Increased cardiovascular risk in patients with severe mental illness.

BACKGROUND: People with severe mental illness (SMI) have a reduced life expectancy. A major cause of mortality is cardiovascular disease. AIMS: The aims of this study were to document the prevalence of cardiovascular risk factors in people with SMI engaged in community psychiatric rehabilitation and compare prevalence rates to the general, and Aboriginal and Torres Strait Islander (ATSI) populations of Australia. METHOD: A cross-sectional audit was conducted on patients receiving care from Melbourne's Inner-West Area Mental Health Service. Profiles were collected on: smoking status, body mass index, waist circumference, blood pressure, diabetic status and fasting lipid profiles. These were compared with the general and ATSI Australian populations. RESULTS: Complete data were available for 60 patients. Most were involuntary patients with a diagnosis of schizophrenia or schizoaffective disorder. Patients were more likely to smoke, be obese, have dyslipidaemia and the metabolic syndrome compared with the general and ATSI populations of Australia. Patients were more likely to have diabetes than the general population but had similar rates to the ATSI population. Patients had similar rates of hypertension to the general population but were less likely to be hypertensive compared with the ATSI population. CONCLUSION: Australians living with SMI have very high rates of cardiovascular risk factors, far in excess of the general Australian population and comparable with the ATSI population.

The dose-response relation for the antinociceptive effect of morphine in a fish, rainbow trout.

There have been suggestions that analgesics be used by fish researchers. But in the absence of dose-response data for morphine, this suggestion seems imprudent. The purpose of the present study was to develop a dose-response relationship in fish using six doses of morphine. The response (movement of the fins or tail) to a noxious stimulus (electrical shock to the face region) was monitored before and after a dose of morphine intraperitoneally (i.p.). The i.p. dose of morphine ED(50) in rainbow trout was 6.7 ± 0.8 mg/kg (n = 12 at each dose). The plasma morphine concentration EC(50) was 4.1 ± 1.5 mg/L. In a second experiment, rainbow trout tested with equal amounts of morphine and naloxone (30 mg/kg) showed that the antinociceptive effect of morphine was blocked by naloxone. It has been suggested that stress-induced analgesia has been a confounding factor in some fish studies. However, plasma cortisol levels in our study indicated that stress was not a confounding factor in the present experiments. The ED(50) for morphine in fish was higher than that reported for humans or other mammals. Our observation showing a dose-response relation for morphine using a noxious stimulus supports arguments for its effectiveness as an antinociceptive drug in fish.

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung.

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Interleukin-1beta (IL-1beta) inhibition: a possible mechanism for the anti-inflammatory potency of liposomally conjugated methotrexate formulations in arthritis.

1. Liposomes with conventional and long-circulation times were employed as carriers for the methotrexate derivative MTX-gamma-DMPE (MTX-EPC and MTX-PEG respectively), their mechanism of action was investigated in vitro and in vivo and their therapeutic efficacy assessed using the rat collagen-induced arthritis (CIA) model. 2. At non-toxic dose, both MTX-EPC and MTX-PEG inhibited the lipopolysaccharide (LPS) induced release of IL-1beta from activated rat peritoneal macrophages (rPMPhi) in a dose and time dependent manner. Free methotrexate (MTX) was not active in this respect. After a single intravenous injection (i.v.), and at equivalent doses, both free MTX (500 microg) and MTX-EPC inhibited the LPS induced rise in plasma IL-1beta levels observed in MTX-PEG and saline treated rats. 3. When used to treat established CIA, MTX-EPC resulted in significantly lower clinical score (CS) (1.0+/-0.42 (P<0.001)) and hind paw diameter (HPD) (6.5+/-0.34 mm (P<0.001)) measurements than controls (3.0+/-0.26; 7.33+/-0.41 mm), after only two i.v. doses, and remained significantly lower for the entire experimental period. By day 24 both CS (2+/-0.61 (P<0.001)) and HPD (6.97+/-0.25 mm (P<0.002)) measurements had also become significantly lower in MTX-PEG treated rats than in saline treated controls (3.62+/-0.17, 7. 92+/-0.38 mm) and remained lower until day 30. Joint inflammation in MTX treated rats was completely ameliorated by day 20 but the health and well being of the animals was compromised and the experiment terminated at this time-point. 4. Our results clearly demonstrate that both MTX-EPC and MTX-PEG liposomes have potential for development into therapeutic modalities for the treatment of inflammatory joint disease in man.

