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Drinking water treatment residuals (DWTRs) are produced from the coagulation and flocculation processes in conventional drinking water treatment. The abundant metal oxide content of these materials resulting from the use of coagulants, like alum and ferric chloride, has driven strong research interest into the reuse of DWTRs as sorptive materials. Using a suite of aluminum-based DWTRs, we provide new insights into Hg(II) sorption mechanisms. Experiments performed at circum-neutral pH show that sorption capacities are related to the amount of organic carbon/matter present in DWTRs. We found that carbon rich samples can scavenge about 9000 mg/kg of Hg, in contrast to 2000 mg/kg for lime based DWTRs. X-ray absorption spectroscopy (XAS) at the Hg L3 edge further characterizes mercury coordination. X-ray absorption near edge structure (XANES) and extended x-ray absorption fine structure (EXAFS) results point to a partial association of mercury with sulfur at low mass loadings, transitioning to a full association with oxygen/carbon at higher concentrations of sorbed Hg(II) and in DWTRs with limited sulfur content. These results suggest that sorption of Hg(II) is primarily controlled by the carbon/organic matter fraction of DWTRs, but not by the coagulants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Adhering to a Mediterranean diet (MD) is associated with reduced CVD risk. This study aimed to explore methods of increasing MD adoption in a non-Mediterranean population at high risk of CVD, including assessing the feasibility of a developed peer support intervention. The Trial to Encourage Adoption and Maintenance of a MEditerranean Diet was a 12-month pilot parallel group RCT involving individuals aged ≥ 40 year, with low MD adherence, who were overweight, and had an estimated CVD risk ≥ 20 % over ten years. It explored three interventions, a peer support group, a dietician-led support group and a minimal support group to encourage dietary behaviour change and monitored variability in Mediterranean Diet Score (MDS) over time and between the intervention groups, alongside measurement of markers of nutritional status and cardiovascular risk. 118 individuals were assessed for eligibility, and 75 (64 %) were eligible. After 12 months, there was a retention rate of 69 % (peer support group 59 %; DSG 88 %; MSG 63 %). For all participants, increases in MDS were observed over 12 months ( P < 0·001), both in original MDS data and when imputed data were used. Improvements in BMI, HbA1c levels, systolic and diastolic blood pressure in the population as a whole. This pilot study has demonstrated that a non-Mediterranean adult population at high CVD risk can make dietary behaviour change over a 12-month period towards an MD. The study also highlights the feasibility of a peer support intervention to encourage MD behaviour change amongst this population group and will inform a definitive trial.

This study aimed to evaluate the feasibility of a peer support intervention to encourage adoption and maintenance of a Mediterranean diet (MD) in established community groups where existing social support may assist the behaviour change process. Four established community groups with members at increased Cardiovascular Disease (CVD) risk and homogenous in gender were recruited and randomised to receive either a 12-month Peer Support (PS) intervention (PSG) ( n 2) or a Minimal Support intervention (educational materials only) (MSG) ( n 2). The feasibility of the intervention was assessed using recruitment and retention rates, assessing the variability of outcome measures (primary outcome: adoption of an MD at 6 months (using a Mediterranean Diet Score (MDS)) and process evaluation measures including qualitative interviews. Recruitment rates for community groups ( n 4/8), participants ( n 31/51) and peer supporters ( n 6/14) were 50 %, 61 % and 43 %, respectively. The recruitment strategy faced several challenges with recruitment and retention of participants, leading to a smaller sample than intended. At 12 months, a 65 % and 76·5 % retention rate for PSG and MSG participants was observed, respectively. A > 2-point increase in MDS was observed in both the PSG and the MSG at 6 months, maintained at 12 months. An increase in MD adherence was evident in both groups during follow-up; however, the challenges faced in recruitment and retention suggest a definitive study of the peer support intervention using current methods is not feasible and refinement based on the current feasibility study should be incorporated. Lessons learned during the implementation of this intervention will help inform future interventions in this area.

Objectives: To explore whether nutritional salivary biomarkers could be used to aid nutritional status assessment and/or support traditional dietary assessment methods for patients., Data and Sources: Searches were performed using four electronic databases; MEDLINE, EMBASE, Scopus and Web of Science. Trial registers (i.e. Cochrane), grey literature and reference lists were searched., Study Selection: Studies which measured nutritional salivary biomarkers related to nutritional status and/or dietary intake outcome were included. No restrictions on participants' age, study design, publication date, setting or health status. Animal studies, non-English language studies, commentaries, and conference abstracts were excluded., Results: Study titles and abstracts were screened (n = 7982), full-texts assessed (n = 176) and 85 studies were included in a narrative synthesis. The most promising salivary biomarkers for nutritional status included: glucose, where saliva and serum levels were positively correlated in those with type 2 diabetes (T2D), higher salivary calcium levels in post-menopausal women in general and specifically those with lower bone mineral density (BMD), and salivary vitamin D to assess vitamin D status in healthy volunteers. Higher salivary total antioxidant capacity (TAC), nitrate/nitrite and fluoride were observed with increased antioxidant, nitrate/nitrite and fluoride dietary intake, respectively. A meta-analysis found significantly higher mean salivary glucose (n = 12) in T2D compared with healthy controls, but there was substantial heterogeneity (I 2 =94%) and evidence of publication bias., Conclusions: The most promising salivary biomarkers identified in this systematic review were, glucose, vitamin D, calcium, TAC, nitrate/nitrite and fluoride. However, this was based on a small number of studies of varying quality, with many lacking a salivary assay performance assessment., Clinical Significance: At present, nutritional salivary biomarkers cannot be used alone to assess nutritional status or dietary intake. Further research into the most promising nutritional salivary biomarkers is required., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Dietary-based primary prevention guidelines for chronic kidney disease (CKD) treatment are lacking due to limited evidence. Single nutrient intake studies do not account for complex dietary interactions. We assessed associations between dietary patterns and renal function in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA)., Design: A cross-sectional observational study used NICOLA baseline dietary data collected between February 2014 and March 2016 via a food frequency questionnaire for 2590 participants aged ≥ 50 years. Principal component analysis identified a posteriori dietary patterns. Renal function was characterised by estimated glomerular filtration rate (eGFR) using serum creatinine and cystatin-C. Associations were assessed according to quintiles of dietary pattern adherence and multivariable regression analysis examined associations with eGFR., Results: Variation in three dietary patterns was significantly associated with eGFR. After adjustment for potential confounders, participants with least adherence to the 'healthy' dietary pattern 1 had a mean eGFR 3.4 ml/min/1.73m 2 (95% confidence interval, [CI] - 5.0, - 1.7, p < 0.001) lower than the most adherent. Those with lowest adherence to the 'unhealthy' dietary pattern 2 had a mean eGFR 1.9 ml/min/1.73m 2 (CI 0.2, 3.5, p = 0.03) higher than those with highest adherence. Participants with lowest adherence to dietary pattern 3, characterised by a high consumption of alcohol and coffee, had a mean eGFR 1.8 ml/min/1.73m 2 (- 3.5, - 0.01, p = 0.05) lower than those with greatest adherence., Conclusions: Our findings identify independent associations between dietary patterns and eGFR. These findings can inform the development of diet-related primary prevention advice for CKD., (© 2021. The Author(s).)

