Community-Based Approach to Promote Rational Use of Antibiotics in Indonesia: The Development and Assessment of an Education Program for Cadres.

BACKGROUND: Cadres play an important part in providing community-based education. This study developed and assessed an education program for cadres in Malang, Indonesia, as 'change agents' to promote rational antibiotic use. METHODS: In-depth-interviews with stakeholders (N = 55) and a subsequent group discussion with key personnel (N = 5) were conducted to develop a relevant education tool for cadres. This was followed with a pilot study with cadres (N = 40) to assess the effectiveness and acceptability of the new tool. RESULTS: Consensus was reached on the education tool media: an audio-recording (containing full information) with a pocketbook (containing key information) as a supplement. A pilot study on the new tool reported its effectiveness in improving knowledge (p < 0.001) and demonstrated a high acceptability (all respondents stated 'Strongly Agree' or 'Agree' on all statements). CONCLUSION: This study has created a model for an education tool which can potentially be implemented for cadres to educate their communities about antibiotics in the Indonesian context.

Metabolism and toxicological analysis of synthetic cannabinoids in biological fluids and tissues.

Synthetic cannabinoids, which began proliferating in the United States in 2009, have gone through numerous iterations of modification to their chemical structures. More recent generations of compounds have been associated with significant adverse outcomes following use, including cognitive and psychomotor impairment, seizures, psychosis, tissue injury and death. These effects increase the urgency for forensic and public health laboratories to develop methods for the detection and identification of novel substances, and apply these to the determination of their metabolism and disposition in biological samples. This comprehensive review describes the history of the appearance of the drugs in the United States, discusses the naming conventions emerging to designate new structures, and describes the most prominent new compounds linked to the adverse effects now associated with their use. We review in depth the metabolic pathways that have been elucidated for the major members of each of the prevalent synthetic cannabinoid drug subclasses, the enzyme systems responsible for their metabolism, and the use of in silico approaches to assist in predicting and identifying the metabolites of novel compounds and drug subclasses that will continue to appear. Finally, we review and critique analytical methods applied to the detection of the drugs and their metabolites, including immunoassay screening, and liquid chromatography mass spectrometry confirmatory techniques applied to urine, serum, whole blood, oral fluid, hair, and tissues.

Pharmacology, Toxicology, and Adverse Effects of Synthetic Cannabinoid Drugs.

Synthetic cannabinoid drugs have become an established part of the recreational drug landscape in the United States and internationally. These drugs are manufactured in clandestine laboratories internationally and distributed in the United States in smoking mixtures, use of which produces effects very similar to use of marijuana. The adverse-effect profile of the drugs has not been studied in humans and infrequently in animal models, so much of the information about their toxicity comes from emergency department and treatment reports and forensic case studies. This review considers the discovery and characterization of the endocannabinoid system, approaches to receptor-binding studies of various synthetic cannabinoids from the first wave of naphthoylindoles (e.g., JWH-018) to the emerging adamantoylindole drugs (e.g., AKB-48), and their analogs, to evaluate the potential activity of drugs in this class. Currently employed approaches to assessing functional activity of the drugs using in vitro and in vivo models is also described, and comparisons made to the effects of THC. The physiological effects of activation of the endocannabinoid system in humans are reviewed, and the physiological effects of cannabinoid use are described. Case reports of adverse events including emergency department admissions, mental health admissions, and clinical and forensic case reports are presented in detail and discussed to summarize the current state of knowledge of adverse effects, both clinical and forensic in humans, including effects on driving ability, and tissue injury and death. The greatest weight is accorded to those reports that include toxicological confirmation of use. Finally, we discuss the current status of attempts to schedule and control the distribution of synthetic cannabinoids and the relevance of receptor binding and functional activity in this context. There is growing toxicological and pharmacological evidence of impairment, psychosis, tissue injury, and isolated deaths attributable to this emerging class of drugs.

Analysis of Synthetic Cannabinoids in Botanical Material: A Review of Analytical Methods and Findings.