Regulation of renal proximal tubular epithelial cell fibroblast growth factor-2 generation by heparin.

Progression of renal disease is closely correlated to the degree of renal interstitial fibrosis, and evidence is increasing that epithelial cells of the renal proximal tubule (PTCs) may contribute to its pathogenesis. Such cytokines as basic fibroblast growth factor (FGF-2) have been implicated in progressive renal injury, and we previously showed that PTCs are a source of this cytokine. FGF-2 is characterized by its high affinity for heparin, and numerous studies have suggested that heparin may modify the progression of renal disease. The current study examined how heparin influenced FGF-2 generation and bioactivity in the human renal epithelial PTC line, HK-2. Incubation of HK-2 cells with heparin led to a dose- and time-dependent increase in FGF-2 concentration in the culture supernatant that was not accompanied by alterations in FGF-2 messenger RNA expression, assessed by reverse-transcriptase polymerase chain reaction and Northern analysis. The heparin-induced increase in FGF-2 concentration was accompanied by a decrease in the amount of FGF-2 bound to the extracellular matrix, although this accounted for only a small proportion of the total FGF-2 generated. Induction of FGF-2 by 2-O-desulfated heparin, together with a reduction in total cell-associated FGF-2 and anti-FGF-2 antibody binding to fixed permeabilized cells after the addition of heparin, suggested that the FGF-2 released was mainly derived from a preformed intracellular source. That FGF-2 was predominantly derived from an intracellular pool was also confirmed by pulse chase experiments. The addition of heparin resulted in the generation of bioinactive FGF-2, judged by in vitro fibroblast proliferation. Conversely, heparitinase treatment of supernatant samples from heparin-treated cells and the addition of 2-O-desulfated heparin resulted in the generation of active FGF-2, suggesting that the generation of bioinactive FGF-2 was related to binding of FGF-2 by extracellular heparin after its release from cells. These data show that heparin depletes both the cell and surrounding matrix of FGF-2 and suggest that FGF-2 released from cells was mainly derived from a preformed intracellular source. Furthermore, FGF-2 released from epithelial PTCs after the application of heparin was bioinactive. This likely resulted from released FGF-2 binding to an excess of extracellular heparin. Results presented here therefore suggest a mechanism by which heparin, through its effect on depletion of matrix and cells of FGF-2 and its generation in an inactive form, may influence progressive renal interstitial fibrosis.

Structure-activity relationships among dithiocarbamate antidotes for acute cadmium chloride intoxication.

Eight sodium dithiocarbamates (NaS2CNR1R2) have been examined as antidotes for acute cadmium intoxication. While all of them possess an ability to increase survival when given to mice 2 hr after a lethal (greater than 99%) intraperitoneal injection of 10 mg/kg of CdCl2 X 2.5H2O, their effects on the organ distribution of cadmium vary considerably. It has been possible to show that the accumulation of cadmium in the brain and kidney as well as the survival rates can be correlated with a numerical measure of the polarity of the groups R1 and R2. Each factor has a different dependence on the polarity, but it is possible to construct a composite factor for antidotal efficacy which incorporates survival rate, brain cadmium levels and kidney cadmium levels. The factor constructed here exhibits an optimal value approximately in the middle of the polarity range studied. Compounds which have R1 = -CH2CH1OH and R2 = -CH2CH2OH, or -CH3 or -C2H5 appear to be the most effective antidotes of the compounds examined.

Structural factors in the in vivo chelate mobilization of aged cadmium deposits.

