Whole-thorax irradiation induces hypoxic respiratory failure, pleural effusions and cardiac remodeling

To study the mechanisms of death following a single lethal dose of thoracic radiation, WAG/RijCmcr (Wistar) rats were treated with 15 Gy to the whole thorax and followed until they were morbid or sacrificed for invasive assays at 6 weeks. Lung function was assessed by breathing rate and arterial oxygen saturation. Lung structure was evaluated histologically. Cardiac structure and function were examined by echocardiography. The frequency and characteristics of pleural effusions were determined. Morbidity from 15 Gy radiation occurred in all rats 5 to 8 weeks after exposure, coincident with histological pneumonitis. Increases in breathing frequencies peaked at 6 weeks, when profound arterial hypoxia was also recorded. Echocardiography analysis at 6 weeks showed pulmonary hypertension and severe right ventricular enlargement with impaired left ventricular function and cardiac output. Histologic sections of the heart revealed only rare foci of lymphocytic infiltration. Total lung weight more than doubled. Pleural effusions were present in the majority of the irradiated rats and contained elevated protein, but low lactate dehydrogenase, when compared with serum from the same animal. Pleural effusions had a higher percentage of macrophages and large monocytes than neutrophils and contained mast cells that are rarely present in other pathological states. Lethal irradiation to rat lungs leads to hypoxia with infiltration of immune cells, edema and pleural effusion. These changes may contribute to pulmonary vascular and parenchymal injury that result in secondary changes in heart structure and function. We report that conditions resembling congestive heart failure contribute to death during radiation pneumonitis, which indicates new targets for therapy

Sucrose Nonfermenting-Related Kinase Enzyme-Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function.

BACKGROUND: Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate-activated kinase) family, was essential for cardiac metabolism in mammals. Snrk global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of Snrk in cardiomyocytes (Snrk cmcKO) leads to cardiac failure and death by 8 to 10 months. METHODS AND RESULTS: We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in Snrk cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in SNRK knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from Snrk cmcKO adult mice and SNRK knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo Snrk cmcKO cardiac function deficits. CONCLUSIONS: Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart

Edge-on disk around the T Tauri star [MR81] Halpha 17 NE in CrA

Using the speckle camera SHARP at the 3.5m ESO NTT, K\"ohler and collaborators found an object ~3.5 mag fainter in K only 1.3" north-east of the T Tauri star [MR81] Ha 17 in the Corona Australis (CrA) star-forming region, which could be either a brown dwarf or a T Tauri star with an edge-on disk. We attempt to study this faint object in detail. We acquired deep VLT NACO near-infrared images at three epochs to determine, whether [MR81] Ha 17 and the nearby faint object are co-moving and to measure the infrared colors of both objects. We obtained optical and infrared spectra of both objects with the VLT using FORS and ISAAC, respectively, to determine spectral types and temperatures as well as ages and masses. The T Tauri star [MR81] Ha 17 and the faint nearby object have a projected separation of 1369.58 mas, i.e. 178 AU at 130 pc. They share the same proper motion (~5 sigma), so that they most certainly form a bound binary pair. The apparently fainter component [MR81] Ha 17 NE has a spectral type of M2e, while the apparently brighter component [MR81] Ha 17 SW, the previously known T Tauri star, has a spectral type of M4-5e. We can identify a nearly edge-on disk around [MR81] Ha 17 NE by visual inspection, which has a diameter of at least 30 to 50 AU. We are able to detect strong emission lines in [MR81] Ha 17 NE, which are almost certainly due to ongoing accretion. The NE object is detectable only by means of its scattered light. If both objects are coeval (2-3 Myr) and located at the same distance (~130 pc as CrA), then the apparently fainter [MR81] Ha 17 NE is more massive (primary) component with a nearly edge-on disk and the apparently brighter component [MR81] Ha 17 SW is less massive (com- panion). Both are low-mass T Tauri stars with masses of ~0.5 and 0.23 \pm 0.05 solar masses, respectively.Comment: A&A in pres

Effects of rare-earth co-doping on the local structure of rare-earth phosphate glasses using high and low energy X-ray diffraction

Rare-earth co-doping in inorganic materials has a long-held tradition of facilitating highly desirable optoelectronic properties for their application to the laser industry. This study concentrates specifically on rare-earth phosphate glasses, (R2O3)x(R'2O3)y(P2O5)1-(x+y), where (R, R') denotes (Ce, Er) or (La, Nd) co-doping and the total rare-earth composition corresponds to a range between metaphosphate, RP3O9, and ultraphosphate, RP5O14. Thereupon, the effects of rare-earth co-doping on the local structure are assessed at the atomic level. Pair-distribution function analysis of high-energy X-ray diffraction data (Qmax = 28 Å-1) is employed to make this assessment. Results reveal a stark structural invariance to rare-earth co-doping which bears testament to the open-framework and rigid nature of these glasses. A range of desirable attributes of these glasses unfold from this finding; in particular, a structural simplicity that will enable facile molecular engineering of rare-earth phosphate glasses with 'dial-up' lasing properties. When considered together with other factors, this finding also demonstrates additional prospects for these co-doped rare-earth phosphate glasses in nuclear waste storage applications. This study also reveals, for the first time, the ability to distinguish between P-O and PO bonding in these rare-earth phosphate glasses from X-ray diffraction data in a fully quantitative manner. Complementary analysis of high-energy X-ray diffraction data on single rare-earth phosphate glasses of similar rare-earth composition to the co-doped materials is also presented in this context. In a technical sense, all high-energy X-ray diffraction data on these glasses are compared with analogous low-energy diffraction data; their salient differences reveal distinct advantages of high-energy X-ray diffraction data for the study of amorphous materials

