Characterization of the prion protein 3F4 epitope and its use as a molecular tag

The monoclonal antibody (MAb) 3F4 has for nearly two decades been one of the most commonly used tools in prion research. This MAb has contributed significantly to our understanding of the normal cell biology of the prion protein (PrP(C)), as well as the disease related abnormalities occurring in prion diseases. The 3F4 antibody binds strongly to human and hamster PrP, with a specific requirement of two Met residues at positions 109 and 112 in the human PrP. Other species in which PrP lack one of the Met residues, like cattle and sheep, or both, like rat and mouse, do not react with the 3F4 antibody. These and other observations have led to the commonly accepted notion that the 3F4 epitope consists of the tetra-peptide Met-Lys-His-Met. In this study, we have identified the minimal epitope for 3F4 by studying its binding to synthetic peptides and by analysis of mutated ovine PrP::GFP constructs expressed in cell culture. We have found that the 3F4 epitope consists of a hepta-peptide (Lys-Thr-Asn-Met-Lys-His-Met), which in sheep encompass residues 109-115. We found that Lys 109 is critically important for 3F4 binding, as omission, or substitution of this residue to Ala resulted in no binding. We also demonstrate that the hepta-peptide constituting the minimal 3F4 epitope, can be used as a discrete, moveable high-affinity molecular tag. Thus, the 3F4 antibody can find its use beyond prion research.     

Diagnostic stability over 3 years in a total group of first-episode psychosis patients

First-episode psychosis (FEP) patients are often given diagnoses that later have to be changed. The aim of this study was to measure the diagnostic stability in a total group of FEP patients; 146 FEP patients were followed longitudinally and prospectively. Their revised baseline diagnoses were compared with their 3-year follow-up diagnoses. The schizophrenic spectrum disorders showed a high diagnostic stability as a group, but there was a great flow of patients between the different schizophrenic spectrum diagnoses. Also schizophrenia was a stable diagnosis. The affective psychosis group was homogenous without interaction of other psychosis groups. The other psychosis diagnoses, both regarded as a group and individually, turned out to be quite heterogeneous, with low stability values and a split course, often ending up in the schizophrenic spectrum. Fifty one per cent did not fulfil the criteria for DSM-IV axis 1 psychosis diagnosis at follow-up. In conclusion, our findings suggest that in the early phase of psychosis. Only three different diagnostic categories would be sufficient; "schizophrenic spectrum type", "affective psychosis," and for the rest "psychotic disorder NOS."     

Factors correlated with fatigue in breast cancer survivors undergoing a rehabilitation course, Denmark, 2002-2005

Objective: The aim of this prospective cohort study was to identify factors associated with fatigue in women with breast cancer who attended a 6‐day rehabilitation course. Furthermore, to investigate level of fatigue 1 year after the rehabilitation course, after accounting for baseline fatigue levels. Methods: Between 2002 and 2005 we included 775 women with breast cancer and measured fatigue, emotional functioning and insomnia using the EORTC subscales and sociodemographics from a baseline questionnaire prior to participation in the rehabilitation course. Information on disease‐specific and treatment factors was obtained from a nationwide clinical database. From the 12‐month follow‐up questionnaire we obtained level of fatigue. We estimated the influence of factors on the relative risk for a 10‐points increase in fatigue score in generalised linear models. For the analysis of fatigue at 12 months follow‐up we added fatigue level at baseline and relapse since baseline. Results: Higher tumour grade and insomnia predicted higher levels of fatigue, whereas better emotional functioning was associated with lower levels. After 12 months of follow‐up fatigue levels were associated with level at baseline and with emotional functioning, insomnia, relapse and being on sick leave or unemployed. Emotional level, insomnia and high grade were associated with level of fatigue. After 1 year, a high level at baseline, insomnia and low emotional functioning was associated with greater fatigue. Conclusions: These longitudinal results support that cancer‐related fatigue can be a persistent phenomenon and that focus on psychological distress and sleeping problems might be beneficial in these women. Copyright © 2010 John Wiley & Sons, Ltd.     