Graphene sheets displaying partial crystallinity and nanowire structures were formed on a silicon substrate with silicon nanowires by utilizing an amorphous carbon source. The carbon source was deposited onto the silicon nanostructured substrate by breaking down a polymer precursor and was crystallized by a nickel catalyst during relatively low temperature inert gas annealing. The resulting free-standing graphene-based material can remain on the substrate surface after catalyst removal or can be removed as a separate film. The film is flexible, continuous, and closely mimics the silicon nanostructure. This follows research on similar solid carbon precursor derived semi-crystalline graphene synthesis procedures and applies it to complex silicon nanostructures. This work examined the progression of the carbon, finding that it migrates through the thin film catalyst and forms the graphene only on the other side, and that the process can successfully be used to form 3D shaped graphene films. Semi-crystalline graphene has the possible application of being flexible transparent electrodes, and the 3D shaping opens the possibility of more complex configurations and applications.

The beneficial use of drinking water treatment residuals (DWTRs) faces barriers due primarily to uncertainties and concerns about their potential environmental impacts. We used total and water leachable toxic metal concentrations and 2 benthic organism-based bioassays to identify suitable DWTR substrates for introduction to freshwater systems. Using total metal contents and the consensus probable effect concentration concept, 3 DWTRs were selected and used in elutriate and toxicity studies. The concentrations of water leachable Ag, As, Cd, Cu, Cr, Ni, Pb, and Zn were below the US Environmental Protection Agency's ambient water quality criteria. Using the long-term 65-d life cycle Chironomus tentans test and 4 different endpoints (survival, adult emergence, egg case production, and number of eggs produced per female), no statistical differences were found between the DWTR treatments and the controls. Similarly, results obtained using the 10-d Hyalella azteca test showed no toxicity. However, although both survival and growth were recorded in all bioassays, the results of the 10-d C. tentans and the 28-d H. azteca tests were ambiguous. For C. tentans, 2 of the 3 DWTRs resulted in significantly lower survival rates compared to the controls. For H. azteca, no significant growth differences were observed between controls and DWTR treatments, but 2 of the 3 DWTRs resulted in significantly lower survival rates than the controls. Overall, these results suggest that certain DWTR substrates could be suitable for introduction to aquatic systems. Environ Toxicol Chem 2021;40:2005-2014. © 2021 SETAC., (© 2021 SETAC.)

Analysis of X-ray absorption spectroscopy data often involves the removal of artifacts or glitches from the acquired signal, a process commonly known as deglitching. Glitches result either from specific orientations of monochromator crystals or from scattering by crystallites in the sample itself. Since the precise energy - or wavelength - location and the intensity of glitches in a spectrum cannot always be predicted, deglitching is often performed on a per spectrum basis by the analyst. Some routines have been proposed, but they are prone to arbitrary selection of spectral artifacts and are often inadequate for processing large data sets. Here, a statistically robust algorithm, implemented as a Python program, for the automatic detection and removal of glitches that can be applied to a large number of spectra, is presented. It uses a Savitzky-Golay filter to smooth spectra and the generalized extreme Studentized deviate test to identify outliers. Robust, repeatable, and selective removal of glitches is achieved using this algorithm.

Drinking water treatment residuals (DWTRs) produced in large quantities worldwide show strong sorption capacities for several contaminants including metals. These by-products of the water-treatment process are primarily discharged as wastes, to either natural or engineered systems, based on the regulations in place in the country where they are produced. To assess how DWTRs can be repurposed to limit the mobility of metals in aquatic systems, we tested their propensity to release toxic metals and their potential ecotoxicity. To account for the wide variability in their physicochemical characteristics, DWTR samples were obtained from 15 water-treatment plants across the United States. A screening procedure based on a combination of 1) the toxicity characteristics leaching procedure (TCLP), 2) total metal contents and sediment quality guidelines, and 3) acute 10-d Americamysis bahia and chronic 28-d Neanthes arenaceodentata survival and growth bioassays was used. All tested samples were found to be nonhazardous based on TCLP results. However, the concentrations of As, Cu, and Ni exceeded the sediment quality guidelines in some samples, resulting in the exclusion of 7 DWTR samples. All of the DWTRs evaluated for toxicity were nontoxic to the tested organisms. The results of the present study suggest that certain DWTRs can be introduced safely into the marine environment and, therefore, used as potential amendments or capping materials to control the mobility of certain sediment contaminants. Environ Toxicol Chem 2021;40:1194-1203. © 2020 SETAC., (© 2020 SETAC.)

Sub-micron sized metal particles were formed through the annealing of sputtered metal thin films on silicon nanowires (SiNWs). During high-temperature annealing, the cylindrical SiNW structures induce the solid-state dewetting behavior to consistently move up the SiNW sides and form partial-spherical particles with uniform sizes on the nanowire tops. By adjusting the size parameters of the SiNW substrate and the metal thin film, the particles can be adjusted in size and layout along an array. This contrasts with the random dewetted particles seen on planar surfaces, and known movement towards pitted nanostructures. Ag, Au, Cu, and Ni have shown equivalent particle formation behavior and some alloying is also shown to be possible. These results open a path for a well-controlled and consistent method of metal particle formation at the nano to micro-scale and offer some insight on metal particle dewetting mechanisms. Suggested applications for the resulting regular particle grids include plasmonic sensors such as SERS., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

