Tetrahydroaminoacridine improves passive avoidance retention defects induced by aging and medial septal lesion but not by fimbria-fornix lesion.

The present study examines whether tetrahydroaminoacridine (THA) can improve the deterioration in passive avoidance (PA) retention performance induced by medial septal (MS) and fimbria-fornix (FF) lesions in young rats or by aging. Retention of young MS-lesioned rats was improved by pretraining injection of THA at 3 mg/kg, but not by THA at 1 mg/kg or by either of the posttraining doses of THA (1 and 3 mg/kg). Pretraining injections of THA at 1 or 3 mg/kg had no effect on the PA retention performance of FF-lesioned rats. Age-induced PA failure was alleviated by pretraining administration of THA at 1 and 3 mg/kg. Posttraining injections of THA (1 or 3 mg/kg) had no effect on PA retention performance of aged rats. These results demonstrate that 1) THA may improve hippocampal cholinergic denervation-induced functional deficits and 2) some of the age-related PA deficits may be due to a cholinergic deficit and can be reversed with THA.     

Age-dependent stimulation by atrium explants or nerve growth factor of nerve fibre outgrowth from cocultured embryonic rat sympathetic ganglia

Whole sympathetic superior cervical ganglia of 14- and 15-day-old rat embryos were cultured in a collagen gel medium for 24 h with or without explants of heart atrium from the same animals or from newborn rats. The extent of nerve fibre outgrowth was estimated by counting the number of nerve fibres crossing each arc of a sector drawn in the microscope ocular. Only few nerve fibres extended from the ganglia of the 14-day-old embryos cultured in the pure control medium. Addition of exogenous nerve growth factor did not stimulate the poor growth. While the growth of nerve fibres in the presence of atrium explants of newborn rats did not significantly differ from that in cultures without any target tissue, the presence of atrium explants of the same, 14-day-old, embryo resulted in clearly enhanced fibre outgrowth from the ganglia, which was inhibited by antiserum to the nerve growth factor. The ganglia of 15-day-old embryos cultured without target tissue in the control medium produced only sparse fibre outgrowth which was excessively increased by exogenous nerve growth factor. Coculture with atrium explants of 15-day-old embryos or newborn rats produced an increased overall nerve fibre growth, as well as predominance of those fibres growing toward the target tissue. The growth-promoting effect of the atrium of 15-day-old embryos was only partially prevented by antiserum to the nerve growth factor, while that elicited by newborn rat atrium was totally inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of GPRA, a novel G protein-coupled receptor related to asthma

We recently identified a novel positional asthma susceptibility gene, GPRA, which belongs to the G protein-coupled receptor family. In the present studies, we show that isoform specific activation of GPRA-A with its agonist, Neuropeptide S (NPS) resulted in significant inhibition of cell growth. GPRA has several variants due to extensive alternative splicing. We observed that only the full-length variants, GPRA-A and GPRA-B, with 7 transmembrane topology are transported into the plasma membrane, while the truncated proteins retain intracellular compartments. To clarify disease mechanism, we studied co-expression of the variants without finding any indication that truncated variants would inhibit the receptor transport into the plasma membrane. By using in situ hybridization and immunohistochemistry, we detected ubiquitous expression of GPRA-B, and frequent expression of GPRA-A in the epithelia of several organs including bronchi and gastrointestinal tract. Furthermore, we observed aberrant mRNA and protein expression levels of GPRA in the asthmatic bronchi. Finally, we demonstrate that GPRA and NPS are co-expressed in bronchial epithelium. In summary, this study provides evidence that GPRA might have functional relevance in modulating asthma by increased expression levels in the relevant tissues under diseased state and by potential inhibitory effect of GPRA-A activation on cell growth.     

Role of Cachexia and Fragility in the Patient Candidate for Cardiac Surgery

Frailty is the major expression of accelerated aging and describes a decreased resistance to stressors, and consequently an increased vulnerability to additional diseases in elderly people. The vascular aging related to frail phenotype reflects the high susceptibility for cardiovascular diseases and negative postoperative outcomes after cardiac surgery. Sarcopenia can be considered a biological substrate of physical frailty. Malnutrition and physical inactivity play a key role in the pathogenesis of sarcopenia. We searched on Medline (PubMed) and Scopus for relevant literature published over the last 10 years and analyzed the strong correlation between frailty, sarcopenia and cardiovascular diseases in elderly patient. In our opinion, a right food intake and moderate intensity resistance exercise are mandatory in order to better prepare patients undergoing cardiac operation.     

