Highways for protein delivery to the mitochondria

Messenger RNA (mRNA) localisation is one of the prime mechanisms to ensure protein localisation in the cytoplasm of polarised embryonic cells, and has been well-studied in the development of Xenopus and Drosophila embryos. But what of other cells? Here, we discuss whether the directed transport of mRNA out of the nucleus, following cytoplasmic highways to a specified organelle in the cytoplasm, might also contribute to the exquisite fidelity of protein targeting observed in all eukaryotic cells.     

alpha IIb beta 3 redistribution triggered by receptor cross-linking

Fibrinogen binding to alpha IIb beta 3 on adherent, spread platelets triggers active, cytoskeletally-directed redistribution of fibrinogen/alpha IIb beta 3 complexes on the platelet surface. Gold-conjugated fibrinogen, unlabeled, soluble fibrinogen, and individual fibrinogen molecules have been demonstrated to trigger receptor redistribution. Here we examine the respective roles of receptor cross-linking and ligand occupancy of receptors in initiating this movement. Monovalent, alpha IIb beta 3-binding fibrinogen fragments RGDS and HHLGGAKQAGDV did not trigger receptor redistribution, suggesting that ligand binding to a single receptor is an insufficient stimulus. Binding of monoclonal antibodies 10E5, AP2, and AP3 to the receptor did not trigger receptor movement. However, cross-linking these receptor-bound monoclonal antibodies by polyclonal anti-mouse IgG or by conjugation of the anti-receptor antibody to large colloidal gold particles triggered receptor redistribution identical in rate, pattern, and final distribution to that previously seen with fibrinogen binding. We conclude that receptor cross-linking provides the signal for initiation of fibrinogen/alpha IIb beta 3 complex redistribution on platelet surfaces.     

Skeletal muscle function and its relation to exercise tolerance in chronic heart failure

OBJECTIVES: This study sought to define the relation between muscle function and bulk in chronic heart failure (HF) and to explore the association between muscle function and bulk and exercise capacity. BACKGROUND: Skeletal muscle abnormalities have been postulated as determinants of exercise capacity in chronic HF. Previously, muscle function in chronic HF has been evaluated in relatively small numbers of patients and with variable results, with little account being taken of the effects of muscle wasting. METHODS: One hundred male patients with chronic HF and 31 healthy male control subjects were studied. They were matched for age (59.0 +/- 1.0 vs. 58.7 +/- 1.7 years [mean +/- SEM]) and body mass index (26.6 +/- 0.4 vs. 26.3 +/- 0.7 kg/m2). We assessed maximal treadmill oxygen consumption (VO2), quadriceps maximal isometric strength, fatigue (20-min protocol, expressed in baseline maximal strength) and computed tomographic cross-sectional area (CSA) at midthigh. RESULTS: Peak VO2 was lower in patients (18.0 +/- 0.6 vs. 33.3 +/- 1.4 ml/min per kg, p < 0.0001), although both groups achieved a similar respiratory exchange ratio at peak exercise (1.15 +/- 0.01 vs. 1.19 +/- 0.03, p = 0.13). Quadriceps (582 vs. 652 cm2, p < 0.05) and total leg muscle CSA (1,153 vs. 1,304 cm2, p < 0.005) were lower in patients with chronic HF. Patients were weaker than control subjects (357 +/- 12 vs. 434 +/- 18 N, p < 0.005) and also exhibited greater fatigue at 20 min (79.1% vs. 92.1% of baseline value, p < 0.0001). After correcting strength for quadriceps CSA, significant differences persisted (5.9 +/- 0.2 vs. 7.0 +/- 0.3 N/cm2, p < 0.005), indicating reduced strength per unit muscle. In patients, but not control subjects, muscle CSA significantly correlated with peak absolute VO2 (R = 0.66, p < 0.0001) and is an independent predictor of peak absolute VO2. CONCLUSIONS: Patients with chronic HF have reduced quadriceps maximal isometric strength. This weakness occurs as a result of both quantitative and qualitative abnormalities of the muscle. With increasing exercise limitation there is increasing muscle weakness. This progressive weakness occurs predominantly as a result of loss of quadriceps bulk. In patients, this muscular atrophy becomes a major determinant of exercise capacity.     

