Incongruence between Clinicians' Assessment and Self-Reported Functioning Is Related to Psychopathology among Patients Diagnosed with Gastrointestinal Disorders

In a previous exploratory study we observed no relevant differences in psychopathology, personality and functioning between inpatients diagnosed with gastrointestinal motor disorders (GMDs) or functional gastrointestinal disorders (FGDs)[1]. However, we observed higher levels of incongruence between clinicianassessed performance status and patients' self-reported levels of functioning among patients diagnosed with FGDs. Likewise, research in other medical conditions has shown incongruence between self-reported and clinician-reported or objective measures [2]. Furthermore, in a study on chronic depression, the authors found that discrepancies between patients' and physicians' assessments of medical comorbidities were related to higher levels of depressive symptomatology [3]. In this line, the aim of this study was to explore whether the inconsistencies between clinician-assessed and patient self-reported levels of functioning could be related to psychopathology among patients admitted for evaluation of gastrointestinal motility

The role of incongruence between the perceived functioning by patients and clinicians in the detection of psychological distress among functional and motor digestive disorders

Objectives Previous research on gastrointestinal and other medical conditions has shown the presence of incongruence between self- and clinician-reported functioning and its relation with psychopathology. The main objective of this study was to test whether inconsistencies between clinician- and self-assessed functionality can be used to detect psychopathology among patients diagnosed of motor or functional gastrointestinal disorders. Methods One hundred and three patients from a gastroenterology inpatient unit were included in this study. All patients underwent clinical assessment, including intestinal manometry, Rome III criteria for functional gastrointestinal disorders, and psychological and psychiatric evaluation. Patients with suspected gastroparesis underwent a scintigraphic gastric emptying test. Definitive diagnoses were made at discharge. Results Patients with higher levels of incongruence differed in various sociodemographic (age, educational level, work activity and having children) and psychopathological (all SCL-90-R subscales except anxiety and hostility) characteristics. Using general lineal models, incongruence was found to be the variable with stronger relations with psychopathology even when controlling for diagnosis. Interactions were found between incongruence and diagnosis reflecting a pattern in which patients with functional disorders whose subjective evaluation of functioning is not congruent with that of the clinician, have higher levels of psychopathology than patients with motor disorders. Conclusions Incongruence between clinician and self-reported functionality seems to be related to higher levels of psychopathology in patients with functional disorders. These findings underscore the need for routine psychosocial assessment among these patients. Gastroenterologists could use the concept of incongruence and its clinical implications, as a screening tool for psychopathology, facilitating consultation-liaison processes

RTP801/REDD1: a stress coping regulator that turns into a troublemaker in neurodegenerative disorders

Mechanistic target of Rapamycin (mTOR) pathway regulates essential processes directed to preserve cellular homeostasis, such as cell growth, proliferation, survival, protein synthesis and autophagy. Importantly, mTOR pathway deregulation has been related to many diseases. Indeed, it has become a hallmark in neurodegenerative disorders, since a fine-tuned regulation of mTOR activities is crucial for neuron function and survival. RTP801/REDD1/Dig2 has become one of the most puzzling regulators of mTOR. Although the mechanism is not completely understood, RTP801 inactivates mTOR and Akt via the tuberous sclerosis complex (TSC1/TSC2) in many cellular contexts. Intriguingly, RTP801 protects dividing cells from hypoxia or H2O2-induced apoptosis, while it sensitizes differentiated cells to stress. Based on experimental models of Parkinson's disease (PD), it has been proposed that at early stages of the disease, stress-induced RTP801 upregulation contributes to mTOR repression, in an attempt to maintain cell function and viability. However, if RTP801 elevation is sustained, it leads to neuron cell death by a sequential inhibition of mTOR and Akt. Here, we will review RTP801 deregulation of mTOR in a context of PD and other neurodegenerative disorders

Anatomical landmarks localization for capsule endoscopy studies

Wireless Capsule Endoscopy is a medical procedure that uses a small, wireless camera to capture images of the inside of the digestive tract. The identification of the entrance and exit of the small bowel and of the large intestine is one of the first tasks that need to be accomplished to read a video. This paper addresses the design of a clinical decision support tool to detect these anatomical landmarks. We have developed a system based on deep learning that combines images, timestamps, and motion data to achieve state-of-the-art results. Our method does not only classify the images as being inside or outside the studied organs, but it is also able to identify the entrance and exit frames. The experiments performed with three different datasets (one public and two private) show that our system is able to approximate the landmarks while achieving high accuracy on the classification problem (inside/outside of the organ). When comparing the entrance and exit of the studied organs, the distance between predicted and real landmarks is reduced from 1.5 to 10 times with respect to previous state-of-the-art methods

Synaptic RTP801 contributes to motor-learning dysfunction in Huntington's disease

