What caused extinction of the Pleistocene megafauna of Sahul?

During the Pleistocene, Australia and New Guinea supported a rich assemblage of large vertebrates. Why these animals disappeared has been debated for more than a century and remains controversial. Previous synthetic reviews of this problem have typically focused heavily on particular types of evidence, such as the dating of extinction and human arrival, and have frequently ignored uncertainties and biases that can lead to misinterpretation of this evidence. Here, we review diverse evidence bearing on this issue and conclude that, although many knowledge gaps remain, multiple independent lines of evidence point to direct human impact as the most likely cause of extinction.

Facing nuclear reality.

Nuclear weapons that are safe and secure, reliable, survivable, and effective will be a critical element of this nation's deterrent for the foreseeable future. The existence of these weapons reflects the tension that exists between the United States and the Soviet Union. Nuclear test bans will not reduce or eliminate nuclear weapons or this tension. Imprudent nuclear test bans, however, could impair the viability of this vital element of U.S. security. New, more restrictive test limitations would not enhance our national security. They do not address the two most important issues-namely, major reductions in strategic and conventional forces of both the Soviet Union and the United States, and a widespread lessening of tension between our two countries. In fact, it is conceivable that the diversion of political attention from arms reduction efforts and the distrust generated by test-ban verification problems could actually increase tensions between the two countries. We believe that more restrictive test limitations or a nuclear test ban should be considered only as part of an integrated and comprehensive approach to arms control. We must reduce the numbers of the most destabilizing weapons and the overall size of the strategic arsenals through negotiations. A restrictive test ban may be a proper last step in our quest for nuclear arms control and a stable peace, but it would, in our opinion, be an imprudent first step. Further test limitations will be consistent with increased stability and decreased tension between the United States and the Soviet Union only if they are instituted after major stabilizing reductions are made in the strategic nuclear and conventional forces of both countries.

Dating pleistocene archeological sites by protein diagenesis in ostrich eggshell.

Eggshells of the African ostrich (Struthio camelus), ubiquitous in archeological sites in Africa, have been shown by laboratory simulation experiments to retain their indigenous organic matrix residues during diagenesis far better than any other calcified tissue yet studied. The rate of L-isoleucine epimerization to D-alloisoleucine follows reversible first-order kinetics and has been calibrated for local temperature effects and used to estimate the age range of stratified archeological sites. Age estimates are consistent with radiocarbon dates from several stratified archeological sites. With adequate calibration, this technique can provide accurate ages to within 10 to 15 percent for strata deposited within the last 200,000 years in the tropics and the last 1,000,000 years in colder regions such as China.

A penalty method to model particle interactions in DNA-laden flows.

We present a hybrid fluid-particle algorithm to simulate flow and transport of DNA-laden fluids in microdevices. Relevant length scales in microfluidic systems range from characteristic channel sizes of millimeters to micron scale geometric variation (e.g., post arrays) to 10 nanometers for the length of a single rod in a bead-rod polymer representation of a biological material such as DNA. The method is based on a previous fluid-particle algorithm in which long molecules are represented as a chain of connected rods, but in which the physically unrealistic behavior of rod crossing occurred. We have extended this algorithm to include screened Coulombic forces between particles by implementing a Debye-Hückel potential acting between rods. In the method an unsteady incompressible Newtonian fluid is discretized with a second-order finite difference method in the interior of the Cartesian grid domain; an embedded boundary volume-of-fluid formulation is used near boundaries. The bead-rod polymer model is fully coupled to the solvent through body forces representing hydrodynamic drag and stochastic thermal fluctuations. While intra-polymer interactions are modeled by a soft potential, polymer-structure interactions are treated as perfectly elastic collisions. We demonstrate this method on flow and transport of a polymer through a post array microchannel in 2D where the polymer incorporates more realistic physical parameters of DNA, and compare to previous simulations where rods are allowed to cross. We also show that the method is capable of simulating 3D flow in a packed bed micro-column.

Bacterial enzymatic resistance: beta-lactamases and aminoglycoside-modifying enzymes.

Numerous novel beta-lactamases and aminoglycoside-modifying enzymes with altered substrate profiles continue to be identified. Plasmid-mediated transmission of many of these enzymes readily occurs due to inclusion of the encoding genes in mobile gene cassettes. Recent crystallographic determinations of the structures of metallo-beta-lactamases and aminoglycoside-modifying enzymes provide the opportunity for the rational design of inhibitors.

What's new in the antibiotic pipeline.

Many advances have recently been made in the development of chemotherapeutic agents for bacterial infections. As a consequence of problematic antimicrobial-resistant bacteria, research is now directed towards narrow-spectrum agents rather than broad-spectrum agents. Further, orally active agents have always been desirable, but today's cost-saving environment, in line with a desire to minimize treatment costs, values reduced administration costs and keeping patients out of the hospital. There has been a recent increase in research into orally active antibacterial agents, such as carbapenems and cephalosporins, and non-glycopeptide natural products.

Aminoglycoside resistance among Danish blood culture isolates of coagulase-negative staphylococci.

