Fire in the Heart: A Characterization of the High Kinetic Temperatures and Heating Sources in the Nucleus of NGC253

The nuclear starburst within the central $\sim 15^{\prime\prime}$ ($\sim 250$ pc; $1^{\prime\prime} \simeq 17$ pc) of NGC253 has been extensively studied as a prototype for the starburst phase in galactic evolution. Atacama Large Millimeter/submillimeter Array (ALMA) imaging within receiver Bands 6 and 7 have been used to investigate the dense gas structure, kinetic temperature, and heating processes which drive the NGC253 starburst. Twenty-nine transitions from fifteen molecular species/isotopologues have been identified and imaged at $1.^{\prime\prime}5$ to $0.^{\prime\prime}4$ resolution, allowing for the identification of five of the previously-studied giant molecular clouds (GMCs) within the central molecular zone (CMZ) of NGC253. Ten transitions from the formaldehyde (H$_2$CO) molecule have been used to derive the kinetic temperature within the $\sim 0.^{\prime\prime}5$ to $5^{\prime\prime}$ dense-gas structures imaged. On $\sim 5^{\prime\prime}$ scales we measure $T_K \gtrsim 50$ K, while on size scales $\lesssim 1^{\prime\prime}$ we measure $T_K \gtrsim 300$ K. These kinetic temperature measurements further delineate the association between potential sources of dense gas heating. We have investigated potential heating sources by comparing our measurements to models which predict the physical conditions associated with dense molecular clouds that possess a variety of heating mechanisms. This comparison has been supplemented with tracers of recently-formed massive stars (Br$\gamma$) and shocks ([FeII]). Derived molecular column densities point to a radially-decreasing abundance of molecules with sensitivity to cosmic ray and mechanical heating within the NGC253 CMZ. These measurements are consistent with radio spectral index calculations which suggest a higher concentration of cosmic ray producing supernova remnants within the central 10 pc of NGC253.Comment: 60 pages, 25 figures (whew!), Accepted for publication in ApJ, Latest version includes minor corrections following proof submissio

Accurate distance control between a probe and a surface using a microcantilever

We demonstrate a method to accurately control the distance between a custom probe and a sample on a {\mu}m to nm scale. The method relies on the closed-loop feedback on the angular deflection of an in-contact AFM microcantilever. High performance in stability and accuracy is achieved in this method by taking advantage of the small mechanical feedback path between surface and probe. We describe how internal error sources that find their origin in the microcantilever and feedback can be minimized to achieve an accurate and precise control up to 3 nm. In particular, we investigated how hysteresis effects in the feedback caused by friction forces between tip and substrate, can be minimized. By applying a short calibration procedure, distance control from contact to several micrometers probe-sample distance can be obtained with an absolute nanometer-scale accuracy. The method presented is compatible with any probe that can be fixed on a microcantilever chip and can be easily built into existing AFM systems

Low rate of cardiac events in first-degree relatives of diagnosis-negative young sudden unexplained death syndrome victims during follow-up

BACKGROUND: Sudden unexplained death syndrome (SUDS) in young individuals often results from inherited cardiac disease. Accordingly, comprehensive examination in surviving first-degree relatives unmasks such disease in approximately 35% of the families. It is unknown whether individuals from diagnosis-negative families are at risk of developing manifest disease or cardiac events during follow-up.OBJECTIVE: This study aimed to study the prognosis of first-degree relatives of young SUDS victims, in whom the initial cardiologic and genetic examination did not lead to a diagnosis.METHODS: We retrieved vital status of surviving first-degree relatives from 83 diagnosis-negative families who presented to our cardiogenetics department between 1996 and 2009 because of SUDS in ≥1 relatives aged 1-50 years. Moreover, we contacted relatives who previously visited our center for detailed information.RESULTS: We obtained detailed information (median follow-up 6.6 years; interquartile range 4.7-9.6 years) in 340 of 417 first-degree relatives (81.5%) from 77 of 83 families (92.8%). Vital status, available in 405 relatives (97.1%), showed that 20 relatives (4.9%) died during follow-up, including 1 natural death before the age of 50. This girl belonged to a family with multiple cases of idiopathic ventricular fibrillation and SUDS, including another successfully resuscitated sibling during follow-up. Two hundred thirty-four of 340 first-degree relatives (68.8%) underwent cardiologic examination. Of these, 76 (32.5%) were reevaluated. Inherited cardiac disease was diagnosed in 3 families (3.6%).CONCLUSION: In first-degree relatives of young SUDS victims with no manifest abnormalities during the initial examination, the risk of developing manifest inherited cardiac disease or cardiac events during follow-up is low. This does not apply to families with obvious familial SUDS.</p

Outcomes in Dutch DPP6 risk haplotype for familial idiopathic ventricular fibrillation:a focused update

