Outbreak of influenza in highly vaccinated crew of U.S. Navy ship

An outbreak of influenza A (H3N2) occurred aboard a U.S. Navy ship in February 1996, despite 95% of the crew's having been appropriately vaccinated. Virus isolated from ill crew members was antigenically distinct from the vaccination strain. With an attack rate of 42%, this outbreak demonstrates the potential for rapid spread of influenza in a confined population and the impact subsequent illness may have upon the workplace.     

Counting the costs: Comparing depot medroxyprogesterone acetate and norethisterone oenanthate utilisation patterns in South Africa

Background

In South Africa, where health care resources are limited, it is important to ensure that drugs provision and use is rational. The Essential Drug List includes depot medroxyprogesterone acetate (DMPA) and norethisterone oenanthate (NET-EN) as injectable progestagen-only contraceptives (IPCs), and both products are extensively used.

Objectives and Methods

Utilisation patterns of the injectable contraceptive products DMPA and NET-EN are compared in the context of current knowledge of the safety and efficacy of these agents. Utilisation patterns were analysed by means of a Pareto (ABC) analysis of IPCs issued from 4 South African provincial pharmaceutical depots over 3 financial years. A case study from rural KwaZulu-Natal, South Africa, is used to examine utilisation patterns and self-reported side effects experienced by 187 women using IPCs.

Results

IPCs accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from 2 depots increased over the 3-year period. Since DMPA was cheaper, if all NET-EN clients in the 1999/2000 financial year (annualised) had used DMPA, the 4 depots could have saved 4.95 million South African Rands on product acquisition costs alone. The KZN case study showed slightly more NET-EN (54%) than DMPA (46%) use; no significant differences in self-reported side effects; and that younger women were more likely to use NET-EN than DMPA (p = 0.0001).

Conclusions

Providing IPCs on the basis of age is not appropriate or cost effective. Rational use of these products should include consideration of the cost of prescribing one over another.     

Estimating mean exposures from censored data: exposure to benzene in the Australian petroleum industry

A retrospective assessment of exposure to benzene was carried out for a nested case control study of lympho-haematopoietic cancers, including leukaemia, in the Australian petroleum industry. Each job or task in the industry was assigned a Base Estimate (BE) of exposure derived from task-based personal exposure assessments carried out by the company occupational hygienists. The BEs corresponded to the estimated arithmetic mean exposure to benzene for each job or task and were used in a deterministic algorithm to estimate the exposure of subjects in the study. Nearly all of the data sets underlying the BEs were found to contain some values below the limit of detection (LOD) of the sampling and analytical methods and some were very heavily censored; up to 95% of the data were below the LOD in some data sets. It was necessary, therefore, to use a method of calculating the arithmetic mean exposures that took into account the censored data. Three different methods were employed in an attempt to select the most appropriate method for the particular data in the study. A common method is to replace the missing (censored) values with half the detection limit. This method has been recommended for data sets where much of the data are below the limit of detection or where the data are highly skewed; with a geometric standard deviation of 3 or more. Another method, involving replacing the censored data with the limit of detection divided by the square root of 2, has been recommended when relatively few data are below the detection limit or where data are not highly skewed. A third method that was examined is Cohen's method. This involves mathematical extrapolation of the left-hand tail of the distribution, based on the distribution of the uncensored data, and calculation of the maximum likelihood estimate of the arithmetic mean. When these three methods were applied to the data in this study it was found that the first two simple methods give similar results in most cases. Cohen's method on the other hand, gave results that were generally, but not always, higher than simpler methods and in some cases gave extremely high and even implausible estimates of the mean. It appears that if the data deviate substantially from a simple log-normal distribution, particularly if high outliers are present, then Cohen's method produces erratic and unreliable estimates. After examining these results, and both the distributions and proportions of censored data, it was decided that the half limit of detection method was most suitable in this particular study.     

