A look into the future? Patients' and health care staff's perception and evaluation of genetic information and the right not to know

The progress of medical genetics leads to a significant increase in genetic knowledge and a vast expansion of genetic diagnostics. However, it is still unknown how these changes will be integrated into medical practice and how they will change patients' and healthy persons' perception and evaluation of genetic diagnoses and genetic knowledge. Therefore, we carried out a comprehensive questionnaire survey with more than 500 patients, clients seeking genetic counseling, health care staff, and healthy persons (N = 523). The questionnaire survey covered detailed questions on the value of genetic diagnoses for the different groups of study participants, the right to know or not to know genetic diagnoses, possible differences between genetic and other medical diagnoses, and the practical use and implications of genetic knowledge with a special focus on hereditary neuropsychiatric diseases. A huge majority of the participants (90.7%) stated to have a right to learn every aspect of her or his genetic make‐up. Similarly, study participants showed high interest (81.8%) in incidental health care findings—independent of whether the diseases are treatable or not. One can derive from the data outcome that study participants did not follow the implications of a “genetic exceptionalism” and often considered genetic findings as equivalent in relation to other medical diagnoses.     

Control of voluntary and reflexive saccades in Parkinson’s disease

Eight patients with idiopathic Parkinson’s disease (PD) were compared with a group of age-matched controls on both reflexive saccade and antisaccade tasks. While reflexive, visually guided saccades led to equivalent performance in both groups, PD patients were slower, made more errors, and showed reduced gain on antisaccades (AS). This is consistent with previous results showing that PD patients have no difficulty with reflexive saccades but show deficiencies in a number of voluntary saccade paradigms. Moreover, visual information in the form of landmarks improves AS performance more for PD patients than controls, a finding analogous to results seen with other motor acts such as target-directed pointing. Results are discussed in terms of a two-process model of attention and eye movements. Received: 13 October 1998 / Accepted: 11 May 1999     

Evaluation of Heart State Variation and Neural Control Parameters with Animal Models

INTRODUCTION　　 The cardiac electrical physiology contains abundantphysiological and pathologi-cal information and enables noninvasive detection.Butitis notenough for diagnos-ing heart diseases in clinic in the past.Common approaches for diagnosing early…     

Control of NF-κB and inflammation by the unfolded protein response

Under inflammatory situations, endoplasmic reticulum (ER) stress occurs at local sites and modulates inflammatory processes. NF-κB is a key regulator for immune and inflammatory responses, and its activity is influenced by ER stress positively or negatively. Recent investigation suggested that ER stress induces activation of NF-κB in the early phase, whereas in the later phase, consequent unfolded protein response (UPR) inhibits NF-κB. This review summarizes current knowledge on potential mechanisms underlying the biphasic, bidirectional regulation of NF-κB by the UPR and possible roles for ER stress in the regulation of inflammation.     

Control of the thymic medulla and its influence on αβT-cell development

The thymus is a primary lymphoid tissue that supports the generation of αβT cells. In this review, we describe the processes that give rise to the thymus medulla, a site that nurtures self-tolerant T-cell generation following positive selection events that take place in the cortex. To summarize the developmental pathways that generate medullary thymic epithelial cells (mTEC) from their immature progenitors, we describe work on both the initial emergence of the medulla during embryogenesis, and the maintenance of the medulla during postnatal stages. We also investigate the varying roles that receptors belonging to the tumor necrosis factor receptor superfamily have on thymus medulla development and formation, and highlight the impact that T-cell development has on thymus medulla formation. Finally, we examine the evidence that the thymic medulla plays an important role during the intrathymic generation of distinct αβT-cell subtypes. Collectively, these studies provide new insight into the development and functional importance of medullary microenvironments during self-tolerant T-cell production in the thymus.     