Background: The genetic risk haplotype DPP6 has been linked to familial idiopathic ventricular fibrillation (IVF), but the associated long-term outcomes are unknown. Methods: DPP6 risk haplotype-positive family members (DPP6 cases) and their risk haplotype-negative relatives (DPP6 controls) were included. Clinical follow-up data were collected through March 2023. Implantable cardioverter-defibrillator (ICD) indication was divided in primary or secondary prevention. Cumulative survival and event rates were calculated. Results: We included 327 DPP6 cases and 315 DPP6 controls. Median follow-up time was 9 years (interquartile range: 4–12). Of the DPP6 cases, 129 (39%) reached the composite endpoint of appropriate ICD shock, sudden cardiac arrest or death, at a median age of 45 years (range: 15–97). Median overall survival was 83 years and 87 years for DPP6 cases and DPP6 controls, respectively (p &lt; 0.001). In DPP6 cases, median overall survival was shorter for males (74 years) than females (85 years) (p &lt; 0.001). Of the DPP6 cases, 97 (30%) died, at a median age of 50 years. With a prophylactic ICD implantation advise based on risk haplotype, sex and age, 137 (42%) of DPP6 cases received an ICD, for primary prevention (n = 109) or secondary prevention (n = 28). In the primary prevention subgroup, 10 patients experienced a total of 34 appropriate ICD shocks, and there were no deaths during follow-up. DPP6 cases with a secondary prevention ICD experienced a total of 231 appropriate ICD shocks.Conclusion: Patients with the DPP6 risk haplotype, particularly males, are at an increased risk of IVF and sudden cardiac death. Using a risk stratification approach based on risk haplotype, sex and age, a substantial proportion of patients with a primary prevention ICD experienced appropriate ICD shocks, showing the benefit of prophylactic ICD implantation with this strategy.</p

ALMA Observations of the Physical and Chemical Conditions in Centaurus A

Centaurus A, with its gas-rich elliptical host galaxy, NGC 5128, is the nearest radio galaxy at a distance of 3.8 Mpc. Its proximity allows us to study the interaction between an active galactic nucleus, radio jets, and molecular gas in great detail. We present ALMA observations of low J transitions of three CO isotopologues, HCN, HCO$^{+}$, HNC, CN, and CCH toward the inner projected 500 pc of NGC 5128. Our observations resolve physical sizes down to 40 pc. By observing multiple chemical probes, we determine the physical and chemical conditions of the nuclear interstellar medium of NGC 5128. This region contains molecular arms associated with the dust lanes and a circumnuclear disk (CND) interior to the molecular arms. The CND is approximately 400 pc by 200 pc and appears to be chemically distinct from the molecular arms. It is dominated by dense gas tracers while the molecular arms are dominated by $^{12}$CO and its rare isotopologues. The CND has a higher temperature, elevated CN/HCN and HCN/HNC intensity ratios, and much weaker $^{13}$CO and C$^{18}$O emission than the molecular arms. This suggests an influence from the AGN on the CND molecular gas. There is also absorption against the AGN with a low velocity complex near the systemic velocity and a high velocity complex shifted by about 60 km s$^{-1}$. We find similar chemical properties between the CND in emission and both the low and high velocity absorption complexes implying that both likely originate from the CND. If the HV complex does originate in the CND, then that gas would correspond to gas falling toward the supermassive black hole

Genetic Susceptibility and Predictors of Paradoxical Reactions in Buruli Ulcer

Buruli ulcer (BU) is the third most frequent mycobacterial disease in immunocompetent persons after tuberculosis and leprosy. During the last decade, eight weeks of antimicrobial treatment has become the standard of care. This treatment may be accompanied by transient clinical deterioration, known as paradoxical reaction. We investigate the incidence and the risks factors associated with paradoxical reaction in BU.The lesion size of participants was assessed by careful palpation and recorded by serial acetate sheet tracings. For every time point, surface area was compared with the previous assessment. All patients received antimicrobial treatment for 8 weeks. Serum concentration of 25-hydroxyvitamin D, the primary indicator of vitamin D status, was determined in duplex for blood samples at baseline by a radioimmunoassay. We genotyped four polymorphisms in the SLC11A1 gene, previously associated with susceptibility to BU. For testing the association of genetic variants with paradoxical responses, we used a binary logistic regression analysis with the occurrence of a paradoxical response as the dependent variable.Paradoxical reaction occurred in 22% of the patients; the reaction was significantly associated with trunk localization (p = .039 by Χ(2)), larger lesions (p = .021 by Χ(2)) and genetic factors. The polymorphisms 3'UTR TGTG ins/ins (OR 7.19, p < .001) had a higher risk for developing paradoxical reaction compared to ins/del or del/del polymorphisms.Paradoxical reactions are common in BU. They are associated with trunk localization, larger lesions and polymorphisms in the SLC11A1 gene

Random glucose sampling as screening tool for diabetes among disadvantaged tuberculosis patients residing in urban slums in India.