Community-living older people’s interpretation of the Norwegian version of older people’s quality of life (OPQOL) questionnaire

The aim of this study is to investigate how community-living older people interpret the Norwegian version of Older People's Quality of Life (OPQOL) questionnaire. The original OPQOL questionnaire was translated based on guidelines for cross-cultural translation. The Three-Step Test-Interview instrument was adopted to investigate how community-living older people interpreted the questionnaire. Data were collected from 14 participants (72–89 years). The questionnaire was filled in under observation. Semi-structured interviews were then conducted to clarify the observational data and elicit the participants’ experiences and opinions. Lastly, data were analysed using a hermeneutic interpretation approach. Our findings indicate that most of the participants managed to complete the OPQOL questionnaire without problems. The data analysis resulted in four primary themes: relevance & applicability, formulation, consistency & accuracy and subjectivity. The questionnaire covered all aspects related to the participants’ quality of life. However, statements related to religion were found to be irrelevant to their quality of life. Most of the participants thought that religion, philosophy and culture should be separate rather than included in the same statement. The participants missed the option of ‘not applicable’ when the statements were irrelevant to them. The statements are formulated in both positive and negative ways, which was sometimes confusing to them. The participants perceived phases such as “around me” “local,” and “things” as ambiguous, and thus they raised concerns about whether the OPQOL questionnaire could capture consistent data regarding their quality of life. The results of this study pinpoint the issues that community-living older people faced when interpreting and answering the Norwegian version of OPQOL questionnaire. These issues were mostly caused by sociocultural differences. Our work provides an overview of the changes that must be made in the questionnaire in order to address these sociocultural differences while using the OPQOL questionnaire in the Norwegian context.     

Persisting axonal degeneration in the hippocampus after transection of the fimbria-fornix

Degeneration within the hippocampus was examined at the light microscopic level using the Gallyas silver stain two, four or nine months after bilateral transection of the fimbria-fornix and commissural connections. At two or four months after the lesion the strata oriens and radiatum of the subicular end of the CA1 subfields were strongly argyrophilic as was the inner third of the molecular layer of the dentate gyrus. At nine months post-lesion argyrophilia diminished but clearly persisted in the same layers. Electron microscopic examination revealed a large number of electron-dense axon terminals in the argyrophilic areas, most of them making asymmetric synaptic contacts with dendritic spines. These findings suggest that at least a portion of the Schaffer collaterals of the CA3 pyramidal cells and associational collaterals of hilar neurons were in a process of acute degeneration at all time points after the initial surgical trauma. This persistent synaptic reorganization of intrahippocampal circuits may be related to abnormal electrical activity observed several months after fimbria-fornix transection.     

Polymorphisms in the KDR and POSTN Genes: Association with Breast Cancer Susceptibility and Prognosis

Angiogenesis is an important step in the development of cancer. Vascular endothelial growth factor is a major regulator of breast cancer angiogenesis, the effects of which are transmitted through the kinase domain receptor (KDR). Up-regulation of KDR by periostin (POSTN) induces angiogenesis. We screened the KDR and the POSTN genes for published single nucleotide polymorphisms (SNPs) and chose two SNPs in each gene for further analyses. We carried out a case–control study consisting of 412 familial and 912 unselected breast cancer cases together with ethnically and geographically selected controls. Genotype, haplotype and genotype combination analyses were carried out to evaluate their effect on susceptibility to and prognosis of breast cancer. A haplotype in the POSTN gene was associated with an increased risk even after correction for multiple comparisons. Nominal associations between the SNPs and prognostic indicators were also observed. Tumors of the KDR 472His allele carriers were less often progesterone receptor negative according to both genotype and haplotype analyses (OR 0.61, 95%CI 0.40–0.92 and OR 0.60, 95%CI 0.40–0.91, respectively). The POSTN -33G allele carriers had more often high grade and estrogen receptor negative tumors (OR 1.75, 95%CI 1.02–3.01 and OR 1.70, 95%CI 1.04–2.78, respectively). The overall and cancer specific survival after 15 years of follow-up was more than 75%, and it did not depend on the genotype. Although a major effect of the SNPs in the KDR and the POSTN genes on breast cancer susceptibility and prognosis was excluded, the effect of the POSTN C-33G SNP on prognosis needs further characterization.     