A sample of 137 coagulase-negative staphylococci isolated from blood cultures in Denmark over a 4-month period during 1992-1993 were tested for aminoglycoside resistance and for the presence of aminoglycoside-modifying enzymes. This was done on the basis of minimum inhibitory concentrations (MICs) measured by agar dilution, inhibition zone diameter by disk diffusion, and DNA dot blot analysis. Using the National Committee for Clinical Laboratory Standards (NCCLS) MIC breakpoints, 5%, 46%, 57%, and 63% of the strains were resistant to netilmicin, amikacin, gentamicin and tobramycin, respectively. The large majority of resistant staphylococci strains produced the bifunctional AAC(6)-III+APH(2") enzyme. The presence of AAC(6)-III+APH(2") explains the high level of resistance to gentamicin, kanamycin and tobramycin. In contrast to our results. Staphylococcus haemolyticus strains are usually reported to be more resistant than Staphylococcus epidermidis strains.

Aminoglycoside resistance mechanisms in Enterobacteriaceae and Pseudomonas spp. from two Danish hospitals: correlation with type of aminoglycoside used.

Sixty-two aminoglycoside-resistant Gram-negative enteric bacteria were isolated over a 3-year period from two hospitals (Bispebjerg and Esbjerg) among a total of almost 270,000 isolates. These hospitals were selected because of their different aminoglycoside policies during the years investigated. At Bispebjerg Hospital the principal aminoglycoside used was tobramycin, while gentamicin was the first choice at Esbjerg Hospital. Escherichia coli was the most frequently found aminoglycoside-resistant species. Among the 61 aminoglycoside-resistant strains studied, resistance was due to aminoglycoside-modifying enzymes in all except two Xanthomonas maltophilia strains. The ANT(2") enzyme occurred significantly more often at Esbjerg Hospital (p = 0.001), while enzymes of the AAC(3) or AAC(6') moieties were more common, but not significantly so, at Bispebjerg Hospital. The phenotypic pattern of aminoglycoside resistance, as determined by disc diffusion, correlated 100% with the ANT(2") and AAC(3)-V (the two most common enzymes among the isolates) genotype of the organisms as established using DNA probes. Median minimum inhibitory concentrations (MICs) (mg/l) for clinically utilized aminoglycosides were: amikacin (1.6), gentamicin (25.0), kanamycin (50.0), netilmicin (1.6-25.0) and tobramycin (12.5-50.0). Isolates from Bispebjerg Hospital revealed significantly higher MICs for netilmicin and tobramycin (p < 0.01) as compared to isolates from Esbjerg Hospital.

Thermoacoustic energy effects in electrical arcs.

Electrical arcs commonly occur in electrical injury incidents. Historically, safe work distances from an energized surface along with personal barrier protection have been employee safety strategies used to minimize electrical arc hazard exposures. Here, the two-dimensional computational simulation of an electrical arc explosion is reported using color graphics to depict the temperature and acoustic force propagation across the geometry of a hypothetical workroom during a time from 0 to 50 ms after the arc initiation. The theoretical results are compared to the experimental findings of staged tests involving a mannequin worker monitored for electrical current flow, temperature, and pressure, and reported data regarding neurologic injury thresholds. This report demonstrates a credible link between electrical explosions and the risk for pressure (acoustic) wave trauma. Our ultimate goal is to protect workers through the design and implementation of preventive strategies that properly account for all electrical arc-induced hazards, including electrical, thermal, and acoustic effects.

Lactation and genital involution effects of a new low-dose oral contraceptive on breast-feeding mothers and their infants.

PIP: Because of confusing experimental evidence on the effect of oral contraceptives on lactation, a new experiment administering a combination of norethindrone 1 mg with mestranol 0.08 mg or a placebo labelled as this contraceptive to 50 nursing mothers (Group I) was conducted in 1967 to try and obtain conclusive results. 50 other nursing patients (Group II) were used as controls. Quantity and quality of breast milk was determined by daily measurements of baby weight gain, supplemental feedings, and length of lactation. Baby weight gain in Group I mothers using the contraceptives was significantly lower than the control group, despite increase in supplemental calories given to the infants. The duration of lactation was also decreased significantly. This effect was more pronounced in primiparas when compared with those with previous lactation success. Involution of infant breast tissue and maternal genitals were examined and revealed no apparent effects from the contraceptive treatment. Oral contraceptives appear to be contraindicated in lactating mothers.^ieng

Mechanism of amikacin resistance in Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

We studied 27 amikacin-resistant isolates of Pseudomonas aeruginosa from patients with cystic fibrosis to determine the mechanism of antibiotic resistance. The absence of aminoglycoside-modifying enzymes (AMEs) in these isolates was inferred from the failure of DNA probes for 16 candidate AMEs to hybridize with DNA harvested from these isolates and, in addition, the uniform reduction in susceptibility to a panel of aminoglycosides. In eight of the 27 isolates that were resistant to amikacin at high levels (minimum inhibitory concentration > or = 250 micrograms/ml), plasmids were not detected. The ribosomes of these isolates were sensitive to amikacin in studies of protein synthesis by cell "ghosts." These data suggest that impermeability is the mechanism of amikacin resistance in isolates of P. aeruginosa from patients with cystic fibrosis. Recognition of this mode of resistance may be difficult, as some isolates appeared to be borderline susceptible when tested against aminoglycosides other than amikacin, or had zone diameters that overlapped those obtained with amikacin-susceptible isolates.

