Estimating the health loss due to poor engagement with cardiac rehabilitation in Australia.

BACKGROUND: Cardiac rehabilitation (CR) programs are effective in reducing cardiovascular mortality and readmissions. However, most patients are denied the benefits of CR due to low referral rates. Of those patients referred, commencement rates vary from 28.4% to 60%. This paper quantifies the scale of health loss in Australia due to poor engagement with the program, and estimates how much public funding can be justifiably reallocated to address the problem. METHODS: Economic decision modelling was undertaken to estimate the expected lifetime health loss and costs to Medicare. Key parameters were derived from Australian databases, CR registries and meta-analyses. Population health gains associated with uptake rates of 60%, and 85% were calculated. RESULTS: CR was associated with a 99.9% probability of being cost-effective, even at a cost-effectiveness threshold lower than conventionally applied. Importantly, an average of 0.52 years of life expectancy are lost due to national uptake being below 60% achieved in some best performing programs in Australia, equivalent to 0.28 quality adjusted life years. The analysis indicates that $12.9 million/year could be justifiably reallocated from public funds to achieve a national uptake rate of 60%, while maintaining cost-effectiveness of CR due to the large health gains that would be expected. CONCLUSION: CR is a cost-effective service for patients with coronary heart disease. In Australia, less than a third of patients commence CR, potentially resulting in avoidable patient harm. Additional investment in CR is vital and should be a national priority as the health gains for patients far outweigh the costs.

NCAM requires a cytoplasmic domain to function as a neurite outgrowth-promoting neuronal receptor.

The neural cell adhesion molecule (NCAM) promotes axonal growth via a homophilic binding mechanism by acting both as a neuronal receptor and a substratum ligand. We have previously shown that the GPI-linked 120-kDa isoform of NCAM, which lacks a cytoplasmic domain, is effective at promoting neurite outgrowth as a cellular ligand. To test its ability to function as a neuronal receptor, we have transfected PC12 cells with a cDNA encoding human GPI-linked NCAM and tested clones displaying stable cell surface expression of this isoform for their ability to respond to NCAM in a cellular substratum. Although they continued to express endogenous transmembrane rat isoforms of NCAM (140 and 180 kDa), PC12 cells expressing the GPI-linked NCAM lost their ability to extend neurites in response to substratum associated NCAM. However, their outgrowth response to N-cadherin and other activators of axonal growth was undiminished. Removal of GPI-linked NCAM from the surface of these clones using phosphatidylinositol-specific phospholipase C (PIPLC) fully restored their responsiveness to NCAM, indicating that the inhibition was a direct consequence of cell surface expression of this "dominant negative" isoform of NCAM. We have previously shown that expression of transfected 140- and 180-kDa isoforms of human NCAM in PC12 cells does not result in a loss of the neurite outgrowth response to NCAM. However, we show that deletion of the cytoplasmic domain of the 140-kDa isoform has the same effect as expression of GPI-linked NCAM. We conclude that the cytoplasmic domain of NCAM is required for an appropriate neurite outgrowth response.

Subverting lymph node trafficking by treatment with the Mel-14 monoclonal antibody to L-selectin does not prevent an effective host response to Sendai virus.

A single 250-micrograms dose of the Mel-14 mAb to L-selectin greatly diminished the extent of L-selectin expression on lymphocytes and decreased (60 to 90%) the massive cellular recruitment to the cervical and mediastinal lymph nodes that follows intranasal infection of naive C57BL/6 mice with Sendai virus. The numbers of CD8+ CTL precursors in the mediastinal lymph nodes were considerably reduced on day 7, when compared with virus-infected mice given a control rat IgG2a, but potent CTL effectors were present in the lungs of both groups by day 10 after infection, and the overall magnitude of CTL precursor generation was not obviously compromised. The early dominance of Sendai virus-specific IgM Ab-forming cells was prolonged in the Mel-14-treated mice, whereas plasma cells producing virus-specific IgA were abnormally prominent in the lymph nodes but not in the spleen. The kinetics of virus-specific Ab-forming cells generation and the serum Ab response for the various IgG isotypes were also delayed. Thus, though L-selectin is clearly important for the localization of naive lymphocytes to regional lymph nodes, the Mel-14-treated mouse can still deal effectively with a virus that causes productive infection only in the respiratory tract. The spleen, where L-selectin does not determine lymphocyte trafficking, is a major site for the compensatory T cell and B cell responses.

