(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), a novel bis-naphthalimide with potent nonselective tumoricidal activity in vitro

(R,R)-2,2'-[1,2-ethanediylbis[imino(1-methyl-2,1-ethanediyl)]]- bis[5-nitro-1H-benz[de]isoquinoline-1,3-(2H)-dione] dimethanesulfonate (DMP 840), is a bis-naphthalimide anticancer tumoricidal agent currently in phase I clinical trials. DMP 840 exhibits curative activity in human tumor xenografts, where it shows selectivity for human solid tumors over murine leukemias. In contrast to the selectivity found for DMP 840 in vivo, DMP 840 exhibits potent antiproliferative activity in vitro against a variety of human and murine leukemia and solid tumor cell lines in culture, with inhibitory doses that reduce the number of treated cells to one half (IC50) values ranging from 2.3 to 53 nM. DMP 840 was growth inhibitory to three doxorubicin-resistant cell lines with IC50 values also in the nanomolar range. Clonogenic survival experiments showed that DMP 840 was equally cytotoxic to both exponentially growing and quiescent human clone A colon carcinoma cells. A 1-h incubation of DMP 840 (1.22-12 microM) caused 5-log cell kill in KB-3-1 human epidermoid carcinoma, clone A human colon carcinoma, and L1210 murine leukemia cell lines. The rapid cell killing by DMP 840 in clonogenic survival experiments and initial mechanism of action studies was consistent with a DNA-interactive mechanism for DMP 840 cytotoxicity. Mechanism of action studies in L1210 leukemia cells demonstrated that DMP 840 inhibited the incorporation of thymidine and uridine into DNA and RNA with IC50 values of 0.55 and 0.08 microM, respectively. DMP 840 produced DNA single-strand breaks in a dose-dependent manner. Double-strand breaks were not observed with DMP 840 treatment, even at higher concentrations of compound. Chinese hamster ovary (CHO) and P388 cells resistant to camptothecin and containing a mutant form of topoisomerase I were also used to evaluate whether DMP 840 was cross-resistant with agents active against topoisomerase I. While the CHOR line was 163-fold resistant to camptothecin, the CHOR line was only 1.7-fold resistant to DMP 840. In summary, DMP 840 is a DNA-interactive agent that demonstrates excellent antiproliferative activity in vitro against cultured tumor cells from both human and murine sources. Its mechanism of tumoricidal activity may be novel.     

Family psychosocial screening: should we focus on high-risk settings?

The objective of this study was to address the question of whether or not psychosocial screening should be focused on "high-risk" populations. A cross-sectional survey of mothers of young children was conducted in various clinics: 758 in teaching clinics, 444 in private practices, and 202 at a military clinic. The self-administered questionnaire covered demographic factors, problems in mothers family of origin, maternal depression, and substance abuse. Mothers in the teaching clinics were younger and had less education and lower incomes than mothers in private practices, with intermediate levels in the military clinic. However, a substantial proportion of mothers seen in all sites reported psychosocial problems. Approximately 20% of mothers in all sites reported a family history of alcoholism. Positive screens for maternal depression ranged from about 15% to 35%. Binge drinking was reported by 10% to 20% at different sites. Psychosocial problems were common even among families seen in "low-risk" settings. Focusing screening only on high-risk clinics would miss many families with psychosocial problems.     

Improvement in the sociomedical support for the urban family under current conditions

Medico-demographic processes and socio-hygienic characteristics of the population of a large city, both at an individual and familial levels, as well as territorial characteristics of residence, should be taken into consideration when developing measures for medicosocial care of the population. Analysis of the attitude of 380 city families to the activities, personality, and professional skills of local therapists and pediatricians and to the idea of primary health care rendered by a physician of a general profile demonstrated an increased activity of the families in the "physician-patient" system and confirmed the necessity of improving medicosocial care of a city family, expansion of prophylactic work with the population with due consideration for factors which have an impact on population health.     

Molecular computation of solutions to combinatorial problems

The tools of molecular biology were used to solve an instance of the directed Hamiltonian path problem. A small graph was encoded in molecules of DNA, and the "operations" of the computation were performed with standard protocols and enzymes. This experiment demonstrates the feasibility of carrying out computations at the molecular level.     

Recovered memories of abuse in women with documented child sexual victimization histories

This study provides evidence that some adults who claim to have recovered memories of sexual abuse recall actual events that occurred in childhood. One hundred twenty-nine women with documented histories of sexual victimization in childhood were interviewed and asked about abuse history. Seventeen years following the initial report of the abuse, 80 of the women recalled the victimization. One in 10 women (16% of those who recalled the abuse) reported that at some time in the past they had forgotten about the abuse. Those with a prior period of forgetting--the women with "recovered memories"--were younger at the time of abuse and were less likely to have received support from their mothers than the women who reported that they had always remembered their victimization. The women who had recovered memories and those who had always remembered had the same number of discrepancies when their accounts of the abuse were compared to the reports from the early 1970s.     

Apolipoprotein E*3-Leiden transgenic mice as a test model for hypolipidaemic drugs

PURPOSE: We report an investigation into the distribution of proteoglycans (PGs) in normal, organ-cultured and dextran-treated human corneas. METHODS: Immunogold labeling was carried out at the electron microscope level to localize keratan sulphate (KS), chondroitin sulphate (CS), and heparan sulphate (HS) PGs. RESULTS: High levels of labeling for CS was found in the epithelium, endothelium, and keratocytes, with light labelling present in the basement membranes and the corneal stroma. Labeling for HS was present in the epithelium, endothelium, and keratocytes, with intense labeling present at the endothelium/Descemet's membrane interface and the epithelium/Bowman's layer interface. Large filaments were also observed in these regions in cuprolinic blue-stained specimens. Keratan sulphate was present at high levels in the stroma and the basement membranes with low levels present within the keratocytes, epithelium, and endothelium. The pattern of KS labeling along the collagen fibrils in the stroma sometimes showed evidence of periodicity. Organ-cultured corneas had extensive collagen-free "lakes," the interior of which immunolabeled positively for KS and showed staining with cuprolinic blue. The lakes were greatly reduced in the dextran-treated samples. CONCLUSION: This investigation determined the ultrastructural distribution of KS, CS, and HS PGs in human cornea and showed that organ culture is associated with a change in distribution of stromal PGs.     

Measurement of activin in biological fluids by radioimmunoassay, utilizing dissociating agents to remove the interference of follistatin

BACKGROUND: The aim of this morphological investigation was to obtain more information about the structural and cellular mechanisms of interalveolar pore formation in postnatal lung development. Assuming that alveolar pore formation is related to the general thinning of interalveolar walls observed in the postnatal period, we have focused our attention on the topographical relationship between epithelial cells and connective tissue in the septum. Thereby we tried to formulate a uniform concept of pore formation. METHODS: After fixation with glutaraldehyde and osmiumtetroxide, tissue blocks of rat lungs aged 44 days were embedded in Epon. Serial sections were obtained in order to analyse precisely pores and supposed sites of pore formation (type II cells and thin spots in transsections of interalveolar walls). RESULTS: We made the following observations: there are pores with or without type II cells in the neighbourhood, and "pre-pores" with either fully transseptal granular pneumocytes, or thin spots in the interalveolar wall consisting of one or two layers of type I cell epithelium or of type II and type I cells without intervening connective tissue. CONCLUSIONS: From these findings we deduce that there is a general principle of interalveolar pore formation which consists in the formation of transseptal interepithelial cell contacts (i.e., between cells of type II and type I or type I and type I), promoted by the thinning of interalveolar walls in the stage of microvascular maturation. Within the zone of contact the cells thin out and give way to form an interalveolar opening.     

Nonsanction seat belt law enforcement: a modern day tale of two cities

This paper describes the implementation and evaluation of a nonsanction seat belt law enforcement program in two experimental communities of contrasting size in a state with a mandatory belt law. The main ingredients of the program were seat belt "salutes," public information and education, and limited use of inexpensive economic incentives. Driver shoulder belt use data collected before, during, and after the experimental programs, compared to similar data collected in a comparison community, showed the approach to be effective. While standard seat belt enforcement activities without incentives have been shown to be effective, many police departments, especially in smaller communities, are reluctant to make wholesale increases in seat belt citations. Although requiring some additional level of manpower and resources, a nonsanction approach to seat belt law enforcement can provide an alternate way of increasing belt use in these communities.     

Potential difference across subcellular particle membranes. II. Compensation method of measurement

"Zero-loop" of the molecular potential transformer of submitochondrial particles (SMP) is separated from the remaining electron transfer chain by rotenone, and its e.m.f. ET=0,003+RT/2F in [NADP X H] [NAD+]/[NADP+] [NAD X H] volts is used in the compensative method of measurement of the potential difference across the SMP membrane (delta USMP). The phospholipid membrane, measuring the concentration of the penetrating anions in the solution contained SMP, is used as "zero-indicators". This concentration drops monotonically with increase in delta USMP. Delta USMP is equal to ET when the addition of substrates of transhydrogenase reaction with definite ET does not change the potential across phospholipid membrane.     

Adapting reflexes controlling the human posture

Doubt about the role of stretch reflexes in movement and posture control has remained in part because the questions of reflex "usefulness" and the postural "set" have not been adequately considered in the design of experimental paradigms. The intent of this study was to discover the stabilizing role of stretch reflexes acting upon the ankle musculature while human subjects performed stance tasks requiring several different postural "sets". Task specific differences of reflex function were investigated by experiments in which the role of stretch reflexes to stabilize sway doing stance could be altered to be useful, of no use, or inappropriate. Because the system has available a number of alternate inputs to posture (e.g., vestibular and visual), stretch reflex responses were in themselves not necessary to prevent a loss of balance. Nevertheless, 5 out of 12 subjects in this study used long-latency (120 msec) stretch reflexes to help reduce postural sway. Following an unexpected change in the usefulness of stretch reflexes, the 5 subjects progressively altered reflex gain during the succeeding 3-5 trials. Adaptive changes in gain were always in the sense to reduce sway, and therefore could be attenuating or facilitating the reflex response. Comparing subjects using the reflex with those not during so, stretch reflex control resulted in less swaying when the task conditions were unchanging. However, the 5 subjects using reflex controls oftentimes swayed more during the first 3-5 trials after a change, when inappropriate responses were elicited. Four patients with clinically diagnosed cerebellar deficits were studied briefly. Among the stance tasks, their performance was similar to normal in some and significantly poorer in others. Their most significant deficit appeared to be the inability to adapt long-latency reflex gain following changes in the stance task. The study concludes with a discussion of the role of stretch reflexes within a hierarchy of controls ranging from muscle stiffness up to centrally initiated responses.