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.A large body of evidence indicates that soluble oligomers of amyloid-β (Aβ) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD).^{1, 2} However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance,^{3, 4, 5, 6, 7, 8} although a few studies have linked plaques with early cognitive decline.^{9, 10, 11, 12} Soluble oligomeric Aβ has been highlighted as the primary toxin for loss of dendritic spines and synaptic function¹³ and has also been directly linked to downstream tau pathology. For example, suppression of a tau kinase pathway can prevent Aβ42 oligomer-induced dendritic spine loss,¹⁴ and injection of Aβ42 fibrils into mutant tau mice induces neurofibrillary tangles in cell bodies retrograde to the injections.¹⁵ In vivo, effects of Aβ oligomers versus fibrils are harder to separate; however, lowering soluble Aβ oligomers by halving β–site amyloid precursor protein (APP) cleaving enzyme reduces accumulation and phosphorylation of wild-type tau in a mouse model.¹⁶ Evidence for Aβ and tau association is particularly strong in the dendritic compartment, where tau was shown to mediate Aβ toxicity via linkage of fyn to downstream N-methyl-d-aspartate receptor toxicity.¹⁷The earliest cognitive losses in AD have long been thought to correlate with synapse loss.^{8, 18, 19, 20, 21} In humans, electron microscopic studies have documented synapse-associated Aβ and tau,^{22, 23} and much work documents activity-dependent release of synaptic Aβ into interstitial fluid, which drives local Aβ deposition in human subjects and in rodents.^{4, 24, 25} Of importance, most synapse-associated Aβ in cortical synapses of AD patients consists of soluble oligomeric species,²⁶ and synaptic tau pathology in AD also includes accumulations of SDS-stable tau oligomers.^{27, 28, 29, 30, 31} With the use of synaptosomes (resealed nerve terminals) from the cortex of postmortem human subjects and a transgenic rat model of AD, the present experiments were aimed at determining the sequence of appearance of Aβ and hyperphosphorylated tau (p-tau) pathology in synaptic terminals. In addition to early- and late-stage disease, the AD samples included nondemented high pathology controls (HPCs) with substantial AD-related pathology. Synaptic accumulation of Aβ occurred in the earliest plaque stages, before the appearance of synaptic p-tau, which did not appear until late-stage disease. Soluble Aβ oligomers in synaptic terminals were elevated in early AD cases compared with HPCs, indicating an association with the onset of a dementia diagnosis.     

Control of Müller glial cell proliferation and activation following retinal injury

Müller glial cells are the major support cell for neurons in the vertebrate retina. Following neuronal damage, Müller cells undergo reactive gliosis, which is characterized by proliferation and changes in gene expression. We have found that downregulation of the tumor supressor protein p27Kip1 and re-entry into the cell cycle occurs within the first 24 hours after retinal injury. Shortly thereafter, Müller glial cells upregulate genes typical of gliosis and then downregulate cyclin D3, in concert with an exit from mitosis. Mice lacking p27Kip1 showed a constitutive form of reactive gliosis, which leads to retinal dysplasia and vascular abnormalities reminiscent of diabetic retinopathy. We conclude that p27Kip1 regulates Müller glial cell proliferation during reactive gliosis.     

Chronic Nicotine Exposure has Dissociable Behavioural Effects on Control and Beta2−/− Mice

Nicotine exerts beneficial effects on various neurological and psychiatric pathologies, yet its effects on cognitive performance remain unclear. Mice lacking the beta2 subunit of the nicotinic receptor (β2−/−) show characteristic deficits in executive functions and are suggested as reliable animal models for some specific endophenotypes of human pathologies, notably ADHD. We use β2−/− and their controls to investigate the consequences of chronic nicotine exposure on cognitive behaviour. We show that in control mice, this treatment elicits somewhat slight effects, particularly affecting nocturnal activity and self-grooming. By contrast, in β2−/− mice, chronic nicotine treatment had restorative effects on exploratory behaviour in the open-field and affected rearing, but did not modify motor functions. We confirmed that β2−/− mice exhibit impaired exploratory and social behaviour, and further demonstrated their nocturnal hyperactivity. These data support the proposal that β2−/− mice represent a relevant model for cognitive disorders in humans and that nicotine administered chronically at low dose may relieve some of these. Edited by Tamara Phillips.     

