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.     

Approach to the Cuban scientific activity by using publication based quantitative indicators (1985–1989)

An estimation about Cuban scientific productivity based on output indicators during the period 1985–1989 is provided. Nine international bibliographic databases and three Cuban repertories have been used. Except for journal articles, no other type of Cuban document gets worldwide recognition as they are not generally included in the international databases. The greater effort in research is made in Agriculture, Biomedicine, Chemistry and Engineering, but this last topic does not reach international visibility, since the majority of its results are published in local journals. The Cuban contribution to the mainstream of world science is increasing annually. Collaboration in high level research projects existed mainly between Cuba and either USSR, German Democratic Republic and Italy. The most productive Cuban institutions in collaborative programs are the Havana University and the Academy of Sciences.     

Water network cost optimization in a paper mill based on a new library of mathematical models

The increasing costs associated with water supply and the disposal of wastewater has stimulated industries to seek more efficient water management systems. Mathematical modelling and simulation can be a very valuable tool for the study of the multiple alternatives available whilst assessing optimum solutions for water management in industry. This study introduces a new steady state model library able to reproduce industrial water circuits. It has been implemented in a novel software framework for the representation, simulation and optimization of industrial water networks. A water circuit representing a paper mill has been modelled and simulated showing the capability to reproduce real case studies. Alternative scenarios for the water network have also been tested to assess the capability of the models to optimize water circuits minimizing total cost.     

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.     

Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.     

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.