Prostate stem cell antigen: A cell surface marker overexpressed in prostate cancer

The identification of cell surface antigens is critical to the development of new diagnostic and therapeutic modalities for the management of prostate cancer. Prostate stem cell antigen (PSCA) is a prostate-specific gene with 30% homology to stem cell antigen 2, a member of the Thy-1/Ly-6 family of glycosylphosphatidylinositol (GPI)-anchored cell surface antigens. PSCA encodes a 123-aa protein with an amino-terminal signal sequence, a carboxyl-terminal GPI-anchoring sequence, and multiple N-glycosylation sites. PSCA mRNA expression is prostate-specific in normal male tissues and is highly up-regulated in both androgen-dependent and -independent prostate cancer xenografts. In situ mRNA analysis localizes PSCA expression in normal prostate to the basal cell epithelium, the putative stem cell compartment of the prostate. There is moderate to strong PSCA expression in 111 of 126 (88%) prostate cancer specimens examined by in situ analysis, including high-grade prostatic intraepithelial neoplasia and androgen-dependent and androgen-independent tumors. Flow cytometric analysis demonstrates that PSCA is expressed predominantly on the cell surface and is anchored by a GPI linkage. Fluorescent in situ hybridization analysis localizes the PSCA gene to chromosome 8q24.2, a region of allelic gain in more than 80% of prostate cancers. A mouse homologue with 70% amino acid identity and similar genomic organization to human PSCA has also been identified. These results support PSCA as a target for prostate cancer diagnosis and therapy.     

Totally epicardial cardiac resynchronization therapy system implantation in patients with heart failure undergoing CABG

BACKGROUND: Systolic dyssynchrony is present in a considerable number of patients with heart failure (HF) undergoing coronary artery bypass grafting (CABG). Surgical revascularization offers an optimal setting for totally epicardial cardiac resynchronization therapy (CRT) system implantation. AIM: To assess the efficacy of totally epicardial CRT implantation during CABG, in patients with HF. METHODS: Twenty three patients with HF and dyssynchrony underwent totally epicardial CRT system implantation during CABG. This randomised, single-blind, cross-over study compared clinical and echocardiographic parameters during two periods: 3 months of active CRT (CRT+) and 3 months of inactive CRT (CRT-) pacing. RESULTS: Twenty two patients underwent randomisation and completed both study periods. In the CRT+ group more patients improved by two NYHA classes (p=0.028), had a longer 6-minute walk test distance (p=0.047) and better quality of life (p=0.003) compared with the CRT- group. Echocardiography revealed an improved LV ejection fraction (p<0.001), smaller LV end-systolic volume (p=0.04), reduced mitral regurgitation (p=0.026) and improved LV synchrony in the CRT+ group compared with the CRT- group. CONCLUSION: CRT delivered by a totally epicardial system implanted during CABG is associated with additional improvement of clinical and echocardiographic parameters in patients with HF and systolic dyssynchrony.     

Modest genetic influence on bronchodilator response: a study in healthy twins

Aim

To determine the reasons for large standard deviation of bronchodilator response (BDR) and establish whether there is a potential heritable component in healthy subjects.

Methods

67 monozygotic and 42 dizygotic adult twin pairs were assessed for bronchodilator response (%change in FEV₁ after inhaling 400 µg salbutamol). Univariate quantitative genetic modeling was performed.

Results

Multiple regression modeling showed a significant association between BDR and sex and baseline FEV1 (P < 0.05), while no association was found with smoking habits, body mass index, or age. Within pair correlation in monozygotic twins was modest (0.332), but higher than in dizygotic twins (0.258). Age-, sex-, and baseline FEV1-adjusted genetic effect accounted for 14.9% (95% confidence interval, CI 0%-53.1%) of the variance of BDR, shared environmental effect for 18.4% (95% CI 0%-46.8%), and unshared environmental effect for 66.8% (95% CI 46.8%-88.7%).

Conclusion

Our twin study showed that individual differences in BDR can be mostly explained by unshared environmental effects. In addition, it is the first study to show low, insignificant hereditary influences, independently from sex, age, and baseline FEV1.The assessment of the reversibility of airway obstruction is a key element in the diagnosis of airway diseases and can also be a sign of the potential therapeutic effect of a specific inhaled drug (1,2). Bronchodilator response (BDR) is tested after the inhalation of a drug and is defined as the change in spirometric parameters including forced vital capacity (FVC), forced expiratory volume in 1 second (FEV₁), and mid-expiratory flow 25%-75%. Although no consensus exists, the latest American Thoracic Society (ATS)/European Respiratory Society (ERS) guideline recommends that, during a single testing session, an increase in FEV₁ or FVC>12% and ≥200 mL from baseline is considered a significant BDR (3).Large population studies proposed a different threshold of BDR that has a role in clinical interpretation of airway response to a bronchodilator (4,5). However, underlying reasons for the large variation of BDR and a potential heritable component in healthy population are still unclear. It is known that certain genetic polymorphisms are associated with BDR in asthmatic (6,7) and non-asthmatic (8,9) individuals. This is supported by the fact that there are differences in BDR among different nations (10). These studies strongly support a hereditary influence on BDR, but they cannot fully describe the relationship of hereditary and environmental factors on the development of BDR. Assessing familial aggregation of BDR, Niu et al found a modest familial clustering (11).Family design can determine inter-generation resemblance or difference, but, in contrast to the twin study design, it does not determine the influence of outside factors such as family, environment, and culture (12). Accordingly, family studies cannot reliably distinguish the influence of heritability from common environmental effects. Numerous twin studies examined airway hyperresponsiveness (AHR) (13-18), but none of them investigated BDR. Although BDR is usually associated with AHR in obstructive airway diseases (19), previous twin results on AHR cannot simply be extended to BDR. Therefore, the first aim of this study is to determine which factors affect BDR in a healthy twin population. As a second aim we investigated whether the large standard deviation of BDR in healthy asymptomatic subjects could be attributable to genetic or environmental factors.     

