Brain penetration of the novel free radical trapping neuroprotectant NXY-059 in rats subjected to permanent focal ischemia

The penetration of the free radical trapping neuroprotectant NXY-059 into the brain has been examined in rats subjected to permanent middle cerebral artery occlusion (pMCAO). NXY-059 (125 mg/kg bolus followed by 125 mg/kg/h) was infused for 4 h 45 min starting 15 min after right pMCAO or sham operation. At 5 h, there was a similar plasma total NXY-059 concentration (μmol/L) in both groups [sham: 623 ± 44 (6); pMCAO: 605 ± 43 (5)] and a similar drug concentration (nmol/g) in the right cortex [sham: 6.92 ± 1.05 (6); pMCAO: 6.14 ± 2.18 (6)]. A subsequent experiment in normal rats, infusing NXY-059 at both a similar and higher concentration (252 mg/kg bolus and 252 mg/kg/h), demonstrated that the concentration of NXY-059 in cortex increased linearly with respect to the plasma concentration. These data demonstrate that NXY-059 does penetrate brain tissue in control animals and ischemic tissue of animals subjected to pMCAO.     

From epidemiology to lysyl oxidase like one (LOXL1) polymorphisms discovery: phenotyping and genotyping exfoliation syndrome and exfoliation glaucoma in Iceland

The first Icelandic articles on exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) appeared some 35 years ago in 1974. Articles since then have included epidemiology, pedigree‐based and twin‐studies as well as investigations into XFG response to medical therapy and XFS/XFG genetics. All studies found XFS/XFG to be common in Iceland and to be age‐related. The Reykjavik Eye Study (RES), a population‐based epidemiological study, was first conducted in 1996. The RES found that XFS and XFG prevalence in patients aged 50 years and older was 11% and that XFS/XFG was more common in women than in men. These results were confirmed in 5‐ and 12‐year incidence studies that also suggested that detailed characterization of the phenotype is important, including pupil dilation. In the RES, eyes with XFS were found to be clinically unilateral in about half of cases and to have higher mean intraocular pressure (IOP) than non‐XFS eyes. However, XFS was not found to be associated with central corneal thickness, corneal curvature, anterior chamber depth, lens thickness, lens opacification or optic disc morphology. About 15% of persons with XFS had XFG, and XFG eyes had higher risk of developing visual impairment and blindness than eyes with primary open‐angle glaucoma. The first genetic studies on Icelanders, conducted about 12 years ago, were linkage studies and were unsuccessful in discovering the genetics behind XFS/XFG. However, in 2007 a genome‐wide association study in Iceland using more than 300 000 markers [single nucleotide polymorphisms (SNPs)] on a relatively small number of patients did discover that lysyl oxidase like 1 (LOXL1) on chromosome 15q24 is a major gene for XFS/XFG. These results have now largely been replicated world‐wide.     

Alterations of E-cadherin and β-catenin in gastric cancer

Background  

The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression.     

A study of chromosomal aberrations in amniotic fluid cell cultures

This paper represents the analysis of 1916 routine amniotic fluid specimens harvested by an in situ fixation technique in a prospective study with regard to cultural chromosome anomalies. Excluding constitutional abnormalities, 2.9 per cent of 19,432 cells analysed showed some form of chromosome anomaly, terminal deletions (57 per cent) and chromatid/chromosome breaks and gaps (18 per cent) being the most frequent, followed by interchange aberrations (13 per cent) and trisomy (5 per cent). No case was found of more than one colony from the same culture showing the same anomaly without it being present in other cultures from the same fluid. The wholly abnormal colonies had a surplus of trisomies and from the mathematical considerations presented one may infer that these are likely to reflect the presence of abnormal cells in the amniotic fluid. Partly abnormal colonies appeared at a frequency that would correspond to virtual absence of selection against chromosomally abnormal cells when cultured in vitro. The aberrations found were similar to those seen as single cell anomalies, except for chromatid breaks and exchanges. The data suggest a basic preferential induction of trisomy for chromosomes 2, 18, 21, and the Y-chromosome. Structural aberrations showed a marked clustering of breakpoints around the centromeres. The frequency of mutant cells was low (1.4 X 10(-3)) before culture was initiated. At harvest, the frequency of abnormal cells was much higher (3 X 10(-2)) corresponding to 3 X 10(-3) mutations per cell per generation accumulating over approximately ten generations in vitro.     

Cellular DNA pattern, S-phase frequency and survival in papillary thyroid cancer

A series of 150 patients with papillary thyroid cancer diagnosed in Iceland during the 30-year period from 1955 through 1984 was retrospectively analyzed. Flow cytometric analysis of archival paraffin-embedded material was used to study the prognostic significance of cellular DNA content and s-phase frequency. DNA-aneuploidy was found in 12% of the tumors. It was significantly more common in the elderly, in moderately and poorly differentiated carcinomas, in males and in tumors with a high proportion of s-phase cells. Multivariate analysis using stepwise Cox's model showed aneuploidy, age at diagnosis, lymph node metastasis and tumor extension beyond the thyroid capsule as independent prognostic factors. The frequency of cells in s-phase was generally low (mean 2.7%). Patients with high s-phase frequency (greater than 2.5%) had less favorable prognosis than patients with low values (less than or equal to 2.5%).     