The Impact of Insulin Pump Therapy on Glycemic Profiles in Patients with Type 2 Diabetes: Data from the OpT2mise Study

Background: The OpT2mise randomized trial was designed to compare the effects of continuous subcutaneous insulin infusion (CSII) and multiple daily injections (MDI) on glucose profiles in patients with type 2 diabetes. Research Design and Methods: Patients with glycated hemoglobin (HbA1c) levels of ≥8% (64 mmol/mol) and ≤12% (108 mmol/mol) despite insulin doses of 0.7-1.8 U/kg/day via MDI were randomized to CSII (n=168) or continued MDI (n=163). Changes in glucose profiles were evaluated using continuous glucose monitoring data collected over 6-day periods before and 6 months after randomization. Results: After 6 months, reductions in HbA1c levels were significantly greater with CSII (-1.1±1.2% [-12.0±13.1 mmol/mol]) than with MDI (-0.4±1.1% [-4.4±12.0 mmol/mol]) (P<0.001). Similarly, compared with patients receiving MDI, those receiving CSII showed significantly greater reductions in 24-h mean sensor glucose (SG) (treatment difference, -17.1 mg/dL; P=0.0023), less exposure to SG >180 mg/dL (-12.4%; P=0.0004) and SG >250 mg/dL (-5.5%; P=0.0153), and more time in the SG range of 70-180 mg/dL (12.3%; P=0.0002), with no differences in exposure to SG<70 mg/dL or in glucose variability. Changes in postprandial (4-h) glucose area under the curve >180 mg/dL were significantly greater with CSII than with MDI after breakfast (-775.9±1,441.2 mg/dL/min vs. -160.7±1,074.1 mg/dL/min; P=0.0015) and after dinner (-731.4±1,580.7 mg/dL/min vs. -71.1±1,083.5 mg/dL/min; P=0.0014). Conclusions: In patients with suboptimally controlled type 2 diabetes, CSII significantly improves selected glucometrics, compared with MDI, without increasing the risk of hypoglycemia

Intraventricular dyssynchrony in light chain amyloidosis: a new mechanism of systolic dysfunction assessed by 3-dimensional echocardiography

<p>Abstract</p> <p>Background</p> <p>Light chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography.</p> <p>Methods</p> <p>Cardiac 3D echocardiography full volumes were acquired in 10 biopsy-proven AL subjects (60 ± 3 years, 5 females) and 10 healthy controls (52 ± 1 years, 5 females). The LV was subdivided into 16 segments and the time from end-diastole to the minimal systolic volume for each of the 16 segments was expressed as a percent of the cycle length. The standard deviations of these times provided a 16-segment dyssynchrony index (16-SD%). 16-SD% was compared between healthy and AL subjects.</p> <p>Results</p> <p>Left ventricular ejection fraction was comparable (control vs. AL: 62.4 ± 0.6 vs. 58.6 ± 2.8%, p = NS). 16-SD% was significantly higher in AL versus healthy subjects (5.93 ± 4.4 vs. 1.67 ± 0.87%, p = 0.003). 16-SD% correlated with left ventricular mass index (R 0.45, p = 0.04) but not to left ventricular ejection fraction.</p> <p>Conclusion</p> <p>Light chain amyloidosis is associated with left ventricular regional systolic dyssynchrony. Regional dyssynchrony may be an unrecognized mechanism of heart failure in AL subjects.</p

Contrast-enhanced ultrasound detects changes in microvascular blood flow in adults with sickle cell disease.

In patients with sickle cell disease (SCD), poor outcome measures compromise the potential success of clinical trials. Contrast-enhanced ultrasound (CEUS) is a technique that can non-invasively quantify deep tissue microvascular blood flow. We tested the hypothesis that CEUS of forearm skeletal muscle could be used to: 1) assess microvascular abnormalities that occur during vaso-occlusive crisis; and 2) test new therapies for SCD that are targeted to improving the status of the microcirculation. We performed a prospective study, CEUS perfusion imaging of resting forearm muscle was performed in adults with SCD: 1) during and after a pain episode, and 2) before, during, and after a 24-hour infusion of the investigative agent, regadenoson, an adenosine A2A agonist. CEUS destruction-replenishment time-intensity data were analyzed to measure microvascular blood flow, as well as its components, microvascular blood volume and flux rate. Serial CEUS measurements were obtained in 32 adults with SCD. For the studies during crisis, there was a 30% reduction in microvascular blood flow compared to steady-state (p = 0.031), a reduction that was largely due to microvascular flux rate. For the regadenoson group, a non-significant 25% increase in flux rate and 9% increase in microvascular blood flow compared to baseline were detected during infusion. In a study of adults with SCD, CEUS detected changes in microvascular blood flow associated with vaso-occlusive crises. No changes were found during an infusion of the adenosine A2A agonist, regadenoson. This study provides preliminary evidence that CEUS could detect blood flow changes consistent with SCD physiology