Recently, a two-step diagnostic algorithm to diagnose diabetes among TB patients was proposed comprising random glucose and point-of-care HbA1c. This study evaluates the first part of this algorithm among disadvantaged TB patients. http://ow.ly/UI7d30nK1UN

Use of busulfan in conditioning for allogeneic hematopoietic stem cell transplantation in adults : a survey by the Transplant Complications Working Party of the EBMT

A survey was carried out among EBMT centers about the use of busulfan for conditioning in allogeneic stem cell transplantation. Of 109 responding centers, 106 used busulfan for conditioning, 102 in conventional myeloablative doses, and 93 in reduced doses (RIC). The route of administration was mostly intravenous, but similar to 10% of the centers gave the drug orally. The number of doses in i.v. administration varied and was in myeloablative conditioning mostly one (50 centers) or four (43 centers) doses a day. Seventeen of the 106 centers used pharmacokinetics for dose adjustment in myeloablative conditioning, nine in RIC. The details of pharmacokinetic monitoring varied markedly. Three quarters of the centers reported adjusting the dose based on obesity in myeloablative conditioning and about 60% in RIC. The most common method for dose calculation was ideal body weight + 0.25 x (actual body weight - ideal body weight). In conclusion, the present survey showed marked heterogeneity in the current practices of busulfan administration for conditioning. The impact of the heterogeneity is not well known. Due to this and the scarcity of support from controlled clinical studies, no clear guidelines can be presented, but some prevailing policies to be recommended were identified.Peer reviewe

Reduced Calcium Signaling Is Associated With Severe Graft-Versus-Host Disease: Results From Preclinical Models and From a Prospective EBMT Study

Despite its involvement in various immune functions, including the allogeneic activation of T-lymphocytes, the relevance of calcium (Ca2+) for GVHD pathobiology is largely unknown. To elucidate a potential association between Ca(2+)and GVHD, we analyzed Ca2+-sensing G-protein coupled receptor 6a (GPRC6a) signaling in preclinical GVHD models and conducted a prospective EBMT study on Ca(2+)serum levels prior alloSCT including 363 matched sibling allogeneic peripheral blood stem cell transplantations (alloSCTs). In experimental models, we found decreasedGprc6aexpression during intestinal GVHD. GPRC6a deficient alloSCT recipients had higher clinical and histopathological GVHD scores leading to increased mortality. As possible underlying mechanism, we found increased antigen presentation potential in GPRC6a(-/-)alloSCT recipients demonstrated by higher proliferation rates of T-lymphocytes. In patients with low Ca(2+)serum levels (≤ median 2.2 mmol/l) before alloSCT, we found a higher incidence of acute GVHD grades II-IV (HR = 2.3 Cl = 1.45-3.85p= 0.0006), severe acute GVHD grades III-IV (HR = 3.3 CI = 1.59-7.14,p= 0.002) and extensive chronic GVHD (HR = 2.0 Cl = 1.04-3.85p= 0.04). In conclusion, experimental and clinical data suggest an association of reduced Ca(2+)signaling with increased severity of GVHD. Future areas of interest include the in depth analysis of involved molecular pathways and the investigation of Ca(2+)signaling as a therapeutic target during GVHD

Buruli ulcer treatment:Rate of surgical intervention differs highly between treatment centers in West Africa

BACKGROUND: Antibiotic treatment proved itself as the mainstay of treatment for Buruli ulcer disease. This neglected tropical disease is caused by Mycobacterium ulcerans. Surgery persists as an adjunct therapy intended to reduce the mycobacterial load. In an earlier clinical trial, patients benefited from delaying the decision to operate. Nevertheless, the rate of surgical interventions differs highly per clinic. METHODS: A retrospective study was conducted in six different Buruli ulcer (BU) treatment centers in Benin and Ghana. BU patients clinically diagnosed between January 2012 and December 2016 were included and surgical interventions during the follow-up period, at least one year after diagnosis, were recorded. Logistic regression analysis was carried out to estimate the effect of the treatment center on the decision to perform surgery, while controlling for interaction and confounders. RESULTS: A total of 1193 patients, 612 from Benin and 581 from Ghana, were included. In Benin, lesions were most frequently (42%) categorized as the most severe lesions (WHO criteria, category III), whereas in Ghana lesions were most frequently (44%) categorized as small lesions (WHO criteria, category I). In total 344 (29%) patients received surgical intervention. The percentage of patients receiving surgical intervention varied between hospitals from 1.5% to 72%. Patients treated in one of the centers in Benin were much more likely to have surgery compared to the clinic in Ghana with the lowest rate of surgical intervention (RR = 46.7 CI 95% [17.5-124.8]). Even after adjusting for confounders (severity of disease, age, sex, limitation of movement at joint at time of diagnosis, ulcer and critical sites), rates of surgical interventions varied highly. CONCLUSION: The decision to perform surgery to reduce the mycobacterial load in BU varies highly per clinic. Evidence based guidelines are needed to guide the role of surgery in the treatment of BU