Antidepressant overdoses and resultant emergency department services: the impact of SSRIs

Suicide is a major source of morbidity and mortality in patients with mental illness. The selective serotonin reuptake inhibitors (SSRIs) and other newer nontricyclic antidepressants appear to have less clinically significant toxicity in overdose, resulting in lower costs of treatment when compared with tricyclic antidepressant (TCA) overdoses. The resource utilization and cost of treatment for SSRI overdoses may not be less if (1) these agents are commonly ingested with other potentially toxic substances, or (2) health care practices have not changed in response to the apparent greater safety of SSRIs. This study evaluates demographic variables of antidepressant overdoses to determine whether differences exist in treatments and monitoring. Additionally, this study evaluates costs associated with care and the impact of co-ingestants on those same factors.     

Heterozygosity for a defective gene for CC chemokine receptor 5 is not the sole determinant for the immunologic and virologic phenotype of HIV-infected long-term nonprogressors

HIV-1-infected long-term nonprogressors are a heterogeneous group of individuals with regard to immunologic and virologic markers of HIV-1 disease. CC chemokine receptor 5 (CCR5) has recently been identified as an important coreceptor for HIV-1 entry into CD4+ T cells. A mutant allele of CCR5 confers a high degree of resistance to HIV-1 infection in homozygous individuals and partial protection against HIV disease progression in heterozygotes. The frequency of CCR5 heterozygotes is increased among HIV-1- infected long-term nonprogressors compared with progressors; however, the host defense mechanisms responsible for nonprogression in CCR5 heterozygotes are unknown. We hypothesized that nonprogressors who were heterozygous for the mutant CCR5 gene might define a subgroup of nonprogressors with higher CD4+ T cell counts and lower viral load compared with CCR5 wild-type nonprogressors. However, in a cohort of 33 HIV-1-infected long-term nonprogressors, those who were heterozygous for the mutant CCR5 gene were indistinguishable from CCR5 wild-type nonprogressors with regard to all measured immunologic and virologic parameters. Although epidemiologic data support a role for the mutant CCR5 allele in the determination of the state of long-term nonprogression in some HIV-1- infected individuals, it is not the only determinant. Furthermore, long-term nonprogressors with the wild-type CCR5 genotype are indistinguishable from heterozygotes from an immunologic and virologic standpoint.     

Effects of DL-penicillamine on cytotoxic reaction between baboon performed xenoantibodies and pig endothelial cells

The purpose of this study was to evaluate effects of DL-Penicillamine (DLP), a compound interrupting S-S bonds (IgM pentamers) on binding and cytotoxicity of adult baboon performed xenoantibodies to pig endothelial cells. Pooled baboon serum was treated with different concentrations of DLP during various periods of time. Complement-mediated cytotoxicity assay was used to determine the reactivity of baboon xenoantibodies to pig aortic endothelial cells (PAEC). To assess IgM and IgG binding to PAEC, ELISA method was applied. Serum treated with DLP revealed significant reduction of cytotoxicity in a dose dependent manner. Cytotoxicity was also reduced during time prolongation of DLP exposure to PAEC. Results indicate that baboon performed IgM and IgG xenoantibodies bind to pig endothelial cells, but only IgM is able to cause degradation of the complement. DLP significantly reduces cytotoxicity and eliminates binding of IgMs to PAEC in spite of continued binding of IgG xenoantibodies to the surface of endothelium.     

Leptomeningeal metastasis: pathophysiology, treatment, and nursing management

PURPOSE/OBJECTIVES: To review the pathophysiology, diagnosis, and clinical treatment of leptomeningeal metastasis. DATA SOURCES: Published articles, abstracts, and book chapters. DATA SYNTHESIS: Leptomeningeal metastasis is an increasingly seen complication of cancer. Treatment is intensive and may increase survival from four to five weeks without treatment to an average of six months. Clinical management and treatment of these patients is complex and best accomplished by a multi-disciplinary healthcare team. CONCLUSIONS: Information regarding the anatomy, pathophysiology, treatment, and treatment complications can facilitate the care of patients with leptomeningeal metastasis. IMPLICATIONS FOR NURSING PRACTICE: Nursing interventions should focus on patient and family education about the disease process, side-effects of treatment, and early identification of disease progression.     

Perinatal asphyxia and heart problems

New bisantrene analogues were synthesized, bearing one or two 4,5-dihydro-1H-imidazol-2-yl hydrazone side chains at positions 1,4 or 9 of the anthracene ring system. A 10-azabioisostere was also prepared. The position of substituents in structurally isomeric drugs modulates topoisomerase II poisoning and specificity, along with cytotoxicity.     