An experimental method is described in which a orderly 3D array of graphene sheets is grown to conform to the shape of an underlying nanowire (NW) substrate that remains on-site. The procedure uses a sacrificial nickel catalyst-based CVD growth process that is capable of producing graphene onto an insulating SiO 2 substrate. Nano-imprint silicon NWs serve both as the scaffolding for the catalyst and as the final underlying substrate. The graphene is polycrystalline and multi-layered as expected from this nickel catalyzed growth method. This presents a novel and quick method that can be used to produce conductive graphene sheets in precise shapes and configurations seen in complex device applications but which are difficult to produce with current transfer methods. The geometry of the nanostructured substrate itself contributes to the on-site growth method by making it difficult for the graphene to wash off during wet etching. The SiNWs used in this research have increased surface area and a light trapping effect that, in combination with the graphene, can be used in future sensor and photovoltaic device applications., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The 2018 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Indianapolis, Indiana, at the Society of Toxicologic Pathology's 37th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and other topics covered during the symposium included seminiferous tubule dysgenesis in rats, ameloblast and odontoblast degeneration/necrosis in a Sprague Dawley rat, intestinal leiomyositis in a beagle dog, gallbladder mucinous hyperplasia, focus of hepatocellular alteration and bile duct alteration in otters, renal tubule cytoplasmic vacuolation with basophilic granules in mice treated swith antisense oligonucleotide therapy, a uterine choriocarcinoma in a rhesus macaque, and rete ovarii proliferative ovarian lesions in various aged rat strains. One particularly provocative lesion was a malignant neoplastic proliferation in the renal pelvic region of a cynomolgus macaque from a 21-day study. Additional challenging lesions included thyroid proliferative lesions in zebra fish and gross findings in fish larvae during routine chemical screening. The Rabbit and Minipig International Harmonization of Nomenclature and Diagnostic Criteria Organ Working Groups also presented a series of challenging lesions.

Subacute and subchronic studies were conducted to assess the toxicity of 2,4-dinitroanisole (DNAN) and to provide information important for protecting the health of military and civilian personnel. In the subchronic study, male and female Sprague-Dawley rats were dosed with DNAN via oral gavage at 0, 1.25, 5, 20, and 80 mg/kg/d. Likely owing to its conversion to 2,4-dinitrophenol, an inhibitor of energy homeostasis, DNAN caused an apparent increase in metabolism, leading to reduced feed efficiency ratios and body mass gains in males. Anemia, splenic enlargement, hemosiderosis, and extramedullary hematopoiesis indicated blood as a target organ, with females more sensitive than males. The DNAN was a testicular toxicant, causing decreased mass of testes and epididymides, as well as degeneration and atrophy of testicular seminiferous tubules and epididymal aspermia. Stereotypical behavior in males, gait irregularities, and cerebellar lesions indicated that DNAN is neurotoxic. Splenic enlargement, anemia, testicular toxicity, and neurotoxicity occurred only at or near lethal doses in the subchronic study., (© The Author(s) 2016.)

3-Nitro-1,2,4-triazol-5-one (NTO) is currently being investigated in the development of insensitive munitions. Rats orally exposed to NTO have demonstrated testicular toxicity in both subacute and subchronic studies; however, toxicity has not been verified in mice. Also, previous studies have not demonstrated the nature of NTO-induced testicular toxicity due to the prolonged dosing regimen utilized and effects of maturation depletion. In this study, a time-course design was used and the earliest pathological changes in testes of adult BALB/c mice orally dosed with NTO in corn oil suspensions at 0, 500 or 1000 mg/kg-day NTO for 1, 3, 7 or 14 d were evaluated. The earliest NTO-induced testicular changes occurred in the 1000 mg/kg-day group at day 7 and the 500 mg/kg-day group at day 14 as evident by the presence of bi- and multinucleated giant cells (MNGCs) of almost all spermatids in an isolated stage II-III tubule/step 2-3 and a stage IX tubule/step 9 in the 1000 and 500 mg/kg-day groups, respectively. Testicular toxicity was characterized by degeneration and the presence of bi- and MNGCs of spermatids (stages II-III and IX), which progressed to additional germ cell degeneration as dosing duration increased. Occasional step 16 spermatid retention was also noted in stage XII and I tubules in the day 14, 1000 mg/kg-day group. These data indicate that NTO is a testicular toxicant in mice and that spermatids are the most sensitive cell. The presence of retained spermatids warrants further investigation regarding NTO's role as a direct Sertoli cell toxicant.

Nitrotriazolone (3-nitro-1,2,4-triazol-5-one; NTO) is an insensitive munition that has demonstrated effects on reproductive organs in adult male rats. NTO was administered to male (0, 250, and 500milligrams per kilogram per day (mg/kg-day)) and female (0, 500, and 1000mg/kg-day) Sprague-Dawley rats (15/sex/group) via oral gavage from weaning through post-natal day 53/54 and 42/43, respectively. Age and body mass at vaginal opening (VO) and preputial separation (PPS), as well as all measures of estrous cyclicity were not affected by treatment with NTO. Males treated with NTO exhibited reductions in testis mass associated with tubular degeneration/atrophy. Less pronounced reductions in accessory sex organ masses were also observed in the 500mg/kg-day group. Treatment with NTO did not affect thyroid hormone or testosterone levels. These findings suggest that NTO is not acting as an estrogen or thyroid active compound, but may indicate effects on steroidogenesis and/or direct testicular toxicity., (Published by Elsevier Inc.)

Background: Hemorrhagic shock results in systemic activation of the immune system and leads to ischemia-reperfusion injury. Lymphocytes have been identified as critical mediators of the early innate immune response to ischemia-reperfusion injury, and immunomodulation of lymphocytes may prevent secondary immunologic injury in surgical and trauma patients., Methods: Yorkshire swine were anesthetized and underwent a grade III liver injury with uncontrolled hemorrhage to induce hemorrhagic shock. Experimental groups were treated with a lymphocyte depletional agent, porcine polyclonal anti-thymocyte globulin (PATG) (n = 8) and compared to a vehicle control group (n = 9). Animals were observed over a 3 day survival period. Circulating lymphocytes were examined with FACS analysis for CD3/CD4/CD8, and central lymphocytes with mesenteric lymph node and spleen staining for CD3. Circulating and lung tissue16 infiltrating neutrophils were measured. Circulating CD3 lymphocytes in the blood and in central lymphoid organs (spleen/lymph node) were stained and evaluated using FACS analysis. Immune-related gene expression from liver tissue was quantified using RT-PCR., Results: The overall survival was 22% (2/9) in the control and 75% (6/8) in the PATG groups, p = 0.09; during the reperfusion period (following hemorrhage) survival was 25% (2/8) in the control and 100% (6/6) in the PATG groups, p = 0.008. Mean blood loss and hemodynamic profiles were not significantly different between the experimental and control groups. Circulating CD3+CD4+ lymphocytes were significantly depleted in the PATG group compared to control. Lymphocyte depletion in the setting of hemorrhagic shock also significantly decreased circulating and lung tissue infiltrating neutrophils, and decreased expression of liver ischemia gene expression., Conclusions: Lymphocyte manipulation with a depletional (PATG) strategy improves reperfusion survival in experimental hemorrhagic shock using a porcine liver injury model. This proof of principle study paves the way for further development of immunomodulation approaches to ameliorate secondary immune injury following hemorrhagic shock.

Sustainable use of military training ranges requires the development of compounds that have a minimal impact to the environment when used in a weapon system. Guanidinium 3,4-dinitropyrazolate (GDNP) is a novel explosive compound of interest for application in some weapon systems. Little is known of its toxicologic properties. To ensure the health of potentially exposed personnel and the environment, initial toxicity investigations were conducted and the results were compared with another widely used energetic (hexahydro-1,3,5-trinitro-1,3,5-triazine [RDX]). In a microplate Ames assay, GDNP was not cytotoxic to bacterial tester strains at concentrations less than 100 μg/mL. However, GDNP was mutagenic to 4 of 5 bacterial strains with and without S9 metabolic incubation at concentrations as low as 0.7 μg/mL. Unlike RDX, GDNP did not have an affinity for the γ-aminobutyric acid(A) receptor convulsant site and was predicted to not induce seizure. After acute oral dosing in female rats, the median lethal dose in female rats of GDNP in tap water solution was determined to be 720 mg/kg. Daily oral exposure to 500 mg/kg per d of GDNP for 14 days caused weight loss, increased liver and spleen weights, and adverse histopathologic events in kidney and spleen. These adverse events were not observed in animals receiving lower doses of GDNP. In this study, the lowest-observed-adverse-effect-level from oral exposure to GDNP for 14 days was 500 mg/kg per d and the no-observable-adverse-effect-level was 152 mg/kg per d.

Dinitrotoluene (DNT) is a nitroaromatic explosive used in propellant mixtures and in the production of plastics. Isomers of DNT were administered daily via oral gavage to male Sprague-Dawley rats for 14 days to determine the subacute toxicity of individual isomers of DNT. The 3,5-DNT isomer was the most toxic isomer, inducing weight loss and mortality within 3 days. Cyanosis and anemia were observed for all isomers. Exposure to 2,4-, 2,6-, and 3,5-DNT resulted in decreased testes mass and degenerative histopathological changes. Increased splenic mass was observed for 2,4-, 2,6-, and 2,5-DNT. Extramedullary hematopoiesis of the spleen was noted for all isomers, while lymphoid hyperplasia of the spleen was noted for all isomers except 2,5-DNT. Increased liver mass was observed for 2,3-DNT and 3,4-DNT. Hepatocellular lesions were observed for 2,6-DNT and 2,4-DNT. Neurotoxic effects were noted for 3,4-DNT, 2,4-DNT, and 3,5-DNT.

Dinitrotoluene (DNT) is a nitroaromatic explosive that exists as six isomers; two major isomers (2,4- and 2,6-DNT) and four minor isomers (2,3-, 2,5-, 3,4-, and 3,5-DNT). DNT has been found in soil, surface water, and groundwater near ammunition production plants. The major isomers of DNT are classified as "likely to cause cancer in humans."In vitro studies have provided conflicting data regarding the genotoxicity of the minor isomers. Studies indicate that metabolism in the gut and liver are necessary to convert DNT to genotoxic compounds. As such, in the present study the genotoxicity of isomers of DNT was assessed using two in vivo genotoxicity assays. The Comet assay was used to detect DNA damage in liver cells from male Sprague-Dawley rats following oral exposure (14-day) to individual isomers of DNT. The micronucleus assay was conducted using flow cytometric analysis to detect chromosomal damage in peripheral blood. Treatment with 2,3-, 3,4-, 2,4-, 2,5- and 3,5-DNT did not induce DNA damage in liver cells or increase the frequency of micronucleated reticulocytes (MN-RET) in peripheral blood at the doses tested. Treatment with 2,6-DNT induced DNA damage in liver tissue at all doses tested, but did not increase the frequency of micronucleated reticulocytes (MN-RET) in peripheral blood. Thus, 2,4-DNT and the minor isomers were not genotoxic under these test conditions, while 2,6-DNT was genotoxic in the target tissue, the liver. These results support previous research which indicated that the hepatocarcinogenicity of technical grade DNT (TG-DNT) could be attributed to the 2,6-DNT isomer., (Published by Elsevier B.V.)

The inflammatory response to severe traumatic injury results in significant morbidity and mortality. Lymphocytes have recently been identified as critical mediators of the early innate immune response to ischemia-reperfusion injury. Experimental manipulation of lymphocytes following hemorrhagic shock may prevent secondary immunologic injury in surgical and trauma patients. The objective of this study is to evaluate the lymphocyte sequestration agent FTY720 as an immunomodulator following experimental hemorrhagic shock in a swine liver injury model. Yorkshire swine were anesthetized and underwent a grade III liver injury with uncontrolled hemorrhage to induce hemorrhagic shock. Experimental groups were treated with a lymphocyte sequestration agent, FTY720, (n = 9) and compared to a vehicle control group (n = 9). Animals were observed over a 3 day survival period after hemorrhage. Circulating total leukocyte and neutrophil counts were measured. Central lymphocytes were evaluated with mesenteric lymph node and spleen immunohistochemistry (IHC) staining for CD3. Lung tissue infiltrating neutrophils were analyzed with myeloperoxidase (MPO) IHC staining. Relevant immune-related gene expression from liver tissue was quantified using RT-PCR. The overall survival was 22.2% in the vehicle control and 66.7% in the FTY720 groups (p = 0.081), and reperfusion survival (period after hemorrhage) was 25% in the vehicle control and 75% in the FTY720 groups (p = 0.047). CD3(+) lymphocytes were significantly increased in mesenteric lymph nodes and spleen in the FTY720 group compared to vehicle control, indicating central lymphocyte sequestration. Lymphocyte disruption significantly decreased circulating and lung tissue infiltrating neutrophils, and decreased expression of liver immune-related gene expression in the FTY720 treated group. There were no observed infectious or wound healing complications. Lymphocyte sequestration with FTY720 improves survival in experimental hemorrhagic shock using a porcine liver injury model. These results support a novel and clinically relevant lymphocyte immunomodulation strategy to ameliorate secondary immune injury in hemorrhagic shock.

