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Previous studies have suggested that excessive losses of FVC and FE[V.sub.1] were occurring in Vermont granite workers despite the fact that mean quartz levels existing in the industry were below [...]

The issue of whether low levels of granite dust exposure lead to radiographic abnormalities after a lifetime of exposure has not been settled. In 1983, we carried out a radiographic [...]

The primary aim of this phase 1 study was to determine the maximum tolerated dose (MTD) and evaluate the safety of nifurtimox alone and in combination with cyclophosphamide and topotecan in multiple relapsedrefractory neuroblastoma pediatric patients. The secondary aim was to evaluate the pharmacokinetics of nifurtimox and the treatment response. To these ends, we performed a phase 1 dose escalation trial of daily oral nifurtimox with toxicity monitoring to determine the MTD, followed by 3 cycles of nifurtimox in combination with cyclophosphamide and topotecan. Samples were collected to determine the pharmacokinetic parameters maximum concentration, time at which maximum concentration is reached, and area under the curve between 0 and 8 hours. Treatment response was evaluated by radiographic and radionuclide (123I-metaiodobenzylguanidine) imaging, measurement of urinary catecholamines, and clearance of bone marrow disease. We determined the MTD of nifurtimox to be 30 mgkgd. The non-dose-limiting toxicities were mainly nausea and neuropathy. The dose-limiting toxicities of 2 patients at 40 mgkgd were a grade 3 pulmonary hemorrhage and a grade 3 neuropathy (reversible). Overall, nifurtimox was well tolerated by pediatric patients at a dose of 30 mgkgd, and tumor responses were seen both as a single agent and in combination with chemotherapy. A Phase 2 study to determine the antitumor efficacy of nifurtimox is currently underway.

Neuroblastoma is the most common extracranial solid tumor in children and, when disseminated, carries a poor prognosis. Even with aggressive combinations of chemotherapy, surgery, autologous bone marrow transplant, and radiation, long-term survival remains at 30 and new therapies are needed. Recently, a patient with neuroblastoma who acquired Chagas disease was treated with nifurtimox with subsequent reduction in tumor size. The effect of nifurtimox on the neuroblastoma cell lines CHLA-90, LA1-55n, LA-N2, SMS-KCNR, and SY5Y was examined. Nifurtimox decreased cell viability in a concentration-dependent manner. Cell morphology, terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling assay, and caspase-3 activation indicate that cell death was primarily due to apoptosis. Nifurtimox also suppressed basal and TrkB-mediated Akt phosphorylation, and the cytotoxicity of nifurtimox was attenuated by a tyrosine hydroxylase inhibitor (alpha-methyl-tyrosine). Nifurtimox killed catecholaminergic, but not cholinergic, autonomic neurons in culture. In vivo xenograft models showed inhibition of tumor growth with a histologic decrease in proliferation and increase in apoptosis. These results suggest that nifurtimox induces cell death in neuroblastoma. Therefore, further studies are warranted to develop nifurtimox as a promising new treatment for neuroblastoma.

A total of 204 infertile women attending the Infertility Clinic of the Medical Center Hospital of Vermont were studied for the possible role ofChlamydia trachomatisand intrauterine contraceptive device (IUCD) use as factors related to their infertility. All patients had had at least 1 year of involuntary infertility. All but one woman had negative cultures forC. trachomatis, but a highly significant correlation (p < 0.001) was evident between evidence of prior pelvic inflammatory disease (PPID) as documented by hysterosalpingograms and/or laparoscopy and the prevalence of chlamydial antibody. Furthermore, a significant (p = 0.01) correlation could be shown between the prevalence of the antibodies and adnexal adhesions. IUCD use could also be shown to correlate significantly (p < 0.001) with PPID, and a detailed statistical analysis indicated that the two factors, antibody toC. trachomatisand a history of IUCD use, were independently related to PPID. Only about one third of the patients with PPID could ever recall having had an illness consistent with PID. Subsequent to the infertility workup, 76 of these women became pregnant and there was a significant (p < 0.001) correlation between the occurrence of ectopic pregnancy and antibody toC. trachomatis. A significant (p = 0.01) correlation was also noted between a history of IUCD use and subsequent ectopic pregnancy. From these data it appears that antecedent infection withC. trachomatis, as measured by antibody prevalence, and a history of IUCD use are important factors in infertility of tubal origin and are also related to ectopic pregnancy.

The incidence of side effects due to two dosage regimens of minocycline was examined over a 5-day period. A total of 60 normal women volunteers were randomly assigned in a double-blind manner to either a group who took 100 mg of minocycline twice a day or a group who took 75 mg of minocycline twice a day for 5 days. Both groups were comparable from the standpoints of age, size, race, and the use of oral contraception, nicotine, and ethanol. They were seen on a daily basis, and symptoms were evaluated by both volunteers (from diaries) and physicians. Minocycline serum concentrations were determined on blood samples taken 2 h after the a.m. dose. Volunteers taking 150 mg of minocycline per day had significantly lower serum antibiotic concentrations than those taking 200 mg per day. However, both low- and high-dose groups exhibited similar incidence and prevalence of recorded symptoms, with the single exception of nausea, where the low-dose group had fewer symptoms than the high-dose group (P= 0.035). Symptomatic volunteers did not have higher serum concentrations of minocycline than their asymptomatic counterparts. When either weight or surface area was examined with antibiotic serum concentration there was a significant inverse correlation between the two on day 2 for both groups and also on day 4 for the low-dose group. It is concluded that, in women, a dose of 150 mg of minocycline per day is associated with the same degree of side effects as a dose of 200 mg per day.

In a study of 204 consecutive infertile couples, 58 women with adnexal abnormalities consistent with prior pelvic infection were identified. The status of those 58 subjects with respect to prior pelvic infection, prior intrauterine device use, and serologic evidence of past chlamydial infection was correlated with the types of adnexal abnormalities identified. Women with serologic evidence of past chlamydial infection were more likely to exhibit severe adhesions and hydrosalpinx formation, and hydrosalpinx formation was related to a history of clinically detected pelvic infection.