Synthetic cannabinoid analogs have gained a great deal of attention from the forensic community within the last four years. The compounds found to be of most interest to forensic practitioners include those of the following series: JWH, CP, HU, AM, WIN, RCS, and most recently, XLR and UR. Structurally the HU compounds are most similar in structure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana. The novel compounds include cyclohexylphenols, naphthoylindoles, naphthylmethylindoles, naphthylmethylindenes, benzoylindoles, naphthoylpyrroles, phenylacetylindoles, adamantoylindoles, and tetramethylcyclopropylindoles. Many of these compounds are cannabinoid receptor agonists and were originally synthesized for medical research purposes but have recently been appropriated into the illicit drug market. Their psychoactive effects, mimicking those of marijuana, as well as their indeterminate legal status, have made them popular for recreational use. Solutions of the compounds dissolved in organic solvents are sprayed onto botanical material and sold as "herbal incense" products via the Internet, and in smoke shops, convenience stores, and gas stations around the world. Many of the products are labeled "Not for human consumption" in an attempt to circumvent legislation that bans the sale and manufacture of certain compounds and their analogs for human use. The compounds that were first detected following forensic analysis of botanical materials included JWH-018, JWH-073, and CP 47,497 (C7 and C8 homologs). However, in the four years since their appearance the number of compounds has grown, and additional diverse classes of compounds have been detected. Governments worldwide have taken action in an attempt to control those compounds that have become widespread in their regions. This article discusses the history of synthetic cannabinoids and how they have been detected in the illicit drug market. It also discusses the analytical methods and techniques used by forensic scientists to analyze botanical products obtained via the Internet or from law enforcement investigations and arrests.

Mercury and other trace elements in sediment cores from central Texas lakes.

Metals released during fossil fuel use are important atmospheric pollutants. Mercury and other trace metals can be transferred to an aquatic environment through atmospheric deposition. In the work reported here, a number of sediment cores were retrieved from central Texas lakes in the proximity of a coal-fired power plant in search of local anthropogenic effects. Cores were collected along a transient parallel to the prevailing wind direction (S-SE) in the area. Trace element concentrations in the lignite and in effluents from the power plant showed that some elements remained constant (Al, Cu) throughout the different lignite combustion and power production processes. Some (like Cd and Se) showed an affinity for the smaller particles, whereas others (Hg) showed very low concentrations in all the solid wastes, indicating that they probably escaped with the flue gases. Sediment cores from a lake next to the power plant showed higher trace metal concentration in the upper part of the cores (more recent sediment). For example, there was as much as a tenfold increase in Hg concentration between the core bottom (10 ng/g), where the sediment was approximately 100 years old and the surface (100 ng/g). Cd and Se at surface sediments were also found to be as high as 1.6 and 3.45 microg/g, respectively. The excess metal inventory was higher for the lakes located next to the power plant than for two lakes about 30 km away.

Metal concentrations in mussel Crenomytilus grayanus and oyster Crassostrea gigas in relation to contamination of ambient sediments.

The relationship between Zn, Cu, Cd, Pb, and Ni concentrations in soft tissues of mussels and oysters and those in ambient sediments was examined. The study area was the coastal habitats of the northwestern Sea of Japan, which has a broad range of contamination due to urban sewage. Significant increases of all metals, except Ni, were observed in mussel Crenomytilus grayanus at concentrations of easily leachable metals in ambient sediments higher than 2, 100, and 800 microg/g for Cd, Cu, and Zn, respectively. Pb was accumulated by the mussels with no distinct threshold in Pb contamination of sediments. After 2 months, C. grayanus transplanted from a pristine to a contaminated locality increased in Pb up to 12%, and Cu up to 68% of concentrations of these metals in the contaminated local mussels, but Zn and Cd concentrations increased only in the excretory tissue, not in the somatic tissue, or in the soft tissue as a whole. Such regulation of metal accumulation puts limitations on the use of C. grayanus for monitoring of slightly and moderately contaminated localities. On the other hand, the oyster Crassostrea gigas showed definite accumulation of all metals, except Ni, at moderate contamination of ambient sediments. As contamination of sediments increased, increases of Pb, Zn and Cu concentrations in C. gigas slowed, possibly due to physiological control at very high metal concentrations in oyster soft tissue. Thus, the mussel C. grayanus should be used mainly for the monitoring of heavy contaminated localities, and the oyster C. gigas is more suitable as an indicator of low and moderate contamination.

Historical contamination of PAHs, PCBs, DDTs, and heavy metals in Mississippi River Delta, Galveston Bay and Tampa Bay sediment cores.