Chronic kidney disease (CKD) is a global health problem; the growing gap between the number of patients awaiting transplant and organs actually transplanted highlights the need for new treatments to restore renal function. Regenerative medicine is a promising approach from which treatments for organ-level disorders (e.g., neurogenic bladder) have emerged and translated to clinics. Regenerative templates, composed of biodegradable material and autologous cells, isolated and expanded ex vivo, stimulate native-like organ tissue regeneration after implantation. A critical step for extending this strategy from bladder to kidney is the ability to isolate, characterize, and expand functional renal cells with therapeutic potential from diseased tissue. In this study, we developed methods that yield distinct subpopulations of primary kidney cells that are compatible with process development and scale-up. These methods were translated to rodent, large mammal, and human kidneys, and then to rodent and human tissues with advanced CKD. Comparative in vitro studies demonstrated that phenotype and key functional attributes were retained consistently in ex vivo cultures regardless of species or disease state, suggesting that autologous sourcing of cells that contribute to in situ kidney regeneration after injury is feasible, even with biopsies from patients with advanced CKD.

Aims: The aim of this study was to determine whether simvastatin would protect against inflammation-induced aortic stiffening and endothelial dysfunction., Methods: Aortic pulse wave velocity (aPWV) and flow-mediated dilatation (FMD) were assessed three times, at baseline, after a 14 day administration of simvastatin or placebo and 8 h after Salmonella typhi vaccination in 50 healthy subjects., Results: Following vaccination there was a significant increase in aPWV in the placebo group (5.80 ± 0.87 vs. 6.21 ± 0.97 m s⁻¹, 95% CI 0.19, 0.62, P= 0.002) but not the simvastatin group (5.68 ± 0.73 vs. 5.72 ± 0.74 m s⁻¹, 95% CI -0.19, 0.27, P= 0.9; P= 0.016 for comparison). Whereas FMD response was reduced in the placebo group (6.77 ± 4.10 vs. 5.27 ± 2.88%, 95% CI -2.49, -0.52, P= 0.02) but not in the simvastatin group (7.07 ± 4.37 vs. 7.17 ± 9.94%, 95% CI -1.1, 1.3. P= 0.9, P < 0.001 for comparison). There was no difference in the systemic inflammatory response between groups following vaccination. However, there was a significant reduction in serum apolipoprotein A-I (Apo A-I) in the placebo, but not in the simvastatin, group., Conclusions: Simvastatin prevents vaccination-induced aortic stiffening and endothelial dysfunction. This protective mechanism may be due to preservation of the Apo A-I lipid fraction, rather than pleiotropic anti-inflammatory effects of statins., (© 2010 The Authors. British Journal of Clinical Pharmacology © 2010 The British Pharmacological Society.)

Established chronic kidney disease (CKD) may be identified by severely impaired renal filtration that ultimately leads to the need for dialysis or kidney transplant. Dialysis addresses only some of the sequelae of CKD, and a significant gap persists between patients needing transplant and available organs, providing impetus for development of new CKD treatment modalities. Some postulate that CKD develops from a progressive imbalance between tissue damage and the kidney's intrinsic repair and regeneration processes. In this study we evaluated the effect of kidney cells, delivered orthotopically by intraparenchymal injection to rodents 4-7 wk after CKD was established by two-step 5/6 renal mass reduction (NX), on the regeneration of kidney function and architecture as assessed by physiological, tissue, and molecular markers. A proof of concept for the model, cell delivery, and systemic effect was demonstrated with a heterogeneous population of renal cells (UNFX) that contained cells from all major compartments of the kidney. Tubular cells are known contributors to kidney regeneration in situ following acute injury. Initially tested as a control, a tubular cell-enriched subpopulation of UNFX (B2) surprisingly outperformed UNFX. Two independent studies (3 and 6 mo in duration) with B2 confirmed that B2 significantly extended survival and improved renal filtration (serum creatinine and blood urea nitrogen). The specificity of B2 effects was verified by direct comparison to cell-free vehicle controls and an equivalent dose of non-B2 cells. Quantitative histological evaluation of kidneys at 6 mo after treatment confirmed that B2 treatment reduced severity of kidney tissue pathology. Treatment-associated reduction of transforming growth factor (TGF)-β1, plasminogen activator inhibitor (PAI)-1, and fibronectin (FN) provided evidence that B2 cells attenuated canonical pathways of profibrotic extracellular matrix production.

Aims: To estimate the pharmacologically active dose range of a new investigational compound S-0139, a selective endothelin A (ET(A)) receptor antagonist, in man, and to examine the duration of its pharmacodynamic effect., Methods: Venous occlusion plethysmography was performed to assess changes in forearm blood flow following intra-brachial administration of endothelin-1 (ET-1). ET(A) antagonists have been shown to block ET-1-induced vasoconstriction in this model. The study was conducted in three parts: (1) a pilot study to explore dose-response (dose range 0.08-13.33 microg kg(-1) min(-1)), (2) a randomized study to confirm dose-response (placebo, 2.5, 6.67 and 15 microg kg(-1) min(-1)), and (3) a delayed administration study (15.7 microg kg(-1) min(-1)) to explore the duration of the pharmacodynamic effect. In all studies a 3-h infusion of S-0139 was given and during the last 90 min of the infusion, ET-1 was infused concurrently for 90 min. In study (3) a second ET-1 infusion was given starting 3 h after completion of the first., Results: Intravenously administered S-0139 resulted in significant inhibition of ET-1-induced vasoconstriction in the forearm (plasma concentration 800-2000 ng ml(-1)). In the delayed administration study, the same extent of inhibition was still present when ET-1 was administered 3 h after the end of infusion of S-0139, even though the S-0139 plasma concentrations (mean 17 ng ml(-1)) were well below pharmacologically active concentrations as determined in studies 1 and 2., Conclusions: S-0139 dose-dependently blocks ET-1-mediated vasoconstriction in the forearm and has a prolonged duration of effect beyond that expected from its pharmacokinetic profile.

Aims: (i) To compare the effects of intra-arterial administration of urotensin II in patients with CVD with healthy volunteers, and (ii) to study the haemodynamic effects of intra-arterial infusion of the urotensin II receptor antagonist, urantide., Methods: Ten healthy volunteers and 10 patients with CVD received a dose-ramped brachial artery infusion of urotensin II. A further six healthy male volunteers received a prolonged urotensin II infusion and 11 healthy male volunteers received a dose-ramped infusion of urantide. Forearm blood flow (FBF) was measured every 20 min and blood pressure and heart rate were assessed every 20 min., Results: In healthy volunteers and patients with CVD, intra-arterial infusion of urotensin II had no effect on FBF ratio. A dose-ramped infusion of urantide similarly had no effect on FBF ratio. During dose-ramped infusions of urotensin II and urantide, systolic and mean arterial blood pressure increased significantly. In healthy volunteers, urotensin II and urantide, respectively, increased systolic blood pressure from 133 +/- 6 to 137 +/- 5 mmHg (P < 0.01) and from 113 +/- 4 to 120 +/- 4 mmHg (P < 0.01). In patients with CVD, heart rate also significantly increased during dose-ramped infusion of urotensin II from 59 +/- 3 to 62 +/- 4 bpm (P < 0.05)., Conclusions: We have shown no in vivo effect of urotensin II or urantide on human forearm resistance vessels. Previous discrepancies do not seem to relate to either the age or CVD status of subjects. Changes in systemic cardiovascular haemodynamics during the dose-ramped infusion studies are unlikely to be caused by urotensin II receptor modulation.