Tuberculosis of the liver in end stage renal disease under treatment with hemodialysis

We present a patient with end stage renal disease treated with hemodialysis, who developed prolonged fever and hepatomegaly. A laparotomy and culture of liver microabscesses led to the diagnosis of tuberculosis of the liver. A complete clinical response was achieved with a course of isoniazid and rifampin.     

The effect of mediolateral episiotomy at delivery on pelvic floor muscle strength evaluated with vaginal cones.

In a prospective study, pelvic floor muscle strength was investigated pre- and post partum in 87 women with uncomplicated pregnancies. Those vaginally delivered were 71 primiparas, while 16 underwent an elective cesarean section. The objective was to evaluate the effect of the delivery procedure on the pelvic floor muscle strength with the aid of vaginal cones. In the group of women with vaginal delivery three subgroups were identified: episiotomy, spontaneous laceration and intact perineum. Pelvic floor muscle strength was weakest in the episiotomy subgroup, the difference in values between this subgroup and each of the other subgroups and the elective cesarean section group being significant. No significant difference was evident between the spontaneous lacerations and intact perineum subgroups.     

The 7‐year cumulative incidence of cornea guttata and morphological changes in the corneal endothelium in the Reykjavik Eye Study

Purpose: To examine the corneal endothelium and establish the 7‐year cumulative incidence of cornea guttata (CG). Methods: Population‐based prospective cohort study with 573 participants (third wave of the Reykjavik Eye Study (RES) in 2008). Four hundred and thirty‐seven subjects had either right or left eyes available for analysis after excluding confounding eye conditions. The baseline for eyes at risk for developing CG is the second wave of the RES in 2001. Participants underwent specular microscopy and a standardized eye examination. Results: The cumulative 7‐year incidence of CG in either eye was estimated as a 95% confidence interval for the expected value for both genders combined (15–23%), for males (8–18%) and for females (19–29%). In right eye only, the 7‐year cumulative incidence for both genders combined was estimated to be 6–11%. For genders combined and for males only, the data indicated no correlation between 7‐year cumulated incidence and age at baseline. In women, however, the change of 7‐year incidence for CG in at least one eye appeared to be correlated to age at baseline. Reduction of endothelial cell density for corneas with CG at baseline was found [CI (0.95)?132 ± 94]. Conclusion: The cumulative 7‐year incidence of primary central CG for a middle‐aged and older Caucasian population without history of potentially confounding eye disease has been established. Women tend to have higher incidence if onset occurs at middle age. If CG is present, the cell density and the cell size variation decrease within a 7‐year period.     

Are early clinical effects of cholesterol lowering mediated through effects on inflammation?

In a randomized, double-blind trial in 3086 patients with unstable angina pectoris or non-Q wave myocardial infarction we investigated if 80 mg of atorvastatin daily could improve outcome of cardiovascular events during a short period of time (16 weeks) compared with placebo. Baseline LDL cholesterol was 3.2 mmol L-1 (124 mg dL-1) and decreased by 40% to 1.9 mmol L-1 (72 mg dL-1) during atorvastatin treatment. The primary endpoint, which was a composite of death, non-fatal acute myocardial infarction, cardiac arrest with resuscitation or recurrent symptomatic myocardial ischaemia with objective evidence and requiring emergency rehospitalization occurred in 228 patients (14.8%) in the atorvastatin group and 269 patients (17.4%) in the placebo group. The relative risk was 0.84 and 95% confidence interval was 0.70-1.00 (P = 0.048). Thus for patients with acute coronary syndromes, lipid-lowering therapy with high dose atorvastatin reduces recurrent ischaemic events in the short-term. A possible mechanism behind this rapid clinical effect induced by statin treatment is on inflammatory processes. Recent studies strongly suggest that acute T-cell activation is involved in the pathogenesis of unstable angina. In another study we investigated whether circulating T cells showed signs of activation in patients with stable angina pectoris (SA). Systemic venous blood samples were taken from 38 men with SA and 42 healthy controls. The T-cell receptor expression was assessed by three-colour flow cytometry using monoclonal antibodies against CD3,CD4, CD8, CD25 and human leucocyte antigen (HLA)-DR. Soluble interleukin-2 receptor (sIL-2R) was measured as the circulating form in serum. Levels of circulating CD3+ and CD4+ T cells tended to be higher in patients compared with controls. Patients were also shown to have a significant increase in CD4+ T cells expressing the activation markers CD25 (P < 0.05) and HLA-DR (P < 0.01). Furthermore, serum levels of sIL-2R were significantly higher (P < 0.001) in patients than in controls. We also observed that the T-cell response was more pronounced in patients without simvastatin treatment (n = 18) compared with simvastatin-treated patients (n = 20). In conclusion, our findings indicate that a continuous immune system activation takes place in patients with chronic angina pectoris, predominantly involving proliferation of CD4+ T cells. Statin treatment seems to be able to decrease this inflammatory response.