Organization of atrial fibrillation using a pure sodium channel blocker: Implications of rotor ablation therapy.
Rotors are the source of atrial fibrillation (AF). However, the ablation of rotors for persistent AF is challenging. The purpose of this study was to identify the dominant rotor by accelerating the organization of AF using a sodium channel blocker and detecting the rotor's preferential area that governs AF. Overall, 30 consecutive patients with persistent AF who underwent pulmonary vein isolation and still sustained AF were enrolled. Pilsicainide 50 mg was administered. An online real-time phase mapping system (ExTRa Mapping™) was used to identify the meandering rotors and multiple wavelets in 11 left atrial segments. The time ratio of non-passive activation (%NP) was evaluated as the frequency of rotor activity in each segment. Conduction velocity became slower-from 0.46 ± 0.14 to 0.35 ± 0.14 mm/ms (p = .004)-and the rotational period of the rotor was significantly prolonged-156 ± 21 to 193 ± 28 ms/cycle (p < .001). AF cycle length was prolonged from 169 ± 19 to 223 ± 29 ms (p < .001). A decrease in %NP was observed in seven segments. Additionally, 14 patients had at least one complete passive activation area. Of them, the use of high %NP area ablation resulted in atrial tachycardia and sinus rhythm in two patients each. A sodium channel blocker organized persistent AF. In selective patients with a wide organized area, high %NP area ablation could convert AF into atrial tachycardia or terminate AF.


Bent structure and dynamic stereochemistry of chiral acridinium cations.
Chiral acridinium cations, easily prepared by reaction of enantiopure primary amines and tris(2,6-dimethoxy)trityl cation, display restricted rotations around the C(sp(3))-N(sp(2)) bond. A bending of the aromatic backbone and "out-of-plane" displacements of C(9) and N(10) atoms are enforced if bulky amines are introduced.


A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes.
To evaluate the effect of recombinant human erythropoietin (rHuEpo) on the haemoglobin level and transfusion requirement in low-risk myelodysplastic syndromes (MDS), 87 patients were enrolled in a randomized double-blind placebo-controlled study, 44 patients were assigned to epoetin alpha (150 U/kg/d s.c. for 8 weeks) and 43 to placebo arms. MDS types were homogenous in both groups: refractory anaemia (RA) 47.7-48.8%. refractory anaemia with ringed sideroblasts (RAS) 20.5-25.6%, refractory anaemia with excess of blasts (RAEB) (blasts < 10%) 31.8-25.6%, 14/38 evaluable patients responded to epoetin alpha versus 4/37 to placebo (P=0.007). 50% of RA responded to epoetin alpha versus 5.9% to placebo (P=0.0072), RAS 37.5% v 18.2% (P=0.6) and RAEB 16.7% v 11.1% (P=1.00). 60% of non-pretransfused patients responded to epoetin alpha (Hb 8.35< or = 0.73 to 10.07+/-1.87 g/dl), whereas a slight decrease was observed in the placebo group (8.4+/-0.66 to 8.19+/-0.92 g/dl) (P=0.0004). Percentage of transfused patients was similar in both arms. Basal erythropoietin (Epo) serum levels > 200 mU/l predicted for a non-response. At week 4 sTfR levels were increased > 50% in responders (P=0.013), whereas an increase < 18% predicted for non-response (P=0.006). Leucocyte and platelet counts were not influenced by epoetin alpha treatment. Adverse events occurred in 31.8% of the rHuEpo-treated versus 42.99%) of the placebo-treated patients (P=0.2), and seven patients did not complete the course. In conclusion, rHuEpo was effective in the treatment of low-risk MDS. RA subtype, no transfusions prior to rHuEpo therapy, and low basal Epo levels were associated with higher probability of response. Soluble transferrin receptor level at the fourth week was an early predictor of response.


An Analysis of MIF Structural Features that Control Functional Activation of CD74.
For more than 15 years, the tautomerase active site of macrophage migration inhibitory factor (MIF) and its catalytic residue Pro1 have been being targeted for the development of therapeutics that block activation of its cell surface receptor, CD74. Neither the biological role of the MIF catalytic site nor the mechanistic details of CD74 activation are well understood. The inherently unstable structure of CD74 remains the biggest obstacle in structural studies with MIF for understanding the basis of CD74 activation. Using a novel approach, we elucidate the mechanistic details that control activation of CD74 by MIF surface residues and identify structural parameters of inhibitors that reduce CD74 biological activation. We also find that N-terminal mutants located deep in the catalytic site affect surface residues immediately outside the catalytic site, which are responsible for reduction of CD74 activation.