Background: The physiological disturbances leading to lymphoedema after breast cancer surgery are poorly understood. Damage to sympathetic nerves during axillary lymph node dissection (ALND), leading to increased capillary fluid filtration, was investigated as a possible contributory factor., Methods: The integrity of the upper limb sympathetic nervous system was tested in 36 patients before, and 3 and 12 months after ALND. Forearm vascular resistance (FVR), calculated from forearm blood flow and mean systemic arterial pressure, was measured before and after exposure to lower-body negative pressure. Forearm venous compliance was measured using (99m)Tc-labelled autologous erythrocytes and radionuclide plethysmography before and after cold water immersion of the feet., Results: There were clear changes in FVR and venous compliance in response to sympathetic stimulation but no differences attributable to surgery or between the nine patients who developed lymphoedema and the 27 who did not; nor were there differences between the two arms. There was a trend towards lower preoperative FVR in patients who developed lymphoedema., Conclusion: Lymphoedema is not the result of sympathetic nerve damage sustained during ALND. Preoperative FVR may help predict who will get lymphoedema following this surgery., (Copyright 2009 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Campylobacter jejuni is 1 of the most common enteric bacterial pathogens worldwide. The mechanisms of pathogenesis remain obscure, in part because of limitations of small animal models. Young ferrets develop diarrhea when fed C. jejuni, but their pathology and the immune response after infection have not been examined in detail. In the present study, we examined the pathogenesis of C. jejuni CG8421 and associated immune responses in ferrets. After oral infection with C. jejuni CG8421, 86.7% of the animals developed diarrhea and inflammatory responses that were similar to those seen in human infection. Pronounced histopathologic changes in the colonic mucosa of infected animals were observed during the acute phase (days 1 through 3) of infection. Electron micrographs of colonic epithelium revealed disruption of the villi and internalized bacteria that were not within membrane vacuoles. During the acute phase, C. jejuni was isolated from the livers of 7 of 9 (78%) animals, and bacteria were visualized immunohistochemically in the livers from 5 of the 7 animals (71%) from which C. jejuni was isolated. A vigorous systemic and mucosal immune response to Campylobacter antigens was elicited after infection of ferrets. The data presented contribute to the current knowledge of the pathogenicity of and immunologic response to C. jejuni CG8421 in ferrets and better understanding of this model.

Background: In baboons, Papio sp. neoplasms tend to affect the hematopoietic system most commonly, with rare documentation of myxomatous neoplasms. In contrast, women can develop myxomatous masses within deep peripelvic tissues with some frequency during their reproductive years., Methods: We have identified and examined, retrospectively, myxomatous perineal masses in twelve female baboons within one research facility and compared their histopathologic, immunohistochemical and electron microscopic features to their human variants., Results: Our results indicate that these myxomatous neoplasms, in humans and non-human primates, share common features., Conclusion: Further research, particularly molecular genetic analysis, may be needed to identify the baboon as a true animal model for myxomatous perineal neoplasms.

Background: Recent in vitro studies suggest that inducible nitric oxide synthase (iNOS) activity mediates endothelial dysfunction. Rheumatoid arthritis (RA) is a chronic inflammatory condition and is associated with endothelial dysfunction and increased risk of cardiovascular disease. The aim of the study was to establish the contribution of iNOS to endothelial function., Methods: Forearm blood flow (FBF) was measured during intra-arterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), N(G)-monomethyl-l-arginine (l-NMMA) and aminoguanidine (AG) in 12 RA patients and 13 healthy control subjects. Levels of C-reactive protein (CRP) and myeloperoxidase (MPO) were assessed. FBF data are presented as mean percentage changes in the ratio (infused/control arm) of FBF + or - SEM., Results: FBF response to ACh was reduced in patients with RA compared to controls (179 + or - 29 v. 384 + or - 72%, respectively; P=0.01), but SNP response was not (P=0.5). FBF response to AG differed between patients and controls (-15 + or - 2% v. 13 + or - 4%, respectively; P<0.001), whereas the response to l-NMMA did not (P=0.4). In a multiple regression model log CRP, AG response and LDL were found to be independent predictors of endothelial function (R(2)=0.617, P<0.001)., Conclusion: RA patients have endothelial dysfunction and increased iNOS activity in comparison to controls. Furthermore, CRP and iNOS activity were independently associated with endothelial function. Our data demonstrates that inflammation is a key mediator in a process of endothelial dysfunction possibly via activation of iNOS and increased production of MPO.

Pulse pressure varies throughout the arterial tree, resulting in a gradient between central and peripheral pressure. Factors such as age, heart rate, and height influence this gradient. However, the relative impact of cardiovascular risk factors and atheromatous disease on central pressure and the normal variation in central pressure in healthy individuals are unclear. Seated peripheral (brachial) and central (aortic) blood pressures were assessed, and the ratio between aortic and brachial pulse pressure (pulse pressure ratio, ie, 1/amplification) was calculated in healthy individuals, diabetic subjects, patients with cardiovascular disease, and in individuals with only 1 of the following: hypertension, hypercholesterolemia, or smoking. The age range was 18 to 101 years, and data from 10 613 individuals were analyzed. Compared with healthy individuals, pulse pressure ratio was significantly increased (ie, central systolic pressure was relatively higher) in individuals with risk factors or disease (P<0.01 for all of the comparisons). Although aging was associated with an increased pulse pressure ratio, there was still an average+/-SD difference between brachial and aortic systolic pressure of 11+/-4 and 8+/-3 mm Hg for men and women aged >80 years, respectively. Finally, stratifying individuals by brachial pressure revealed considerable overlap in aortic pressure, such that >70% of individuals with high-normal brachial pressure had similar aortic pressures as those with stage 1 hypertension. These data demonstrate that cardiovascular risk factors affect the pulse pressure ratio, and that central pressure cannot be reliably inferred from peripheral pressure. However, assessment of central pressure may improve the identification and management of patients with elevated cardiovascular risk.