Profiles of trace contaminant concentrations in sediment columns can be a natural archive from which pollutant inputs into coastal areas can be reconstructed. Reconstruction of historical inputs of anthropogenic chemicals is important for improving management strategies and evaluating the success of recent pollution controls measures. Here we report a reconstruction of historical contamination into three coastal sites along the US Gulf Coast: Mississippi River Delta, Galveston Bay and Tampa Bay. Within the watersheds of these areas are extensive agricultural lands as well as more than 50% of the chemical and refinery capacity of the USA. Despite this pollution potential, relatively low concentrations of trace metals and trace organic contaminants were found in one core from each of the three sites. Concentrations and fluxes of most trace metals found in surface sediments at these three sites, when normalized to Al, are typical for uncontaminated Gulf Coast sediments. Hydrophobic trace organic contaminants that are anthropogenic (polycyclic aromatic hydrocarbons, DDTs, and polychlorinated biphenyls) are found in sediments from all locations. The presence in surface sediments from the Mississippi River Delta of low level trace contaminants such as DDTs, which were banned in the early 1970's, indicate that they are still washed out from cultivated soils. It appears that the DDTs profile in that sediment core was produced by a combination of erosion processes of riverine and other sedimentary deposits during floods. Most of the pollutant profiles indicate that present-day conditions have improved from the more contaminated conditions in the 1950-1970's, before the advent of the Clean Water Act.

The geographic distribution of population health and contaminant body burden in gulf of Mexico oysters.

As part of NOAA's National Status and Trends Mussel Watch Program, oysters were sampled along the Gulf of Mexico coast each winter from 1986 to 1993 (The present analysis deals with 1986-1993 Mussel Watch data; the Mussel Watch project itself continues at this printing) and analyzed for trace metal, polynuclear aromatic hydrocarbons and pesticide body burden, plus a series of biological variables designed to assess population status and health. We identified contaminant and biological variables in which large-scale spatial processes played an important role in establishing population values by examining the likelihood that neighboring bays tended to have populations with body burdens or population attributes more similar than expected by chance. Local or watershed-dependent factors, such as land use and freshwater inflow, are important in controlling the bay-to-bay variation in body burden in most contaminants. However, the bay-to-bay variations in body burden of some metals (As, Cd, Hg, Ni, Se) appear to be principally influenced by larger-scale climatic factors. These metals and the biological variable shell length demonstrated a strong degree of similarity between bays over a large regional area reminiscent of the pattern shown by climatic factors, such as temperature and precipitation. In contrast, among the organics, none of the PAHs showed even a moderately strong climatic signal. Among the pesticides, only two did (dieldrin, total DDTs). These pesticides and the biological variables, reproductive stage and Perkinsus marinus prevalence and infection intensity, had spatial patterns that suggested both a local and a regional influence to their geographic distributions. This same pattern is exhibited by freshwater runoff. Metal contaminants also behaved distinctively compared to organics in the temporal influence of climate in establishing the interannual variability in body burden. For the organics, trends in interannual variability were strongly influenced by climate, whereas spatial trends were not. In contrast, most metals were unaffected by climatic forcing both spatially and temporally. However, all of the metals having a spatial pattern strongly influenced by climate (As, Cd, Hg, Ni, Se) also exhibited interannual variations related to variations in climate.

Concentrations of arsenic, cadmium, copper, lead, mercury, and zinc in human placentas from two cities in Ukraine.

Ukraine is a highly industrialized country with major environmental problems and deteriorating reproductive health. Heavy metals are known reproductive toxins; a study was undertaken to determine whether they were present at sufficient concentrations to be playing a major role in these health problems. Placental concentrations of arsenic, cadmium, copper, lead, mercury, and zinc were determined in 200 women from the general population of two urban areas of Ukraine, Kyiv and Dniprodzerzhinsk. Arsenic was detected in only 5% of the samples, lead in 22%, and mercury in 28%. Cadmium was detected in almost all samples, with a median of 5.2 ng/g. Concentrations of lead, mercury, and cadmium were low compared to those reported elsewhere, while zinc and copper concentrations were comparable.

Exploring steric constraints on protein mutations using MAGE/PROBE.

When planning a mutation to test some hypothesis, one crucial question is whether the new side chain is compatible with the existing structure; only if it is compatible can the interpretation of mutational results be straightforward. This paper presents a simple way of using the sensitive geometry of all-atom contacts (including hydrogens) to answer that question. The interactive MAGE/PROBE system lets the biologist explore conformational space for the mutant side chain, with an interactively updated kinemage display of its all-atom contacts to the original structure. The Autobondrot function in PROBE systematically explores that same conformational space, outputting contact scores at each point, which are then contoured and displayed. These procedures are applied here in two types of test cases, with known mutant structures. In ricin A chain, the ability of a neighboring glutamate to rescue activity of an active-site mutant is modeled successfully. In T4 lysozyme, six mutations to Leu are analyzed within the wild-type background structure, and their Autobondrot score maps correctly predict whether or not their surroundings must shift significantly in the actual mutant structures; interactive examination of contacts for the conformations involved explains which clashes are relieved by the motions. These programs are easy to use, are available free for UNIX or Microsoft Windows operating systems, and should be of significant help in choosing good mutation experiments or in understanding puzzling results.

