Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Prognostic significance of preoperative left ventricular ejection fraction and valve lesion in patients with aortic valve replacement

After aortic valve replacement, depressed left ventricular function, as assessed from the preoperative left ventricular ejection fraction, has been reported to improve significantly in patients with aortic stenosis, but to improve little or to a lesser degree In patients with aortic regurgitation. Accordingly, the effect of preoperative left ventricular ejection fraction and other variables on postoperative survival was examined in 229 patients after aortic valve replacement. The preoperative left ventricular ejection fraction, cardiac index and left ventricular end-diastolic pressure were found not to affect the 3 year postoperative survival rate in patients with aortic stenosis and mixed aortic valve disease. However, patients with aortic regurgitation and a left ventricular ejection fraction of less than 0.50 had a significantly poorer 3 year survival rate (64 ± 10 percent) than patients with aortic regurgitation and an ejection fraction of 0.50 or more (91 ± 8 percent) (p <0.02). The 3 year postoperative survival rate in patients with a reduced cardiac index (less than 2.5 liters/min per m²) and aortic regurgitation was also significantly lower (63 ± 10 percent) than the rate in patients with aortic regurgitation and a normal cardiac index (p <0.02). There was less significance in the difference between the 3 year postoperative survival rate of patients with aortic regurgitation whose left ventricular end-diastolic pressure was 15 mm Hg or less and those whose pressure was greater than 15 mm Hg (p <0.05). Thus, it may be advisable to monitor left ventricular ejection fraction noninvasively in patients with aortic regurgitation and to advise aortic valve replacement before the ejection fraction becomes severely depressed.     

X-linked chronic granulomatous disease: correction of NADPH oxidase defect by retrovirus-mediated expression of gp91-phox

Chronic granulomatous disease (CGD) is an inherited immunodeficiency resulting from the inability of an individual's phagocytes to produce superoxide anions because of defective NADPH oxidase. The disease may be treated by bone marrow transplantation and as such is a candidate for somatic gene therapy. Two thirds of patients have defects in an X- linked gene (X-CGD) encoding gp91-phox, the large subunit of the membrane cytochrome b-245 component of NADPH oxidase. Epstein-Barr virus-transformed B-cell lines from patients with CGD provide a model system for the disease. We have used retrovirus-mediated expression of gp91-phox to reconstitute functionally NADPH oxidase activity in B-cell lines from three unrelated patients with X-CGD. The protein is glycosylated and membrane associated, and the reconstituted oxidase is appropriately activated via protein kinase C. The kinetics of superoxide production by such reconstituted cells is similar to that of normal B-cell lines. These data show the potential of gene therapy for this disease.     

Glycoprotein Ib (GPIb)-dependent and GPIb-independent pathways of thrombin-induced platelet activation

In this study, the question of whether glycoprotein Ib (GPIb) mediates both high and moderate affinity pathways of alpha-thrombin-induced platelet activation was examined. Flow cytometric studies, using a panel of monoclonal antibodies (MoAbs), showed that Serratia marcescens protease treatment removed greater than 97% of the glycocalicin portion of GPIb but did not affect the changes in the expression of GPIX or GMP-140 that were induced by high concentrations of alpha-thrombin (10 nmol/L). However, Serratia treatment almost completely abolished the increase in platelet surface GMP-140 induced by low concentrations of alpha-thrombin (0.5 nmol/L) and diminished the downregulation of platelet surface GPIX by 60.9% +/- 5.6% (mean +/- SEM, n = 3). When present in 20-fold molar excess, an MoAb directed against the alpha-thrombin/von Willebrand factor (vWf) binding domains of GPIb completely blocked the ristocetin-dependent binding of vWf to platelets but inhibited only to about 50% the binding of alpha-thrombin and the activation-dependent binding of vWf. In platelets treated with Serratia marcescens protease to remove GPIb, a concentration of this MoAb 16,000-fold in excess of the maximum possible remaining copies of GPIb failed to inhibit platelet activation by alpha-thrombin. These studies demonstrate that activation of intact platelets by alpha-thrombin proceeds by both GPIb-dependent and GPIb-independent mechanisms.     

A phase II study of continuous infusion recombinant human granulocyte- macrophage colony-stimulating factor as an adjunct to autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma in first remission

Recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) clearly hastens myeloid recovery in patients with relapsed hematologic malignancies undergoing autologous bone marrow transplantation (ABMT). In efforts to further improve neutrophil engraftment and shorten hospital stay in ABMT patients, rhGM-CSF was administered by a potentially more potent route (continuous infusion) to non-Hodgkin's lymphoma (NHL) patients with better BM reserve (first remission). Time to myeloid engraftment was compared with that of NHL patients treated in first remission at our institution on a similar ABMT protocol but without growth factor support (controls). Median neutrophil engraftment (absolute neutrophil count, 500 cells/microL) in first remission patients treated with rhGM-CSF was 14 days, compared with 22 days in controls (P = .0001). Hospital stays were also significantly reduced for rhGM-CSF patients (P = .0003). Platelet engraftment did not differ between the two groups. Persistent fever and generalized serositis were the primary toxicities. rhGM-CSF, delivered by this route, was efficacious but more toxic than 2-hour rhGM-CSF infusions previously reported by other investigators. Future alterations in both dose and schedule may retain comparable efficacy yet diminish toxicity.     

