Transforming growth factor-β signaling modifies the hematopoietic acute inflammatory response to drive bone marrow failure

Bone marrow failure syndromes are characterized by ineffective hematopoiesis due to impaired fitness of hematopoietic stem cells. They can be acquired during bone marrow stress or innate and are associated with driver genetic mutations. Patients with a bone marrow failure syndrome are at higher risk of developing secondary neoplasms, including myelodysplastic syndromes and leukemia. Despite the identification of genetic driver mutations, the hematopoietic presentation of the disease is quite heterogeneous, raising the possibility that non-genetic factors contribute to the pathogenesis of the disease. The role of inflammation has emerged as an important contributing factor, but remains to be understood in detail. In this study, we examined the effect of increased transforming growth factor-b (TGFb) signaling, in combination or not with an acute innate immune challenge using polyinosinc:polycytidilic acid (pIC), on the hematopoietic system without genetic mutations. We show that acute rounds of pIC alone drive a benign age-related myeloid cell expansion and increased TGFb signaling alone causes a modest anemia in old mice. In sharp contrast, increased TGFb signaling plus acute pIC challenge result in chronic pancytopenia, expanded hematopoietic stem and progenitor cell pools, and increased bone marrow dysplasia 3-4 months after stress, which are phenotypes similar to human bone marrow failure syndromes. Mechanistically, this disease phenotype is uniquely associated with increased mitochondrial content, increased reactive oxygen species and enhanced caspase-1 activity. Our results suggest that chronic increased TGFb signaling modifies the memory of an acute immune response to drive bone marrow failure without the need for a preexisting genetic insult. Hence, non-genetic factors in combination are sufficient to drive bone marrow failure.     

Exploring the Risk of Suicide in Real Time on Spanish Twitter: Observational Study

BackgroundSocial media is now a common context wherein people express their feelings in real time. These platforms are increasingly showing their potential to detect the mental health status of the population. Suicide prevention is a global health priority and efforts toward early detection are starting to develop, although there is a need for more robust research.ObjectiveWe aimed to explore the emotional content of Twitter posts in Spanish and their relationships with severity of the risk of suicide at the time of writing the tweet.MethodsTweets containing a specific lexicon relating to suicide were filtered through Twitter''s public application programming interface. Expert psychologists were trained to independently evaluate these tweets. Each tweet was evaluated by 3 experts. Tweets were filtered by experts according to their relevance to the risk of suicide. In the tweets, the experts evaluated: (1) the severity of the general risk of suicide and the risk of suicide at the time of writing the tweet (2) the emotional valence and intensity of 5 basic emotions; (3) relevant personality traits; and (4) other relevant risk variables such as helplessness, desire to escape, perceived social support, and intensity of suicidal ideation. Correlation and multivariate analyses were performed.ResultsOf 2509 tweets, 8.61% (n=216) were considered to indicate suicidality by most experts. Severity of the risk of suicide at the time was correlated with sadness (ρ=0.266; P<.001), joy (ρ=–0.234; P=.001), general risk (ρ=0.908; P<.001), and intensity of suicidal ideation (ρ=0.766; P<.001). The severity of risk at the time of the tweet was significantly higher in people who expressed feelings of defeat and rejection (P=.003), a desire to escape (P<.001), a lack of social support (P=.03), helplessness (P=.001), and daily recurrent thoughts (P=.007). In the multivariate analysis, the intensity of suicide ideation was a predictor for the severity of suicidal risk at the time (β=0.311; P=.001), as well as being a predictor for fear (β=–0.009; P=.01) and emotional valence (β=0.007; P=.009). The model explained 75% of the variance.ConclusionsThese findings suggest that it is possible to identify emotional content and other risk factors in suicidal tweets with a Spanish sample. Emotional analysis and, in particular, the detection of emotional variations may be key for real-time suicide prevention through social media.     

Semisynthesis of rosmanol and its derivatives. Easy access to abietatriene diterpenes isolated from the genus Salvia with biological activities

The known diterpenes rosmanol (3), rosmaquinone (4), 7-methoxyrosmanol (5), 7-ethoxyrosmanol (6), galdosol (7), and epirosmanol (8) have been obtained by partial synthesis from carnosol (2), an abundant natural product present in Salvia species. The physical and spectroscopic data of these semisynthetic diterpenes were identical to those of authentic natural samples and with data reported in the literature. These abietane diterpenes have very interesting biological activities and are present in the genus Salviain low quantities; thus, the semisynthetic approach described here represents an efficient alternative method to obtain these compounds. Additionally, the known diterpene 16-hydroxyrosmanol (10) and a new aromatic diterpene 11 were obtained from 16-hydroxycarnosol (9) by reaction with Ph3P/NBS in CH2Cl2. The structure of the new compound 11 was established from its spectroscopic data as 12,16-epoxycarnosol.     

An intravitreal biodegradable sustained release naproxen and 5-fluorouracil system for the treatment of experimental post-traumatic proliferative vitreoretinopathy

BACKGROUND/AIMS: To determine the potential of an intravitreal sustained release naproxen and 5-fluorouracil (NA/5-FU) codrug for the treatment of experimental proliferative vitreoretinopathy (PVR) in a model for trauma associated tractional retinal detachment (TRD). METHODS: Sustained release pellets were prepared by covalently linking naproxen to 5-fluorouracil. Drug release was tested in vitro and toxic effects were evaluated by electroretinography and light microscopy. Traumatic PVR was induced in pigmented rabbits by performing a scleral laceration, followed by repair and intravitreal injection of 0.4 ml of autologous blood. Thirty six eyes were treated with a sustained release implant containing 1.5 mg NA/5-FU as a codrug and 36 control eyes were submitted to surgery alone. Eyes were evaluated for TRD by serial indirect ophthalmoscope examination at different time points followed by postmortem fundus evaluation of the enucleated eye RESULTS: The NA/5-FU pellets were found to provide linear release of 5-FU and naproxen over the 30 day duration of the in vitro release test. Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly lower in eyes treated with the codrug pellet. There were no drug related toxic effects evident on histopathological or electroretinograph examination of eyes containing the NA/5-FU pellet. CONCLUSIONS: The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted.     

Mechanical pulmonic valve thrombosis: expanding role of cardiac CT and multimodality imaging

We report a case of a 44-year-old man with a clinical history of Tetralogy of Fallot status post staged surgical correction with mechanical pulmonic valve replacement who presented with progressive exertional dyspnea in the setting of non-compliance with anticoagulation. In the context of this suggestive clinical presentation, the diagnosis of mechanical pulmonic valve thrombosis (MPVT) was made possible via multimodality imaging, including transthoracic echocardiogram and cardiac computed tomography angiography. Due to the uncommon nature of the condition, the patient was treated with systemic thrombolysis and anticoagulation using evidence-based guidelines, largely extrapolated from left-sided mechanical valve thrombosis. Our case underscores the importance of anticoagulation in MPVT and recognizing the features of MPVT on clinical history, physical examination, and multimodality imaging. It is essential to understand the pivotal role of multimodality imaging in the assessment of MPVT and realize the limitations of available data regarding the management of MPVT in the current era.     

Everything that is not given is lost

A small health center is located in Velingara,Senegal.It is approximately 7 o'clock in the morning.In the old,dusty room that constitutes the operating room,a s...     

Headache-related circuits and high frequencies evaluated by EEG,MRI, PET as potential biomarkers to differentiate chronic and episodic migraine: Evidence from a systematic review

BackgroundThe diagnosis of migraine is mainly clinical and self-reported, which makes additional examinations unnecessary in most cases. Migraine can be subtyped into chronic (CM) and episodic (EM). Despite the very high prevalence of migraine, there are no evidence-based guidelines for differentiating between these subtypes other than the number of days of migraine headache per month. Thus, we consider it timely to perform a systematic review to search for physiological evidence from functional activity (as opposed to anatomical structure) for the differentiation between CM and EM, as well as potential functional biomarkers. For this purpose, Web of Science (WoS), Scopus, and PubMed databases were screened.FindingsAmong the 24 studies included in this review, most of them (22) reported statistically significant differences between the groups of CM and EM. This finding is consistent regardless of brain activity acquisition modality, ictal stage, and recording condition for a wide variety of analyses. That speaks for a supramodal and domain-general differences between CM and EM that goes beyond a differentiation based on the days of migraine per month. Together, the reviewed studies demonstrates that electro- and magneto-physiological brain activity (M/EEG), as well as neurovascular and metabolic recordings from functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), show characteristic patterns that allow to differentiate between CM and EM groups.ConclusionsAlthough a clear brain activity-based biomarker has not yet been identified to distinguish these subtypes of migraine, research is approaching headache specialists to a migraine diagnosis based not only on symptoms and signs reported by patients. Future studies based on M/EEG should pay special attention to the brain activity in medium and fast frequency bands, mainly the beta band. On the other hand, fMRI and PET studies should focus on neural circuits and regions related to pain and emotional processing.