Age-related differences in sensitivity to the antinociceptive effects of opioids in male rats. Influence of nociceptive intensity and intrinsic efficacy at the mu receptor

RATIONALE: Despite the widespread popularity of opioid analgesics, significant differences in the potency and effectiveness of these drugs are often observed across age groups. OBJECTIVES: The purpose of this investigation was to examine age-related differences in sensitivity to the antinociceptive effects of mu opioids and to identify the conditions under which these differences are most apparent. METHODS: In a warm-water tail-withdrawal procedure, young (3 months) and aged (24 months) male rats were habituated to restraint and the latencies to remove their tails from 50 degrees C (low nociceptive intensity) and 55 degrees C (high nociceptive intensity) water were measured. Opioids possessing a range of intrinsic efficacy at the mu receptor (morphine, levorphanol, buprenorphine, butorphanol, nalbuphine, nalorphine) were examined. RESULTS: Young and aged rats were equally sensitive to the antinociceptive effects of morphine, levorphanol, and buprenorphine when tested at the low nociceptive intensity. When these drugs were tested at the high nociceptive intensity, differences between the two age groups became apparent, such that aged rats were significantly more sensitive to the antinociceptive effects of these drugs than young rats. Differences between age groups were most apparent when butorphanol, nalbuphine, and nalorphine were tested, in that each of these drugs produced maximal levels of antinociception in aged rats under conditions in which they failed to produce antinociceptive activity in young rats. Under conditions in which lower efficacy opioids failed to produce antinociceptive activity in young rats, they antagonized the effects of morphine in drug combination tests. CONCLUSIONS: These data may be taken as evidence that aged male rats are more sensitive to the antinociceptive effects of mu opioids than young male rats, and that age-related differences in opioid sensitivity are most apparent when lower efficacy opioids and higher nociceptive intensities are employed during behavioral testing.     

Vitellogenin induction in painted turtle, Chrysemys picta, as a biomarker of exposure to environmental levels of estradiol

Ponds within cattle farms often support turtle and fish populations and are impacted by manure runoff. Cattle excrete metabolized (glucuronide-conjugated) hormones in feces and urine into these ponds, and bacteria cleave the glucuronide metabolites to active steroids, which can be stable for several weeks in wastewater. The objectives of this study were to (1) assess levels of xenoestrogens found in ponds near livestock pastures; and (2) assess whether these levels of xenoestrogens induce vitellogenin (VTG) in painted turtles in the laboratory and field. We collected water twice, 6 weeks apart, and placed turtle traps weekly into two ponds, which receive runoff from beef cattle pastures, and into one pond with no cattle farm effluents. Water E(2) levels were analyzed using C(18) solid phase extraction disks and detected in a radioimmunoassay (RIA). Plasma was collected from painted turtles (Chrysemys picta) captured from these ponds and VTG levels were measured via enzyme linked immunosorbent assay (ELISA). Nine additional turtles were collected from a pond at the South Carolina Botanical Gardens, which receives no farm runoff, and were exposed in the laboratory to nominal concentrations of 0.15, 1.5, and 15 ng/l estradiol (static renewal) over a 28-day period, followed by 14 days in clean water. Plasma samples were taken weekly for VTG measurement via ELISA. Levels of free estradiol in the water column of farm ponds range from 0.05 to 1.80 ng/l, as measured by RIA, and up to 7.4 ng/l as measured by ER-beta binding affinity. This is similar to what has been reported in streams receiving sewage treatment works (STW) effluents. In the laboratory, plasma VTG in male painted turtles could not be induced even at the high E(2) dose (9.45 ng/l) after 28 days. In the field, VTG levels were induced only in females when compared with animals from the SC Botanical Gardens. Adult male turtles need to be primed with high doses of E(2) prior to being able to respond to exogenous E(2). Given that males would not typically be sensitized in the wild, environmentally relevant levels of E(2) may not be sufficient to affect them. However, higher VTG levels in females could potentially change their reproductive fitness by altering egg size or by shifting energy allocations away from other survival needs. Long-term studies are needed to study potential impacts of VTG induction on female turtle reproductive success.     