Heart failure in women

Increasingly high mortality from cardiovascular disease in women has sparked nationwide campaigns to raise awareness of this significant threat to women’s health. Heart failure has the most lethal prognosis of the major cardiovascular diseases, yet women demonstrate an apparent survival advantage compared with men. Sex-linked disparities in heart failure risk factors and pathophysiology contribute to this divergent clinical outcome. Heart failure etiology and clinical manifestations unique to female sex exist. At age 40, the lifetime risk of developing heart failure is equal for men and women, whereas the lifetime risk of developing coronary heart disease is one in two for men and one in three for women. Understanding sex-inherent characteristics related to heart failure may help determine whether the optimal therapy for this prevalent syndrome should be modified according to sex. Until prospective trial data prove otherwise, heart failure treatment guidelines should be uniformly applied to both women and men.     

Association of apolipoprotein (Apo)E genotype with plasma apo E levels

The purpose of this study was to investigate the effects of apolipoprotein (apo) E genotype on plasma apo E levels as well as serum total, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglyceride, and glucose values in 734 middle-aged and elderly, female and male subjects. Apo E allele frequencies were similar to those reported in other Caucasian populations. After adjustment for medications, alcohol use, smoking, age, and body mass index, apo E genotype was noted to have significant effects on apo E, total cholesterol, LDL cholesterol, and glucose levels in females, and on apo E, LDL cholesterol, and HDL cholesterol levels, as well as the total cholesterol (TC)/HDL cholesterol ratio in males. Female and male subjects with the apo E4 allele had significantly (P<0.05) lower plasma apo E (25 and 15%) and higher LDL cholesterol levels (5 and 2%), while those with the apo E2 allele had significantly (P<0.05) higher apo E (32 and 27%) and lower LDL cholesterol levels (10 and 10%) than the apo E3/3 group. Moreover, female apo E4 carriers had significantly (P<0.05) lower glucose values (11%) than the apo E3/3 group. These data are consistent with the concept that, in addition to the well known effects of apo E genotype on LDL-C values, this locus plays a very significant role in modulating plasma apo E levels.     

Fragile X‐associated tremor/ataxia syndrome (FXTAS) in grey zone carriers

The grey zone (GZ; 45–54 CGG repeats in the FMR1 gene) is considered a normal allele; however, several studies have found a high frequency of GZ in movement disordered populations. Here, we describe neurological features of fragile X‐associated tremor/ataxia syndrome (FXTAS) in two carriers of GZ alleles, although FXTAS has been defined as occurring only in premutation carriers (55–200 CGG repeats). Both patients had family members who had premutation and were diagnosed with FXTAS. The presence of relatively high GZ alleles with elevated fragile X mental retardation 1 mRNA (FMR1‐mRNA) combined with a family history of FXTAS that may represent a facilitating genetic background for FXTAS are the factors that led to the presence of FXTAS in these individuals with a GZ allele. Further research into clinical involvement of GZ alleles is recommended and the definition of FXTAS may require revision.     

Deletion of the D domain of the human parainfluenza virus type 3 (HPIV3) PD protein results in decreased viral RNA synthesis and beta interferon (IFN-β) expression

Parvoviridae is a family of small non-enveloped viruses and divided into two subfamilies. The family members infect a wide range of organisms from insects to humans and some of the members (e.g., nonpathogenic adeno-associated viruses) are effective gene therapy delivery vectors. We detailed the synonymous codon usage pattern of Parvoviridae family from the available 58 sequenced genomes through multivariate statistical methods. Our results revealed that nine viruses showed some degree of strong codon bias, and the others possessed a general weak trend of codon bias. ENc-plot and neutrality plot results showed that selective pressure dominated over mutation in shapes coding sequence’s composition. The overall GC content and GC content at the third synonymous codon position were the principal determinants behind the variations within the codon usage patterns, as they both significantly correlated with the first axis of correspondence analysis. In addition, gene length had no direct influence on the codon usage pattern. Densovirinae subfamily and Parvovirinae subfamily possessed nine identical preferred codons, though most of the two subfamilies codon usage frequencies were significantly different. The result of cluster analysis based on synonymous codon usage was discordant with that of taxonomic classification. Adeno-associated viruses formed a separated clade far from other Parvoviridae members in the dendrogram. Thus, we concluded that natural selection rather than mutation pressure accounts for the main factor that affects the codon bias in Parvoviridae family.     

To transfer or not to transfer: Aged care nurses’ decision-making in transferring residents to the emergency department

BackgroundNurses are key decision makers in residential aged care facilities and play a significant role in the transfer of residents from residential aged care facilities to emergency departments. There is scant literature about the role of nurses in the transfer decision-making process.AimTo describe the experiences of residential aged care facility nurses who engage in decision-making to transfer residents to emergency department.MethodsThis research has adopted interpretive qualitative approach of phenomenography. In-depth interviews were undertaken with 20 residential aged care facility nurses across two sites. Uniquely, drawing was used as one way to collect rich, textured data in these in-depth interviews.FindingsSix categories emerged to represent residential aged care facility nurses’ conceptions of decision-making about transferring a resident to the emergency department: “Being a marionette”; “Too dumb to have an opinion”; “Making the family happy”; “Not about the resident”; “Having experience”; and “Being on your own”.DiscussionResidential aged care facility nurses experienced decision-making as not being able to do what is right for the resident most of the time due to a myriad of factors, with heavy influence of other key stakeholders.ConclusionDecision-making is described as a professional responsibility wherein residential aged care facility nurses face dilemmas related to the transfer of a resident to the emergency department and perceived as a constraint.