David W. Kaufman

Antenatal exposure to the phenothiazines in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score

In a prospective cohort study of 50,282 gravidas and their offspring, over-all rates of congenital malformations were similar in 1,309 children of women exposed to phenothiazine drugs during the first four lunar months of pregnancy and in 48,973 children of women who were not exposed. There was a suspicion of association between phenothiazine exposure and cardiovascular malformations. In a cohort reduced to 41,337 mother-child pairs for technical reasons, perinatal mortality rates and mean birth weight were similar according to phenothiazine exposure or nonexposure, as were intelligence quotient scores measured at four years of age in 28,358 of the children. Control of potential confounding factors with a variety of multivariate techniques did not materially alter the findings.

Substance P augments interleukin-10 and tumor necrosis factor-α release by human cord blood monocytes and macrophages

We have investigated the effects of SP on the constitutive and/or lipopolysaccharide (LPS)-induced expression of interleukin-10 (IL-10) and tumor necrosis factor (TNF-alpha) in both freshly isolated cord blood monocytes (FICBM) and cord blood monocyte-derived macrophages (CBMDM). The cells were treated with SP at various concentrations (10(-14) to 10(-6) M) in the presence or absence of LPS and culture supernatants were analyzed for IL-10 and TNF-alpha as measured by an enzyme immunosorbent assay (ELISA). FICBM and CBMDM treated with SP alone increased TNF-alpha secretion. The stimulatory effects of SP on TNF-alpha secretion are inhibited by a anti-SP polyclonal antibody and SP antagonists, spantide ([D-Arg-1-D-Trp-7-D-Trp-9-Leu-11]-SP) and CP-96,345 (a nonpeptide antagonist of the SP receptor). Although the treatment with SP alone did not enhance IL-10 secretion by both freshly isolated and cultured cord monocytes, treatment with SP in combination with LPS leads to a synergistic interaction in upregulation of IL-10 secretion. Fragments of SP (SP1-4 and SP5-11) in the presence or absence of LPS show little effects on IL-10 secretion by FICBM. SP reverses the inhibitory effect of IFN-gamma on LPS-induced IL-10 secretion by FICBM. In addition, the two SP antagonists and the anti-SP polyclonal antibody blocked the SP effect on IL-10 secretion by FICBM, indicating that these effects are specific and SP receptor mediated. Thus, SP is likely to play an important role in certain inflammatory conditions in the immune and nervous systems.

Evidence for an Increased Risk of Crohn's Disease in Oral Contraceptive Users

The risk of Crohns disease in relation to oral contraceptive use was evaluated in a hospital-based, case-control study of 57 women with Crohns disease and 2189 controls with other conditions. The relative risk for oral contraceptive users compared with women who had never used these drugs was 1.9 (95% confidence interval 1.0-3.5). The magnitude of the relative risk estimate was related to the timing and duration of oral contraceptive use. For use within the year before admission to a hospital (recent use), the relative risk estimate was 4.3 (2.1-8.7); the estimate dropped to 1.2 (0.5-2.6) 4 yr after discontinuation of oral contraceptive use. The relative risk estimate for recent use that lasted greater than or equal to 5 yr was 8.0 (3.1-21). The findings are in accordance with earlier reports of an increased risk of Crohns disease in oral contraceptive users.

Intrauterine contraceptive device use and pelvic inflammatory disease

We examined the relationship between use of IUDs and PID, based on 44 women who were admitted to hospitals with first episodes of PID and 259 hospital control subjects. All the women used either IUDs or oral contraceptives. The age-adjusted relative risk for those using IUDs at the time of admission was 6.5 (95% confidence interval, 3.2 to 13.0). The association remained when several variables, and particularly parity, were taken into account. There was a suggestion that users who had had an IUD in place for at least 5 years had a higher risk of PID than did users of shorter duration. The data also suggest that copper-containing IUDs may be safer than other devices.

Antenatal exposure to doxylamine succinate and dicyclomine hydrochloride (Bendectin) in relation to congenital malformations, perinatal mortality rate, birth weight, and intelligence quotient score

In a prospective cohort study of 20, 282 gravidas and their offspring, congenital malformation rates were similar in the children of over 1,000 women exposed and those not exposed to two components of Bendectin (doxylamine succinate and dicyclomine hydrochloride) during the first four lunar months of pregnancy. In a cohort reduced to 41,337 mother-child pairs for technical reasons, mean birth weight and perinatal mortality rates were similar according to exposure or nonexposure to either drug, as were intelligence quotient scores measured at four years of age in 28,358 of the children. Control of potential confounding factors with a variety of multivariate techniques did not materially alter these findings.

