TNF deficiency causes alterations in the spatial organization of neurogenic zones and alters the number of microglia and neurons in the cerebral cortex

•TNF deficiency alters the spatial organization of neurogenic zones.•TNF deficiency decreases WNT signaling-related proteins.•TNF deficiency alters neuronal and microglial numbers.•Long-term use of non-selective TNF inhibitors impairs learning and memory.•Long-term use of the soluble TNF selective inhibitor XPro1595 does not affect neurogenesis, learning and memory. Although tumor necrosis factor (TNF) inhibitors are used to treat chronic inflammatory diseases, there is little information about how long-term inhibition of TNF affects the homeostatic functions that TNF maintains in the intact CNS. To assess whether developmental TNF deficiency causes alterations in the naïve CNS, we estimated the number of proliferating cells, microglia, and neurons in the developing neocortex of E13.5, P7 and adult TNF knock out (TNF−/−) mice and wildtype (WT) littermates. We also measured changes in gene and protein expression and monoamine levels in adult WT and TNF−/− mice. To evaluate long-term effects of TNF inhibitors, we treated healthy adult C57BL/6 mice with either saline, the selective soluble TNF inhibitor XPro1595, or the nonselective TNF inhibitor etanercept. We estimated changes in cell number and protein expression after two months of treatment. We assessed the effects of TNF deficiency on cognition by testing adult WT and TNF−/− mice and mice treated with saline, XPro1595, or etanercept with specific behavioral tasks. TNF deficiency decreased the number of proliferating cells and microglia and increased the number of neurons. At the same time, TNF deficiency decreased the expression of WNT signaling-related proteins, specifically Collagen Triple Helix Repeat Containing 1 (CTHRC1) and Frizzled receptor 6 (FZD6). In contrast to XPro1595, long-term inhibition of TNF with etanercept in adult C57BL/6 mice decreased the number of BrdU+ cells in the granule cell layer of the dentate gyrus. Etanercept, but not XPro1595, also impaired spatial learning and memory in the Barnes maze memory test. TNF deficiency impacts the organization of neurogenic zones and alters the cell composition in brain. Long-term inhibition of TNF with the nonselective TNF inhibitor etanercept, but not the soluble TNF inhibitor XPro1595, decreases neurogenesis in the adult mouse hippocampus and impairs learning and memory after two months of treatment

A randomized, controlled trial of a multi-modal exercise intervention in Huntington's disease

Introduction This study aimed to evaluate the feasibility and benefit of a structured exercise intervention in people with Huntington’s Disease (HD). Methods This study was conducted at 6 sites, and participants were randomized into either exercise or control (usual care) groups, and were assessed at baseline, 13 and 26 weeks. The intervention was a 12 week, three times per week progressive exercise program, including aerobic (stationary cycling) and upper and lower body strengthening exercise with tapered 1:1 support for 20 of 36 sessions. Results 314 adults were assessed for eligibility: 248 did not meet inclusion criteria, 34 declined, and 32 were recruited and randomized. Three individuals in the intervention group were withdrawn within the first month due to concomitant medical conditions, resulting in 14 participants in intervention and 15 in control groups. There were two AEs in the intervention group, both related to previous medical conditions, and there were two SAEs, both in the control group. The intervention group had better fitness (predicted VO2 max difference: 492.3 ml min−1, 95% CI: [97.1, 887.6]), lower UHDRS mMS (difference 2.9 points, 95% [−5.42, −0.32]) and lower weight at Week 13 (difference 2.25 kg, 95% CI: [−4.47, −0.03]). Conclusion This study demonstrates that a short-term exercise intervention is safe and feasible. Individuals with HD may benefit from structured exercise, and intensity, monitoring and support may be key factors in optimizing response. Larger scale trials are now required to fully elucidate the extended clinical potential of exercise in HD

Lay beliefs of TB and TB/HIV co-infection in Addis Ababa, Ethiopia: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Knowledge about lay beliefs of etiology, transmission and treatment of TB, and lay perceptions of the relationship between TB and HIV is important for understanding patients' health seeking behavior and adherence to treatment. We conducted a study to explore lay beliefs about TB and TB/HIV co-infection in Addis Ababa, Ethiopia.</p> <p>Findings</p> <p>We conducted a qualitative study using in-depth interviews with 15 TB/HIV co-infected patients and 9 health professionals and focus group discussions with 14 co-infected patients in Addis-Ababa, Ethiopia. We found that a predominant lay belief was that TB was caused by exposure to cold. Excessive sun exposure, exposure to mud, smoking, alcohol, khat and inadequate food intake were also reported as causes for TB. Such beliefs initially led to self-treatment. The majority of patients were aware of an association between TB and HIV. Some reported that TB could transform into HIV, while others said that the body could be weakened by HIV and become more susceptible to illnesses such as TB. Some patients classified TB as either HIV-related or non-HIV-related, and weight loss was a hallmark for HIV-related TB. The majority of patients believed that people in the community knew that there was an association between TB and HIV, and some feared that this would predispose them to HIV-related stigma.</p> <p>Conclusion</p> <p>There is a need for culturally sensitive information and educational efforts to address misperceptions about TB and HIV. Health professionals should provide information about causes and treatment of TB and HIV to co-infected patients.</p

Use and feasibility of delayed prescribing for respiratory tract infections: A questionnaire survey

<p>Abstract</p> <p>Background</p> <p>Delayed prescribing of antibiotics for respiratory tract infections (RTIs) lowers the amount of antibiotics consumed. Several national treatment guidelines on RTIs recommend the strategy. When advocating treatment innovations, the feasibility and credibility of the innovation must be taken into account. The objective of this study was to explore GPs use and patients uptake of wait-and-see prescriptions for RTIs, and to investigate the feasibility of the strategy from GPs' and patients' perspectives.</p> <p>Methods</p> <p>Questionnaire survey among Norwegian GPs issuing and patients receiving a wait-and-see-prescription for RTIs. Patients reported symptoms, confidence and antibiotics consumption, GPs reported diagnoses, reason for issuing a wait-and-see-prescription and their opinion about the method.</p> <p>Results</p> <p>304 response pairs from consultations with 49 GPs were received. The patient response rate was 80%. The most common diagnosis for the GPs to issue a wait-and-see prescription was sinusitis (33%) and otitis (21%). 46% of the patients reported to consume the antibiotics. When adjusted for other factors, the diagnosis did not predict antibiotic consumption, but both being 16 years or more (p = 0,006) and reporting to have a fever (p = 0,012) doubled the odds of antibiotic consumption, while feeling very ill more than quadrupled the odds (p = 0,002). In 210 cases (69%), the GP found delayed prescribing a very reasonable strategy, and 270 patients (89%) would prefer to receive a wait-and-see prescription in a similar situation in the future. The GPs found delayed prescribing very reasonable most frequently in cases of sinusitis (79%, p = 0,007) and least frequently in cases of lower RTIs (49%, p = 0,002).</p> <p>Conclusion</p> <p>Most patients and GPs are satisfied with the delayed prescribing strategy. The patients' age, symptoms and malaise are more important than the diagnosis in predicting antibiotic consumption. The GP's view of the method as a reasonable approach depends on the patient's diagnosis. In our setting, delayed prescribing seems to be a feasible strategy, especially in cases of sinusitis and otitis. Educational efforts to promote delayed prescribing in similar settings should focus on these diagnoses.</p

Patients’ Perceptions and Experiences of Familial Hypercholesterolemia, Cascade Genetic Screening and Treatment

Background: Familial hypercholesterolemia (FH) is a serious genetic disorder affecting approximately 1 in every 300 to 500 individuals and is characterised by excessively high low-density lipoprotein (LDL) cholesterol levels, substantially increased risk of early-onset coronary heart disease (CHD) and premature mortality. If FH is untreated, it leads to a greater than 50 % risk of CHD in men by the age of 50 and at least 30 % in women by the age of 60. FH can be diagnosed through genetic screening and effectively managed through pharmacological treatment and lifestyle changes. Purpose: Familial hypercholesterolemia (FH) is a genetic health condition that increases the risk of cardiovascular disease. Although FH can be effectively managed with appropriate pharmacological and dietary interventions, FH detection rate through genetic screening remains low. The present study explored perceptions and experiences of FH patients (N = 18) involved in a genetic cascade screening programme. Methods: Face-to-face interviews were conducted to assess patients’ knowledge and understanding of FH, explore factors linked to adherence to health-protective behaviours and examine perceptions of genetic screening. Results: Thematic analysis of interviews revealed four themes: disease knowledge, severity of FH, lifestyle behavioural change and barriers to cascade screening and treatment. Participants recognised FH as a permanent, genetic condition that increased their risk of CHD and premature mortality. Many participants dismissed the seriousness of FH and the importance of lifestyle changes because they perceived it to be effectively managed through medication. Despite positive attitudes toward screening, many participants reported that relatives were reluctant to attend screening due to their relatives’ ‘fatalistic’ outlook or low motivation. Participants believed that they had insufficient authority or control to persuade family members to attend screening and welcomed greater hospital assistance for contact with relatives. Conclusions: Findings support the adoption of direct methods of recruitment to cascade screening led by medical professionals, who were perceived as having greater authority. Other implications included the need for clinicians to provide clear information, particularly to those who are asymptomatic, related to the seriousness of FH and the necessity for adherence to medication and lifestyle changes

Biomechanical comparison of screw-based zoning of PHILOS and Fx proximal humerus plates

Background Treatment of proximal humerus fractures with locking plates is associated with complications. We aimed to compare the biomechanical effects of removing screws and blade of a fixed angle locking plate and hybrid blade plate, on a two-part fracture model. Methods Forty-five synthetic humeri were divided into nine groups where four were implanted with a hybrid blade plate and the remaining with locking plate, to treat a two-part surgical neck fracture. Plates’ head screws and blades were divided into zones based on their distance from fracture site. Two groups acted as a control for each plate and the remaining seven had either a vacant zone or blade swapped with screws. For elastic cantilever bending, humeral head was fixed and the shaft was displaced 5 mm in extension, flexion, valgus and varus direction. Specimens were further loaded in varus direction to investigate their plastic behaviour. Results In both plates, removal of inferomedial screws or blade led to a significantly larger drop in varus construct stiffness than other zones. In blade plate, insertion of screws in place of blade significantly increased the mean extension, flexion valgus and varus bending stiffness (24.458%/16.623%/19.493%/14.137%). In locking plate, removal of screw zones proximal to the inferomedial screws reduced extension and flexion bending stiffness by 26–33%. Conclusions Although medial support improved varus stability, two inferomedial screws were more effective than blade. Proximal screws are important for extension and flexion. Mechanical consequences of screw removal should be considered when deciding the number and choice of screws and blade in clinic

Barriers and enablers in the management of tuberculosis treatment in Addis Ababa, Ethiopia: a qualitative study

Tuberculosis (TB) is an infectious disease which causes about two million deaths each year. In 1993, the World Health Organization (WHO) declared TB to be a “Global Emergency” due to an increasing number of TB cases and a rise in multidrug resistant cases in the developed world. Treatment interruption was considered one of the major challenges. WHO introduced the current TB control program DOTS (directly observed treatment, short course) as the tool to control the disease. To prevent further development of resistance against anti-TB drugs it was decided to observe each patient taking their daily dose of medication. The overall aim of this thesis is to explore how patients and health workers perceive and manage TB symptoms and treatment in a high-endemic and a low-endemic setting in the era of DOT(S). The data is based on fieldwork, including in-depth interviews and focus groups with TB patients and health workers, in Addis Ababa, Ethiopia (2001-2002) and in Oslo/Akershus, Norway (2007-2008). We found that people’s interpretation and management of TB symptoms is influenced by cultural, social and economic factors. TB was, in both contexts, associated with poverty, and subsequently with a disease that affects certain countries or certain segments of a population. TB was viewed as a severe disease in both contexts, but there was variation between individuals to what extent one considered oneself as a likely victim. In the absence of circumstantial causes, such as poverty, patients in a lowendemic setting like Norway, found it difficult to understand why they had developed the disease. There was scarce knowledge about the fact that the disease could be latent. Awareness of early symptoms, such as persistent cough, was low in both contexts. Perceptions of vulnerability, together with the presence or absence of socio-economic barriers or enablers influenced at what time patients would seek help. The study suggests that health personnel lacked awareness or misinterpreted early symptoms of TB. In Ethiopia, lay categorizations of early TB symptoms converged with diagnostic practices in parts of the professional health sector. The diagnostic process could endure for many months after patients’ first contact with the health services. Similarly, in Norway, we found that patients’ interpretations of early symptoms often were confirmed in the meeting with health personnel. The consequences were prolonged diagnostic processes. The study shows that patients’ ability to manage TB treatment is a product of dynamic processes, in which social and economic costs and other burdens interplay over time. A decision to interrupt treatment can be shaped by past struggles and accrued costs; in which seems financially, socially or emotionally unbearable at the moment of treatment interruption. The burdens related to DOT could also be significant, in patients who did not interrupt treatment. Patients in both Ethiopia and Norway experienced an authoritarian and rigid practice of DOT, which made it difficult to simultaneously attend to demands related to treatment and demands related to other areas of life. The most vulnerable patients, such as those without permanent jobs, suffered from high economic, social and emotional costs. In conclusion, health personal need more knowledge about typical and atypical symptoms of TB. In low-endemic settings doctors need to be trained to adjust their level of suspicion to the migration history of the patient. In high-endemic settings one should be aware that health personnel may understand and manage TB within a traditional perspective. Patients in both high- and low-endemic contexts need concrete information about the cause of TB, how it is transmitted, how symptoms can be manifested, how the disease can progress and how it can be cured. The study indicates that inequalities that predispose for TB may be reinforced in the patient’s interaction with the health services due to a rigid, disempowering practice of DOT. Subsequently, DOT per se may add to the chain of structural barriers that patients have to overcome to access and complete treatment. To ensure that TB patients complete treatment one must address the coexisting and interacting crises that follow a TB diagnosis. This could require TB programs to adopt a more holistic approach. Measures that secure early diagnosis may reduce some of the physical, psycho-social and economic costs patients face while undergoing treatment. Measures that empower patients to participate in their own health care may avoid disempowering and humiliating practices

A summer heat wave decreases the immunocompetence of the mesograzer, Idotea baltica

Extreme events associated with global change will impose increasing stress on coastal organisms. How strong biological interactions such as the host–parasite arms-race are modulated by environmental change is largely unknown. The immune system of invertebrates, in particular phagocytosis and phenoloxidase activity response are key defence mechanisms against parasites, yet they may be sensitive to environmental perturbations. We here simulated an extreme event that mimicked the European heat wave in 2003 to investigate the effect of environmental change on the immunocompetence of the mesograzer Idotea baltica. Unlike earlier studies, our experiment aimed at simulation of the natural situation as closely as possible by using long acclimation, a slow increase in temperature and a natural community setting including the animals’ providence with natural food sources (Zostera marina and Fucus vesiculosus). Our results demonstrate that a simulated heat wave results in decreased immunocompetence of the mesograzer Idotea baltica, in particular a drop of phagocytosis by 50%. This suggests that global change has the potential to significantly affect host–parasite interactions