Glassgriffith7565
Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1β and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation. The obtained xStAx-VHLL sustained β-catenin degradation and manifested strong inhibition of Wnt signaling in cancer cells and in APC -/- organoids. Furthermore, xStAx-VHLL could effectively restrain tumor formation in BALB/C nude mice, and diminish the existing tumors in APC min/+ mice. More importantly, xStAx-VHLL could potently inhibit the survival of colorectal cancer patient-derived organoids. These findings suggest that xStAx-VHLL exhibits the ability of cancer prevention and cure, highlighting the potential of β-catenin degrader PROTACs as a new class of promising anticancer agent.Hyperuricemia, which has been considered as a cause of gout and nephrolithiasis has recently been suggested to be associated with hypertension, coronary heart disease, heart failure, atrial fibrillation, insulin resistance, and nonalcoholic fatty liver disease. Several clinical and experimental studies have supported uric acid (UA) as an independent risk factor for predicting disease development along with the traditional risk factors. The mechanism by which UA causes cardiometabolic disease has not been fully elucidated to date; however, it has been explained by several hypotheses such as oxidative stress, reduced nitric oxide bioavailability, inflammation, endothelial dysfunction, and so on. Although evidence of the preventive and therapeutic effects of UA lowering therapy on cardiometabolic diseases is still insufficient, it is expected to be considered as a new treatment strategy for such diseases through additional, carefully designed, large-scale clinical studies.[This corrects the article DOI 10.1186/s40851-020-00158-4.].Background Insertional Achilles tendinopathy is well known to be difficult to treat, especially when there is intra-tendinous bone pathology. This study is a case series on patients with chronic insertional Achilles tendon pain and major intra-tendinous bony pathology together with bursa and tendon pathology, treated with excision of the subcutaneous bursa alone. Methods Eleven patients (eight men and three women) with a mean age of 44 years (range 24-62) and a chronic (>6 months) painful condition from altogether 15 Achilles tendon insertions were included. In all patients, ultrasound examination showed intra-tendinous bone pathology together with pathology in the tendon and subcutaneous bursa, and all were surgically treated with an open excision of the whole subcutaneous bursa alone. This was followed by full weight-bearing walking in a shoe with open heel for 6 weeks. Results At follow-up 21 (median, range 12-108) months after surgery, 9/11 patients (12/15 tendons) were satisfied with the result of the operation and 10/11 (13/15 tendons) were back in their previous sport and recreational activities. The median VISA-A score had improved from 41 (range 0-52) to 91 (range 33-100) (p less then 0.01). Conclusion In patients with chronic painful insertional Achilles tendinopathy with intra-tendinous bone pathology, tendon and bursa pathology, open removal of the subcutaneous bursa alone can relieve the pain and allow for Achilles tendon loading activities. The results in this case series highlight the need for more studies on the pain mechanisms in insertional Achilles tendinopathy and the need for randomised studies to strengthen the conclusions. Level of evidence IV Case series.Background Charcot neuroarthropathy is a complication of peripheral neuropathy associated with diabetes which most frequently affects the lower limb. It can cause fractures and dislocations within the foot, which may progress to deformity and ulceration. Recommended treatment is immobilisation and offloading, with a below knee non-removable cast or boot. Duration of treatment varies from six months to more than 1 year. Small observational studies suggest that repeated assessment with magnetic resonance imaging improves decision-making about when to stop treatment, but this has not been tested in clinical trials. This study aims to explore the feasibility of using serial magnetic resonance imaging without contrast in the monitoring of Charcot neuroarthropathy to reduce duration of immobilisation of the foot. A nested qualitative study aims to explore participants' lived experience of Charcot neuroarthropathy and of taking part in the feasibility study. Methods We will undertake a two-arm, open study and randome analysed using thematic analysis. Discussion The study will inform the decision whether to proceed to a full-scale trial. It will also allow deeper understanding of the lived experience of Charcot neuroarthropathy, and factors that contribute to engagement in management and contribute to the development of more effective patient-centred strategies. Trial registration ISRCTN, ISRCTN74101606. Registered on 6 November 2017.Background Approximately, half of stroke survivors experience fatigue. Fatigue may persist for many months and interferes with participation in everyday activities and has a negative impact on social and family relationships, return to