Oestrogen and the cardiovascular system: the good, the bad and the puzzling

The concept that oestrogen replacement therapy is cardioprotective has been challenged recently by the negative results of randomized clinical trials in coronary heart disease. These data have come at a time of rapid advances in our understanding of the cellular mechanisms of oestrogen. In particular, the cloning of the classical oestrogen receptor (ERalpha), the identification of a novel ER isoform (ERbeta), the availability of specific ERalpha and ERbeta knockout mice models, and the elucidation of receptor functions and signalling pathways linked to non-genomic actions of oestrogen are helping to unravel this complex biology. In this article, these advances will be discussed with particular emphasis on the regulation of nitric oxide synthesis by oestrogen. Furthermore, the puzzling issues that have emerged and the potential for development of novel and specific therapeutic approaches will be highlighted.     

Quaternary ammonium palmitoyl glycol chitosan--a new polysoap for drug delivery

A new polysoap, quaternary ammonium palmitoyl glycol chitosan (GCPQ, M(w)=178,000 g mole(-1)) with drug solubilising potential has been synthesised and characterised. In solution hydrophobic domains of GCPQ polymeric micelles were identified by the hypsochromic shift in the lambda(max) of methyl orange and by the increase in the ratio of the fluorescence emission intensity of the third and first pyrene vibronic peaks (I(3)/I(1)). At high aqueous concentrations (>10 mg ml(-1)) GCPQ presents as a gel which solubilises pyrene (2.5 mM, normal solubility in water approximately 2 microM) on probe sonication. Dilution of the gel to a liquid solution of polymeric micelles (< or =3.75 mg ml(-1) of GCPQ), results in the observation of fluorescent pyrene excimers (excited dimers) and a high excimer to monomer fluorescence ratio (I(E)/I(M)). However, attempts to solubilise pyrene at a concentration of 2.5 mM in a liquid solution of GCPQ (3.75 mg ml(-1)) results in a reduced I(E)/I(M) value and pyrene precipitation. Viscometry measurements show a more compact conformation for the polymer solubilising pyrene than the polymer alone. The polymer is non-haemolytic when present as the liquid solution and relatively non cytotoxic. In conclusion, a new biocompatible polysoap (potential drug solubiliser) is described which forms hydrophobic domains in solution and shows hysteresis in its solubilisation of pyrene.     

Tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis of human melanoma is regulated by smac/DIABLO release from mitochondria

In previous studies we have shown that the sensitivity of melanoma cell lines to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis was determined largely by the level of expression of death receptor TRAIL receptor 2 on the cells. However, approximately one-third of melanoma cell lines were resistant to TRAIL, despite expression of high levels of TRAIL receptor 2. The present studies show that these cell lines had similar levels of TRAIL-induced activated caspase-3 as the TRAIL-sensitive lines, but the activated caspase-3 did not degrade substrates downstream of caspase-3 [inhibitor of caspase-activated DNase and poly(ADP-ribose) polymerase]. This appeared to be due to inhibition of caspase-3 by X-linked inhibitor of apoptosis (XIAP) because XIAP was bound to activated caspase-3, and transfection of XIAP into TRAIL-sensitive cell lines resulted in similar inhibition of TRAIL-induced apoptosis. Conversely, reduction of XIAP levels by overexpression of Smac/DIABLO in the TRAIL-resistant melanoma cells was associated with the appearance of catalytic activity by caspase-3 and increased TRAIL-induced apoptosis. TRAIL was shown to cause release of Smac/DIABLO from mitochondria, but this release was greater in TRAIL-sensitive cell lines than in TRAIL-resistant cell lines and was associated with down-regulation of XIAP levels. Furthermore, inhibition of Smac/DIABLO release by overexpression of Bcl-2 inhibited down-regulation of XIAP levels. These results suggest that Smac/DIABLO release from mitochondria and its binding to XIAP are an alternative pathway by which TRAIL induces apoptosis of melanoma, and this pathway is dependent on the release of activated caspase-3 from inhibition by XIAP and possibly other inhibitor of apoptosis family members.