Risk perception among women receiving genetic counseling: a population-based follow-up study

Background: We aimed to explore the impact of genetic counseling on perceived personal lifetime risk of breast cancer, the accuracy of risk perception, and possible predictors of inaccurate risk perception 1 year following counseling. Methods: We conducted a population-based prospective follow-up study of 213 women who received genetic counseling for hereditary breast and ovarian cancer, 319 women who underwent mammography (Reference Group I), and a random sample of 1070 women from the general population (Reference Group II). Results: Women who received genetic counseling decreased their perceived risk by an average of 6.6 percentage points (95% CI: 3.0%; 10.2%) between baseline and 12 months of follow-up. In contrast, perceived risk remained relatively stable in the reference groups. The proportion of women who accurately perceived their risk increased by 16% in the group receiving genetic counseling, compared to a reduction of 5% (p = 0.03) and 2% (p = 0.01) in Reference Groups I and II, respectively. Risk communicated only in words, inaccurate risk perception at baseline, and presence of a familial mutation appeared to be predictors of inaccurate risk perception 12 months after counseling. Conclusion: This population-based study of women with a family history of breast or ovarian cancer indicates that genetic counseling can help them both to reduce their perceived risk and to achieve a more realistic view of their risk of developing breast cancer.     

Pharmacokinetic/pharmacodynamic feedback modelling of the functional corticosterone response in rats after acute treatment with escitalopram

The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of the drug-induced corticosterone response after administration of escitalopram in rats. To achieve this, a mechanistic feedback turnover model mimicking the acute mechanism of action of selective serotonin reuptake inhibitors was assessed. Conscious and freely moving rats received constant rate infusions of 2.5, 5 or 10 mg/kg escitalopram or vehicle over 60 min. Automated serial blood sampling was conducted to determine escitalopram and corticosterone concentrations. The PK/PD model consisted of a turnover model of escitalopram-evoked changes in response, which included an inhibitory feedback moderator function. Accordingly, response acted linearly on the production (k(tol)) of the moderator, which acted inversely on the production (k(in)) of response. The escitalopram plasma kinetics served as input to an inhibitory function acting on the loss (k(out)) of response. The corticosterone responses were successfully described using the model by fitting responses from all doses simultaneously resulting in estimation of drug parameters (I(max), IC(50) and n) in addition to system parameters (k(in), k(out) and k(tol)) for the whole exposure range. Thus, the applicability of the model for analysis of the acute selective serotonin reuptake inhibitor-induced corticosterone response including acute auto-inhibitory feedback was demonstrated.     

Mobile phone use and risk of glioma in 5 North European countries

Public concern has been expressed about the possible adverse health effects of mobile telephones, mainly related to intracranial tumors. We conducted a population-based case-control study to investigate the relationship between mobile phone use and risk of glioma among 1,522 glioma patients and 3,301 controls. We found no evidence of increased risk of glioma related to regular mobile phone use (odds ratio, OR = 0.78, 95% confidence interval, CI: 0.68, 0.91). No significant association was found across categories with duration of use, years since first use, cumulative number of calls or cumulative hours of use. When the linear trend was examined, the OR for cumulative hours of mobile phone use was 1.006 (1.002, 1.010) per 100 hr, but no such relationship was found for the years of use or the number of calls. We found no increased risks when analogue and digital phones were analyzed separately. For more than 10 years of mobile phone use reported on the side of the head where the tumor was located, an increased OR of borderline statistical significance (OR = 1.39, 95% CI 1.01, 1.92, p trend 0.04) was found, whereas similar use on the opposite side of the head resulted in an OR of 0.98 (95% CI 0.71, 1.37). Although our results overall do not indicate an increased risk of glioma in relation to mobile phone use, the possible risk in the most heavily exposed part of the brain with long-term use needs to be explored further before firm conclusions can be drawn.     

Surgical anatomy and pathology of the middle ear

Middle ear surgery is strongly influenced by anatomical and functional characteristics of the middle ear. The complex anatomy means a challenge for the otosurgeon who moves between preservation or improvement of highly important functions (hearing, balance, facial motion) and eradication of diseases. Of these, perforations of the tympanic membrane, chronic otitis media, tympanosclerosis and cholesteatoma are encountered most often in clinical practice. Modern techniques for reconstruction of the ossicular chain aim for best possible hearing improvement using delicate alloplastic titanium prostheses, but a number of prosthesis‐unrelated factors work against this intent. Surgery is always individualized to the case and there is no one‐fits‐all strategy. Above all, both middle ear diseases and surgery can be associated with a number of complications; the most important ones being hearing deterioration or deafness, dizziness, facial palsy and life‐threatening intracranial complications. To minimize risks, a solid knowledge of and respect for neurootologic structures is essential for an otosurgeon who must train him‐ or herself intensively on temporal bones before performing surgery on a patient.