work, and quality of life. Fatigue is among the top 10 priorities for 'Life after Stroke' research for stroke survivors, carers, and clinicians. We previously developed and tested in a small uncontrolled pilot study a manualised, clinical psychologist-delivered, face-to-face intervention, informed by cognitive behavioural therapy (CBT). We then adapted it for delivery by trained therapists via telephone. We now aim to test the feasibility of this approach in a parallel group, randomised controlled feasibility trial (Post Stroke Intervention Trial In Fatigue, POSITIF). Methods/design POSITIF aims to recruit 75 stroke survivors between 3 months and 2 years post-stroke who would like treatment for their fatigue. Eligible consenting stroke survivors will be randomised to either a 7ty and design of a future adequately powered randomised controlled trial. Trial registration ClinicalTrials.gov, NCT03551327. Registered on 11 June 2018.Background Anxiety is highly prevalent in people diagnosed with bipolar disorder (BD), and can persist between acute episodes of mania and depression. Recent studies indicate that people with BD are prone to experiencing frequent, intrusive and emotional mental images which further fuel their levels of anxiety and mood instability. These intrusive emotional mental images represent a specific target for treatment for this disorder with the potential to reduce anxiety and improve mood stability. A new brief structured psychological intervention for BD called Imagery Based Emotion Regulation (IBER) has been developed, which translates experimental work in the area of imagery and emotion into a skills training programme to improve the regulation of intrusive and distressing emotional mental images in BD. A feasibility trial is required in order to assess whether a full randomised controlled trial is indicated in order to evaluate this approach. Methods The design is a two-arm feasibility randomised controlled tri on October 16, 2018. 10.1186/ISRCTN16321795.Background Nutritional status is the key concern among the people living with HIV but this issue has been failed to be prioritized in HIV strategic plan of Nepal. This study aims to assess the nutritional status among people living with HIV and determine their associated factors. Methods A hospital based cross-sectional study was conducted where 350 people living with HIV attending the ART clinic were selected using systematic random sampling technique. Nutritional status among people living with HIV was assessed through anthropometry, body mass index; Underweight (body mass index 23 kg/m2). HIV related clinical factors such CD4 count, WHO stage, opportunistic infection, antiretroviral therapy regimen etc. were collected from the medical records. Socio-demographic data were collected using pretested structured questionnaire through interview technique. MDL-800 Sirtuin activator Multiple linear regression method was employed to determine the association between different independent factors and body mass index score. Results The prevalence of underweight was found to be 18.3% (95% CI 14.3-22.6). Most of the study participants were overweight/obese (39.1%). After subjection to multiple linear regression analysis, it was found that age, being male, being married, being in business occupation, smoking, hemoglobin level and antiretroviral therapy duration were significantly associated with body mass index score. Majority of the participants in our study lacked diversified food (62.3%). Conclusion Overweight/obesity is an emerging problem among people living with HIV. This group of participants should be screened for the presence of non-communicable disease. This study also highlights the importance of nutritional program being an integral part of HIV/AIDS continuum of care. Therefore, an effort should be made to address the burden of malnutrition by addressing the identified determinants.[This retracts the article DOI 10.1186/s40748-019-0111-y.].Primary microcephaly (MCPH) is a genetically heterogeneous disorder showing an autosomal recessive mode of inheritance. Patients with MCPH present head circumference values two or three standard deviations (SDs) significantly below the mean for age- and sex-matched populations. MCPH is associated with a nonprogressive mild to severe intellectual disability, with normal brain structure in most patients, or with a small brain and gyri without visceral malformations. We present the case of an adult patient born from Argentinian nonconsanguineous healthy parents. He had a head circumference >5 SD below the mean, cerebral neuroimaging showing hypoplasia of the corpus callosum, bilateral migration disorder with heterotopia of the sylvian fissure and colpocephaly. The patient was compound heterozygous for pathogenic variants in the CENPJ gene (c.289dupA inherited from his mother and c.1132 C > T inherited from his father). Our patient represents an uncommon situation for the usual known context of CENPJ and MCPH, including family origin (Argentinian), pedigree (nonconsanguineous), and genotype (a compound heterozygous case with two variants predicting a truncated protein).