Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.     

Family structure and the mental health of children. Concurrent and longitudinal community-wide studies

This study provides a map of variations of families and some of the core relationships between types of family and the mental health of children. Family types in a poor, black urban community were defined in terms of the adults present at home. The resulting taxonomy is based on two populations: half of the community's 1964 first-grade children and families and the entire 1966 first-grade children and families. Eighty-six family types were found, falling into ten major classes. Family type was found to be strongly related over time to the child's social adaptational status (SAS) and his or her psychological well-being. The results suggest that (1) mother alone families entail the highest risk in terms of social maladaptation and psychological well-being of the child; (2) the presence of certain second adults has important ameliorative functions--mother/grandmother families being nearly as effective as mother/father families, with mother/stepfather families similar to mother alone in regard to risk; and (3) the absence of the father was less important than the aloneness of the mother in relation to risk.     

Purity aspects of higher alpha olefins

The various processes which are used commercially to manufacture detergent range alpha olefins are compared in terms of the quality of the products obtained. Thermal cracking ofn-paraffins gives the least pure olefins. Processes based on ethylene oligomerization are superior and, of these, the Shell SHOP (Shell Higher Olefins Process) process gives alpha olefins which are somewhat better in quality than those obtained from processes based on aluminum alkyl chemistry. The practical consequences of the presence of internal and vinylidene olefins, dienes and paraffins in alpha olefins are considered for the manufacture of alpha olefin sulfonates, linear alkyl-benzene, epoxides, alkyl bromides, rnercaptans and copolymers with ethylene (linear low density polyethylene). Low levels of impurities are desirable in most cases to minimize formation of unwanted byproducts, or to reduce the cost of bleeding of inert components, or to ensure that the quality of the final product meets the requirements of the marketplace. Presented at the AOCS Meeting in Toronto, May 1982.     

Metallographic characterization of rubber-modified poly(methyl methacrylates)

The microstructure of rubber-modified samples of poly(methyl methacrylates) was characterized by depositing a thin layer of gold on a polished surface and then applying the conventional techniques of metalography. Samples were prepared with a known volume fraction of rubber comprising particles of known size. It was shown that the methods of quantitative microscopy were successful in estimating these parameters. The method was also shown to provide information about crazing or cracking, which was viewed near the tip of an arrested crack. It is recommended that adoption of the metallographic method be extended to characterize other polymeric systems.     

Marital status and schizophrenia: A study of incidence and outcome.

Investigated the relationships between marital status and the incidence and prognosis of schizophrenia, based on a considerably more representative sample (N = 213) than previously available. Results provide strong evidence that the rate differentials and differences in outcome so often observed for marital status categories do not derive from inadequate or inappropriate sampling or statistical manipulation. In additional analyses, controlling for differential social class and severity of pathology, however, the relationships with prognosis could no longer be observed. These latter findings suggest that a process of selection by marriage is the more tenable interpretation of the relationships under consideration. (15 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Salivary theophylline estimation in the management of asthma in children

Simultaneous sampling was performed to determine whether saliva could replace plasma in the monitoring of theophylline dosages. Forty-eight children with moderate to severe asthma received oral theophylline preparation (usually sustained release) on a daily basis. They provided simultaneous saliva and plasma samples at routine out-patient visits. Saliva and plasma theophylline concentrations showed a wide variation between individuals, and their ratios also differed. Saliva theophylline concentrations below 7 micrograms/ml reflect plasma concentrations below 10 micrograms/ml, i.e. sub-therapeutic, while saliva concentrations above 7 micrograms/ml are consistent with therapeutic dosage. Estimation of saliva theophylline concentration on routine visits avoids the discomfort of blood sampling. It reflects whether daily oral theophylline dosage in childhood asthma is below or within the therapeutic range. The need for changes in dosage and the degree of patient-compliance with therapy can be usefully indicated.     