Music,Emotion, and Self‐Control: Does Listening to Uplifting Music Replenish Self‐Control Strength for Exercise?

The study investigated the effects of listening to self‐selected uplifting music on positive emotional states and self‐control. The participants (n = 72; M_age 22.26 ± 5.97) performed two endurance handgrip squeezes separated by a varied set of experimental manipulations. In two conditions, participants performed a Stroop (self‐control depletion) task and then either listened to self‐selected uplifting music or rested quietly. Controls performed a reading task and then rested quietly. Listening to uplifting music evoked positive emotional states, F(2, 69) = 6.98, p = .002, partial η² = .71; however, participants in both self‐control depletion conditions performed worse than controls on the exercise task (p ≤ .07). Findings support the strength model of self‐control but raise questions about the effects of positive emotional states on self‐control.     

Control of Aβ release from human neurons by differentiation status and RET signaling

Few studies have compared the processing of endogenous human amyloid precursor protein (APP) in younger and older neurons. Here, we characterized LUHMES cells as a human model to study Alzheimer's disease-related processes during neuronal maturation and aging. Differentiated LUHMES expressed and spontaneously processed APP via the secretase pathways, and they secreted amyloid β (Aβ) peptide. This was inhibited by cholesterol depletion or secretase inhibition, but not by block of tau phosphorylation. In vitro aged cells increased Aβ secretion without upregulation of APP or secretases. We identified the medium constituent glial cell line-derived neurotrophic factor (GDNF) as responsible for this effect. GDNF-triggered Aβ release was associated with rapid upregulation of the GDNF coreceptor “rearranged during transfection” (RET). Other direct (neurturin) or indirect (nerve growth factor) RET activators also increased Aβ, whereas different neurotrophins were ineffective. Downstream of RET, we found activation of protein kinase B (AKT) to be involved. Accordingly, inhibitors of the AKT regulator phosphatidylinositol-3-kinase completely blocked GDNF-triggered AKT phosphorylation and Aβ increase. This suggests that RET signaling affects Aβ release from aging neurons.     

Control constructs: Do they mediate the relation between educational attainment and health behaviour?

Health promoting behaviours seem to be more prevalent among people with higher socio-economic status (SES). The main purpose of this article was to study (a) the relationship between education (as a dimension of SES) and intention and health behaviour (fruit/vegetable consumption), (b) the relationship between education and control conceptualizations (health locus of control (HLC), response-efficacy and self-efficacy) and (c) to what extent the relationship between education and intention/health behaviour (fruit/vegetable consumption) was mediated through different control beliefs. The results showed that women with higher education had higher intentions to consume fruit/vegetables and consumed fruit/vegetables more frequently. Higher education was associated with higher self-efficacy and response-efficacy beliefs and less belief in HLC-chance. These control beliefs partly mediated the education-intention/behaviour relationship.     

α(1,3)-Fucosyltransferases FUT4 and FUT7 Control Murine Susceptibility to Thrombosis

