Protection of cerebral microcirculation, mitochondrial function, and electrocortical activity by small-volume resuscitation with terlipressin in a rat model of haemorrhagic shock.

BACKGROUND: During early treatment of haemorrhagic shock, cerebral perfusion pressure can be restored by small-volume resuscitation with vasopressors. Whether this therapy is improved with additional fluid remains unknown. We assessed the value of terlipressin and lactated Ringer's solution (LR) on early recovery of microcirculation, tissue oxygenation, and mitochondrial and electrophysiological function in the rat cerebral cortex. METHODS: Animals treated with LR replacing three times (3LR) the volume bled (n=26), terlipressin (n=27), terlipressin plus 1LR (n=26), 2LR (n=16), or 3LR (n=15) were compared with untreated (n=36) and sham-operated rats (n=17). In vivo confocal microscopy was used to assess cortical capillary perfusion, changes in tissue oxygen concentration, and mitochondrial membrane potential and redox state. Electrophysiological function was assessed by cortical somatosensory evoked potentials, spinal cord dorsum potential, and peripheral electromyography. RESULTS: Compared with sham treatment, haemorrhagic shock reduced the mean (SD) area of perfused vessels [82% (sd 10%) vs 38% (12%); P<0.001] and impaired oxygen concentration, mitochondrial redox state [99% (4%) vs 59% (15%) of baseline; P<0.001], and somatosensory evoked potentials [97% (13%) vs 27% (19%) of baseline]. Administration of terlipressin plus 1LR or 2LR was able to recover these measures, but terlipressin plus 3LR or 3LR alone were not as effective. Spinal cord dorsum potential was preserved in all groups, but no therapy protected electromyographic function. CONCLUSIONS: Resuscitation from haemorrhagic shock using terlipressin with small-volume LR was superior to high-volume LR, with regard to cerebral microcirculation, and mitochondrial and electrophysiological functions.

Cost-effectiveness analysis of treatment strategies for initial Clostridium difficile infection.

Clostridium difficile infection (CDI) is costly. Current guidelines recommend metronidazole as first-line therapy and vancomycin as an alternative. Recurrence is common. Faecal microbiota transplantation (FMT) is an effective therapy for recurrent CDI (RCDI). This study explores the cost-effectiveness of FMT, vancomycin and metronidazole for initial CDI. We constructed a decision-analytic computer simulation using inputs from published literature to compare FMT with a 10-14-day course of oral metronidazole or vancomycin for initial CDI. Parameters included cure rates (baseline value (range)) for metronidazole (80% (65-85%)), vancomycin (90% (88-92%)) and FMT(91% (83-100%)). Direct costs of metronidazole, vancomycin and FMT, adjusted to 2011 dollars, were $57 ($43-72), $1347 ($1195-1499) and $1086 ($815-1358), respectively. Our effectiveness measure was quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were conducted from the third-party payer perspective. Analysis using baseline values showed that FMT($1669, 0.242 QALYs) dominated (i.e. was less costly and more effective) vancomycin ($1890, 0.241 QALYs). FMT was more costly and more effective than metronidazole ($1167, 0.238 QALYs), yielding an incremental cost-effectiveness ratio (ICER) of $124 964/QALY. One-way sensitivity analyses showed that metronidazole dominated both strategies if its probability of cure were >90%; FMT dominated if it cost <$584. In a probabilistic sensitivity analysis at a willingness-to-pay threshold of $100 000/QALY, metronidazole was favoured in 55% of model iterations; FMT was favoured in 38%. Metronidazole, as the first-line treatment for CDIs, is less costly. FMT and vancomycin are more effective. However, FMT is less likely to be economically favourable, and vancomycin is unlikely to be favourable as first-line therapy when compared with FMT.

Cost-effectiveness of adding decolonization to a surveillance strategy of screening and isolation for methicillin-resistant Staphylococcus aureus carriers.

We compared the cost-effectiveness of a methicillin-resistant Staphylococcus aureus (MRSA) programme of active surveillance plus decolonization with the current Veterans Health Administration (VHA) strategy of active surveillance alone, as well as a common strategy of no surveillance. A decision-analytical model was developed for an inpatient stay time horizon, using the VHA's perspective. Model inputs were taken from published literature where available, and supplemented with expert opinion when necessary. Effectiveness outcomes were hospital-acquired MRSA infections and deaths avoided. One-way and two-way sensitivity analyses and Monte Carlo simulations were performed. In the base-case analysis, the strategy of active surveillance plus decolonization dominated (i.e. lower cost and greater effectiveness) both the comparison strategies of active surveillance and no surveillance. In addition, the active surveillance strategy dominated the strategy of no surveillance. One-way and two-way sensitivity analyses demonstrated that at low levels of direct benefit of decolonization (1-4%), the strategy of active surveillance plus decolonization would no longer be dominant. In the probabilistic sensitivity analysis, active surveillance plus decolonization dominated both the other two strategies, and the active surveillance strategy dominated no surveillance in all of 1000 Monte Carlo simulations. These results provide a strong economic argument for adding an MRSA decolonization protocol to the current VHA active surveillance strategy.