Expression of senescent antigen on erythrocytes infected with a knobby variant of the human malaria parasite Plasmodium falciparum.

Erythrocytes infected with a knobby variant of Plasmodium falciparum selectively bind IgG autoantibodies in normal human serum. Quantification of membrane-bound IgG, by use of 125I-labeled protein A, revealed that erythrocytes infected with the knobby variant bound 30 times more protein A than did noninfected erythrocytes; infection with a knobless variant resulted in less than a 2-fold difference compared with noninfected erythrocytes. IgG binding to knobby erythrocytes appeared to be related to parasite development, since binding of 125I-labeled protein A to cells bearing young trophozoites (less than 20 hr after parasite invasion) was similar to binding to uninfected erythrocytes. By immunoelectron microscopy, the membrane-bound IgG on erythrocytes infected with the knobby variant was found to be preferentially associated with the protuberances (knobs) of the plasma membrane. The removal of aged or senescent erythrocytes from the peripheral circulation is reported to involve the binding of specific antibodies to an antigen (senescent antigen) related to the major erythrocyte membrane protein band 3. Since affinity-purified autoantibodies against band 3 specifically bound to the plasma membrane of erythrocytes infected with the knobby variant of P. falciparum, it is clear that the malaria parasite induces expression of senescent antigen.     

Corrosive effects of fluoride on titanium: investigation by X-ray photoelectron spectroscopy, atomic force microscopy, and human epithelial cell culturing

High fluoride (F(-)) concentrations and acidic pH impair the corrosion resistance of titanium (Ti). Effects of F(-)-containing caries-preventive prophylactic rinses, and gels on Ti were investigated by X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM). Human epithelial cell attachment and proliferation were investigated by dimethylthiazol-diphenyl tetrazolium bromide (MTT) and protein content assays. Aqueous 1% NaF solution (3800 ppm F(-), pH 4.5) or high (12,500 ppm) F(-) content gel (pH 4.8) strongly corroded the surface and modified its composition. XPS revealed formation of a strongly bound F(-)-containing complex (Na(2)TiF(6)). AFM indicated an increase in roughness (R(a)) of the surfaces: 10-fold for the NaF solution and smaller for the gel or a mouthwash (250 ppm F(-), pH 4.4). MTT revealed that cell attachment was significantly increased by the gel, but was not disturbed by either the mouthwash or the NaF. Cell proliferation determined by MTT decreased significantly only for the NaF-treated samples; protein content assay experiments showed no such effect. This study indicates that epithelial cell culturing results can depend on the method used, and the adverse effects of a high F(-) concentration and low pH should be considered when prophylactic gels are applied by patients with Ti implants or other dental devices.     

The presence of pacemaker HCN channels identifies theta rhythmic GABAergic neurons in the medial septum

The medial septum (MS) is an indispensable component of the subcortical network which synchronizes the hippocampus at theta frequency during specific stages of information processing. GABAergic neurons exhibiting highly regular firing coupled to the hippocampal theta rhythm are thought to form the core of the MS rhythm-generating network. In recent studies the hyperpolarization-activated, cyclic nucleotide-gated non-selective cation (HCN) channel was shown to participate in theta synchronization of the medial septum. Here, we tested the hypothesis that HCN channel expression correlates with theta modulated firing behaviour of MS neurons by a combined anatomical and electrophysiological approach. HCN-expressing neurons represented a subpopulation of GABAergic cells in the MS partly overlapping with parvalbumin (PV)-containing neurons. Rhythmic firing in the theta frequency range was characteristic of all HCN-expressing neurons. In contrast, only a minority of HCN-negative cells displayed theta related activity. All HCN cells had tight phase coupling to hippocampal theta waves. As a group, PV-expressing HCN neurons had a marked bimodal phase distribution, whereas PV-immunonegative HCN neurons did not show group-level phase preference despite significant individual phase coupling. Microiontophoretic blockade of HCN channels resulted in the reduction of discharge frequency, but theta rhythmic firing was perturbed only in a few cases. Our data imply that HCN-expressing GABAergic neurons provide rhythmic drive in all phases of the hippocampal theta activity. In most MS theta cells rhythm genesis is apparently determined by interactions at the level of the network rather than by the pacemaking property of HCN channels alone.