Visualizing and quantifying molecular goodness-of-fit: small-probe contact dots with explicit hydrogen atoms.

The technique of small-probe contact dot surfaces is described as a method for calculating and displaying the detailed atomic contacts inside or between molecules. It allows one both to measure and to visualize directly the goodness-of-fit of packing interactions. It requires both highly accurate structures and also the explicit inclusion of all hydrogen atoms and their van der Waals interactions. A reference dataset of 100 protein structures was chosen on the basis of resolution (1.7 A or better), crystallographic R-value, non-homology, and the absence of any unusual problems. Hydrogen atoms were added in standard geometry and, where needed, with rotational optimization of OH, SH, and NH+3 positions. Side-chain amide orientations were corrected where required by NH van der Waals clashes, as described in the accompanying paper. It was determined that, in general, methyl groups pack well in the default staggered conformation, except for the terminal methyl groups of methionine residues, which required rotational optimization. The distribution of serious clashes (i.e. non-H-bond overlap of >/=0.4 A) was studied as a function of resolution, alternate conformations, and temperature factor (B), leading to the decision that packing and other structural features would not be analyzed for residues in 'b' alternate conformations or with B-factors of 40 or above. At the level of the fine details analyzed here, structural accuracy improves quite significantly over the range from 1.7 to 1.0 A resolution. These high-resolution structures show impressively well-fitted packing interactions, with some regions thoroughly interdigitated and other regions somewhat sparser. Lower-resolution structures or model structures could undoubtedly be improved in accuracy by the incorporation of this additional information: for example, nucleic acid structures in non-canonical conformations are often very accurate for the bases and much less reliable for the backbone, whose conformation could be specified better by including explicit H atom geometry and contacts. The contact dots are an extremely sensitive method of finding problem areas, and often they can suggest how to make improvements. They can also provide explanations for structural features that have been described only as empirical regularities, which is illustrated by showing that the commonest rotamer of methionine (a left-handed spiral, with all chi values near -60 degrees) is preferred because it provides up to five good H atom van der Waals contacts. This methodology is thus applicable in two different ways: (1) for finding and correcting errors in structure models (either experimental or theoretical); and (2) for analyzing interaction patterns in the molecules themselves.

Spatial and temporal variations of trace metals in bottom sediments of Peter the Great Bay, the Sea of Japan.

New data on trace metal distribution in bottom sediments of Peter the Great Bay (the Sea of Japan) are presented. Much higher concentrations were detected near the most likely anthropogenic sources of trace metal inputs (waste water discharges from Vladivostok and Nakhodka, and the Vladivostok coastal landfill). Sediments in these contaminated areas were up to 700 ppm in Zn, 530 ppm in Pb, 7 ppm in Cd and 3 ppm in Hg. River runoff is of minor importance as a metal source in the investigated areas. The spatial distribution of trace metals outside the areas directly influenced by sewage discharges is regulated by natural processes such as sediment sorting by grain size. Based on radiometric dating of sediment cores, increases in the trace metal content of bottom sediments near Vladivostok begun in approximately 1945.

Trace metals in Gulf of Mexico oysters.

