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.

Long-term persistence of gene expression from adeno-associated virus serotype 5 in the mouse airways.

Recombinant adeno-associated virus vectors based on serotype 2 (rAAV2) have been used to deliver transgenes to the airways in a variety of pre-clinical and clinical studies. Gene transfer in these studies has been severely restricted by the basolateral localization of rAAV2 receptors. Here, we studied vectors constructed from the AAV5 genome and capsid, which utilize N-linked sialic acid-containing receptors found on the apical surface of airway epithelial cells. We investigated gene transfer efficacy and duration of transgene expression following delivery of rAAV5/5 vectors to the mouse respiratory tract. Robust, dose-dependent transgene expression was observed in the epithelium lining the nose for at least 32 weeks, and for at least 52 weeks in the lung. Importantly, in the lung, transgene expression mediated by rAAV5/5 was 40-fold greater than by rAAV2/2 vectors. A distinct cellular preference for rAAV5/5-mediated transduction was observed, with transgene expression being predominantly restricted to sustentacular cells of the olfactory epithelium in the nose and alveolar type II cells in the lung. Administration of rAAV5/5 vectors to both the nose and lungs led to the rapid development of rAAV5/5-neutralizing antibodies, suggesting that repeated administration may be severely hampered by host immune responses.

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.

Primary care: promoting sexual health and HIV prevention through risk assessment and client education.

After 20 years, human immunodeficiency virus (HIV) is still a global health problem, mandating the need to incorporate HIV prevention into primary care. This report presents tips and examples to assist in conducting a clinical, drug use, and sexual risk assessment, using the term TOSSIS to cover HIV transmission sources. Nurse practitioners can also assist in HIV prevention by serving as patient and parent educators.

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.

Targeted prophylaxis with amphotericin B lipid complex in liver transplantation.

The purpose of this study is to prospectively evaluate a strategy in which prophylaxis with amphotericin B lipid complex at 3 different dosages was targeted to liver transplant recipients at high risk for the development of invasive fungal infection (IFI). High risk was defined as a postoperative requirement for prolonged (>/=5 days) intensive care unit (ICU) treatment. Consecutive high-risk patients were administered prophylaxis with amphotericin B lipid complex from day 5 after orthotopic liver transplantation (OLT) until ICU discharge or death. The first 10 eligible patients were administered 5 mg/kg/d, the next 10 patients were administered 2.5 mg/kg/d, and a final 10 patients were administered 1 mg/kg/d. Drug safety and efficacy were assessed before each dosage reduction. During the study period, 130 adult patients underwent 137 OLTs. Thirty patients fulfilled the entry criteria and were administered prophylaxis with amphotericin B lipid complex. No patient developed proven IFI during prophylaxis. Cultures from normally sterile sites (blood and abdominal drain fluid) always showed negative results. All fungal isolates were sensitive in vitro to amphotericin B. There was no significant difference in colonization scores among the groups of patients administered different dosages of amphotericin B lipid complex. No death, serious adverse reaction, or nephrotoxicity was attributed to amphotericin B lipid complex. We conclude that prophylaxis with amphotericin B lipid complex targeted to patients requiring prolonged ICU treatment after OLT appears to be well tolerated and may prevent IFI. Our current policy is to use amphotericin B lipid complex, 1 mg/kg/d, as antifungal prophylaxis in this high-risk group.

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.

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.

TGF-beta1 stimulates the release of pre-formed bFGF from renal proximal tubular cells.

BACKGROUND: It is now clear that the progression of renal disease is closely correlated to the degree of renal interstitial fibrosis. We have previously demonstrated that the renal proximal tubular epithelial cell may contribute to the fibrotic response by the generation of profibrotic cytokines. Transforming growth factor-beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF) are two of a group of profibrotic cytokines that have been associated with the development of renal interstitial fibrosis. In this study, we have examined the influence of TGF-beta1 on the generation of bFGF by renal tubular epithelial cells. METHODS: HK2 cells were grown to confluence and were serum deprived and stimulated with recombinant TGF-beta1 under serum-free conditions. Subsequently, supernatant, cell-associated, intracellular, and matrix-associated bFGF concentrations were determined by enzyme-linked immunosorbent assay (ELISA). bFGF mRNA expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The exposure of confluent serum-deprived HK2 cells to TGF-beta1 led to a significant increase in bFGF concentration in the cell culture supernatant. Twenty-four hours following the addition of 10 ng/ml TGF-beta1, this represented a twofold increase in bFGF concentration (control, 102 pg/ml, N = 24, vs. 202 pg/ml, N = 19, P = 0.0001). Despite the increase in bFGF concentration in the supernatant, there was no change in the expression of bFGF mRNA following the addition of TGF-beta1. The addition of 10 ng/ml of TGF-beta1 led to a 30% decrease in the total cell-associated bFGF concentration (control, 8.51 ng/ml, N = 16, TGF-beta1, 6.01 ng/ml, N = 13, P = 0.0042). This decrease in intracellular bFGF was associated with a 15% reduction in anti-bFGF antibody binding to fixed permeabilized cells, following the addition of 10 ng/ml of recombinant TGF-beta1 (N = 9, P = 0.0007), suggesting that the mechanism of stimulation of bFGF by TGF-beta1 involved the release of preformed bFGF from within the cells. In addition, following the addition of TGF-beta1, there was a significant dose-dependent decrease in the amount of bFGF sequestered in the extracellular matrix. At a dose of 10 ng/ml TGF-beta, this represented a greater than sevenfold decrease (N = 9, P = 0.0007) in matrix-bound bFGF, although this represented less than 3% of the total bFGF released into the supernatant. CONCLUSION: The data presented suggest that the main mechanism by which TGF-beta1 stimulates bFGF generation by proximal tubular epithelial cells is by stimulation of the secretion of preformed cytokine from within the cells.

Body temperature alterations in hospitalized HIV/AIDS patients.

Because of the questions raised by the staff nurses regarding their observations of fever and alterations in body temperature in AIDS patients, a nursing research study was conducted to examine the incidence and degree of temperature elevation in hospitalized AIDS patients. Study findings suggest that temperature elevation and fever are common occurrences in hospitalized HIV/AIDS patients, although the fever may be self-limiting. An elevation in the white blood cell count was not seen, making fever in HIV/AIDS patients different than other medical/surgical patients. Phenomena noted by staff nurses in the clinical setting should be verified by nursing research because the data derived from nursing observation can be used in designing nursing interventions.