mechanics. CONCLUSION: In porcine ALI, 60 ppm NO diminishes pulmonary vasoconstriction and improves gas exchange by reducing pulmonary venous admixture and alveolar dead space, but does not prevent a fall in Crs. NO inhalation may help prevent long-lasting pulmonary failure.     

NO/cGMP pathway is involved in exocrine secretion from rat pancreatic acinar cells

OBJECTIVE: To identify factors associated with the initiation of breast-feeding in a predominantly Puerto Rican population living in inner-city Hartford, Conn. DESIGN: Retrospective study of 144 Latino women (mean +/- standard deviation age = 26.3 +/- 5.7 years) with children at least 1 year old but younger than 6 years old (mean +/- standard deviation age = 3.0 +/- 1.2 years) at the time of the survey. Women were recruited from agencies sponsoring health programs for mothers and children. They were interviewed in their homes (69%) or at the Hispanic Health Council, Hartford, Conn (31%). SUBJECTS/SETTING: Low-income Latino women who had at least 1 preschooler at the time of the interview. The women lived in inner-city Hartford, and the overwhelming majority were Puerto Rican and received welfare assistance and food stamps. Seventy-eight percent of the women chose to be interviewed in Spanish; the other 22% were interviewed in English. STATISTICAL ANALYSES: Explanatory variables that related to breast-feeding initiation (P < or = .2) in bivariate chi 2 analyses were entered into a multivariate logistic regression model that was reduced using backward stepwise elimination procedures. RESULTS: Multivariate analyses indicated that breast-feeding the previous child, shorter length of maternal residence in the United States, not receiving prenatal bottle-feeding advice, more recent birth, and higher birth weight were positively associated with breast-feeding initiation. A major reason for choosing not to breast-feed was that women felt socially uncomfortable doing it. APPLICATIONS: Breast-feeding initiation was more likely in Latino women who received prenatal breast-feeding counselling and postpartum support. Mothers of low-birth-weight infants and women breast-feeding for the first time may need additional help. These findings can be used by programs like the Special Supplemental Nutrition Program for Women, Infants, and Children to increase breast-feeding initiation.     

Delivery of multiple CD8 cytotoxic T cell epitopes by DNA vaccination

Development of CD8 alphabeta CTL epitope-based vaccines requires an effective strategy capable of co-delivering large numbers of CTL epitopes. Here we describe a DNA plasmid encoding a polyepitope or "polytope" protein, which contained multiple contiguous minimal murine CTL epitopes. Mice vaccinated with this plasmid made MHC-restricted CTL responses to each of the epitopes, and protective CTL were demonstrated in recombinant vaccinia virus, influenza virus, and tumor challenge models. CTL responses generated by polytope DNA plasmid vaccination lasted for 1 yr, could be enhanced by co-delivering a gene for granulocyte-macrophage CSF, and appeared to be induced in the absence of CD4 T cell-mediated help. The ability to deliver large numbers of CTL epitopes using relatively small polytope constructs and DNA vaccination technology should find application in the design of human epitope-based CTL vaccines, in particular in vaccines against EBV, HIV, and certain cancers.