The effect of prostate volume, age, total prostate specific antigen level and acute inflammation on the percentage of free serum prostate specific antigen levels in men without clinically detectable prostate cancer

PURPOSE: We determine the influence of age, prostate volume, total serum prostate specific antigen (PSA) level and histological evidence of acute inflammation in biopsy specimens on the percent free serum PSA level in men without clinically detectable prostate cancer. MATERIALS AND METHODS: We studied 70 men with total PSA levels of 2.6 to 9.9 ng./ml. who had undergone at least 3 sets of prostate biopsies that were negative for cancer as part of our PSA based prostate cancer screening program. Total and free PSA levels were measured using Hybritech immunoassays. Prostate volume and the presence of acute inflammation were determined from the most recent transrectal ultrasonography and prostate needle biopsy. RESULTS: Percent free PSA levels correlated significantly with age (r = 0.48, p = 0.0001) and prostate volume (r = 0.44, p = 0.0002) but not with total PSA (r = 0.04, p = 0.7). The mean percent free PSA did not differ for those with or without acute inflammation. Multivariate regression models demonstrated that age and prostate volume were significant predictors of percent free PSA. CONCLUSIONS: Among men without detectable prostate cancer and a total PSA level between 2.6 and 9.9 ng./ml. percent free serum PSA was higher in older men and in men with a larger prostate gland but was not influenced by total PSA level or the presence of acute inflammation in the prostatic biopsy specimen.     

Ethanol inhibits mitogen activated protein kinase activity and growth of vascular smooth muscle cells in vitro

The intrathecal (i.t.) injection of endothelins to conscious rats was found to cause respiratory arrest. To gain some insights into this central phenomenon, peripheral vascular permeability and lung oedema were measured after i.t. and i.v. injections of these peptides. When injected at T-8 spinal cord level, endothelin-1 (65 and 650 pmol) and endothelin-3 (650 pmol) enhanced vascular permeability in the lungs by 22-fold and 7-fold, respectively, and caused sudden death at the highest dose. Less prominent increases (between 1.4- and 2.2-fold) of vascular permeability were observed in other tissues (trachea, kidney, ears, skin of hind paws and back skin) with endothelin-1. Endothelin-1 (650 pmol) caused a similar increase (27-fold) in lung vascular permeability when injected at T-2, although the response was significantly less (P < 0.05) if injected at the L-4 (15-fold) spinal cord level. Only endothelin-1 produced lung oedema when injected at the T-2 or T-8 level. In contrast, intravenous injection of endothelins-1 and -3 (650 pmol) did not produce lung oedema and the lung vascular permeability was increased by only 1.4-1.6-fold and all rats survived. The prior i.t. injection of 6.5 nmol BQ-123 (cyclo[D-Trp, D-Asp, L-Pro, D-Val, L-Leu]), a selective endothelin ET(A) receptor antagonist, prevented the increases of lung vascular permeability and oedema and the mortality induced by i.t. endothelin-1 (650 pmol). Whereas i.v. treatment with phentolamine (2 mg/kg) or pentolinium (25 mg/kg + 50 mg/kg per h x 15 min) abolished the lung vascular permeability changes evoked by endothelin-1 (650) pmol), atropine (1 mg/kg), NG-nitro-L-arginine (50 mg/kg) or indomethacin (5 mg/kg) had no effect. Moreover, the effects of endothelin-1 were attenuated in capsaicin pretreated rats (125 mg/kg, 10 days earlier) and almost abolished in rats subjected to sympathectomy with 6-hydroxydopamine (100 mg/kg, 24-48 h earlier). All these treatments except atropine and NG-nitro-L-arginine prevented the endothelin-1-induced lung oedema and reduced the lethality by around 50%. These results suggest that the increases of pulmonary vascular permeability and oedema induced by i.t. endothelin-1 are due to an intense pulmonary vasoconstriction mediated by alpha-adrenoceptors following the release of catecholamines in response to the activation of endothelin ET(A) receptor in the spinal cord. This central phenomenon seems to be reflexogenic, including the involvement of primary afferent C-fibers and spinal cord ascending fibers to the brain. Thus, endothelin-1 could play a role in neurogenic pulmonary oedema through a central mechanism.