Objectives: Our aim was to determine reproducibility of the flow-mediated dilation (FMD) response profile, and discriminatory ability of the components., Background: Brachial FMD is widely used to study conduit artery endothelial function. Automated B-mode image edge detection (B-ED) provides a full response profile. Reproducibility and biological relevance of these additional components have not been fully explored., Methods: Forty-two healthy adults underwent FMD using B-ED repeated at fixed time intervals up to 3 months. The FMD profile was assessed for diameter changes, area under the curve, and time course. Measures were compared in 25 adults with hypercholesterolemia, 25 subjects with diabetes, and 50 matched control subjects., Results: The maximum change in FMD was the most reproducible (coefficient of variation = 9.8%, 10.6%, 6.6%, and 9.2% at 4 to 6 h, 1 week, 1 month, and 3 months, respectively). Most of the variability occurred between subjects rather than within. All FMD measures except time course were significantly reduced in hypercholesterolemia and diabetes. Power curves were generated to indicate the appropriate number of subjects for parallel and crossover study designs., Conclusions: Maximum FMD percentage change from baseline is the most reproducible of the response curve measures and best identifies those with risk factors. Flow-mediated dilation measured by B-ED is robust and practical to assess the effect of interventions on endothelial function in clinical trials.

Objectives: The aim of this study was to investigate the effect of simvastatin and ezetimibe on inflammation, disease activity, endothelial dysfunction, and arterial stiffness in a cohort of rheumatoid arthritis (RA) patients., Background: Rheumatoid arthritis is a chronic inflammatory condition associated with increased cardiovascular risk. Statins reduce inflammation and disease activity in RA patients, but whether this is due to pleiotropism or cholesterol lowering per se is unclear., Methods: Twenty patients received 20 mg simvastatin or 10 mg ezetimibe each for 6 weeks in a randomized double-blind crossover study. Disease activity, blood pressure, aortic pulse wave velocity (PWV), brachial artery flow-mediated dilation (FMD), and serum inflammatory markers were measured before and after each treatment., Results: Both ezetimibe and simvastatin significantly reduced total cholesterol (-0.62 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l, respectively; p < 0.001), low-density lipoprotein cholesterol (-0.55 +/- 0.55 mmol/l and -1.28 +/- 0.49 mmol/l; p < 0.0001), and C-reactive protein (-5.35 +/- 9.25 mg/l and -5.05 +/- 6.30 mg/l; p < 0.001). Concomitantly, Disease Activity Score (-0.55 +/- 1.01 and -0.67 +/- 0.91; p = 0.002), aortic PWV (-0.69 +/- 1.15 m/s and -0.71 +/- 0.71 m/s; p = 0.001), and FMD (1.37 +/- 1.17% and 2.51 +/- 2.13%; p = 0.001) were significantly improved by both drugs., Conclusions: This study demonstrates that both ezetimibe and simvastatin reduce disease activity and inflammatory markers to a similar extent in patients with RA. Therapy is also associated with a concomitant reduction in aortic PWV and improvement in endothelial function. This suggests that cholesterol lowering per se has anti-inflammatory effects and improves vascular function in RA.

Isolated systolic hypertension is associated with increased cardiovascular risk. It is thought to result from large artery stiffening, which is determined by structural components within the vasculature but also by functional factors including NO and endothelin-1. We hypothesized that endothelial dysfunction would account for increased arterial stiffness in patients with isolated systolic hypertension. The aim of this study was to investigate the relationship between endothelial function and arterial stiffness in these patients along with control subjects. We studied 113 subjects: 35 patients with isolated systolic hypertension (mean age+/-SD: 68+/-6 years), 30 age-matched control subjects (65+/-5 years), and 48 young control subjects (37+/-9 years). Aortic pulse wave velocity (PWV) was derived by sequential carotid/femoral waveform recordings. Conduit artery endothelial function was determined by flow-mediated dilatation. Aortic PWV was higher (9.65+/-2.56 m/s versus 8.26+/-0.85 m/s; P=0.009), and flow-mediated dilatation was lower (2.67+/-1.64% versus 4.79+/-3.1%; P=0.03) in patients with isolated systolic hypertension compared with age-matched control subjects. Similarly, aortic PWV was also higher, and flow-mediated dilatation lower, in older versus young control subjects (8.26+/-0.85 m/s versus 7.09+/-1.01 m/s and 4.79+/-3.1% versus 6.94+/-2.7%; P=0.004 for both). Overall, aortic PWV correlated inversely with flow-mediated dilatation (r=-0.3; P=0.001), which remained significant after adjustment for confounding factors (P=0.01). Patients with isolated systolic hypertension have higher aortic PWV and decreased endothelial function compared with age-matched control subjects. Our results suggest that endothelial function contributes significantly to increased arterial stiffness in patients with isolated systolic hypertension and with age.

Nonlinear dynamic methods and perturbation methods are compared in terms of the effects of signal length, sampling rate, and noise. Results of theoretical and experimental studies quantitatively show that measurements representing frequency and amplitude perturbations are not applicable to chaotic signals because of difficulties in pitch tracking and sensitivity to initial state differences. Perturbation analyses are only reliable when applied to nearly periodic voice samples of sufficiently long signal lengths that were obtained at high sampling rates and low noise levels. In contrast, nonlinear dynamic methods, such as correlation dimension, allow the quantification of chaotic time series. Additionally, the correlation dimension method presents a more stable analysis of nearly periodic voice samples for shorter signal lengths, lower sampling rates, and higher noise levels. The correlation dimension method avoids some of the methodological issues associated with perturbation methods, and may potentially improve the ability for real time analysis as well as reduce costs in experimental designs for objectively assessing voice disorders.

Objective: Nitrates are used widely in clinical practice. However, the mechanism underlying the bioactivation of nitrates to release NO remains unclear. Recent animal data suggest that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in nitrate bioactivation, but its role in humans is not known. We investigated the role of ALDH2 in the vascular effects of nitroglycerin (NTG) in humans in vivo., Methods and Results: Forearm blood flow (FBF) responses to intra-arterial infusions of NTG, sodium nitroprusside (SNP), and verapamil were measured in 12 healthy volunteers before and after ALDH2 inhibition by disulfiram. All drugs caused a dose-dependent vasodilatation. However, only the response to NTG was significantly reduced after disulfiram therapy (33% reduction in area under the curve [AUC]; P=0.002). Separately, 11 subjects of East Asian origin, with the loss-of-function glu504lys mutation in the ALDH2 gene, received intra-arterial NTG, SNP, and verapamil. Only the FBF response to NTG was lower in the volunteers with the glu504lys mutation compared with East Asian and non-Asian wild-type control subjects (40% reduction in AUC; P=0.02)., Conclusions: The findings suggest that ALDH2 is involved in the bioactivation of NTG in humans in vivo but accounts for less than half of the total bioactivation. This may be of clinical importance in patients with mutations in the ALDH2 gene and in those taking drugs that inhibit ALDH2.