Oysters (Crassostrea virginica) from 50 to 69 locations (sites) along the Gulf of Mexico coastline, collected annually in 1986, 1987 and 1988, have been analyzed for 13 trace metals, including most of the metals of concern from an environmental quality perspective. Essentially the entire U.S. Gulf coastline was sampled, from far south Texas to far south Florida. Pooled samples of 20 oysters from three different stations at each site were analyzed by atomic absorption spectrophotometry. The concentrations found were generally less than or equal to literature values from other parts of the world thought to be uncontaminated by anthropogenic trace metal inputs. A few sites did, however, show apparent trace metal pollution and other sites gave anomalous values that cannot readily be explained by either known anthropogenic or natural causes. The range of values for the overall data set (maximum/minimum) varied from 15-fold for Mn to 624-fold for Pb, whereas the coefficient of variation (standard deviation/mean) was generally in the 50-60% range for most metals. Variations were much greater between stations than between years at a given station. Enrichments usually occurred in suites of three to four elements with Ag, Cd, Cu and Zn being the most common suite, thus several strong inter-element correlations were found. There was, however, little correlation between metal levels in oysters and in sediments from the collection sites even when sediment data were rationed to Al (sediment data are not given here). There was likewise little correlation between oyster metal levels and size, sex or reproductive stage of the oysters (data given elsewhere). Geographically, appreciably elevated (greater than 3 times average) metal levels were generally restricted to single sites within bays or estuaries, implying local control. On the other hand, regionally, Ag, Cd and Se levels were somewhat higher in Texas oysters than in those from Florida, whereas the reverse was true for As and Hg. Concentrations were lower than average for several metals in oysters from central Louisiana, especially Ag, Cd and Cu. Thus, the Mississippi River outflow and extensive offshore oil development do not seem to enrich oysters in trace metals.

Vending machines and the self-care concept.

PIP: For the past 3 years (1980-83), students at the University of Rochester in Rochester, New York, have had 24-hour access to a vending machine which dispenses over the counter medicines and contraceptives. The machine is located in a small health facility near the undergraduate residence halls. The health facility is staffed by a registered nurse who provides treatment for minor illnesses, health education information, and referrals to the university's medical center. The facility stresses self-care, and a bulletin board located near the vending machine provides numerous health education brochures. The vending machine program represents a continuation of the emphasis on self-care. Instead of fostering dependency on the nursing staff the vending machine helps the students become self-reliant in reference to assessing their own health needs. Items dispensed by the machine include condoms, condoms and foam, aspirin, Sudafed, Robitussin, Acetaminiphen, Chlortrimeton, Cepacol, bandages, and thermometers. The items are sold to the students at cost. Condoms are the most popular item, and in 1982-83, 404 condom packages, priced at US$.50, were sold. Students who know what kind of medicine or health aid they want no longer are required to obtain these items by visiting the nursing staff. The image of the nurses at the facility is no longer that of a dispenser of over the counter drugs but that of someone who provides counseling, health education, and referrals. A survey conducted in 1983 revealed that the majority of the student body knew about the vending machine. This awareness reached 100% among senior class males. The purpose of the vending machine project is to make nonprescription medicines readily available to students, to make contraceptives available on a 24-hour basis, and to emphasize that the primary role of the facility's nursing staff is to provide education, counseling, and referral services.^ieng

Absence of the booster phenomenon in serial tuberculin skin testing.

The Center for Disease has recently recommended that tuberculin skin testing of new hospital employees be done in two steps because of the so-called "booster phenomenon." To assess the feasibility of the two-step method in our hospital, we performed a pilot study using this method on all our new hospital employees during a 6-month period. From July 1, 1980, to December 31, 1980, all newly hired employees of the Strong Memorial Hospital were given a two-step tuberculin skin test as part of their preemployment health evaluation. During this time, 571 new employees were tested, 416 (73%) of whom completed both steps. The mean age of the 416 employees was 26 yr. Fourteen of 448 employees (3.1%) had positive reactions on the first test. None of the 416 employees had positive reactions on the second test. Additional visits for skin test administration, costs of informational materials, administrative expenses, and supplies added approximately $2,600 to the costs of our tuberculin skin testing program during the study period. The absence of the booster phenomenon in our employee population may be due to (1) the relatively young age of our hospital employee population who may be less likely to have remote infection with Mycobacterium tuberculosis and/or (2) the relatively uncommon occurrence of nontuberculous mycobacterial infection in our area of the country. Depending on the age of employees of an institution and its geographic location, the two-step method may not detect any additional reactors. We recommend that hospitals contemplating adoption of this method first perform a similar pilot study in order to assess the frequency of the booster phenomenon in their employee populations.

Anoxic, hypersaline basin in the northern gulf of Mexico.

A 400-square-kilometer depression in the continental slope of the northern Gulf of Mexico (approximately 27 degrees N, 91 degrees W) has been found to contain anoxic, hypersaline ( approximately 250 grams per kilogram) water in the bottom 200 meters. The interface between the brine and overlying seawater acts as a midwater seismic reflector similar to those seen in the Red Sea. The bulk chemical composition of the brine is similar to that from the Red Sea, but differences between the two in both heat content and geomorphological setting indicate different modes of origin.