Subchronic inhalation toxicity study of a water-dispersible polyester in rats

AQ55 is a high molecular weight, water-dispersible, amorphous polyester used in applications where the exclusion of solvents and conventional surfactants is desirable, such as water-based adhesives, coatings, emulsions, paint primers, cosmetics and detergents. Potential health effects were evaluated in rats exposed by inhalation for about 13 wk to mean concentrations of 0, 2.4, 19.6 or 199 mg/m3 AQ55 polymer. No mortality occurred and body weights were unaffected. Mean relative liver weights in all treated male groups were slightly higher than control weights, but were not judged to be treatment related. Absolute liver weights and all other organ weights except lung weights were normal. Haematology, clinical chemistries and gross pathology were unremarkable. Exposure-related changes in the 199 mg/m3 groups included increased mean absolute and relative lung weights, accumulations of macrophages and acute inflammatory cells in alveolar and bronchial lumina, and increased numbers of macrophages in sinusoids of peribronchial lymph nodes. Minor accumulation of macrophages in alveolar lumina was the only exposure-related change in the 19.6 mg/m3 group. No exposure-related effects were seen in the 2.4 mg/m3 group. AQ55 produced no systemic toxicity, and aerosols of AQ55 do not appear to be toxic to pulmonary tissues following subchronic inhalation exposure.     

Pax6 influences the time and site of origin of glial precursors in the ventral neural tube

Neuroepithelial precursors in the ventral ventricular zone (VZ) of the spinal cord generate motor neurons (MNs) and interneurons, and then a subset of precursors starts to produce oligodendrocyte progenitors (OLPs). We show that OLPs originate in the ventral-most part of the Pax6-positive VZ, which at earlier times generates somatic (Isl2/Lim3-positive) MNs. In Small eye (Pax6-deficient) mice, the origin of OLPs is shifted dorsally and both OLPs and Isl2/Lim3 MNs are delayed. We suggest that somatic MNs and OLPs are generated sequentially from a common set of MN-OL precursors whose position in the VZ is influenced by Pax6. Neuron-glia fate switching might be a preprogrammed property of these precursors or a response to feedback from newly generated neurons. OLs developed normally in explants of Isl1(-/-) spinal cords, which lack MNs, arguing against feedback control and suggesting that the neuron-glia switch is an intrinsic developmental program in a specific subset of neural precursors.     

A cost-benefit analysis of colposcopy for cervical squamous intraepithelial lesions found on Papanicolaou smear

BACKGROUND: We performed a cost-benefit analysis of a protocol for studying patients with squamous intraepithelial lesions (SIL) on Papanicolaou smears to determine whether it compared favorably with resources spent on other health programs for screening and treatment. METHODS: During a 3-year period, 424 patients with dysplastic Papanicolaou smears were examined, studied by biopsy, and treated. We calculated costs based on a model protocol and derived a cost per year of life saved for preventing death from invasive cervical carcinoma. A sensitivity analysis was performed on selected assumptions of the analysis. RESULTS: The marginal, or incremental, cost of colposcopic evaluation and treatment of Papanicolaou smears with low-grade SIL, high-grade SIL (moderate), and high-grade SIL (severe), depending on assumptions, ranged from $406 to $5746, $160 to $2263, and $85 to $1197 per year of life saved, respectively. Depending on the assumption of the rate of Papanicolaou smears with SIL in the screened population being 1.8%, 5.1%, or 11.5%, the estimated total cost of screening and treating the referral base was $1.3 million, $538,126, and $307,037, respectively. This results in the average cost per year of life saved to screen and treat low-grade SIL, high-grade SIL (moderate), and high-grade SIL (severe) to be $1105 to $68,909, $375 to $21,673, and $177 to $8831, respectively. CONCLUSIONS: Both marginal cost and average screening costs of evaluating and treating abnormal Papanicolaou smears by the protocol described in this article compare favorably with costs per year of life saved for other health care screening and treatment strategies for many assumptions. The marginal cost to perform colposcopy on patients with a Papanicolaou smear with low-grade SIL is so low that it is relatively a very effective strategy.     

Characterization of novel N,N'-disubstituted piperazines as sigma receptor ligands

sigma Receptors have been the focus of extensive studies because of their potential functional role in several important physiological and biochemical processes. To further evaluate the properties of sigma receptors, especially sigma-1 and sigma-2 subtypes, we have synthesized a series of N,N'-disubstituted piperazine compounds (1-32). The design of these compounds was based upon the early structure-activity relationship (SAR) studies of the minimum structural requirements of a molecule necessary to elicit sigma receptor binding activity. In the N-(3-phenylpropyl)piperazine series, compounds with the ethylenediamine moiety (8-11, 15-17) showed 6-20-fold higher affinity for sigma-1 and 2-40-fold higher affinity for sigma-2 relative to their corresponding amides (1-7). The (m-nitrophenethyl)piperazine 10 exhibits a subnanomolar affinity for the sigma-1 site, whereas the corresponding o-nitro compound 9 shows the highest affinity for the sigma-2 site (Ki = 4.9 nM). Compounds with a free amino terminus were designed as precursors for use as bioconjugated affinity compounds. Some of these compounds displayed high affinity for sigma-1 and moderate affinity for sigma-2 sites and are currently used for the purification and characterization of the receptor subtypes.     

A proposed model for the prediction of response to endocrine therapy in breast cancer from the estrogen receptor status of one site and the number of metastatic sites

A mathematical model for prediction of response to endocrine therapy of breast cancer has been developed based on a clonal concept of metastatic spread. The model includes an expression of the likelihood of response of an estrogen receptor-positive site and an expression of the concordance of receptor assays when multiple sites are assayed. Both of these are raised to a power function based on the number of sites of metastases to yield a predicted response rate. An excellent fit of the predictions of this mathematical model and response data from a series of patients receiving endocrine therapy was observed. This model provides a worthwhile insight into the biology of response to endocrine therapy. The model may be extended and refined through additional analyses.     

Migraines and other headaches: an approach to diagnosis and classification

Headache is a symptom that accounts for over 18 million visits to physicians each year. In an effort to resolve inconsistencies and problems with the differentiation of specific types of headache, the International Headache Society (IHS) has established a classification system. For each major type of headache, the IHS classification specifies diagnostic criteria and recognized subtypes where appropriate. Migraine headaches are commonly encountered in clinical practice. Recognition and accurate diagnosis of migraine headache depend on a thorough history, appropriate physical examination and diagnostic testing.