Metallothionein (MT) protects against the harmful effects of a wide spectrum of stress factors. The most studied of these factors is cadmium, whose toxicity is reduced on sequestration by MT. However, there is poorer consensus in the literature about protection afforded by MT against stressors other than cadmium. In this study, a CHO-K1 cell line continuously overexpressing MT (MToex) was developed in order to evaluate the relative protection afforded by MT against different toxic agents. Cadmium was used as a positive control and, as expected, the MToex cells were more than 13-fold more resistant to the effects of cadmium chloride than were wild-type (WT) cells using the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay (IC50 values of 10 and 132 microM for WT and MToex cells, respectively). In contrast, overexpression of MT afforded no protection against mercuric chloride, staurosporine and hydrogen peroxide (IC50 values of about 50, 11 and 925 microM, respectively). Cd and Hg uptake by MToex and WT cells exposed to 1-10 microM of metal chloride was similar and yet a significant amount of these metals was associated with the cytosol MT fraction in the MToex cells but not in the WT cells. From this study it can be concluded that while MT overexpression protects against Cd toxicity, it has no influence on Hg, staurosporine or hydrogen peroxide toxicity and it is proposed that this reflects mechanistic differences of toxicity or depletion of labile intracellular zinc by the presence of excess binding ligand in the form of MT.

The infecting pathogen and its susceptibility to antibiotics is used to suggest prognosis in endocarditis. A case study was performed in a tertiary referral cardiology centre to assess the contribution of the measurement of minimum inhibitory concentration (MIC) to the decision to treat endocarditis surgically. The records were examined of 125 patients admitted between 1981 and 1999 in whom the minimum inhibitory concentration for the pathogen had been measured. The measures of outcome were mortality at time of hospital discharge and at 6 months, surgical referral and cure by medical treatment. Endocarditis caused by Staphylococcus aureus with a raised MIC of flucloxacillin (methicillin) was associated with higher mortality even if glycopeptides were used in treatment (< or = 35 mg/l 0/7 versus MIC 1-2 mg/l 4/13, P = 0.01). Elevated MICs of flucloxacillin in S. aureus infection or of gentamicin in streptococcal disease were associated with surgical intervention. There were no significant differences between bacterial pathogens in mortality, surgical referral or cure by medical treatment. The measurement of MIC appears prognostically important in deciding the surgical management of endocarditis.

Objective: To identify clinical markers available within the first 48 hours of admission that are associated with poor outcome in infective endocarditis., Designs: Retrospective cohort study., Setting: Teaching hospital., Patients: 208 of 220 patients with infective endocarditis., Methods: Consecutive patients with infective endocarditis presenting between 1981 and 1999 to a tertiary centre were studied. Clinical, echocardiographic, and haematological data recorded within 48 hours of admission were obtained. Data were analysed using logistic regression models., Main Outcomes Measures: Mortality at discharge and at six months., Results: Data were obtained for 93% of patients who were eligible for inclusion. 194 (93%) were positive for Duke criteria. Mean age was 52 (1.2) years, and 138 (66%) were men. 82 (39%) were transferred from other hospitals. 181 (87%) were blood culture positive, and 47 (23%) infections were Staphylococcus aureus. The infection was located on aortic (n = 85, 41%), mitral (n = 77, 37%), tricuspid (n = 18, 9%), and multiple valves (n = 20, 10%). 67 (32%) had prosthetic valve endocarditis. 48% of the cohort were managed with antibiotics alone. Mortality at discharge was 18% and at six months 27%. Duration of illness before admission, age, sex, valve infected, infecting organism, and left ventricular function were not predictors of adverse mortality. However, abnormal white cell count, serum albumin concentration, serum creatinine concentration, or cardiac rhythm, the presence of two major Duke criteria, or visible vegetation conferred a poor prognosis., Conclusions: Conventional prognostic factors in this study did not appear to predict outcome early during hospital admission. However, simple clinical indices, which are readily available, are reliable, cheap, and potentially powerful predictors of poor outcome.

The main objectives of this research were to confirm previous reports of an increased risk of antidepressant use subsequent to propranolol therapy, and to determine whether this higher relative risk (RR) is indicative of depressive symptoms as a side-effect of the drug's use. 'New' users of beta-blockers, other antihypertensives or diuretics in two separate years were identified from records of Saskatchewan Health. Incidence of concurrent antidepressants prescribing was determined in the year after initiating therapy with a cohort drug. Medical claims were examined to identify physician services and diagnoses associated with cohort drug and antidepressant prescriptions. Risk of concurrent antidepressant use in new propanolol users aged 20-39 years was approximately double that of new diuretic users [RR 2.2 (1.5-3.3) in 1984 and 2.0 (1.1-3.5) in 1990/91]. When cases with a diagnosis of migraine headache were excluded, the risk of concurrent propranolol/antidepressant use was age- and sex-dependent, but not consistent for the two study years. It was concluded that although the risk of concurrent antidepressant use was greater in younger propranolol users, the risk cannot be solely attributed to depressive side-effects of the drug. The purposes of this paper were to present the methods employed in linking the databases of Saskatchewan Health, describe the results of the analysis, and to highlight the methodologic problems that arose., (Copyright 1997 by John Wiley & Sons, Ltd.)

A prospective, randomized, controlled evaluation comparing a 4-mg/kg loading dose (LD) of gentamicin to the standard regimen of 2.5 mg/kg every 12, 18 or 24 h was conducted in critically ill neonates. The objective of the study was to compare the time required to achieve a therapeutic peak serum concentration (i.e. the number of dosing intervals) and to compare the number of serum concentrations outside the therapeutic range as an indicator of potential toxicity between the treatment groups. Eighteen of 26 patients, 5 of 13 in the control group and 13 of 13 in the LD group (p = 0.012) achieved an initial peak concentration of > or = 5 micrograms/ml following the first gentamicin infusion. There were no significant differences between the control and LD group in the number of potentially toxic serum concentrations. When patients were subdivided according to gestational age (GA), patients of < or = 34 weeks had significantly lower initial peak concentrations. A LD of 4 mg/kg in neonates, particularly those of < or = 34 weeks GA, produced a therapeutic peak concentration following the initial dose. There is a minimal risk of attaining serum concentrations commonly associated with toxicity providing the dosage interval is adjusted based on serum creatinine determinations. Based on this study, infants of > 34 weeks GA generally achieve therapeutic peak concentrations after the first dose with conventional dosing; however, in younger infants an appropriate LD is required to reach therapeutic concentrations early in therapy.