Uranium-thorium disequilibrium in north-east Atlantic waters.

In this paper we report and compare the concentrations of 234Th and 238U measured in surface and subsurface waters collected in the course of a sampling campaign in the north east Atlantic in June-July 1998. Dissolved 234Th concentrations in surface waters ranged from 5 to 20 Bq m(-3), showing a large deficiency relative to 238U concentrations (typically 42 Bq m-3). This disequilibrium is indicative of active 234Th scavenging from surface waters. Observed 234Th/238U activity ratios, together with corresponding 234Th particulate concentrations, were used to calculate mean residence times for 234Th with respect to scavenging onto particles (tau(diss)) and subsequent removal from surface waters (tau(part)). Residence times in the range 5-30 days were determined for tau(diss) and 4-18 days for tau(part) (n=14). In addition, ultrafiltration experiments at six stations in the course of the same expedition revealed that in north-east Atlantic surface waters a significant fraction (46+/-17%; n=6) of the thorium in the (operationally-defined) dissolved phase (<0.45 microm) is in colloidal form. These observations are consistent with the 'colloidal pumping' model in which it is assumed that 234Th is rapidly absorbed by colloidal particles, which then aggregate, albeit at a slower rate, into larger filterable particles. In essence, colloids act as intermediaries in the transition from the fully dissolved to the filter-retained (>0.45 microm) phase. Thus, the time (tau(c)) for fully dissolved 234Th to appear in the filter-retained fraction is dependent on the rate of colloidal aggregation. Here, we determined tau(c) values in the range 3-17 days.

Actinide analysis of a depleted uranium penetrator from a 1999 target site in southern Serbia.

Following the detection of 236U in depleted uranium (DU) ammunition used during the Balkans conflict in the 1990s, concern has been expressed about the possibility that other nuclides from the nuclear fuel cycle and, in particular, transuranium nuclides, might be present in this type of ammunition. In this paper, we report the results of uranium and plutonium analyses carried out on a depleted uranium penetrator recovered from a target site in southern Serbia. Our data show the depleted nature of the uranium and confirm the presence of trace amounts of plutonium in the penetrator. The activity concentration of (239+240)PU, at 45.4+/-0.7 Bq kg(-1), is the highest reported to date for any penetrator recovered from the Balkans. This concentration, however, is comparable to that expected to be present naturally in uranium ores and, from a radiological perspective, would only give rise to a very small increase in dose to exposed persons compared to that from the DU itself.

Chemical synthesis and biological activity of rat INSL3.

The recently identified protein, insulin 3 (INSL3), has structural features that make it a bona fide member of the insulin superfamily. Its predicted amino acid sequence contains the classic two-peptide chain (A- and B-) structure with conserved cysteine residues that results in a disulphide bond disposition identical to that of insulin. Recently, the generation of insl3 knockout mice has demonstrated that testicular descent is blocked due to the failure of a specific ligament, the gubernaculum, to develop. The mechanism by which INSL3 exerts its action on the gubernaculum is currently unknown. The purpose of this study was to, for the first time, synthesize rat INSL3 and test its action on organ cultures of foetal rat gubernaculum. INSL3 also contains a cassette of residues Arg-X-X-X-Arg within the B-chain, a motif that is essential for characteristic activity of another related member of the superfamily, relaxin. Hence, the relaxin activity of rat INSL3 was also tested in two different relaxin bioassays. The primary structure of rat INSL3 was determined by deduction from its cDNA sequence and successfully prepared by solid phase peptide synthesis of the two constituent chains followed by their combination in solution. Following confirmation of its chemical integrity by a variety of analytical techniques, circular dichroism spectroscopy confirmed the presence of high beta-turn and alpha-helical content, with a remarkable spectral similarity to the synthetic ovine INSL3 peptide and to synthetic rat relaxin. The synthetic rat INSL3 bound with very low affinity to rat relaxin receptors and had no activity in a relaxin bioassay. Furthermore, it did not augment or antagonize relaxin activity. The rat INSL3 did however induce growth of foetal rat gubernaculum in whole organ cultures demonstrating that INSL3 has a direct action on this structure.

Peroxisomal proliferator-activated ligand therapy for HIV lipodystrophy.