Collagenase-2 (matrix metalloproteinase-8) plays a protective role in tongue cancer

Squamous cell carcinoma (SCC) of the tongue is the most common cancer in the oral cavity and has a high mortality rate. A total of 90 mobile tongue SCC samples were analysed for Bryne's malignancy scores, microvascular density, and thickness of the SCC sections. In addition, the staining pattern of cyclooxygenase-2, alphavbeta6 integrin, the laminin-5 gamma2-chain, and matrix metalloproteinases (MMPs) -2, -7, -8, -9, -20, and -28 were analysed. The expression of MMP-8 (collagenase-2) was positively associated with improved survival of the patients and the tendency was particularly prominent in females. No sufficient evidence for a correlation with the clinical outcome was found for any other immunohistological marker. To test the protective role of MMP-8 in tongue carcinogenesis, MMP-8 knockout mice were used. MMP-8 deficient female mice developed tongue SCCs at a significantly higher incidence than wild-type mice exposed to carcinogen 4-Nitroquinoline-N-oxide. Consistently, oestrogen-induced MMP-8 expression in cultured HSC-3 tongue carcinoma cells, and MMP-8 cleaved oestrogen receptor (ER) alpha and beta. According to these data, we propose that, contrary to the role of most proteases produced by human carcinomas, MMP-8 has a protective, probably oestrogen-related role in the growth of mobile tongue SCCs.     

Total esterase activity in human saliva: Validation of an automated assay,characterization and behaviour after physical stress

Although saliva has esterase activity, this activity has not been characterized or studied in individuals subjected to physical stress. The aim of this report was to develop and validate an automated spectrophotometric assay for total esterase activity measurement in human saliva, as well as to study the contribution of different enzymes on this activity and its behaviour under physical stress in healthy subjects. The assay used 4-nitrophenyl acetate as substrate and was precise, accurate and provided low limits of detection and quantification. Inhibition with diisopropylfluorophosphate showed that cholinesterase, carboxylesterase and cholesterol esterase contributions not represented more than 20% of total esterase. Addition of standards of lipase and albumin to saliva samples showed that both proteins significantly contributed to esterase activity only when equal or higher than 11.6?IU/L and 250?μg/mL, respectively. Western blot analyses showed absence of paraoxonase-1 and high amount of carbonic anhydrase-VI. The high affinity of purified carbonic anhydrase-VI for the substrate supported a major contribution of this enzyme. Total esterase activity and alpha-amylase was measured in saliva samples from 12 healthy male students before and after participation in an indoor football match. The activity significantly increased after match and positively correlated with salivary alpha-amylase. This method could be used as a biomarker of physical stress in humans, with carbonic anhydrase-VI being the esterase that contributed more to the activity of the assay.     

Subgroup and cost-benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma

Osteolytic lesions and pathological fractures are the major problems in the clinical management of multiple myeloma. We previously reported the main results of a randomized, controlled multicentre trial in 350 Finnish patients with multiple myeloma. All patients received standard melphalan-prednisolone treatment and were randomized to receive either clodronate 2.4 g daily or a placebo for 24 months. The proportion of patients with progression of osteolytic bone lesions was twice as high in the placebo group as in the clodronate group (24.0%v 12.0%, P= 0.026). The purpose of the present study was to investigate factors associated with the progression of osteolytic lesions and to identify subgroups of patients who would benefit most from clodronate treatment. In univariate logistic regression analysis, including treatment (placebo, clodronate), sex, age, pain index, serum calcium and creatinine, myeloma stage, number of osteolytic lesions at baseline, and number of vertebral fractures at baseline as independent variables and the progression of osteolytic lesions as a dependent variable, only the treatment with a placebo was associated with the progression of osteolytic bone lesions. Separate analyses with respect to the progression of osteolytic bone lesions were carried out in the following subgroups: male v female, ± 64 v > 64 years, stage I v stage II-III myeloma, no osteolytic lesions at baseline versus osteolytic lesions at baseline, no vertebral fractures at baseline versus vertebral fractures at baseline, and a 50% treatment response to cytotoxic drugs versus no treatment response to cytotoxic drugs. The treatment with clodronate delayed the progression of osteolytic lesions similarly in these subgroups, with the exception of a subgroup of patients who did not have a 50% treatment response to cytotoxic drugs. The treatment with clodronate did not significantly increase treatment costs. We conclude that the treatment effect of clodronate seems to be independent of sex and age of the patients, the stage of myeloma, and the severity of bone lesions at diagnosis, but not of treatment response to cytotoxic drugs.