The role of structural factors in determining the relative efficacy of dithiocarbamates as chelating agents for the in vivo mobilization of aged cadmium deposits is examined for 23 newly synthesized compounds of this type. The critical feature in determining the efficacy of the compounds in mobilizing intracellular cadmium is the balance between hydrophobic and hydrophilic groups. This balance also governs the other properties of these compounds such as the organ specificity of action and the relative propensity to carry cadmium to the brain. The transport of cadmium to the brain by dithiocarbamate can be greatly reduced by the incorporation of appropriate hydrophilic groups that prevent the formation of lipid-soluble cadmium complexes that pass readily into the brain. If the chelating agents carry an additional ionic charge, their ability to pass through cellular membranes and react with intracellular deposits of cadmium is significantly reduced, with other structural factors being equal. The structural features that optimize mobilization of cadmium from the kidney do not appear to be identical with those that optimize its mobilization from the liver. The correlation of cadmiummobilizing properties of these chelating agents with the sum of the Hansch pi constants for the parts of the molecular structures other than the dithiocarbamate grouping (sigma pi) is reasonably good for the removal of renal cadmium by derivatives of D-glucamine and D-xylamine. Another aspect of the molecular structure that appears to play a role is the presence of uncharged polar groups having the ability to form hydrogen bonds. The relevance of these factors in designing chelating agents to enhance the excretion of other toxic metals from their intracellular sites is discussed.

Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality.

We retrospectively evaluated 75 allogeneic stem cell transplant recipients to ascertain the incidence, risk factors and outcome of infection with Clostridium difficile. Ten patients (13%) had Clostridium difficile infection at a median of 38 days (range day -6 to day +72) following the transplant. There was no difference in the duration or severity of diarrhoea in patients with Clostridium difficile infection compared to the uninfected patients and no relationship to the prior antibiotic or chemotherapy usage, age, gender, underlying disease, donor type, CMV serostatus, total body irradiation or time to engraftment. The incidence of viral infections was increased in patients infected with Clostridium difficile (7/10 vs 15/65, P = 0.005, odds ratio 7.7), but the strongest association was with GVHD >grade 2 (5/10 vs 6/65 uninfected patients, P = 0.004, odds ratio 9.8). Patients infected with Clostridium difficile also suffered a higher non-relapse mortality with 7/10 patients succumbing to either GVHD or infections, compared to 19/65 patients in the uninfected group (P = 0.02, odds ratio 5.6). Thus Clostridium difficile infections in our study had a strong association with GVHD and increased non-relapse mortality. It is possible that Clostridium difficile toxin might predispose to increased severity of GVHD leading to an adverse outcome.

Dependence on chelating agent properties of nephrotoxicity and testicular damage in male mice during cadmium decorporation.

An examination of the histopathological appearance of the kidneys of mice treated with cadmium chloride (s.c.) and simultaneously given 1 of 3 chelating agents (i.p.) reveals that the extent of nephrotoxicity is greatest when L-cysteine is the chelating agent. When either of 2 dithiocarbamates capable of mobilizing cadmium from its intracellular deposits, i.e. sodium N-methyl-D-glucamine dithiocarbamate (NaG) or sodium N-benzyl-D-glucamine dithiocarbamate (NaB) is used as the chelating agent, no morphological renal damage was evident. Under these same conditions the testes of the mice were protected to the extent of 95% by both of the dithiocarbamates, whereas the protection afforded by the L-cysteine was only about 50%. One factor governing the extent of nephrotoxicity appears to be the stability of the cadmium complexes which are formed and the manner in which this affects their behavior in vivo. Complexes which are preferentially excreted in the bile, cause little or no renal damage.

Intracellular cadmium mobilization sequelae.

The consequences of the mobilization of aged intracellular cadmium from its in vivo deposits in mice by chelating agents were examined. The chelating agents used were BAL, sodium N-benzyl-D-glucamine dithiocarbamate (NaB), Diisopropyl meso-2,3-dimercaptosuccinate(Di-PDMS) and sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate(4-Me0), all previously shown capable of causing statistically significant decreases in either renal or hepatic cadmium burdens in rodents. They were given at a level of 400 mumol/kg (i.p.) daily for 10 days to mice previously loaded with a total of 10 mg CdCl2.2.5 H2O/kg. Under these conditions a significant decrease in the renal cadmium level occurred following treatment with BAL, NaB, and 4-MeO; hepatic cadmium levels decreased significantly following treatment with NaB and 4-MeO. Pathological examination of the kidneys, liver, and testes in these animals showed that chelate mobilization of the cadmium produced no noticeable changes in the histopathology of these organs in comparison with that observed for the animals which had been given only cadmium and had undergone no chelate treatment. The results suggest that the mobilization of such aged cadmium from in vivo deposits need not result in any deleterious changes in the kidneys, liver or testes.

