A Factor Analytic Approach to Symptom Patterns in Dementia

Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales

Double-Detargeted Oncolytic Adenovirus Shows Replication Arrest in Liver Cells and Retains Neuroendocrine Cell Killing Ability

BACKGROUND: We have previously developed an oncolytic serotype 5 adenovirus (Ad5) with chromogranin-A (CgA) promoter-controlled E1A expression, Ad[CgA-E1A], with the intention to treat neuroendocrine tumors, including carcinoids. Since carcinoids tend to metastasize to the liver it is important to fully repress viral replication in hepatocytes to avoid adenovirus-related liver toxicity. Herein, we explore miRNA-based regulation of E1A expression as a complementary mechanism to promoter-based transcriptional control. METHODOLOGY/PRINCIPAL FINDINGS: Ad[CgA-E1A-miR122], where E1A expression is further controlled by six tandem repeats of the target sequence for the liver-specific miR122, was constructed and compared to Ad[CgA-E1A]. We observed E1A suppression and replication arrest of the miR122-detargeted adenovirus in normal hepatocytes, while the two viruses killed carcinoid cells to the same degree. Repeated intravenous injections of Ad[CgA-E1A] induced liver toxicity in mice while Ad[CgA-E1A-miR122] injections did not. Furthermore, a miR122-detargeted adenovirus with the wild-type E1A promoter showed reduced replication in hepatic cells compared to wild-type Ad5 but not to the same extent as the miR122-detargeted adenovirus with the neuroendocrine-selective CgA promoter. CONCLUSIONS/SIGNIFICANCE: A combination of transcriptional (promoter) and post-transcriptional (miRNA target) regulation to control virus replication may allow for the use of higher doses of adenovirus for efficient tumors treatment without liver toxicity

Changes in the geographical distribution and abundance of the tick Ixodes ricinus during the past 30 years in Sweden

<p>Abstract</p> <p>Background</p> <p><it>Ixodes ricinus </it>is the main vector in Europe of human-pathogenic Lyme borreliosis (LB) spirochaetes, the tick-borne encephalitis virus (TBEV) and other pathogens of humans and domesticated mammals. The results of a previous 1994 questionnaire, directed at people living in Central and North Sweden (Svealand and Norrland) and aiming to gather information about tick exposure for humans and domestic animals, suggested that <it>Ixodes ricinus </it>ticks had become more widespread in Central Sweden and the southern part of North Sweden from the early 1980s to the early 1990s. To investigate whether the expansion of the tick's northern geographical range and the increasing abundance of ticks in Sweden were still occurring, in 2009 we performed a follow-up survey 16 years after the initial study.</p> <p>Methods</p> <p>A questionnaire similar to the one used in the 1994 study was published in Swedish magazines aimed at dog owners, home owners, and hunters. The questionnaire was published together with a popular science article about the tick's biology and role as a pathogen vector in Sweden. The magazines were selected to get information from people familiar with ticks and who spend time in areas where ticks might be present.</p> <p>Results</p> <p>Analyses of data from both surveys revealed that during the near 30-year period from the early 1980s to 2008, <it>I. ricinus </it>has expanded its distribution range northwards. In the early 1990s ticks were found in new areas along the northern coastline of the Baltic Sea, while in the 2009 study, ticks were reported for the first time from many locations in North Sweden. This included locations as far north as 66°N and places in the interior part of North Sweden. During this 16-year period the tick's range in Sweden was estimated to have increased by 9.9%. Most of the range expansion occurred in North Sweden (north of 60°N) where the tick's coverage area doubled from 12.5% in the early 1990s to 26.8% in 2008. Moreover, according to the respondents, the abundance of ticks had increased markedly in LB- and TBE-endemic areas in South (Götaland) and Central Sweden.</p> <p>Conclusions</p> <p>The results suggest that <it>I. ricinus </it>has expanded its range in North Sweden and has become distinctly more abundant in Central and South Sweden during the last three decades. However, in the northern mountain region <it>I. ricinus </it>is still absent. The increased abundance of the tick can be explained by two main factors: First, the high availability of large numbers of important tick maintenance hosts, i.e., cervids, particularly roe deer (<it>Capreolus capreolus</it>) during the last three decades. Second, a warmer climate with milder winters and a prolonged growing season that permits greater survival and proliferation over a larger geographical area of both the tick itself and deer. High reproductive potential of roe deer, high tick infestation rate and the tendency of roe deer to disperse great distances may explain the range expansion of <it>I. ricinus </it>and particularly the appearance of new TBEV foci far away from old TBEV-endemic localities. The geographical presence of LB in Sweden corresponds to the distribution of <it>I. ricinus</it>. Thus, LB is now an emerging disease risk in many parts of North Sweden. Unless countermeasures are undertaken to keep the deer populations, particularly <it>C. capreolus </it>and <it>Dama dama</it>, at the relatively low levels that prevailed before the late 1970s - especially in and around urban areas where human population density is high - by e.g. reduced hunting of red fox (<it>Vulpes vulpes</it>) and lynx (<it>Lynx lynx</it>), the incidences of human LB and TBE are expected to continue to be high or even to increase in Sweden in coming decades.</p