Extracellular recordings from patterned neuronal networks using planar microelectrode arrays

Neuronal cell networks have been reconstructed on planar microelectrode arrays (MEAs) from dissociated hippocampal pyramidal neurons. Microcontact printing (microCP) and a photoresist-liftoff method were used to selectively localize poly-L-lysine (PLL) on the surface of MEAs. Haptotaxis led to the organization of the neurons into networks localized adjacent to microelectrodes. Various grids of PLL with 2-25-microm-wide lines spaced by 50-200 microm with 15-25-microm nodes at intersection points were used to guide cell body attachment and neurite outgrowth. Bursting activity with spike amplitude attenuation was observed, and multichannel recordings detected instances of coincident firing activity. Finally, we present here an extracellular recording from a approximately 2 microm bundle of guided neurites.     

Quantifying the role of risk-taking behaviour in causation of serious road crash-related injury

This study was designed to quantify the increased risk of road crash-related injury, which can be attributed to risk-taking behaviour. A case-control study was conducted to compare motor vehicle drivers (car and bike) who had been hospitalised for injuries following crashes with population-based controls. Cases were recruited prospectively over 12 months and controls were randomly selected from license holders (car and bike) living in the same geographical location as cases. A self-administered questionnaire was used to ascertain participants' driving behaviour, general risk-taking behaviour and selected demographic characteristics. After adjusting for demographic variables, number of years of driving and total distance driven per week, logistic regression analysis showed that a high risk acceptance was associated with an eight-fold increased risk of having a crash that resulted in serious injury (OR 7.8, 95% CI 4.2-15.8). The findings of this study support the suggestion that certain host factors increase the risk of crash-related serious injury. There would appear to be a reasonable argument for persisting with injury prevention programmes, which concentrate on host as well as environment risk factor reduction.     

Measurement of femtogram quantities of protactinium in silicate rock samples by multicollector inductively coupled plasma mass spectrometry

We describe a new method for the chemical separation and analysis of Pa in silicate rock samples by isotope dilution. Our new technique has the following advantages over previous methods: (a) The initial separation of Pa from the rock matrix is carried out using anionic exchange resin and HCl-HF mixtures, avoiding the need to remove F(-) quantitatively from the sample solution prior to this step, (b) Efficient ionization of Pa is achieved using a multicollector inductively coupled plasma mass spectrometer, so that smaller sample sizes and shorter measurement times are required, compared to previous methods using thermal ionization mass spectrometry or alpha spectrometry. (c) Plasma ionization requires less efficient separation of the high field strength elements from Pa, thus reducing reagent volumes, blanks, and sample preparation times. Instrumental mass fractionation can be corrected for using admixed U of known isotopic composition. Using this method, Pa concentrations can be measured to a precision of approximately 0.5% and an accuracy of approximately 1% using only a few tens of femtograms of Pa.     

Accuracy and precision of manual baseline determination

Vibrational spectra often require baseline removal before further data analysis can be performed. Manual (i.e., user) baseline determination and removal is a common technique used to perform this operation. Currently, little data exists that details the accuracy and precision that can be expected with manual baseline removal techniques. This study addresses this current lack of data. One hundred spectra of varying signal-to-noise ratio (SNR), signal-to-baseline ratio (SBR), baseline slope, and spectral congestion were constructed and baselines were subtracted by 16 volunteers who were categorized as being either experienced or inexperienced in baseline determination. In total, 285 baseline determinations were performed. The general level of accuracy and precision that can be expected for manually determined baselines from spectra of varying SNR, SBR, baseline slope, and spectral congestion is established. Furthermore, the effects of user experience on the accuracy and precision of baseline determination is estimated. The interactions between the above factors in affecting the accuracy and precision of baseline determination is highlighted. Where possible, the functional relationships between accuracy, precision, and the given spectral characteristic are detailed. The results provide users of manual baseline determination useful guidelines in establishing limits of accuracy and precision when performing manual baseline determination, as well as highlighting conditions that confound the accuracy and precision of manual baseline determination.