Human exposure to polychlorinated biphenyls in greater New Bedford,Massachusetts: A prevalence study

A study was conducted in the community of Greater New Bedford, Massachusetts, from 1984 through 1987 to assess the prevalence of elevated levels of polychlorinated biphenyls (PCBs) in the serum of individuals aged 18 to 64 years who had resided in the area for at least 5 years. Eight hundred and forty subjects were interviewed, examined, and tested in a cross-sectional sample of the towns of Acushnet, Dartmouth, and Fairhaven and the city of New Bedford. Serum PCBs were measured to estimate the extent of human exposure. Because of documented environmental contamination by PCBs in the New Bedford area, and the practice of recreational fishing in the harbor for food, a significant number of persons with elevated serum PCB levels were expected to be identified. Instead, the prevalence of elevated serum PCBs in the sample was found to be typical of unexposed urban populations in the United States. Only 1.3% of the subjects had serum PCB levels greater than 30 ppb. The same percentage was observed among males (n =391) and females (n=449). The geometric means of PCB levels were 4.3 ppb among males (Range=0.50–60.9) and 4.2 ppb among females (Range=0.38–154). We conclude that the prevalence of elevated serum PCBs is low in the population of Greater New Bedford.     

New spectrophotofluorometric assay for probenecid

A new spectrophotofluorometric assay for probenecid is presented based on conversion of the drug to a fluorescent anthranilic acid derivative. The assay is especially applicable with "clean" biological fluids such as cerebrospinal fluid and offers severalfold greater sensitivity than the commonly used UV method.     

Symptomatic and puomonary response to acute phlebotomy in secondary polycythemia.

A double-blind study of the effects of phlebotomy was carried out in 18 patients with polycythemia secondary to severe hypoxemic lung disease. Eleven subjects underwent a single phlebotomy of 10 percent of their blood volume, and eight patients serving as controls underwent a sham procedure. Eight of the phlebotomized subjects, but none of the controls, reported subjective clinical improvement (P less than 0.005). Subjects who noted improvement after venesection had higher hematocrit readings than those who did not (P less than 0.02). Symptomatic relief seemed to be most dramatic in those with clinical evidence of congestive heart failure. In contrast to this clear-cut subjective improvement, phlebotomy did not alter objective indices of airway obstruction, lung elastic recoil, pulmonary gas exchange, or exercise tolerance in either the phlebotomized or the control group. Thus, although phlebotomy produced subjective benefit in the majority of patients studied, it was not associated with objective improvement in lung function or exercise tolerance.     

Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists

An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with <15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.     

Comparison of Tibial Sesamoid Position on Anteroposterior and Axial Radiographs Before and After Triplane Tarsal Metatarsal Joint Arthrodesis

We reviewed the radiographic results of a group of patients who had undergone triplane correctional tarsometatarsal arthrodesis for symptomatic hallux abducto valgus with metatarsus primus abducto valgus. Of the 21 feet included in the present review, 17 (81%) displayed radiographic findings of metatarsal pronation preoperatively based on axial sesamoid views and positive lateral round sign on anteroposterior radiographs. At a mean follow-up period of 5.2 ± 1.6 months, a significant improvement in the tibial sesamoid position (TSP) on both anteroposterior (AP) and axial radiographs was measured. A negative metatarsal round sign, indicating correction of coronal plane metatarsal rotation, was observed in 20 of the 21 feet (95.2%) on AP radiographic evaluation. All 21 patients (100%) had obtained resolution of sesamoid subluxation on the sesamoid axial view at the final follow-up examination. The sesamoid axial position was consistently normal when the round sign was absent, and the TSP was in the normal range of 1 to 3 on the AP radiograph. Sesamoid subluxation from the normal position with the tibial sesamoid on or lateral to the crista was noted in 4 feet (19%) preoperatively and 0 feet postoperatively. This confirmed that lateral round sign of the first metatarsal head and a high TSP noted on the AP radiograph are both related to metatarsal pronation and can be corrected concurrently with coronal plane varus rotation of the first metatarsal as a part of the procedure.     

Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma.

BACKGROUND. Recent studies have identified germline mutations of the p53 tumor-suppressor gene in families with the Li-Fraumeni syndrome, a rare inherited disorder characterized by a high risk of sarcomas of bone and soft tissue, breast cancer, and other tumors. In this report, we address the possibility that some sporadic sarcomas may be associated with new germline mutations of the p53 gene, which would not be manifested as familial cancer unless the patient survived to reproduce. METHODS. We studied DNA from peripheral leukocytes of 196 patients with sarcoma and from 200 controls. Of the 196 patients with sarcoma, 15 were selected because they had had multiple primary cancers or had a family history of cancer. The entire coding sequence and splice junctions of the p53 gene were analyzed for mutations. RESULTS. Eight germline mutations were found, three in patients with no known family history of cancer and five in patients with an unusual personal or family history of cancer. Four mutations caused amino acid substitutions, and four caused stop codons. These mutations were not present in any of the 200 controls. CONCLUSIONS. New germline mutations of the p53 gene are rare among patients with "sporadic" sarcoma but may be common in patients with sarcoma whose background includes either multiple primary cancers or a family history of cancer. Diverse mutations of this gene were associated with an increased likelihood of cancer; hence, the entire gene should be considered a target for heritable mutation. It appears that the group of patients with cancer who carry germline mutations of the p53 gene is more diverse than is suggested by the clinical definition of the Li-Fraumeni syndrome. The identification of carriers could be of substantial clinical importance.     

Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies

Emerging evidence suggests that the immune system can recognize polyethylene glycol (PEG), leading to the accelerated blood clearance (ABC) of PEGylated particles. Our aim here was to study the generation of anti-PEG immunity and changes in PEGylated microbubble pharmacokinetics during repeated contrast-enhanced ultrasound imaging in rats. We administered homemade PEGylated microbubbles multiple times over a 28-d period and observed dramatically accelerated clearance (4.2?×?reduction in half-life), which was associated with robust anti-PEG IgM and anti-PEG IgG antibody production. Dosing animals with free PEG as a competition agent before homemade PEGylated microbubble administration significantly prolonged microbubble circulation, suggesting that ABC was largely driven by circulating anti-PEG antibodies. Experiments with U.S. Food and Drug Administration-approved Definity microbubbles similarly resulted in ABC and the generation of anti-PEG antibodies. Experiments repeated with non-PEGylated Optison microbubbles revealed a slight shift in clearance, indicating that immunologic factors beyond anti-PEG immunity may play a role in ABC, especially of non-PEGylated agents.