The α(1,3)-fucosyltransferases, types IV and VII (FUT4 and FUT7, respectively), are required for the synthesis of functional selectin-type leukocyte adhesion molecule ligands. The selectins and their ligands modulate leukocyte trafficking, and P-selectin and its ligand, P-selectin glycoprotein ligand-1, can modulate hemostasis and thrombosis. Regulation of thrombosis by FUT4 and/or FUT7 activity was examined in mouse models of carotid artery thrombosis and collagen/epinephrine-induced thromboembolism. Mice lacking both FUT4 and FUT7 (Fut^−/− mice) had a shorter time to occlusive thrombus formation in the injured carotid artery and a higher mortality due to collagen/epinephrine-induced pulmonary thromboemboli. Mice lacking P-selectin or P-selectin glycoprotein ligand-1 did not have a prothrombotic phenotype. Whole blood platelet aggregation was enhanced, and plasma fibrinogen content, clot weight, and clot strength were increased in Fut^−/− mice, and in vitro clot lysis was reduced compared with wild type. Fut4^−/−, but not Fut7^−/−, mice had increased pulmonary thromboembolism-induced mortality and decreased thromboemboli dissolution in vivo. These data show that FUT4 and FUT7 activity regulates thrombosis in a P-selectin– and P-selectin glycoprotein ligand-1–independent manner and suggest that FUT4 activity is important for thrombolysis.Abnormal post-translational glycosylation can change protein structure, subcellular localization, stability, enzymatic activity, or immunogenic properties. Many proteins of the coagulation system are heavily glycosylated,¹ and variations in the presence or composition of their glycans are known to modulate their function, thereby affecting hemostasis and thrombosis.^2–5 The fucosyltransferases are a family of glycosyltransferases that catalyze the transfer of L-fucose to an acceptor glycan on glycoproteins or glycolipids. They are classified according to the location and configuration of the catalyzed bond between fucose and the acceptor molecule. In humans, α(1,3/4)-fucosyltransferase III (FUT3) catalyzes steps in the synthesis of carbohydrate blood antigens, including the Lewis and Lewis-related antigens (ie, Le^a, Le^b, Le^x, Le^Y, sialyl-Le^x, and sialyl-Le^a).⁶ Individuals who are Lewis negative or have an FUT3 polymorphism that reduces fucosyltransferase availability (T59G) or enzymatic activity (T1067A and T202C) experience an increased incidence of atherothrombotic disease.^7,8The FUT3 homologue in mice (Fut3) is a pseudogene,⁹ and the functional α(1,3)-fucosyltransferases, FUT4 and FUT7, catalyze the synthesis of Le^x and sialyl-Le^x on leukocytes and high endothelial venules. FUT7 plays a predominant role, and FUT4 plays a subsidiary role, in the synthesis of the sialyl-Le^x tetrasaccharide moiety on selectin ligands¹⁰ that is critical for ligand-binding activity.^11,12 Mice with targeted mutations in both Fut4 and Fut7 (Fut^−/−) have marked defects in selectin-dependent leukocyte rolling in vitro and leukocyte recruitment in response to acute inflammation and delayed-type hypersensitivity challenges.^12,13 Mice lacking these FUTs are protected from inflammation-induced pathological conditions, such as atherosclerosis^14,15 and renal ischemia-reperfusion injury.¹⁶ FUT7 expression is restricted primarily to leukocytes and high endothelial venules, and it has precursor specificity for sialyl-Le^x synthesis. In contrast, FUT4 has a broader tissue expression pattern and catalyzes the synthesis of sialyl-Le^x, Le^x, and Le^y moieties.^6,17Two functions of FUT4 and FUT7 suggest an interesting potential role for these enzymes in modulating thrombosis and hemostasis. First, FUT4 and FUT7 catalyze the synthesis of functional P-selectin glycoprotein ligand-1 (PSGL-1; gene Selplg). Binding interactions of PSGL-1 with its receptor, P-selectin (gene Selp), contribute to microvascular thrombosis by enhancing the generation of tissue factor–bearing microparticles and their recruitment into a growing thrombus. Both actions enhance the local generation of fibrin to stabilize the growing thrombus.^18,19 Second, human genetic association studies demonstrate links between Lewis-related antigens and the risk of atherothrombotic disease.^7,8 We examined thrombosis and hemostasis in Fut^−/− mice and found an unexpected prothrombotic phenotype, enhanced platelet aggregation, and a high plasma fibrinogen concentration. Blood clot size and strength were increased, and whole blood clots derived from Fut^−/− mice were resistant to tissue-type plasminogen activator-initiated thrombolysis. These results show that loss of α(1,3)-fucosylation, mediated by FUT4 and FUT7, results in enhanced thrombosis due to decreased thrombolysis. They suggest that altered fucosylation of Lewis and Lewis-related antigen structures modulates the thrombotic phenotype in mice, and that altered fucosylation of these structures may modulate the thrombotic phenotype in humans with generalized fucosylation deficiencies²⁰ or specific α(1,3/4)-FUT polymorphisms.^20,21     

