Early onset dementia: A narrative review of the literature

Over the past forty years, significant research has been conducted on the epidemiology of late onset dementia. Less is known however, about the prevalence, incidence and burden of illness of early onset dementia (occurring prior to 65 years of age). The purpose of this narrative review is to examine existing literature regarding the experiences and implications of living with early onset dementia for patients, caregivers, and family members. The following questions were addressed: (1) What is the impact of early onset dementia on patients, families and carers? and; (2) What are the needs of patients with early onset dementia and their family and carers? Key findings form this review are presented.

Molecular and functional characterizations of a Kunitz-type serine protease inhibitor FcKuSPI of the shrimp Fenneropenaeus chinensis

Serine proteinase inhibitors play important and diverse roles in biological processes such as coagulation, defense mechanisms, and immune responses. Here, we identified and characterized a Kunitz-type proteinase inhibitor, designated FcKuSPI, of the BPTI/Kunitz family of serine proteinase inhibitors from the hemocyte cDNA library of the shrimp Fenneropenaeus chinensis. The deduced amino acid sequence of FcKuSPI comprises 80 residues with a putative signal peptide of 15 amino acids. The predicted molecular weight of the mature peptide is 7.66 kDa and its predicted isoelectric point is 8.84. FcKuSPI includes a Kunitz domain containing six conserved cysteine residues that are predicted to form three disulfide bonds. FcKuSPI shares 44e53% homology with BPTI/Kunitz family members from other species. FcKuSPI mRNAwas expressed highly in the hemocytes and moderately in muscle in healthy shrimp. Recombinant FcKuSPI protein demonstrated anti-protease activity against trypsin and anticoagulant activity against citrated human plasma in a dose-dependent manner in in vitro assays.

Ectopic calcification among families in the Azores: Clinical and radiologic manifestations in families with diffuse idiopathic skeletal hyperostosis and chondrocalcinosis

Objective. Twelve families that were multiply affected with diffuse idiopathic skeletal hyperostosis (DISH) and/or chondrocalcinosis, were identified on the island of Terceira, The Azores, potentially supporting the hypothesis that the 2 disorders share common etiopathogenic factors. The present study was undertaken to investigate this hypothesis. Methods. One hundred three individuals from 12 unrelated families were assessed. Probands were identified from patients attending the Rheumatic Diseases Clinic, Hospital de Santo Espirito, in The Azores. Family members were assessed by rheumatologists and radiologists. Radiographs of all family members were obtained, including radiographs of the dorsolumbar spine, pelvis, knees, elbows, and wrists, and all cases were screened for known features of chondrocalcinosis. Results. Ectopic calcifications were identified in 70 patients. The most frequent symptoms or findings were as follows: axial pain, elbow, knee and metacarpophalangeal (MCP) joint pain, swelling, and/or deformity, and radiographic enthesopathic changes. Elbow and MCP joint periarticular calcifications were observed in 35 and 5 patients, respectively, and chondrocalcinosis was identified in 12 patients. Fifteen patients had sacroiliac disease (ankylosis or sclerosis) on computed tomography scans. Fifty-two patients could be classified as having definite (17%), probable (26%), or possible (31%) DISH. Concomitant DISH and chondrocalcinosis was diagnosed in 12 patients. Pyrophosphate crystals were identified from knee effusions in 13 patients. The pattern of disease transmission was compatible with an autosomal-dominant monogenic disease. The mean age at which symptoms developed was 38 years. Conclusion. These families may represent a familial type of pyrophosphate arthropathy with a phenotype that includes peripheral and axial enthesopathic calcifications. The concurrence of DISH and chondrocalcinosis suggests a shared pathogenic mechanism in the 2 conditions.