Thromboinflammation : in a Model of Hepatocyte Transplantation

Hepatocyte transplantation is an attractive method for the treatment of metabolic liver disease and acute liver failure. The clinical application of this method has been hampered by a large initial loss of transplanted cells. This thesis has identified and characterized an instant blood-mediated inflammatory reaction (IBMIR), which is a thromboinflammatory response from the innate immunity that may partly explain the observed loss of cells. In vitro perifusion experiments were performed and established that hepatocytes in contact with blood activate the complement and coagulation systems and induce clot formation in conjunction with the recruitment of neutrophils.  Within an hour, the hepatocytes were surrounded by platelets and entrapped in a clot infiltrated by neutrophils. Furthermore, hepatocytes expressed tissue factor (TF), and the reactions were shown to be initiated through the TF pathway. Monitoring of hepatocyte transplantation in vivo revealed activation of the same parameters as were noted in vitro. For the first time, von Willebrand factor (vWF) was identified on the hepatocyte surface, being demonstrated by flow cytometry and confocal microscopy. mRNA for vWF was also confirmed in hepatocytes. Complex formation between platelets and hepatocytes was also identified. Addition of antibodies targeting the binding site for vWF on the platelets reduced the complex formation. Two different strategies, systemic and local intervention, were applied to diminish the thromboinflammation elicited from the hepatocytes in contact with ABO-matched blood. Systemic inhibition with LMW-DS, in a clinically applicable dose, was found to be superior in controlling the IBMIR in vitro when compared to heparin. Cryopreserved hepatocytes elicited the IBMIR to the same extent as did fresh hepatocytes, and the IBMIR was equally well controlled with LMW-DS in both cryopreserved and fresh cells. Hepatocytes were coated with two layers of immobilized heparin in an attempt to protect the cells from the IBMIR. In vitro perifusion experiments showed heparinized hepatocytes triggered a significantly lower degree of IBMIR

Thromboinflammation : in a Model of Hepatocyte Transplantation

Hepatocyte transplantation is an attractive method for the treatment of metabolic liver disease and acute liver failure. The clinical application of this method has been hampered by a large initial loss of transplanted cells. This thesis has identified and characterized an instant blood-mediated inflammatory reaction (IBMIR), which is a thromboinflammatory response from the innate immunity that may partly explain the observed loss of cells. In vitro perifusion experiments were performed and established that hepatocytes in contact with blood activate the complement and coagulation systems and induce clot formation in conjunction with the recruitment of neutrophils.  Within an hour, the hepatocytes were surrounded by platelets and entrapped in a clot infiltrated by neutrophils. Furthermore, hepatocytes expressed tissue factor (TF), and the reactions were shown to be initiated through the TF pathway. Monitoring of hepatocyte transplantation in vivo revealed activation of the same parameters as were noted in vitro. For the first time, von Willebrand factor (vWF) was identified on the hepatocyte surface, being demonstrated by flow cytometry and confocal microscopy. mRNA for vWF was also confirmed in hepatocytes. Complex formation between platelets and hepatocytes was also identified. Addition of antibodies targeting the binding site for vWF on the platelets reduced the complex formation. Two different strategies, systemic and local intervention, were applied to diminish the thromboinflammation elicited from the hepatocytes in contact with ABO-matched blood. Systemic inhibition with LMW-DS, in a clinically applicable dose, was found to be superior in controlling the IBMIR in vitro when compared to heparin. Cryopreserved hepatocytes elicited the IBMIR to the same extent as did fresh hepatocytes, and the IBMIR was equally well controlled with LMW-DS in both cryopreserved and fresh cells. Hepatocytes were coated with two layers of immobilized heparin in an attempt to protect the cells from the IBMIR. In vitro perifusion experiments showed heparinized hepatocytes triggered a significantly lower degree of IBMIR

Prevalence of dementia subtypes: A 30-year retrospective survey of neuropathological reports.