RTP801/REDD1 is a stress-responsive protein that mediates mutant huntingtin (mhtt) toxicity in cellular models and is up regulated in Huntington's disease (HD) patients' putamen. Here, we investigated whether RTP801 is involved in motor impairment in HD by affecting striatal synaptic plasticity. To explore this hypothesis, ectopic mhtt was over expressed in cultured rat primary neurons. Moreover, the protein levels of RTP801 were assessed in homogenates and crude synaptic fractions from human postmortem HD brains and mouse models of HD. Finally, striatal RTP801 expression was knocked down with adeno-associated viral particles containing a shRNA in the R6/1 mouse model of HD and motor learning was then tested. Ectopic mhtt elevated RTP801 in synapses of cultured neurons. RTP801 was also up regulated in striatal synapses from HD patients and mouse models. Knocking down RTP801 in the R6/1 mouse striatum prevented motor-learning impairment. RTP801 silencing normalized the Ser473 Akt hyperphosphorylation by downregulating Rictor and it induced synaptic elevation of calcium permeable GluA1 subunit and TrkB receptor levels, suggesting an enhancement in synaptic plasticity. These results indicate that mhtt-induced RTP801 mediates motor dysfunction in a HD murine model, revealing a potential role in the human disease. These findings open a new therapeutic framework focused on the RTP801/Akt/mTOR axis

Increased levels of rictor prevent mutant huntingtin-induced neuronal degeneration

Rictor associates with mTOR to form the mTORC2 complex, which activity regulates neuronal function and survival. Neurodegenerative diseases are characterized by the presence of neuronal dysfunction and cell death in specific brain regions such as for example Huntington's disease (HD), which is characterized by the loss of striatal projection neurons leading to motor dysfunction. Although HD is caused by the expression of mutant huntingtin, cell death occurs gradually suggesting that neurons have the capability to activate compensatory mechanisms to deal with neuronal dysfunction and later cell death. Here, we analyzed whether mTORC2 activity could be altered by the presence of mutant huntingtin. We observed that Rictor levels are specifically increased in the striatum of HD mouse models and in the putamen of HD patients. Rictor-mTOR interaction and the phosphorylation levels of Akt, one of the targets of the mTORC2 complex, were increased in the striatum of the R6/1 mouse model of HD suggesting increased mTORC2 signaling. Interestingly, acute downregulation of Rictor in striatal cells in vitro reduced mTORC2 activity, as shown by reduced levels of phospho-Akt, and increased mutant huntingtin-induced cell death. Accordingly, overexpression of Rictor increased mTORC2 activity counteracting cell death. Furthermore, normalization of endogenous Rictor levels in the striatum of R6/1 mouse worsened motor symptoms suggesting an induction of neuronal dysfunction. In conclusion, our results suggest that increased Rictor striatal levels could counteract neuronal dysfunction induced by mutant huntingtin

RTP801 is involved in mutant huntingtin-induced cell death

RTP801 expression is induced by cellular stress and has a pro-apoptotic function in non-proliferating differentiated cells such as neurons. In several neurodegenerative disorders, including Parkinson's disease and Alzheimer's disease, elevated levels of RTP801 have been observed, which suggests a role for RTP801 in neuronal death. Neuronal death is also a pathological hallmark in Huntington's disease (HD), an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Currently, the exact mechanisms underlying mutant huntingtin (mhtt)-induced toxicity are still unclear. Here, we investigated whether RTP801 is involved in (mhtt)-induced cell death. Ectopic exon-1 mhtt elevated RTP801 mRNA and protein levels in nerve growth factor (NGF)-differentiated PC12 cells and in rat primary cortical neurons. In neuronal PC12 cells, mhtt also contributed to RTP801 protein elevation by reducing its proteasomal degradation rate, in addition to promoting RTP801 gene expression. Interestingly, silencing RTP801 expression with short hairpin RNAs (shRNAs) blocked mhtt-induced cell death in NGF-differentiated PC12 cells. However, RTP801 protein levels were not altered in the striatum of Hdh(Q7/Q111) and R6/1 mice, two HD models that display motor deficits but not neuronal death. Importantly, RTP801 protein levels were elevated in both neural telencephalic progenitors differentiated from HD patient-derived induced pluripotent stem cells and in the putamen and cerebellum of human HD postmortem brains. Taken together, our results suggest that RTP801 is a novel downstream effector of mhtt-induced toxicity and that it may be relevant to the human disease

RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer's disease

We found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD

Rtp801/redd1 is involved in neuroinflammation and modulates cognitive dysfunction in huntingtons disease

RTP801/REDD1 is a stress-regulated protein whose levels are increased in several neurodegenerative diseases such as Parkinson's, Alzheimer's, and Huntington's diseases (HD). RTP801 downregulation ameliorates behavioral abnormalities in several mouse models of these disorders. In HD, RTP801 mediates mutant huntingtin (mhtt) toxicity in in vitro models and its levels are increased in human iPSCs, human postmortem putamen samples, and in striatal synaptosomes from mouse models of the disease. Here, we investigated the role of RTP801 in the hippocampal pathophysiology of HD. We found that RTP801 levels are increased in the hippocampus of HD patients in correlation with gliosis markers. Although RTP801 expression is not altered in the hippocampus of the R6/1 mouse model of HD, neuronal RTP801 silencing in the dorsal hippocampus with shRNA containing AAV particles ameliorates cognitive alterations. This recovery is associated with a partial rescue of synaptic markers and with a reduction in inflammatory events, especially microgliosis. Altogether, our results indicate that RTP801 could be a marker of hippocampal neuroinflammation in HD patients and a promising therapeutic target of the disease

Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity

Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron-to-neuron communication via EVs is still not well understood. Here, we provide evidence that primary neurons uptake neuron-derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron-derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB-signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient-deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration