Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers

Reward and punishment learning in daily life:A replication study

Day-to-day experiences are accompanied by feelings of Positive Affect (PA) and Negative Affect (NA). Implicitly, without conscious processing, individuals learn about the reward and punishment value of each context and activity. These associative learning processes, in turn, affect the probability that individuals will re-engage in such activities or seek out that context. So far, implicit learning processes are almost exclusively investigated in controlled laboratory settings and not in daily life. Here we aimed to replicate the first study that investigated implicit learning processes in real life, by means of the Experience Sampling Method (ESM). That is, using an experience-sampling study with 90 time points (three measurements over 30 days), we prospectively measured time spent in social company and amount of physical activity as well as PA and NA in the daily lives of 18-24-year-old young adults (n = 69 with anhedonia, n = 69 without anhedonia). Multilevel analyses showed a punishment learning effect with regard to time spent in company of friends, but not a reward learning effect. Neither reward nor punishment learning effects were found with regard to physical activity. Our study shows promising results for future research on implicit learning processes in daily life, with the proviso of careful consideration of the timescale used. Shortterm retrospective ESM design with beeps approximately six hours apart may suffer from mismatch noise that hampers accurate detection of associative learning effects over time

Splint: the efficacy of orthotic management in rest to prevent equinus in children with cerebral palsy, a randomised controlled trial

<p>Abstract</p> <p>Background</p> <p>Range of motion deficits of the lower extremity occur in about the half of the children with spastic cerebral palsy (CP). Over time, these impairments can cause joint deformities and deviations in the children's gait pattern, leading to limitations in moblity. Preventing a loss of range of motion is important in order to reduce secondary activity limitations and joint deformities. Sustained muscle stretch, imposed by orthotic management in rest, might be an effective method of preventing a decrease in range of motion. However, no controlled study has been performed.</p> <p>Methods</p> <p>A single blind randomised controlled trial will be performed in 66 children with spastic CP, divided over three groups with each 22 participants. Two groups will be treated for 1 year with orthoses to prevent a decrease in range of motion in the ankle (either with static or dynamic knee-ankle-foot-orthoses) and a third group will be included as a control group and will receive usual care (physical therapy, manual stretching). Measurements will be performed at baseline and at 3, 6, 9 and 12 months after treatment allocation. The primary outcome measure will be ankle dorsiflexion at full knee extension, measured with a custom designed hand held dynamometer. Secondary outcome measures will be i) ankle and knee flexion during gait and ii) gross motor function. Furthermore, to gain more insight in the working mechanism of the orthotic management in rest, morphological parameters like achilles tendon length, muscle belly length, muscle fascicle length, muscle physiological cross sectional area length and fascicle pennation angle will be measured in a subgroup of 18 participants using a 3D imaging technique.</p> <p>Discussion</p> <p>This randomised controlled trial will provide more insight into the efficacy of orthotic management in rest and the working mechanisms behind this treatment. The results of this study could lead to improved treatments.</p> <p>Trial Registration Number</p> <p>Nederlands Trial Register <a href="http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2091">NTR2091</a></p

The copper-transporting capacity of ATP7A mutants associated with Menkes disease is ameliorated by COMMD1 as a result of improved protein expression

Menkes disease (MD) is an X-linked recessive disorder characterized by copper deficiency resulting in a diminished function of copper-dependent enzymes. Most MD patients die in early childhood, although mild forms of MD have also been described. A diversity of mutations in the gene encoding of the Golgi-resident copper-transporting P1B-type ATPase ATP7A underlies MD. To elucidate the molecular consequences of the ATP7A mutations, various mutations in ATP7A associated with distinct phenotypes of MD (L873R, C1000R, N1304S, and A1362D) were analyzed in detail. All mutants studied displayed changes in protein expression and intracellular localization parallel to a dramatic decline in their copper-transporting capacity compared to ATP7A the wild-type. We restored these observed defects in ATP7A mutant proteins by culturing the cells at 30°C, which improves the quality of protein folding, similar to that which as has recently has been demonstrated for misfolded ATP7B, a copper transporter homologous to ATP7A. Further, the effect of the canine copper toxicosis protein COMMD1 on ATP7A function was examined as COMMD1 has been shown to regulate the proteolysis of ATP7B proteins. Interestingly, in addition to adjusted growth temperature, binding of COMMD1 partially restored the expression, subcellular localization, and copper-exporting activities of the ATP7A mutants. However, no effect of pharmacological chaperones was observed. Together, the presented data might provide a new direction for developing therapies to improve the residual exporting activity of unstable ATP7A mutant proteins, and suggests a potential role for COMMD1 in this process

Differential family and peer environmental factors are related to severity and comorbidity in childresn with ADHD

Contains fulltext : 70260.pdf (publisher's version ) (Closed access)Behavioral genetic studies imply that salient environmental influences operate within families, making siblings in a family different rather than similar. This study is the first one to examine differential sibling experiences (as measured with the Sibling Inventory of Differential Experience) and its effect on behavioral outcomes within ADHD families. Subjects were 45 Dutch ADHD probands and their unaffected siblings (n = 45) aged 10-18 years. ADHD probands and their unaffected siblings reported differences in sibling interaction, parental treatment, and peer characteristics. These nonshared environmental influences were related to both the severity of ADHD symptoms as well as to comorbid problem behaviors. These findings suggest that environmental influences that operate within ADHD families appear relevant to the severity of problem behaviors of ADHD children and their siblings

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (me/cfs) and sickness behavior

It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions