Wnt signalling in the articular cartilage: A matter of balance.

Degradation of the articular cartilage is a hallmark of osteoarthritis, a progressive and chronic musculoskeletal condition, affecting millions of people worldwide. The activation of several signalling cascades is altered during disease development: among them, the Wnt signalling plays a pivotal role in the maintenance of tissue homeostasis. Increasing evidence is showing that its activation needs to be maintained within a certain range to avoid the triggering of degenerative mechanisms. In this review, we summarise our current knowledge about how a balanced activation of the Wnt signalling is maintained in the articular cartilage, with a particular focus on receptor-mediated mechanisms.

A call for citizen science in pandemic preparedness and response: beyond data collection.

The COVID-19 pandemic has underlined the need to partner with the community in pandemic preparedness and response in order to enable trust-building among stakeholders, which is key in pandemic management. Citizen science, defined here as a practice of public participation and collaboration in all aspects of scientific research to increase knowledge and build trust with governments and researchers, is a crucial approach to promoting community engagement. By harnessing the potential of digitally enabled citizen science, one could translate data into accessible, comprehensible and actionable outputs at the population level. The application of citizen science in health has grown over the years, but most of these approaches remain at the level of participatory data collection. This narrative review examines citizen science approaches in participatory data generation, modelling and visualisation, and calls for truly participatory and co-creation approaches across all domains of pandemic preparedness and response. Further research is needed to identify approaches that optimally generate short-term and long-term value for communities participating in population health. Feasible, sustainable and contextualised citizen science approaches that meaningfully engage affected communities for the long-term will need to be inclusive of all populations and their cultures, comprehensive of all domains, digitally enabled and viewed as a key component to allow trust-building among the stakeholders. The impact of COVID-19 on people's lives has created an opportune time to advance people's agency in science, particularly in pandemic preparedness and response.

Conceptual and normative approaches to AI governance for a global digital ecosystem supportive of the UN Sustainable Development Goals (SDGs).

AI governance is like one of those mythical creatures that everyone speaks of but which no one has seen. Sometimes, it is reduced to a list of shared principles such as transparency, non-discrimination, and sustainability; at other times, it is conflated with specific mechanisms for certification of algorithmic solutions or ways to protect the privacy of personal data. We suggest a conceptual and normative approach to AI governance in the context of a global digital public goods ecosystem to enable progress on the UN Sustainable Development Goals (SDGs). Conceptually, we propose rooting this approach in the human capability concept-what people are able to do and to be, and in a layered governance framework connecting the local to the global. Normatively, we suggest the following six irreducibles: a. human rights first; b. multi-stakeholder smart regulation; c. privacy and protection of personal data; d. a holistic approach to data use captured by the 3Ms-misuse of data, missed use of data and missing data; e. global collaboration ('digital cooperation'); f. basing governance more in practice, in particular, thinking separately and together about data and algorithms. Throughout the article, we use examples from the health domain particularly in the current context of the Covid-19 pandemic. We conclude by arguing that taking a distributed but coordinated global digital commons approach to the governance of AI is the best guarantee of citizen-centered and societally beneficial use of digital technologies for the SDGs.

Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction.

Targeting G protein-coupled receptors (GPCRs) through allosteric sites offers advantages over orthosteric sites in identifying drugs with increased selectivity and potentially reduced side effects. In this study, we developed a probe confined dynamic mapping protocol that allows the prediction of allosteric sites at both the GPCR extracellular and intracellular sides, as well as at the receptor-lipid interface. The applied harmonic wall potential enhanced sampling of probe molecules in a selected area of a GPCR while preventing membrane distortion in molecular dynamics simulations. The specific probes derived from GPCR allosteric ligand structures performed better in allosteric site mapping compared to commonly used cosolvents. The M2 muscarinic, ß2 adrenergic, and P2Y1 purinergic receptors were selected for the protocol's retrospective validation. The protocol was next validated prospectively to locate the binding site of [5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl]-(4-fluoro-1H-indol-1-yl)methanone at the D2 dopamine receptor, and subsequent mutagenesis confirmed the prediction. The protocol provides fast and efficient prediction of key amino acid residues surrounding allosteric sites in membrane proteins and facilitates the structure-based design of allosteric modulators.

Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Pure red cell aplasia and seronegative myasthenia gravis in association with thymoma.

Pure red cell aplasia is an uncommon paraneoplastic syndrome of thymoma. Myasthenia gravis is the most common paraneoplastic syndrome associated with thymoma. We present a case of a 79-year-old Pacific Islander female who presented with profound fatigue, generalized weakness, significant unintentional weight loss, bilateral ptosis, and anemia. The bone marrow biopsy showed near absence of erythroid elements consistent with pure red cell aplasia. Ice-pack test was consistent with myasthenia gravis and computed tomography of the chest demonstrated a thymoma. The patient was started on immunosuppressive treatment with prednisone and cyclosporine. This case demonstrates a rare combination of paraneoplastic manifestations of thymoma: pure red cell aplasia and myasthenia gravis.

IgG4-Related Diseases-Continues To Be a Cancer Mimicker.

Immunoglobulin G4-related disease (IgG4-RD) is a chronic multisystem immune-mediated disease. Histologically, it presents as infiltration with IgG4-secreting plasma cells affecting many organs such as the pancreas, lacrimal glands, salivary glands, kidneys, and arteries, resulting in chronic fibrosis and scarring within the tissue which over time forms into a mass. It is a slow-growing process that usually remains indolent until it causes a mass effect or tissue infiltration. Our patient was found to have a pancreatic mass on imaging concerning pancreatic neoplastic lesions. He subsequently underwent biopsy for histology/pathology and IgG4 levels, which led to our diagnosis of IgG4-RD. Imaging, blood tests, and, most importantly, histopathological features of the involved organ are important in determining the diagnosis. This is important as a treatment plan will be based on the given diagnosis, and patients with IgG4-RD respond very well to systemic steroid therapy.

A rare case of pulmonary Kaposi sarcoma presented with respiratory failure.

Kaposi sarcoma (KS) is the most commonly diagnosed malignancy in HIV-infected patients. With new treatments, incidence and severity of KS have significantly decreased. A 57-year-old African American male with medical history of AIDS presented with progressively worsening cough, shortness of breath, fever, night sweats, and 60 lb weight loss. On physical examination, he had diffused dark purple skin lesions and decreased air entry in the right lower lung fields. Chest x-ray and subsequent chest computed tomography (CT) showed moderate right lung pleural effusion with scattered bilateral diffuse infiltrates. The patient's absolute CD4 count was 27 cells/microliter. Thoracentesis was negative for infection or malignancy. He was started on chemotherapy paclitaxel along with HAART for extensive pulmonary KS. Since starting the treatment, his condition has significantly improved with near complete resolution of the pleural effusion, oral, and skin lesions. In conclusion, the diagnosis of AIDS-related pulmonary KS is often clinical, typically based on the presence of mucocutaneous disease and compatible features on CT chest. The differential diagnosis of pulmonary KS is broad. A detailed evaluation should exclude an infectious etiology or other tumors. Chemotherapy along with HAART can be used for treatment of severe pulmonary KS.

Life-threatening hemorrhage from acquired hemophilia A as a presenting manifestation of prostate cancer.

Acquired factor VIII deficiency (acquired hemophilia A) is a rare condition characterized by the acquisition of autoantibodies that affect the clotting activity of factor VIII (fVIII). The most common manifestation in affected patients is a hemorrhagic diathesis. This disorder is associated with autoimmune diseases, pregnancy, postpartum period, drugs, and malignancy. Management of this condition begins with attempts to arrest an acute bleed based on the site and severity of bleeding and inhibitor titer. The next priority is eradication of the fVIII antibodies using immunosuppressive therapies. We report the case of a 66-year-old male who presented with spontaneous right thigh hematoma with prolonged activated partial prothrombin time and normal prothrombin time. Mixing studies confirmed the presence of an inhibitor. Further investigation for the underlying etiology of acquired hemophilia A leads to diagnosis of prostate cancer. Treatment consisted of bypassing agents including activated factor VII and activated prothrombin plasma concentrate to arrest the bleeding. Steroids and cyclophosphamide were added to suppress the fVIII inhibitors. Concomitant treatment of locally advanced prostate cancer with chemotherapy confirmed the eradication of the inhibitors. To our knowledge, this is the first reported case of prostate cancer diagnosed and treated simultaneously with acquired hemophilia A resulting in favorable patient outcome.

Development of a finite element human head model partially validated with thirty five experimental cases.

This study is aimed to develop a high quality, extensively validated finite element (FE) human head model for enhanced head injury prediction and prevention. The geometry of the model was based on computed tomography (CT) and magnetic resonance imaging scans of an adult male who has the average height and weight of an American. A feature-based multiblock technique was adopted to develop hexahedral brain meshes including the cerebrum, cerebellum, brainstem, corpus callosum, ventricles, and thalamus. Conventional meshing methods were used to create the bridging veins, cerebrospinal fluid, skull, facial bones, flesh, skin, and membranes-including falx, tentorium, pia, arachnoid, and dura. The head model has 270,552 elements in total. Thirty five loading cases were selected from a range of experimental head impacts to check the robustness of the model predictions based on responses including the brain pressure, relative skull-brain motion, skull response, and facial response. The brain pressure was validated against intracranial pressure data reported by Nahum et al. (1977, "Intracranial Pressure Dynamics During Head Impact," Proc. 21st Stapp Car Crash Conference, SAE Technical Paper No. 770922) and Trosseille et al. (1992, "Development of a F.E.M. of the Human Head According to a Specific Test Protocol," Proc. 36th Stapp Car Crash Conference, SAE Technical Paper No. 922527). The brain motion was validated against brain displacements under sagittal, coronal, and horizontal blunt impacts performed by Hardy et al. (2001, "Investigation of Head Injury Mechanisms Using Neutral Density Technology and High-Speed Biplanar X-Ray," Stapp Car Crash Journal, 45, pp. 337-368; and 2007, "A Study of the Response of the Human Cadaver Head to Impact," Stapp Car Crash Journal, 51, pp. 17-80). The facial bone responses were validated under nasal impact (Nyquist et al. 1986, "Facial Impact Tolerance and Response," Proc. 30th Stapp Car Crash Conference, SAE Technical Paper No. 861896), zygoma and maxilla impact (Allsop et al. 1988, "Facial Impact Response - A Comparison of the Hybrid III Dummy and Human Cadaver," Proc. 32nd Stapp Car Crash Conference, SAE Technical Paper No. 881719)]. The skull bones were validated under frontal angled impact, vertical impact, and occipital impact (Yoganandan et al. 1995, "Biomechanics of Skull Fracture," J Neurotrauma, 12(4), pp. 659-668) and frontal horizontal impact (Hodgson et al. 1970, "Fracture Behavior of the Skull Frontal Bone Against Cylindrical Surfaces," 14th Stapp Car Crash Conference, SAE International, Warrendale, PA). The FE head model was further used to study injury mechanisms and tolerances for brain contusion (Nahum et al. 1976, "An Experimental Model for Closed Head Impact Injury," 20th Stapp Car Crash Conference, SAE International, Warrendale, PA). Studies from 35 loading cases demonstrated that the FE head model could predict head responses which were comparable to experimental measurements in terms of pattern, peak values, or time histories. Furthermore, tissue-level injury tolerances were proposed. A maximum principal strain of 0.42% was adopted for skull cortical layer fracture and maximum principal stress of 20 MPa was used for skull diploë layer fracture. Additionally, a plastic strain threshold of 1.2% was used for facial bone fracture. For brain contusion, 277 kPa of brain pressure was calculated from reconstruction of one contusion case.

Does an elevated serum vitamin B(12) level mask actual vitamin B(12) deficiency in myeloproliferative disorders?

Elevation of the methylmalonic acid level is a sensitive marker of vitamin B(12) deficiency. Our cross-sectional observational study of 33 patients with myeloproliferative disorders found that 9 patients, 27.27% had occult deficiency despite having normal to elevated serum vitamin B(12) levels. Early detection of vitamin B(12) deficiency by using the methylmalonic acid measurement may prevent significant neurologic and hematologic complications in patients with myeloproliferative disorders. In patients with myeloproliferative disorders, normal to high serum vitamin B(12) concentrations have often been reported. The primary objective of this study was to determine whether normal or elevated serum vitamin B(12) levels in myeloproliferative disorders might actually mask the true underlying vitamin B(12) deficiency in some patients. Thirty-three patients (12 men, 21 women; mean age, 70.55 years [range, 37-90 years]) with polycythemia vera (n = 13), essential thrombocythemia (n = 12), chronic myelogenous leukemia (n = 5), and idiopathic myelofibrosis (IMF) (n = 3) were accrued over a period of 1 year, from March 2009 to February 2010. From all of the subjects, serum vitamin B(12) level, methylmalonic acid level, a basic complete blood cell count panel, and liver and renal function tests were obtained. Normal to elevated serum vitamin B(12) levels were recorded in all the patients. However, elevated serum methylmalonic acid levels were found in 9 (27.27%) patients, with a prevalence of 2 patients with polycythemia vera, 23% in polycythemia vera, 4 patients with essential thrombocythemia, 33.3% in essential thrombocythemia, 1 patient with chronic myelogenous leukemia, 20% in chronic myelogenous leukemia, and 2 patients with idiopathic myelofibrosis, 66.7% in IMF. Our data suggest that 27.27% of the total enrolled patients had occult vitamin B(12) deficiency despite normal to elevated vitamin B(12) levels on regular serum vitamin B(12) testing.

A patient with hemoptysis and renal failure.

Pulmonary-renal syndrome is a medical emergency; etiology of which has broad differential diagnosis. Delay in both diagnosis and initiation of management may result in end-organ damage. Management decisions may have to be empiric till a rapid, definitive tissue diagnosis is established. We present such a case where prompt recognition and immediate treatment was initiated, although the patient sustained irreversible end-organ damage. The case also highlights the need to interpret the kidney biopsy data (namely, immunofluroscence findings) in the context of clinical presentation.

A 9-year survival analysis of the presternal Missouri swan-neck catheter.

Peritoneal dialysis (PD) catheter survival is challenging because of infection and malfunction. The swan-neck presternal catheter has a coiled intra-abdominal segment with a bead and a flanged cuff at the peritoneum; a titanium adapter joins the abdominal segment to the upper segment. The upper segment has two cuffs, one on either side of the presternal swan-neck segment. The present study evaluated the survival of Missouri presternal swan-neck PD catheters implanted at the University of Missouri--Columbia and followed at Dialysis Clinics, Inc., through 2006. Catheter type and insertion date were prospectively recorded. Survival was defined as the interval from insertion date to date of removal, censoring, or analysis. Catheters were censored for transplant, death, or transfer to another unit. A total of 131 presternal catheters were implanted in 129 patients. Mean patient age was 60.9 +/- 16.3 years. No catheters were removed during the first 3 months for either infection or technical problems. One catheter was removed at 6 months for malposition and another at 2 years for an external leak; all other catheter losses were attributable to peritonitis. Cumulative catheter survival was 93.5%, 82.5%, 63.9%, and 60.0% at 1, 2, 3, and 4 years respectively. The mean observation period was 19. 7 +/- 17.8 months, and the longest catheter survival was 87.5 months. New episodes of peritonitis were 91 in number, a rate of 1 episode per 28 patient-months. Although catheter survival exceeded the recommendation of better than 80% at 1 year, we noted a trend toward lower catheter survival and a higher peritonitis rate than were reported earlier in this series with a smaller number of catheters. That trend is partly explained by repeated episodes of peritonitis in 11 catheters; 8.5% of the patients experienced 40% of the peritonitis episodes.