Selective removal of cadmium from aged hepatic and renal deposits: N-substituted talooctamine dithiocarbamates as cadmium mobilizing agents.

The preparation and examination of three dithiocarbamates derived from N-substituted D-gluco-L-talooctamine reveals that the 4-methoxybenzyl derivative (MeOBGD) is superior to any previously prepared dithiocarbamates as an agent for the mobilization of aged intracellular hepatic cadmium deposits from mice. All of these compounds are also quite effective in reducing whole body burdens of cadmium. The use of these compounds does not result in any increase in the cadmium content of the brain. The selection of these chelating agents for synthesis was suggested by an analysis of the log dose-response curves for the mobilization of renal cadmium by previously studied dithiocarbamates. This revealed that the slope of the percentage renal cadmium mobilized vs the log dosage curve is determined to a considerable extent by the sum of the Hansch pi parameters for the substituents, while the intercept is largely determined by the molecular weight of the compound. The implication of such a correlation is that the ability of a chelating agent to remove cadmium from its aged deposits is determined to some extent by its molecular weight, provided the polarity of the overall molecule is appropriate.

Dithiocarbamate treatment of chronic cadmium intoxication in mice.

The dithiocarbamate analogs, N-benzyl-N-dithiocarboxy-D-glucamine (BDCG) and N-cyclohexyl-N-(2-hydroxy-3-sulfonatopropyl)dithiocarbamate (CAPSO-DTC), were evaluated as cadmium (Cd) antagonists in mice which had received repetitive injections of Cd to effect accumulation of substantial levels of metallothionein-bound Cd in kidneys and livers. BDCG was highly effective in lowering whole body Cd stores and renal Cd concentrations. While the percent of renal Cd mobilized decreased with increasing Cd concentrations, the total amount of Cd mobilized increased. CAPSO-DTC was also effective in reducing whole body Cd levels, but appeared to have less affinity for renal Cd than did BDCG. Treatment of Cd-laden mice with BDCG provoked only a modest elevation of serum creatinine levels, suggesting that the complex of Cd with BDCG may be less nephrotoxic than the complex of Cd with EDTA or dimercaprol. The log of the percent reduction of renal Cd by BDCG was found to be a linear function of the pretreatment renal Cd concentration, and reductions of whole body Cd burdens correlated closely with reductions of liver and kidney Cd concentrations. It was suggested that a Cd complexing agent of the dithiocarbamate class may have ultimate application in a provocative methodology to estimate body or organ Cd stores based upon the amount of Cd excreted following a standard dose of the chelator.

Mobilization of aged in vivo cadmium deposits by diethyl dimercaptosuccinate.

Diethyl dimercaptosuccinate (DEDMS) was prepared and found to be capable of mobilizing cadmium from mice one month after they had been given an injection (i.p.) of 0.03 mg CdCl2.2.5H2O containing 1.0 microCi of 109 CdCl2. When pure, DEDMS is a waxy solid with a melting point of 61-62 degrees C which is soluble in warm peanut oil. Its LD50 value (i.p.) in mice is approximately 2.6 mmol/kg, a value which allows it to be given at a higher dosage than other known lipid-soluble dithiols. This compound is especially effective in reducing hepatic and whole body levels of cadmium; it is not as effective as 2,3-dimercaptopropanol (BAL) in reducing renal cadmium levels.

Singlet oxygen yields of furocoumarins and related molecules--the effect of excitation wavelength.

Singlet oxygen yields (phi delta) were compared for a wide range of furocoumarins and related compounds using excitation wavelengths of 313, 334 and 365 nm. The phi delta values ranged from 0.02 or less to 0.4, but no wavelength dependence was detected for any of the compounds studied.

Thermographic assessment of hand burns.