Antibacterial drug discovery: is small pharma the solution?

Although antibacterial research has declined in many larger pharmaceutical companies, small companies have begun to fill in the gap. Antibacterial discovery research is currently being conducted in at least 35 small companies. One successful approach taken by small pharma has been to continue clinical programmes that were abandoned by large companies. Issues surrounding these activities, as well as proposed changes, are outlined.

The changing nature of aminoglycoside resistance mechanisms and prevalence of newly recognized resistance mechanisms in Turkey.

OBJECTIVE: To determine the most frequently occurring individual and combined resistance mechanisms in Gram-negative bacteria resistant to any of the clinically available aminoglycosides in Turkey, and to compare these mechanisms with those found in smaller, earlier studies. METHODS: Aminoglycoside resistance mechanisms in Gram-negative isolates resistant to either gentamicin, tobramycin, netilmicin or amikacin collected in different regions of Turkey were evaluated both phenotypically and genotypically using 12 aminoglycosides and up to 22 aminoglycoside resistance gene probes. RESULTS: Among 696 aminoglycoside-resistant Gram-negative bacteria, resistance rates were very high for gentamicin (94.5%), tobramycin (82.4%), netilmicin (53.6%), and amikacin (49.7%). Although isepamicin was the most active aminoglycoside against Gram-negative bacteria, increased resistance (29.7%) was found and resistance rates were higher than those in most of the other countries surveyed in earlier studies. The most common aminoglycoside resistance mechanisms (AAC(3)-II (GTN), AAC(6')-I (TNA), and ANT(2")-I (GT)) in the earlier studies were also found in the present isolates of Klebsiella spp., Enterobacter spp. and Escherichia coli, with increased complexity. In addition to these old mechanisms, two new aminoglycoside resistance mechanisms, namely AAC(6')-III (TNAI) and AAC(6')-IV (GTNA), were also found at significant frequencies (11.9% and 26.9%, respectively) in these isolates of Enterobacteriaceae (n = 435). Among the isolates of Pseudomonas spp. (n = 150), in addition to the increased complexity of enzymatic resistance mechanisms (AAC(3)-I (16.6%), AAC(6')-II (29.3%), AAC(6')-III (19.3%), ANT(2")-I (40%)), permeability resistance seemed to be responsible for the high rates of resistance to aminoglycosides. CONCLUSION: The results of this study indicated increased resistance to clinically available aminoglycosides, including isepamicin, even though it was the most active, as a result of both the presence of new aminoglycoside resistance mechanisms and the increased complexity of all mechanisms, including permeability resistance, particularly in Pseudomonas in Turkey.

Antibacterial structure-activity relationships obtained with resistant microorganisms I: Inhibition of R-factor resistant Escherichia coli by tetracyclines.

Aparent partition coefficients and inhibitory activities against sensitive and resistant Escherichia coli were determined for 14 tetracyclines. The difference in the kinetics of inhibition of the two organisms is discussed in terms of their permeabilities. The partition coefficients were determined in an octanol-buffer system. Values for eight compounds were in general agreement with the literature; values for the remaining six compounds had not been reported previously. Growth of the organisms was determined by a single-point turbidimetric method in the presence and absence of tetracyclines. Inhibitory activities were obtained by a kinetic treatment. Derived rate constants for the sensitive organism were linearly related to antibiotic concentration. For the resistant organism and 12 compounds, the derived rate constants and antibiotic concentration were related in a manner typical of saturation kinetics. These inhibitory activities were related to the partition coefficients, while activities against the sensitive strain were not. These findings suggest that activity against the resistant strain is permeability controlled but that activity against the sensitive strain has a different rate-determining step.

The application of molecular techniques for the study of aminoglycoside resistance.

Aminoglycosides have been cinically used since 1944. Although this class of antibacterial agents has some nephrotoxicity and ototoxtcity issues, they continue to be part of the hospital armamentarium because of then rapid bactericidal activity, especially in combination with ß-lactams. Bacterial resistance to aminoglycosides can be caused by modifying enzymes, changes in cell permeability, and changes in the cellular target. The clinical observation of high levels of aminoglycoside resistance most often results from the acquisition of genes that encode modifying enzymes and are often plasmid-borne. Aminoglycosides are inactivated by three classes of enzymes:

Surface-active substrates for Raman and luminescence analysis.

This paper describes the development of active materials for optically enhanced Raman and fluorescence spectroscopy. The substrates for surface-enhanced Raman scattering investigated in this study involved silver-coated microspheres on glass plates. The effect of various experimental parameters, such as angle of incidence and excitation wavelength, were investigated. The substrate used for surface luminescence analysis consisted of a cellulose membrane coated with fumed silica microparticles, to enhance the sensitivity of analysis. Examples of analysis of benzo[a]pyrene and its derivatives are used to illustrate the efficacy of the analytical techniques.