Negative Affectivity,Emotion Regulation,and Coping in Migraine and Probable Migraine: A New Zealand Case–Control Study

Background

Migraine is a prevalent and disabling health condition. While there have been some suggestions that personality may be linked to migraine incidence, dose–response links to disability or impact are yet to be conducted and multivariate analyses are uncommon.

Purpose

The purposes of this study are to evaluate the personality characteristics differentiating migraine and probable migraine sufferers from matched controls in multivariate models and assess the possibility of a dose–response relationship.

Methods

Fifty migraine sufferers and 50 age-, sex-, and ethnicity-matched controls in New Zealand completed personality measures including negative affectivity, coping, and monitoring–blunting.

Results

Logistic regressions indicated that migraine status was concurrently predicted by Type D negative affectivity, more frequent venting and planning coping, and lower monitoring. There was little evidence to suggest a consistent dose-response type effect of personality on migraine; lower impact and disability were associated with greater openness to experiences, acceptance, and behavioural disengagement.

Conclusions

A personality profile characterised by moderate levels of negative emotion and irritability together with failures in inhibitory self-regulation may be associated with an increased risk of strict and probable migraine.     

Are Motor Control and Regulation Problems Part of the ASD Motor Profile? A Handwriting Study

The primary aim of this study was to kinematically assess how children with autism spectrum disorder (ASD) plan and control their handwriting actions. Forty-three boys aged between 8 to 12 years were included in the present analysis; 23 with ASD and 20 typically developing (TD) controls. Sophisticated objective and quantifiable assessment of movement metrics and dynamics was applied across a series of basic cursive handwriting sequences. Children with ASD demonstrated atypical control of handwriting metrics and dynamics, as well as significantly greater neuromotor noise relative to age-matched peers. They also engaged in less regular monitoring and regulation of their movement during the handwriting task. This study provides new insights into the way children with ASD plan and sequence their handwriting movements. Overall, results revealed that even at a basic level, children with ASD appear to have a breakdown in their ability to control and regulate their handwriting movements. This has important implications for the school-aged child who constantly engages in handwriting tasks within the classroom environment and provides insight into possible directions for future intervention.     

Control of manipulative forces during unimanual and bimanual tasks in patients with Huntington’s disease

The aim of the study was to investigate grip-load force regulation in Huntington's disease (HD) patients as compared to control subjects during the performance of a manipulative task that required rhythmical unimanual or bimanual isodirectional/non-isodirectional actions in the sagittal plane. Results showed that the profile of grip-load ratio force was characterized by maxima and minima that were attained at upward and downward hand positions, respectively. Minimum force ratio was higher in patients than in controls, which points to an elevated baseline that may be related to the inherent bradykinesia observed in HD. Maximum force ratio was also increased in patients, but this effect depended on the performance condition, with largest amplifications occurring during non-isodirectional movements. The latter rescaling may be associated with the complexity of the coordination mode and its asymmetrical load characteristics. In addition, the temporal delay between the grip and load force peaks was augmented in patients versus controls, indicating a disturbed coupled activation of both forces. Furthermore, the interval was largest during non-isodirectional movements followed by isodirectional and unimanual movements, which denotes that the grip-load force coupling deteriorated as a function of coordinative complexity. Together, these data indicate a deficit in the grip-load force constraint due to HD and illustrate the degrading effect of striatal dysfunction on (bi)manual manipulative function.     