Lipodystrophies associated with HIV disease have been reported in recent years and have included a general redistribution of fat with more central fat and increased dorsocervical fat. These lipodystrophies are commonly associated with hyperlipidemia and in some cases with insulin resistant diabetes. Although a similar redistribution of fat is seen in hypercortisolism, in general, serum and urinary cortisol levels are normal in these HIV-positive patients. However cortisol/dehydroepaindrosterone (DHEA) ratios are increased in HIV disease and may result in a relative hypercortisolism. Seven HIV-positive male patients on multidrug antiviral therapy including HIV protease inhibitors had developed increased central and dorsocervical fat over 1 year. All patients had increased serum lipids and three had insulin resistant diabetes. Four patients were treated initially with DHEA 100-200 mg/day, with addition of a cyclo-oxygenase (COX) inhibitor (indomethacin 100 mg/day) and three others were treated from the onset with a combination of DHEA 200 mg/day and a COX inhibitor (indomethacin 100 mg/day or naprosyn 1000 mg/day). All patients reported moderation or normalization of their serum lipids and some moderation of blood sugars while on DHEA alone. More marked improvement in blood sugar and noticeable decreases in the dorsocervical fat; however, occurred only with addition a COX inhibitor. Both DHEA and COX inhibitors have a number of mechanisms of action; among these is their role as a peroxisome proliferator-activator receptor ligand. Dysregulation of peroxisome function is associated with the spectrum of biochemical changes seen within these HIV associated lipodystrophies. Use of HIV protease inhibitors is reported in the majority of patients with these lipodystrophies, and protease inhibitors may accentuate the underlying peroxisome dysregulation. Supplementation with DHEA and a COX inhibitor may improve peroxisomal function.

Hypereosinophilic syndrome associated with HIV infection. Military Medical Consortium for Applied Retroviral Research.

A hypereosinophilic syndrome associated with dermatitis has been observed rarely in association with HIV infection. We describe the case of a young man with AIDS who came to us with a diffuse cutaneous eruption, fever, angioedema, eosinophilia, and a mildly elevated serum IgE level. No allergic or infectious cause of this illness could be determined, and the patient was treated with corticosteroids and PUVA therapy, resulting in complete resolution of the dermatitis and associated findings. In this case, there were clinical and histopathologic similarities to the idiopathic hypereosinophilic syndrome and to acute graft-versus-host disease. The serum level of the cytokine interleukin-5 (IL-5), which is associated with eosinophil production, was found to be mildly elevated during the peak of the eruption, while samples drawn previously and subsequently were not. Although it appears that the syndrome we describe is associated with the measurably elevated level of IL-5, further investigation is required to determine whether there is a cause and effect relationship between IL-5 and this entity. A brief review of the literature concerning eosinophils and HIV infection is also presented in the context of this case.

The issues in autologous transfusion.

Autologous transfusion should be recognized by patients and physicians as an important measure to provide safer transfusion therapy. This should be suggested to patients in general good health (who are not obviously frail) who have no significant medical problems and no likelihood of severe reaction, who can take iron supplements, and who have at least a 10% chance of using blood during surgery or are having surgery in which the average use is one or more units. Such patients should receive iron supplementation beginning 1 week before the first autologous donation, and should donate one to five units on a weekly basis, but no more frequently than every 72 hours, with their last unit donated 72 hours before surgery. Elderly individuals may donate if the risk of donor reaction seems low. In children and adults, the amount of blood removed should be reduced in proportion to the blood volume if the individual does not meet the standard weight of 50 kg for a 450-mL donation. "Fail-safe" identification systems should be used; these will insure that the correct donor/patient receives the transfusion. Processing of the units is preferred but still optional. Use of these units as homologous units should not be done unless the donor has a hematocrit level acceptable to an autologous donor, meets all the criteria for recipient safety, the unit is processed and negative for all viral markers, and the donor has recently (eg, within 3 years) participated in the volunteer donor program. The unit should be transfused to the patient in situations in which homologous blood would be indicated. Safeguards to prevent volume overload are needed when the unit is stored as whole blood. Future research objectives should include the use of recombinant erythropoietin to prevent donation-induced anemia, delineation of medical conditions which should contraindicate the donation, and determination of the real costs involved in autologous transfusion. Education of the general public, patients, and physicians about the desirability of autologous transfusion should proceed. Third-party carriers also need to be educated about the cost implications and the need to pay for this activity. However, such education should also stress that autologous units will only cover planned, elective surgery and that major blood needs for emergency surgery, trauma, and chronic transfusion will still need to be met by homologous blood from altruistic community blood donors.

Factor IX metal ion-dependent antigen assays for measurement of warfarin effect.

Factor IX metal ion-dependent antigen was assayed using monoclonal antibodies in 521 samples obtained after prothrombin time testing in patients treated with warfarin. Factor IX metal ion-dependent antigen was less than measured Factor IX clotting activity and less than total Factor IX antigen adsorbable to aluminium hydroxide, suggesting that the metal ion-dependent antigen assay measures a subpopulation of circulating Factor IX in patients treated with oral anticoagulants. There was a graded decrease of Factor IX metal ion-dependent antigen as prothrombin times increased in patient samples. In two hospitals, the median prothrombin times and Factor IX antigen levels were 19 and 20 seconds and 0.10 and 0.11 U/mL (kU/L), respectively. This study shows that immunoassays measure the biologic effect of warfarin and provide information that may supplement the prothrombin time test for patient monitoring. Factor IX metal ion-dependent antigen assays may be useful in efforts to standardize laboratory tests for warfarin effect.