A novel LEMD3 mutation common to patients with osteopoikilosis with and without melorheostosis

Recent studies have reported loss of function mutations in the LEMD3 gene, encoding an inner nuclear membrane protein that influences Smad signaling, as a cause of osteopoikilosis, Buschke-Ollendorff syndrome, and melorheostosis. We investigated LEMD3 in a three-generation family with osteopoikilosis from the Azores, an affected father and daughter from Ireland with osteopoikilosis (the daughter also had melorheostosis), and two other individuals from the UK with isolated melorheostosis. We found a novel C to T substitution at position 2032 bp (cDNA) in exon 8 of LEMD3, resulting in a premature stop codon at amino acid position 678. This mutation co-segregates with the osteopoikilosis phenotype in both the Azorean family and the Irish family. It was not detected in any of the six unaffected family members or in 342 healthy Caucasian individuals. No LEMD3 mutations were detected in the two patients with sporadic melorheostosis. The LEMD3 mutation reported was clearly the cause of osteopoikilosis in the two families but its relationship to melorheostosis in one of the family members is still unclear. Perhaps unsurprisingly in what is a segmental disease, we did not find LEMD3 mutations in peripheral-blood-derived DNA from the two other individuals with sporadic melorheostosis. The nature of the additional genetic and/or environmental influences required for the development of melorheostosis in those with osteopoikilosis requires further investigation.

Postnatal depressive symptoms amongst women in Central Vietnam: A cross-sectional study investigating prevalence and associations with social, cultural and infant factors

Background This study investigated the prevalence and socio-cultural correlates of postnatal mood disturbance amongst women 18–45 years old in Central Vietnam. Son preference and traditional confinement practices were explored as well as factors such as poverty, parity, family and intimate partner relationships and infant health. Methods A cross-sectional study was conducted in twelve randomly selected Commune Health Centres from urban and rural districts of Thua Thien Hue Province, Vietnam. Mother-infant dyads one to six months postpartum were invited to participate. Questionnaires from 431 mothers (urban n = 216; rural n = 215) assessed demographic and family characteristics, traditional confinement practices, son preference, infant health and social capital. The Edinburgh Postnatal Depression Scale (EPDS) and WHO5 Wellbeing Index indicated depressive symptoms and emotional wellbeing. Data were analysed using general linear models. Results Using an EPDS cut-off of 12/13, 18.1 % (n = 78, 95 % CI 14.6 - 22.1) of women had depressive symptoms (20.4 % urban; 15.8 % rural). Contrary to predictions, infant gender and traditional confinement were unrelated to depressive symptoms. Poverty, food insecurity, being frightened of family members, and intimate partner violence increased both depressive symptoms and lowered wellbeing. The first model accounted for 30.2 % of the variance in EPDS score and found being frightened of one’s husband, husband’s unemployment, breastfeeding difficulties, infant diarrhoea, and cognitive social capital were associated with higher EPDS scores. The second model had accounted for 22 % of the variance in WHO5 score. Living in Hue city, low education, poor maternal competence and a negative family response to the baby lowered maternal wellbeing. Conclusions Traditional confinement practices and son preference were not linked to depressive symptoms among mothers, but were correlates of family relationships and wellbeing. Poverty, food insecurity, violence, infant ill health, and discordant intimate and family relationships were linked with depressive symptoms in Central Vietnam.

An investigation into drink driving among aboriginal and Torres strait islander peoples in regional and remote Queensland and the development of the 'Hero to Healing' program

This program of research investigated the factors facilitating drink driving in Indigenous communities in Far North Queensland. Drink driving-related road crashes are a significant health burden for Indigenous people, as they die in road crashes at three times the rate of other Australians and are 30% more likely to be seriously injured. This research provided information to develop and pilot a culturally-specific program, 'Hero to Healing'. The main motivation to drink drive was related to 'kinship pressure; where drivers were pressured by family members to drive after drinking. The underlying responsibility for transporting family members was related to cultural values and involved responding to family needs as a priority. Exposure to older family members drink driving was considered to play a role in normalising the behaviour, leading to imitation into adulthood. The research highlighted the need to treat drink driving as a community issue, rather than an individual phenomenon.

The first episode of psychosis: The experience of relatives

Objective The aim was to determine the extent of and the correlates of the distress and impact of care families of patients with first episode psychosis were experiencing when they first came for treatment. Method Subjects were 238 individuals who had presented with a first episode of psychosis and their family members. Family members were assessed with the Psychological General Well-Being Scale, and the Experience of Caregiving Inventory. Patient data included assessment of positive and negative symptoms, depression, quality of life, and substance use. Results Family members of these first-episode patients were experiencing distress and difficulties. It was the family's appraisal of the impact of the illness that was associated with their psychological well-being. Conclusion As the majority of these first episode families are keen to be involved early and have engaged in an intervention programme, the next step should be an evaluation of their involvement to determine if it is effective.

Language and Letters of the Bluestocking Network : Sociolinguistic Issues in Eighteenth Century Epistolary English

This study deals with language change and variation in the correspondence of the eighteenth-century Bluestocking circle, a social network which provided learned men and women with an informal environment for the pursuit of scholarly entertainment. Elizabeth Montagu (1718 1800), a notable social hostess and a Shakespearean scholar, was one of their key figures. The study presents the reconstruction of Elizabeth Montagu s social networks from her youth to her later years with a special focus on the Bluestocking circle, and linguistic research on private correspondence between Montagu and her Bluestocking friends and family members between the years 1738 1778. The epistolary language use is investigated using the methods and frameworks of corpus linguistics, historical sociolinguistics, and social network analysis. The approach is diachronic and concerns real-time language change. The research is based on a selection of manuscript letters which I have edited and compiled into an electronic corpus (Bluestocking Corpus). I have also devised a network strength scale in order to quantify the strength of network ties and to compare the results of the linguistic research with the network analysis. The studies range from the reconstruction and analysis of Elizabeth Montagu s most prominent social networks to the analysis of changing morphosyntactic features and spelling variation in Montagu s and her network members correspondence. The linguistic studies look at the use of the progressive construction, preposition stranding and pied piping, and spelling variation in terms of preterite and past participle endings in the regular paradigm (-ed, - d, -d, - t, -t) and full / contracted spellings of auxiliary verbs. The results are analysed in terms of social network membership, sociolinguistic variables of the correspondents, and, when relevant, aspects of eighteenth-century linguistic prescriptivism. The studies showed a slight diachronic increase in the use of the progressive, a significant decrease of the stigmatised preposition stranding and increase of pied piping, and relatively informal but socially controlled epistolary spelling. Certain significant changes in Elizabeth Montagu s language use over the years could be attributed to her increasingly prominent social standing and the changes in her social networks, and the strength of ties correlated strongly with the use of the progressive in the Bluestocking Corpus. Gender, social rank, and register in terms of kinship/friendship had a significant influence in language use, and an effect of prescriptivism could also be detected. Elizabeth Montagu s network ties resulted in language variation in terms of network membership, her own position in a given network, and the social factors that controlled eighteenth-century interaction. When all the network ties are strong, linguistic variation seems to be essentially linked to the social variables of the informants.

Potential Human Exposure to Australian Bat Lyssavirus, Queensland, 1996-1999

Two human deaths caused by Australian bat lyssavirus (ABL) infection have been reported since 1996. Information was obtained from 205 persons (mostly adults from south Brisbane and the South Coast of Queensland), who reported potential ABL exposure to the Brisbane Southside Public Health Unit from November 1,1996, to January 31, 1999. Volunteer animal handlers accounted for 39% of potential exposures, their family members for 12%, professional animal handlers for 14%, community members who intentionally handled bats for 31%, and community members with contacts initiated by bats for 4%. The prevalence of Lyssavirus detected by fluorescent antibody test in 366 sick, injured, or orphaned bats from the area was 6%. Sequelae of exposure, including the requirement for expensive postexposure prophylaxis, may be reduced by educating bat handlers and the public of the risks involved in handling Australian bats.

Minästä toiseen : Lacanilaisen subjektin syntymä Anaïs Ninin House of Incestissä ja Hélène Cixous'n Dedans'issa

The study approaches two modern novels using the conceptual frame of Lacanian psychoanalysis, especially the Lacanian notion of subject. The novels can be described as subversive “Bildungsromans” (development novels) highly influenced by psychoanalytic thought. Anaïs Nin’s (1903—1977) “poetic novel” House of Incest (1936) is a story of sexual and artistic awakening while Hélène Cixous’s (b. 1937) first novel Dedans (1969) depicts the growth of a little girl whose father dies. Both are first novels and first person narratives. Concentrating in the narrator’s internal life the novels writings break with the realistic conventions of narrative, bringing forth the themes of anguish, alienation from the world and escape into the prison like realm of the self. The study follows roughly the Lacanian process of becoming a subject. Each chapter opens up with a quick introduction to the Lacanian concepts used in the following part that analyses the novels. The study can thus also be used as a brief introduction to Lacanian theory in finnish. The psychoanalytic narrative/story of the birth of the subject and the novels stories can be seen as mirroring each other. The method of the study is thus based on a dialogue between the theoretical concepts and the analyses. Novels are being approached as texts that break with the Cartesian notion of an autonomous subject making room for a dialectics of self and other, for a movement in which the “I” builds an identity mirroring itself with others. While both of the novels recount the birth of a character called I, they also have a first person narrator apart from the character “I”. Having constituted the self’s identity, the narrator finds from inside of the self also an other or “you” – this discovery is the final clue to the coffin of the autonomous self. From the Lacanian perspective man’s great Other is the order of language, Symbolic, which constitutes the individual, the speaking subject. Using this perspective the novels are interpreted as describing the process of becoming a subject of the Symbolic; subjected to Symbolic order. This “birth process” happens in particular in the Imaginary register, where the self’s identity is built. In the Imaginary or Mirror phase the “I” mirrors himself with different others (e.g. with his mirror image and the family members, the surrounding others) learning to see his body and his selfhood both as familiar and strange, other. In the Imaginary phase the novels’ characters are also trying to deal with the opposite realm of the Symcolic, the Real. The Lacanian Real is not the reality “before words” but a reality left over from the Symbolic, aside of it but constituted by the Symbolic, to be deducted only from within it. In the novels the Real is experienced as a womblike state where the self is immersed in the other’s body. The process of coming a subject of the Symbolic is depicted also as a process of renouncing the “dream of the womb”, which, if realized, could only mean the non-existence of the subject, i.e. death. The study concentrates on analysing the novels’ writing, where meanings are constantly changing: “I” becomes you, the father becomes a mother, inside becomes outside. This technique enables also the deconstruction of certain opposing notions in the novels. The Lacanian point of view exposes language as a constantly moving universe where the subject has no more stability than the momentary meanings language creates. The self’s identity depicted in the novels is a Lacanian fixed identity, whose growth is necessary but opposes the flux imminent to the Symbolic. The anguish experienced in the novels, in the “house of incest” or “inside”, is due to clinging on the unchanging “I”. However, the writing of the novels shows how the meaning of the “I” changes constantly and the fixity thus becomes movement. This way House of Incest and Dedans, despite their pessimistic stories, manage to create an image of a new, moving subject.

Healthcare users’ experiences of communicating with healthcare professionals about children who have life-limiting conditions: A qualitative systematic review protocol

REVIEW QUESTION / OBJECTIVE The objective of this review is to identify and synthesize the best international qualitative evidence on healthcare users’ experiences of communication with healthcare professionals about children who have life-limiting conditions. For the purposes of this review, “healthcare users” will be taken to include children who have life-limiting conditions and their families. The question to be addressed is: - What are healthcare users’ experiences of communicating with healthcare professionals about children who have life-limiting conditions? INCLUSION CRITERIA - Types of participants: This review will consider all qualitative studies that focus on users of healthcare services for children who have life-limiting conditions. These users are anticipated to include children who have a life-limiting condition and their family members. In instances where children are not under the legal care of one or both parents, service users may also include other types of legal guardians. - Phenomena of interest: This review will consider experiences of communicating with healthcare professionals about children who have life-limiting conditions. - Context: This review will consider studies relating to communication with healthcare professionals about children who have a life-limiting condition, irrespective of whether the healthcare service is based in a hospital, hospice, or community setting. There is no restriction on the country in which a study was conducted.

Mammalian reverse genetics without crossing reveals Nr3a as a short-sleeper gene

The identification of molecular networks at the system level in mammals is accelerated by next-generation mammalian genetics without crossing, which requires both the efficient production of whole-body biallelic knockout (KO) mice in a single generation and high-performance phenotype analyses. Here, we show that the triple targeting of a single gene using the CRISPR/Cas9 system achieves almost perfect KO efficiency (96%–100%). In addition, we developed a respiration-based fully automated noninvasive sleep phenotyping system, the Snappy Sleep Stager (SSS), for high-performance (95.3% accuracy) sleep/wake staging. Using the triple-target CRISPR and SSS in tandem, we reliably obtained sleep/wake phenotypes, even in double-KO mice. By using this system to comprehensively analyze all of the N-methyl-D-aspartate (NMDA) receptor family members, we found Nr3a as a short-sleeper gene, which is verified by an independent set of triple-target CRISPR. These results demonstrate the application of mammalian reverse genetics without crossing to organism-level systems biology in sleep research.

The Mechanisms of Hedgehog Signal Transduction

Studies in both vertebrates and invertebrates have identified proteins of the Hedgehog (Hh) family of secreted signaling molecules as key organizers of tissue patterning. Initially discovered in Drosophila in 1992, Hh family members have been discovered in animals with body plans as diverse as those of mammals, insects and echinoderms. In humans three related Hh genes have been identified: Sonic, Indian and Desert hedgehog (Shh, Ihh and Dhh). Transduction of the Hh signal to the cytoplasm utilizes an unusual mechanism involving consecutive repressive interactions between Hh and its receptor components, Patched (Ptc) and Smoothened (Smo). Several cytoplasmic proteins involved in Hh signal transduction are known in Drosophila, but mammalian homologs are known only for the Cubitus interruptus (Ci) transcription factor (GLI(1-3)) and for the Ci/GLI-associated protein, Suppressor of Fused (Su(fu)). In this study I analyzed the mechanisms of how the Hh receptor Ptc regulates the signal transducer Smo, and how Smo relays the Shh signal from the cell surface to the cytoplasm ultimately leading to the activation of GLI transcription factors. In Drosophila, the kinesin-like protein Costal2 (Cos2) is required for suppression of Hh target gene expression in the absence of ligand, and loss of Cos2 causes embryonic lethality. Cos2 acts by bridging Smo to the Ci. Another protein, Su(Fu) exerts a weak suppressive influence on Ci activity and loss of Su(Fu) causes subtle changes in Drosophila wing pattern. This study revealed that domains in Smo that are critical for Cos2 binding in Drosophila are dispensable for mammalian Smo function. Furthermore, by analyzing the function of Su(Fu) and the closest mouse homologs of Cos2 by protein overexpression and RNA interference I found that inhibition of the Hh response pathway in the absence of ligand does not require Cos2 activity, but instead critically depends on the activity of Su(Fu). These results indicate that a major change in the mechanism of action of a conserved signaling pathway occurred during evolution, probably through phenotypic drift made possible by the existence in some species of two parallel pathways acting between the Hh receptor and the Ci/GLI transcription factors. In a second approach to unravel Hh signaling we cloned > 90% of all human full-length protein kinase cDNAs and constructed the corresponding kinase-activity deficient mutants. Using this kinome resource as a screening tool, two kinases, MAP3K10 and DYRK2 were found to regulate Shh signaling. DYRK2 directly phosphorylated and induced the proteasome dependent degradation of the key Hh-pathway regulated transcription factor, GLI2. MAP3K10, in turn, affected GLI2 indirectly by modulating the activity of DYRK2.