Breast Cancer and Cigarette Smoking

It has been suggested that cigarette smoking may reduce the incidence of breast cancer, perhaps by as much as 20 per cent. To evaluate the relation between breast-cancer risk and smoking, we studied 2160 women with breast cancer and 717 controls who had been admitted to the hospital for cancer of the ovary, cancer of the colon or rectum, malignant melanoma, or lymphoreticular cancers. As compared with women who had never smoked, the estimated relative risk of breast cancer was 1.1 for current smokers of any amount (95 per cent confidence interval, 0.9 to 1.3), and 1.0 (0.8 to 1.3) for heavy smokers (15 or more cigarettes per day). Allowance for all identified potential confounding factors did not materially alter the results. There was no indication that age at commencement of smoking was related to the risk, nor was there evidence of an effect of smoking within the categories of age at first pregnancy or age at menopause. The data provide evidence against the hypothesis that smoking may reduce the incidence of breast cancer by 20 per cent.

Performance evaluation of MMP-II:A second-generation small animal PET

We have completed construction of a second-generation, single-plane small animal PET instrument based on LSO detectors. The second-generation design addresses some of the limitations in the first-generation. The purpose of the work reported here was to characterize the physical performance of this instrument. Results of the performance measurements include: Spatial resolution=1.25 mm at field center and 1.5 mm at 2 cm radius; point source sensitivity=56 cps/uCi,; scatter fractions of 0.019 and 0.056 in 3.8 and 6 cm diameter cylinders respectively; linearity of reconstructed signal within 5% up to 100 uCi/cc and acceptable dead-time performance up to 25 k true cps. Examples of phantom and animal images are also presented.

A Portable Device for the Measurement of Regional Cerebral Blood Flow in the Icu and or Using Cd Te Detectors and a Fourier Transform Based Data Analysis

A portable system for the measurement of cerebral blood flow in critical care environments such as the intensive care unit or operating room has been developed and tested in a limited series of patients. The flow measurements are based on the 133Xe inhalation or IV injection method. The system uses miniature solid state detectors, microprocessor technology and Fourier transform based data analysis to provide compactness and rapid on-line analysis of data. Preliminary patient studies comparing this system with a larger sodium iodide detector system show comparable results.

ELEVATIONS OF INTERLEUKIN-8 IN INFANTS WITH BACTERIAL SEPSIS. † 1761

Despite improvements in intensive care and the use of broad spectrum antimicrobial agents, bacterial sepsis remains an important cause of morbidity and mortality in infants. Cytokines are endogenous mediators elaborated during the pathogenesis of infection. We reported elevated levels of interleukin-6 and tumor necrosis factor in critically ill infants with sepsis and necrotizing enterocolitis. Interleukin-8(IL-8), a cytokine which attracts and activates neutrophils, may also be implicated in the inflammatory response. We hypothesized that plasma levels of IL-8 are elevated in infants with bacterial sepsis. We prospectively measured plasma IL-8 levels at presentation in infants <6 months of age who were evaluated for sepsis. Twenty infants had culture proven bacterial sepsis (GA 32.7±1.3 wk, M±SEM, postnatal age (PNA) 49±10 d); 20 control infants had signs of infection(sepsis syndrome) but negative cultures (GA 35.1±1.3 wk, PNA 24±8 d). Cytokine levels were determined by ELISA (T Cell Diagnostics, Woburn, MA). IL-8 levels were significantly elevated in infants with bacterial sepsis (306±113 pg/ml) versus sepsis syndrome controls (38±14 pg/ml, p<0.025). Furthermore, IL-8 levels were nearly tenfold greater in infants with gram negative (554±200 pg/ml, n=10) versus gram positive sepsis (58±21 pg/ml, n=10, p<0.025). Elaboration of IL-8 was independent of BW, GA, and PNA. Thus, IL-8 levels are elevated in infants with bacterial sepsis versus sepsis syndrome controls; these levels are highest during gram negative septicemia. In the future, cytokine determinations may identify infants who would benefit from immunotherapeutic strategies. (Funded by NIH RR-00240).

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Infection In Vitro in Cord Blood Monocyte Derived Macrophages by IL-3, IL-4, IL-10, and IL-13.♦ 1319

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Infection In Vitro in Cord Blood Monocyte Derived Macrophages by IL-3, IL-4, IL-10, and IL-13.♦ 1319