An examination of the time course from human dietary exposure to polycyclic aromatic hydrocarbons to urinary elimination of 1-hydroxypyrene.

The significance of diet as an exposure route for polycyclic aromatic hydrocarbons (PAHs) and the associated kinetics of urinary 1-hydroxypyrene (1-OHPY) elimination were examined through a controlled human exposure study. Results showed that a 100 to 250-fold increase in a dietary benzo(a)pyrene (BaP) dose paralleled a four to 12-fold increase in urinary 1-OHPy elimination. Mean elimination rates during minimal exposure periods ranged from 6 to 17 ng/h whereas peak elimination rates of 60 to 189 ng/h were seen after a meal high in PAHs. A biexponential model fitted to a limited number of urinary 1-OHPY elimination points gave mean kinetic parameter estimates for t1/2 of 4.4 hours and tmax of 6.3 hours. It is concluded that dietary exposure to PAHs is potentially as substantial as some occupational exposures and therefore requires consideration in studies of exposure to PAHs. The dietary control strategies and the kinetic parameters defined in this investigation provide data for the control of this exposure route when examining other sources of exposure.     

A preliminary study of serotonergic antidepressants in treatment of dysthymia

Rosenthal, Jesse et al. A Preliminary Study of Serotonergic Antidepressants in the Treatment of Dysthymia. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 933–941.

1. 1. There is increasing evidence that antidepressants may alleviate symptoms of dysthymia, but few prior studies on selective serotonergic agents.

2. 2. Twenty patients meeting criteria for dysthymia, but not meeting criteria for major depression, received open label trials of a serotonergic antidepressant, either fluoxetine or trazodone.

3. 3. Seventeen (85%) completed three-month medication trials, and of these, twelve (70.6% of completers) responded to treatment. Seven (41.2% of completers) were still in remission on followup at five months.

4. 4. Both fluoxetine and trazodone were well tolerated in dysthymics, and showed similar short-term effectiveness in treating dysthymic symptoms.

An optimal three-stage design for phase II clinical trials

A phase II clinical trial in cancer therapeutics is usually a single-arm study to determine whether an experimental treatment (E) holds sufficient promise to warrant further testing. When the criterion of treatment efficacy is a binary endpoint (response/no response) with probability of response p, we propose a three-stage optimal design for testing H₀: p ≤ p₀ versus H₁: p ≥ p₁, where p₁ and p₀ are response rates such that E does or does not merit further testing at given levels of statistical significance (α) and power (1 ? β). The proposed design is essentially a combination of earlier proposals by Gehan and Simon. The design stops with rejection of H₁ at stage 1 when there is an initial moderately long run of consecutive treatment failures; otherwise there is continuation to stage 2 and (possibly) stage 3 which have decision rules analogous to those in stages 1 and 2 of Simon's design. Thus, rejection of H₁ is possible at any stage, but acceptance only at the final stage. The design is optimal in the sense that expected sample size is minimized when p = p₀, subject to the practical constraint that the minimum stage 1 sample size is at least 5. The proposed design has greatest utility when the true response rate of E is small, it is desirable to stop early if there is a moderately long run of early treatment failures, and it is practical to implement a three-stage design. Compared to Simon's optimal two-stage design, the optimal three-stage design has the following features: stage 1 is the same size or smaller and has the possibility of stopping earlier when 0 successes are observed; the expected sample size under the null hypothesis is smaller; stages 1 and 2 generally have more patients than stage 1 of the two-stage design, but a higher probability of early termination under H₀; and the total sample size and criteria for rejection of H₁ at stage 3 are similar to the corresponding values at the end of stage 2 in the two-stage optimal design.     

Pelvic Gliomatosis within Foci of Endometriosis

The third reported case of pelvic gliomatosis found within foci of endometriosis is documented 16 years after the removal of a benign cystic teratoma. Grossly at laparoscopy the lesions appear as typical deep fibrotic endometriotic implants.     

Gestational age and intrauterine growth retardation among white and black very low birthweight infants: a population-based cohort study

Summary. Very low birthweight (VLBW) is a commonly used endpoint in perinatal epidemiology, but the population of VLBW infants comprises a wide range of gestational ages and rates of fetal growth. We used data from a population-based study of all 1072 black and white VLBW liveborn infants born in 29 counties in Georgia between April 1986 and March 1988. Less than 1% of the VLBW infants were ≥ 37 weeks gestation; most were 29–32 weeks (26%) or 25 to 28 weeks (40%); 12% were 22 weeks or less. All infants 33 weeks gestation or greater were growth retarded. The population of VLBW infants seems to comprise three groups: approximately 11% very immature infants of 22 weeks or less; the majority of infants, born between 23 and 30 weeks, 90% of which are of normal weight for their gestational age; and a group of less premature, growth-retarded infants from 31 to 36 weeks. We found little or no difference in the distribution of gestational age or the percentage of intrauterine growth rates (IUGR) between black and white infants. In the USA the VLBW rate among black infants is over three times greater than that among white infants and consequently the rates of the three types of VLBW among black infants are likely to be triple those among white infants.     

Graft versus graft and graft versus host reactions after HLA-identical bone marrow transplantation in a patient with severe combined immunodeficiency with transplacentally acquired lymphoid chimerism

We describe a patient with severe combined immunodeficiency and transplacental transfer of maternal T cells who received an unfractionated HLA-identical sibling bone marrow transplant without prior conditioning. He presented prior to transplantation with a dermatitis later diagnosed as mild graft versus host disease. He had a normal absolute lymphocyte count, but proliferative responses to mitogens were very low. Antigens of the noninherited maternal HLA haplotype were detected on his blood lymphocytes. After transplantation, he developed a severe reaction including fever, cutaneous erythema and hepatosplenomegaly. Lymphocytes carrying the noninherited maternal HLA haplotype disappeared from his circulation, and his unprimed mononuclear cells became spontaneously cytotoxic to maternal lymphoblasts. He subsequently developed a lymphocytosis of 69,000/mm³, diarrhea, elevated transaminases and a worsening rash, necessitating treatment with immunosuppressive agents. Full T-cell engraftment and evidence of B-cell function later ensued and spontaneously cytotoxic lymphocytes against maternal cells disappeared by 47 days post-transplantation. We postulate that the patient's constellation of signs and symptoms after transplantation represented a combination of severe graft versus graft and mild graft versus host reactions.     

Low peripheral plasma renin activity as a critical marker in pediatric hypertension

In evaluating hypertensive children and adolescents, the etiological considerations should include a set of inherited disorders that share very low plasma renin activity (PRA) as a common feature. In particular among these disorders, glucocorticoid remediable aldosteronism (GRA) appears to be emerging as an important etiology of hypertension in the pediatric population. We report the evaluation of a 9-year-old Caucasian girl who presented with severe hypertension and a strong family history of early-onset hypertension. Her suppressed PRA, her family history, and her failure to respond to conventional antihypertensive therapy raised GRA as a potential etiology. The diagnosis was confirmed by an elevated ratio of urinary 18-oxotetrahydrocortisol to urinary tetrahydroaldosterone and genetic testing, which demonstrated the chimeric gene duplication. The molecular pathogenesis of GRA and the clinical implications are reviewed. Received May 15, 1996; received in revised form and accepted September 16, 1996