Wedding portrait of Freddy Gottschalk and Barbara Joan Doble with guests; Welwyn Garden City, England.

Portrait includes a number of family members who were able to get to England before the war and who chose to remain there.

Nicotine Dependence and Smoking Behaviour : A genetic and epidemiological study

The worldwide health burden caused by the tobacco epidemic highlights the importance of study-ing determinants of smoking behaviour and key factors sustaining nicotine dependence. Despite vast-ranging preventive efforts, smoking remains one of the most deleterious health behaviours, and its genetic and environmental factors warrant continuous investigation. The heritability of smoking behaviour and nicotine dependence has been suggested to be relatively high. Earlier smoking behaviour, nicotine dependence, socio-economic position and demographic factors have all been shown to be associated with smoking cessation. This thesis aimed to examine various aspects of smoking behaviour and nicotine dependence from an epidemiological and genetic per-spective. Data for Studies I and IV were obtained from the Older Finnish Twin Cohort, a postal health sur-vey conducted in 1975, 1981 and 1990 on same-sexed pairs and in 1996-1997 on male-female adult pairs. The number of ever-smoking participants was 8941 in Study I and 3069 in Study IV. Data for Studies II and III came from the Family Study of Cigarette Smoking - Vulnerability to Nicotine Addiction. This study is linked to the Older Finnish Twin Cohort with new data collec-tion during 2001-2006 that focused on smoking twin pairs and their family members. The meas-ures included intensive telephone interviews, blood samples and additional postal questionnaires. The numbers of ever-smoking participants was 1370 in Study II and 529 in Study III. Study I examined whether a genetic component underlies smoking behaviour among Finnish adults. Genetic factors were important in the amount smoked and smoking cessation, with about half of the phenotypic differences explained by genetic variance. A novel finding was that genetic influences on amount smoked and smoking cessation were largely independent of genetic influ-ences on age at initiation. This result has implications for defining phenotypes in the search for genes underlying smoking behaviour. Furthermore, even if smoking initiation is postponed to a later age, potential vulnerability to subsequent nicotine dependence cannot be completely inhib-ited. Study II investigated the effect of genetic and environmental factors on nicotine dependence, as measured by the novel multidimensional Nicotine Dependence Syndrome Scale (NDSS). This scale was validated in the Finnish data. The NDSS correlated highly with other established nico-tine dependence scales (FTND and DSM-IV), suggesting that this new scale would be a feasible and valid measure for identifying nicotine-dependent smokers among the ever-smoking popula-tion. About one-third of the phenotypic variation in nicotine dependence in this sample was ex-plained by genetic influences. Study III aimed at identifying chromosomal regions harbouring genes that influence smoking be-haviour and nicotine dependence. Linkage analysis of family data revealed that for smoker and nicotine dependence phenotypes as well as for co-morbidity between nicotine dependence and alcohol use signals on specific chromosome regions (chromosomes 2q33, 5q12, 5q34 7q21, 7q31, 10q25, 11p15, 20p13) exist. Results further support the hypothesis that smoking behaviour phe-notypes have a genetic background. Study IV examined associations of smoking behaviour, socio-economic position and transition of marital status with smoking cessation. Indicators of socio-economic position were important pre-dictors of smoking cessation even when adjusted for previous smoking behaviour. Getting married was associated with an increased probability of cessation in men, a finding confirmed among dis-cordant twin pairs. Thus, having a partner appears to have a positive impact on smoking cessation. In conclusion, nicotine dependence and smoking behaviour demonstrate significant genetic liabil-ity, but also substantial environmental influences among Finnish adults. Smoking initiation should be prevented or at least postponed to a later age. Although genetic factors are important in nicotine dependence and smoking behaviour, societal actions still have a primary role in tobacco control and smoking prevalence. Future studies should examine the complex interactions between genetic and environmental factors in nicotine dependence.