We investigated the distribution of neuropathologically defined dementia subtypes among individuals with dementia disorder. The neuropathological reports were studied on all patients (n=524; 55.3% females; median age 80, range 39-102 years) with clinically diagnosed dementia disorder who underwent complete autopsy including neuropathological examination within the Department of Pathology at the University Hospital in Lund, Sweden, during the years 1974-2004. The neuropathological diagnosis was Alzheimer's disease (AD) in 42.0% of the cases, vascular dementia (VaD) in 23.7%, dementia of combined Alzheimer and vascular pathology in 21.6%, and frontotemporal dementia in 4.0% of the patients. The remaining 8.8% of the patients had other dementia disorders, including combinations other than combined Alzheimer and vascular pathology. The registered prevalence of dementia subtypes depends on many variables, including referral habits, clinical and neuropathological judgments and diagnostic traditions, all of these variables potentially changing over time. This, however, does not seem to obscure the delineation of the major dementia subgroups. In this material of 30 years from Lund in the south of Sweden, AD by far dominated among dementia subtypes, while cerebrovascular pathology corresponded with the dementia disorder, either entirely or partly, in almost half of the demented patients

Blood pressure and drug treatment in clinically diagnosed Lewy body dementia and Alzheimer's disease

The aim of the study was to investigate arterial blood pressure (BP) and the use of pharmacological treatment in patients with Lewy body dementia (cLBD) and Alzheimer's disease (cAD) diagnosed on clinical grounds. BP and pharmacological treatment was analysed based on the medical records of 200 deceased dementia patients. Forty-eight cases with LBD and 45 AD were diagnosed using clinical criteria. The patients, who died between 1985 and 1994, were part of a prospective longitudinal dementia project. The majority of the cases were examined and cared for at the psychogeriatric and psychiatric departments. BP levels were very similar at an early stage of dementia but there was a marked decrease during the course of dementia in cAD and cLBD. The cLBD cases became hypotensive during the course of dementia to a significantly greater extent and also had a more pronounced drop in systolic BP at orthostatic testing compared to the cAD cases. cLBD and cAD were prescribed neuroleptics and medication potentially associated with hypotension to the same extent. The total number of these drugs was however higher in cLBD than in cAD. Antiparkinsonian treatment was, as expected, more common in cLBD compared to cAD. The findings suggest that insufficient BP regulation and drug treatment could affect the clinical picture of dementia, particularly in cLBD patients

Controlled outcome of Hirschsprung's disease beyond adolescence : a single center experience

PurposeThe aim of this study was to assess the function and quality of life of Hirschsprung's Disease (HD) beyond adolescence and relate it to matched controls.MethodsAll 203 patients diagnosed with HD at our department from 1961 to 1995 were identified. 21 had died, 43 had unclear diagnosis and 16 could not be traced. The remaining 123 patients were sent bowel function and SF-36 quality of life questionnaires. 69 patients (mean age 37.8, range 22-58, 13 female) responded and were matched with 138 age and sex-matched controls.ResultsFunction: HD-patients had significantly higher number of bowel movements per week, higher incidence of soiling, urgency, permanent stomas, use of laxatives, enemas and loperamide. HD-patients also scored significantly lower in their satisfaction with their bowel function. There was, however, no significant difference in Miller Incontinence score.QOL: HD-patients reported a significantly higher incidence of negative impact by their bowel function on daily life, social interaction and ability to go on vacation. There were no significant differences in SF-36-scores.ConclusionsBowel function has a lifelong negative impact on the lives of patients with HD. This strongly indicates a need for structured follow-up beyond adolescence

Clinical Lewy body dementia and the impact of vascular components

OBJECTIVE: To study the prevalence of patients fulfilling the clinical consensus criteria for dementia with Lewy bodies (DLB) in a dementia population followed up with postmortem examination. To compare the clinical and neuropathological findings in the clinical Lewy body dementia (LBD) group with findings in a clinically defined group with Alzheimer's disease (AD). DESIGN: Medical records from 200 patients were studied retrospectively. Clinical consensus criteria for DLB and clinical criteria for other dementias were applied. SETTING: The majority of the cases were examined and cared for in psychogeriatric and psychiatric departments. PATIENTS: The patients, who died between 1985 and 1994, were part of a longitudinal dementia project. Each case was neuropathologically examined. Main outcome measures Prevalence of clinical signs and neuropathology was compared between the clinical groups. RESULTS: Forty-eight (24%) patients fulfilled the clinical criteria for DLB while 45 (22%) fulfilled the clinical criteria for Alzheimer's disease. The clinical LBD group had a higher Hachinski score compared to the clinical AD group. They also showed a tendency towards a 'frontal profile' with disinhibition, confusion, personality change and vocally disruptive behaviour. More than 80% of the AD and LBD groups respectively exhibited Alzheimer pathology. The LBD group had frontal white matter pathology and degeneration of the substantia nigra more often than the clinical AD group. Both LBD and AD groups showed a progressive and marked increase in severity of dementia and decrease in ADL capacity according to an evaluation based on the Berger scale and Katz index. The condition of the LBD group was significantly worse earlier in dementia. CONCLUSION: The results of this study indicate that patients fulfilling the clinical criteria for DLB also exhibit clinical features of possible vascular origin and a frontal profile. Subcortical vascular pathology, nigral degeneration and AD pathology in this group could partly explain the clinical features used to define DLB