A threshold effect of the major isoforms of NCAM on neurite outgrowth.

Interactions between recognition molecules on the surface of neuronal growth cones and guidance cues present in the local cellular environment are thought to account for the growth of neurites in the highly stereospecific manner that contributes to correct target cell innervation. In vitro assays have been used to identify candidate molecular components of this system, either directly by demonstrating their ability to promote neurite outgrowth, or indirectly by the ability of specific antibodies to inhibit neurite outgrowth. The role of the neural cell adhesion molecule (NCAM) in pathway finding is not fully understood. Some immunological studies support a positive role; others do not, and it has been reported that purified NCAM does not support neurite outgrowth. We have previously shown that an arbitrary biochemical index of neurite outgrowth, the relative level of immunoreactive neurofilament protein, is increased when human and rat dorsal root ganglion neurons are cultured on monolayers of cells expressing transfected human NCAM. But, the complexity of growth precluded a simple morphological analysis and we did not determine the 'dose-response' relationship between NCAM expression and neuronal response. Here, we report on the morphology of rat cerebellar neurons cultured on monolayers of 3T3 cells transfected with complementary DNAs encoding all of the main NCAM isoforms found in cells such as astrocytes, Schwann cells and skeletal muscle. The data indicate that both transmembrane and glycosyl-phosphatidylinositol linked NCAM isoforms are potent substrates for neurite extension. A critical threshold value of NCAM expression is required for increased neurite outgrowth. Above this threshold, small increases in NCAM induce substantial increases in neurite outgrowth.

Inhibition of allergic encephalomyelitis by the iron chelating agent desferrioxamine: differential effect depending on type of sensitizing encephalitogen.

Induction of experimental allergic encephalomyelitis (EAE) in Lewis rats by injection of guinea pig (GP) spinal cord homogenate (SCH) plus adjuvant (SCH-CFA) can be inhibited by treatment with the iron chelating agent desferrioxamine (DFOM). Interestingly, induction of EAE with purified myelin basic protein (BP-CFA) is not inhibited with DFOM. This dichotomy does not appear to be due to any quantitative differences in the two inocula since minimal clinical EAE produced by threshold levels of BP is not inhibited with DFOM. Passive EAE is not inhibited irrespective of the type of encephalitogen used to sensitize the donors. This suggests that the inhibitory effect of DFOM is acting on the afferent limb of the immune response to SCH-CFA. Injection of BP-CFA and SCH-CFA into the same site, mixing BP with central nervous system (CNS) lipids, or incorporating BP into liposomes, all induce EAE which can be partially inhibited by treatment with DFOM. These results support the hypothesis that the close association of lipids with the encephalitogen (i.e. BP) in SCH required extensive lipid breakdown before adequate antigen presentation can occur, and it is at this level that DFOM exerts its inhibitory effect.

Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent.

Lewis rats that are primed with guinea pig spinal cord homogenized in complete Freund's adjuvant (GPSCH-CFA) develop overt symptoms of experimental allergic encephalomyelitis (EAE). Treatment with the iron-chelating agent, desferrioxamine B mesylate (DFOM), at various times before the onset of EAE, dramatically suppressed both the severity and duration of disease. When DFOM was administered to rats soon after the development of neurological signs, a rapid recovery occurred, though mild, transient symptoms could be seen approximately 1 wk after withdrawal of the drug. Treatment with DFOM was always accompanied by a diminution of T cell responsiveness on the part of the delayed-type hypersensitivity/helper subset and, on histological examination, an absence of inflammatory cells from lesions. Iron is believed to influence both the migration and function of immune effector cells. It can also act as a catalyst in the formation of free radicals, which are highly toxic agents causing tissue damage in sites of inflammation. The mechanisms underlying the effect of DFOM on the severity of EAE, and the possible implications for treatment of multiple sclerosis are discussed.