A ‘Textbook Pattern’? Malaria Control and Eradication in Jamaica, 1910–65

In 1965 Jamaica was declared free of malaria by the World Health Organisation (WHO), thus ending centuries of death and suffering from the disease. This declaration followed the successful completion of the WHO’s Malaria Eradication Programme (MEP) on the island, initiated in 1958. This account first explores the antecedent control measures adopted by the government up to the MEP. These, as advocated by the previous malaria ‘experts’ who had reported on the disease on the island concentrated on controlling the vector and the administration of quinine for individual protection. Although Jamaica suffered no catastrophic epidemics of island-wide scope, malaria was a constant cause of mortality and morbidity. Major change came in the wake of the Second World War within the changing political context of national independence and international development. In 1957 the Jamaican government joined the global WHO programme to eradicate malaria. The Jamaican campaign exposes many of the problems noted in other studies of such top–down initiatives in their lack of attention to the particular circumstances of each case. Despite being described as ‘a textbook pattern’ of malaria eradication, the MEP in Jamaica suffered from a lack of sufficient preparation and field knowledge. This is most obviously illustrated by the fact that all literature on the programme sent to Jamaica in the first two years was in Spanish. That the MEP exploited the technological opportunity provided by dichlorodiphenyltrichloroethane (DDT) with advantage in Jamaica is not disputed but as this analysis illustrates this success was by no means guaranteed. Keywords : Jamaica, Malaria, Control, Eradication, World Health Organisation     

Patients' needs following colorectal cancer diagnosis: where does primary care fit in?

Background

Colorectal cancer is the third most common cancer in the UK. Patients with colorectal cancer spend most of their time in the community, but the role of primary care in their management and follow-up is unclear.

Aim

To explore colorectal cancer patients'' experiences of psychosocial problems and their management in primary and specialist care.

Design and setting

Longitudinal qualitative study of participants recruited from three hospitals in the west of Scotland and interviewed in their own homes.

Method

In-depth interviews with 24 participants with a new diagnosis of colorectal cancer, and then follow-up interviews 12 months later.

Results

Participants'' needs following a diagnosis for colorectal cancer included physical, psychological, and social issues. GPs played a key role in diagnosis, after which they were less involved. Participants valued GPs making unsolicited contact and offering support. Participants described being well supported by clinical nurse specialists who are expert in the illness, and who provide continuity of care and psychological support. A year after diagnosis, when there was less contact with GPs and clinical nurse specialists, participants still faced challenges associated with the ongoing impact of colorectal cancer

Conclusion

While some patients enjoyed straightforward recoveries from surgery, others experienced longer-term implications from their disease and treatment, particularly bowel-function issues, fatigue, anxiety, and sexual problems. The potential for primary care to contribute more to the ongoing care of colorectal cancer patients was identified.     

Proportion of Cytotoxic Peripheral Blood Natural Killer Cells and T-Cell Large Granular Lymphocytes in Recurrent Miscarriage and Repeated Implantation Failure: Case–Control Study and Meta-analysis

Archivum Immunologiae et Therapiae Experimentalis - We aimed to compare the proportion of peripheral blood natural killer (NK) cells (CD3–CD56+) and T-cell large granular lymphocytes...     

Control of Giardiasis by Interleukin-17 in Humans and Mice—Are the Questions All Answered?

For years, studies of the immune response to Giardia lamblia infection focused on the production of IgA by infected hosts and antigenic variation by the parasite to escape destruction by this IgA. A new study by Hanevik and colleagues (C. S. Saghaug, S. Sørnes, D. Peirasmaki, S. Svärd, N. Langeland, and K. Hanevik, Clin Vaccine Immunol 23:11–18, 2016, http://dx.doi.org/10.1128/CVI.00419-15) highlights the emerging role of interleukin-17 (IL-17) in immunity to this parasite. Along with recent studies of Giardia infections of animals, this work shows that IL-17 appears to be essential for the control of these infections and to be a key factor linking cellular and humoral immune responses.