Twenty-three patients with 32 burned hands were studied thermographically within 48 h of injury to investigate the potential value of thermography in the assessment of the depth of hand burns. Superficial and deep partial thickness burns were treated conservatively, with excision and grafting of those which had not healed by 2-3 weeks after injury. This delayed surgery group and the healed group were retrospectively analysed to determine the predictive value of the initial clinical and thermographic assessments of the depth of the burns. Full skin thickness burns were excised and grafted within 5 days and were not included in the study. Initial thermographic assessment correctly predicted the outcome (whether healed or excised and grafted) in 33 of 36 burns. This relationship was highly significant. Initial clinical assessment of depth had no significant relationship with the time taken to heal. Thermography may help in the selection of patients who might benefit from early surgery.

Thermographic assessment of burns using a nonpermeable membrane as wound covering.

Infrared thermography is a useful technique for the investigation of disorders which affect skin blood flow. The damage to skin blood vessels caused by thermal injury is a major determinant of the capacity of the wound to heal. Thermographic assessment of this damage has been found to correlate with the healing time of burn wounds. However, the application of thermography to the assessment of burns for early surgery has been limited because of the difficulties involved in correcting for cooling artefacts resulting from the effect of evaporative water loss (EWL) at the wound surface. A water impermeable polyvinylchloride film (sold in the USA as Saran Wrap, in Australia as Glad Wrap and in the UK as Clingfilm (CF)) was investigated as a wound covering to avoid this cooling effect. It was found that the CF abolished the cooling effect of EWL and did not significantly interfere with the measurement of surface temperature. This material provides a solution to the problems of thermographic examination of wounds such as burns where damage to the skin surface allows exudation or EWL to occur.

Implementing a multidisciplinary HIV diarrhea critical pathway in the acute care setting.

Clinical pathways are the new strategy for managing hospital length of stay and cost in the changing, dollar-driven arena of health care. For patients with AIDS, HIV-related diarrhea is a potential source of increased morbidity that results in increased hospitalization and health care costs. This article describes the development and implementation of a multidisciplinary HIV Diarrhea Critical Pathway at Mount Sinai Medical Center of Greater Miami in South Florida. The focus of this article is on the nursing issues that arose during the piloting of the Diarrhea Critical Pathway and on the "how-tos" of its use. Initial evaluation of the first 3 years of using the diarrhea pathway is reported.

Nursing practice for HIV/AIDS fever care: a descriptive study.

Nurses often perceive fever in relation to the impact it has on specific patient populations. Fever in HIV/AIDS patients is a common symptom. This descriptive study explored how nurses in AIDS care defined and described fever in HIV/AIDS patients and used nursing interventions for fever management. Seventy-five registered nurses, nurse practitioners, and LPNs employed in AIDS care throughout Florida were surveyed concerning interventions for AIDS-related fever. The study revealed that nurses in AIDS care treat fever by providing patient comfort, initiating nursing interventions for low-grade to moderate fever, and notifying the primary care provider if nursing interventions do not keep the temperature below 100.9 degrees F. The sample provided a variety of nursing interventions to make the patient more comfortable. In addition, the study also revealed a unique perspective for fever care, which influences the practice of nurses in AIDS care and might differentiate nursing practice in AIDS care from other nursing specialties. However, some interventions differed from fever nursing management strategies published by the Association of Nurses in AIDS Care. Further research needs to explore the efficacy of these interventions.

Continuous quality improvement project: decreasing the potential for the development in the inpatient setting of drug resistance by improving nursing practice for HAART administration.

HIV/AIDS patients' dissatisfaction with highly active antiretroviral therapy (HAART) medication administration in the inpatient setting was the impetus for a continuous quality improvement (CQI) project. The purpose of the CQI project was to initiate a change in nursing practice for HAART medication administration. The goal of the project was to decrease the potential for development of drug resistance in the inpatient setting related to nonadherence with food requirements for drug administration and to incomplete or "missed" doses of prescribed HAART. A secondary goal was to increase the provision of patient education on HAART medications by nurses. The interdisciplinary CQI team found that medication administration in the inpatient setting involved more than nurses simply "passing meds." Inpatient medication administration was a complex process involving a variety of hospital systems, departments, and traditions, all of which had an impact on patient care. The article describes the CQI methodology that was used for the project and how each step of the project was planned and implemented. Specific problems related to administering HAART in the hospital setting are listed as areas for needed nursing research.