Effects of estrogen-induced hyperprolactinemia on endocrine and sexual functions in adult male rats.

Chronic estrogen treatment can lead to development of prolactin (PRL) secreting pituitary tumors. We have tested the ability of diethylstilbestrol (DES) to produce persistent hyperprolactinemia (hyperPRL) in adult male rats and examined the effects of this treatment on hypothalamic-pituitary-testicular function, adenohypophyseal structure, copulatory behavior and fertility. Silastic capsules containing approximately 5 mg DES were subcutaneously implanted into adult male CDF (F-344)/CrlBR rats and removed 15 or 20 weeks later. Extreme hyperPRL, as well as suppression of plasma LH and FSH levels, persisted after DES capsules were removed. In contrast, plasma testosterone levels increased rapidly after removal of DES capsules and reached normal levels within 4-6 weeks. Copulatory behavior was assessed on two occasions between 7 and 14 weeks after removal of the DES capsules and was found to be suppressed in DES-treated rats, as evidenced by significant increases in latencies to mount, to intromit and to ejaculate. Moreover, when the animals were placed with normal females, the interval until conception was significantly greater in DES-treated than in control males. In spite of these differences in copulatory behavior, 10 of 11 DES-treated males were fertile. At autopsy, 44 weeks after capsule implantation (i.e. 24 or 29 weeks after capsule removal), DES-treated rats had marked enlargement of the anterior pituitary, increased weights of the lateral prostate and the adrenals, increased levels of testicular hCG-binding sites, reduced concentration of dopamine and norepinephrine in the median eminence and increased concentration of LHRH in the preoptic area.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival of autotransfused red blood cells recovered from the surgical field during cardiovascular operations.

The survival of autologous red blood cells (RBCs) collected during operation from the surgical field and processed immediately by the Haemonetics Cell Saver was compared to the survival of autologous nonprocessed RBCs obtained by venipuncture in nine patients undergoing reconstructive vascular operations and four patients undergoing coronary artery bypass. A double isotope technique (Cr-51 and In-111) was used to determine the survival of the different cell populations. Seven patients undergoing coronary artery bypass served as controls to characterize the isotopes by labeling the same population of RBCs with each radionuclide. Comparison of the data in all groups failed to show any significant difference in either the immediate or long-term survival between autotransfused (Cell Saver--processed) blood and nonprocessed RBCs. This study indicates that shed blood collected and processed at operation with the Haemonetics Cell Saver can be autotransfused and that the in vivo survival of these cells is not significantly different from the survival of nonprocessed blood.

Uptake and retention of androgen in neurons of the brain of the golden hamster.

The distribution of cells capable of concentrating androgen was studied in the male hamster after injection of 5 alpha-dihydro-[1,2,4,5,6,7,(n)-3H]testosterone([3H]DHT) using the technique of thaw-mount autoradiography. Castrated adult male hamsters were injected with 0.2 microgram/100 g body weight of [3H]DHT (107 Ci/mmol) and killed 1.5 h later. Brains were rapidly removed and processed for autoradiography. Localization of radioactivity in high concentrations occurred chiefly in limbic forebrain structures and hypothalamic nuclei associated with the control of reproductive function including the following areas: the septal-preoptic region, the amygdala, and the anterior, ventromedial and arcuate nuclei of the hypothalamus. In addition, labeled cells in lesser concentrations were found in the lateral preoptic area, lateral hypothalamus, hippocampus, mesencephalon and various cortical regions. Treatment with 100-fold excess of testosterone, but not estradiol or diethylstilbestrol, inhibited nuclear localization. These studies provide information on the precise anatomical localization of androgen concentrating cells in the hamster brain and demonstrate the similarity of distribution of androgen binding in the rat, mouse and hamster.