Treatment of cerebral aneurysms with the FRED Jr flow-diverting stent: A case series and meta-analysis.
With the development of the Flow Re-Direction Endoluminal Device Junior (FRED Jr), treatment of distal aneurysms and/or aneurysms with small parent vessels has become a viable option. To assess the efficacy and safety of FRED Jr in the treatment of distal aneurysms with small parent vessels. This is a single center retrospective study and meta-analysis of patients treated with FRED Jr for intracranial aneurysms. The primary outcome was complete aneurysm occlusion at final follow-up. Secondary outcomes included stroke rates, mortality rates, need for retreatment and clinical outcomes. There were a total of 7 patients with 7 aneurysms treated with FRED Jr. Mean aneurysm neck, width, height, and parent artery diameter were 2.6 ± 0.8 mm, 3.1 ± 0.9 mm, 2.5 ± 1.0 mm, and 1.8 ± 0.6 mm respectively. The complete occlusion rate was 57.1 % at 6 months, and favorable outcome (mRS 0-2) was observed in all patients in follow-up. Stroke complication occurred in none of the patients. Seven studies from 1360 articles were identified for inclusion in the meta-analysis, comprising 227 patients with 244 aneurysms treated with FRED Jr. Mean aneurysm height, width, neck and parent artery diameter were 6.9 ± 3.3 mm (pooled=5.6 [<0.1-11.47] mm), 6.6 ± 2.2 mm (pooled=6.6 [4.2-9.1] mm), 4.4 ± 1.4 mm (pooled=4.1 [3.3 -4.9] mm), and 2.0 ± 0.2 mm (pooled=2.1 [1.7-2.5]), respectively. At final follow-up, the pooled complete occlusion and complication rates were 69.9 % and 0 %, respectively. FRED Jr demonstrated moderate efficacy and good safety in the treatment of distal aneurysms with small parent vessels at mid-term follow-up.


Practice parameters for the treatment of colonic diverticular disease: Italian Society of Colon and Rectal Surgery (SICCR) guidelines.
The mission of the Italian Society of Colorectal Surgery (SICCR) is to optimize patient care. Providing evidence-based practice guidelines is therefore of key importance. About the present report it concernes the SICCR practice guidelines for the diagnosis and treatment of diverticular disease of the colon. The guidelines are not intended to define the sole standard of care but to provide evidence-based recommendations regarding the available therapeutic options.


Rat T cells express neither CD55 nor CD59 and are dependent on Crry for protection from homologous complement.
All human blood cells express decay-accelerating factor (DAF, CD55), CD59, and, with the exception of erythrocytes, membrane cofactor protein (MCP, CD46) to protect themselves from damage by the constant low-level activation of complement in serum. In rats and mice MCP is expressed only in testis, whereas DAF and CD59 are broadly distributed. Rats and mice also express a unique complement regulator, Crry. Previously we have shown that DAF was absent from at least 75% of rat T cells. To further investigate this surprising finding, we assessed the expression levels of DAF, CD59 and Crry on all blood cell types in the rat. We found that Crry was abundantly expressed on all blood cells. CD59 was expressed abundantly on erythrocytes and granulocytes but was absent from all T cellsand platelets and a minority of B cells and NK cells. Double staining and depletion studies showed that T cells in all rat strains tested were DAF-CD59-. Neutralization of Crry using a blocking monoclonal antibody rendered T cells susceptible to lysis by homologous complement, indicating that Crry was solely responsible for protecting DAF-CD59- T cells from complement damage in the rat.


Tumor markers in testis cancer.
Human chorionic gonadotropin and alpha-fetoprotein are well established as serum markers for germ-cell tumors of the testis. Other protein markers of this disease are lactic acid dehydrogenase and placental alkaline phosphatase. There also are cytogenetic or chromosomal markers, particularly i(12p), and molecular markers in the form of oncogenes and tumor suppressor genes. Markers are valuable in diagnosis, staging, predicting tumor behavior, and monitoring therapy and disease recurrence.


Removal of arsenic from groundwater using low cost ferruginous manganese ore.
A low cost ferruginous manganese ore (FMO) has been studied for the removal of arsenic from groundwater. The major mineral phases present in the FMO are pyrolusite and goethite. The studied FMO can adsorb both AS(III) and As(V) without any pre-treatment, adsorption of As(III) being stronger than that of As(V). Both As(II) and As(V) are adsorbed by the FMO in the pH range of 2-8. Once adsorbed, arsenic does not get desorbed even on varying the pH in the range of 2-8. Presence of bivalent cations, namely, Ni2+, Co2+ Mg2+ enhances the adsorption capability of the FMO. The FMO has been successfully used for the removal of arsenic from six real groundwater samples containing arsenic in the range of 0.04-0.18 ppm. Arsenic removals are almost 100% in all the cases. The cost of the FMO is about 50-56 US$ per metric tonne.


Involvement of T lymphocytes in curative effect of a new immunomodulator OM 163 on rat colon cancer metastases.
In a model of colon cancer in syngeneic rats, a new immunomodulator, OM 163, induced the complete disappearance of peritoneal carcinomatosis (nodules measuring 1-5 mm) in 41 out of 82 rats. Those results were confirmed in a survival experiment in which 3 out of 10 treated rats died free of tumour 10, 18 and 28 months after the tumour cell injection while all the untreated control rats died of their tumours within 3 months. OM 163 had a systemic effect, since injected intraperitoneally it completely inhibited the growth of lung metastases in 13 out of 20 rats. The antitumour effect of OM 163 was also observed in two rat strains on original tumours. Lymphocyte infiltration was observed in the tumours mainly constituted of CD4+ and CD8+ cells. The treatment had no effect in nude rats, confirming the involvement of T lymphocytes. Furthermore, rats cured by OM 163 were protected against a second challenge of tumour cells and in a Winn's assay, splenocytes from cured rats protected normal rats against tumour cells.


Projections from the amygdaloid complex to the magnocellular cholinergic basal forebrain in rat.
The amygdaloid complex has a key role in the modulation of behavioral responses in life-threatening situations, including the direction of attentional responses to sensory stimuli. The pathways from the amygdala to the basal forebrain cholinergic system, which projects to the cortex, are proposed to contribute to the modulation. To further explore the topography and postsynaptic targets of these pathways, we investigated the projections from the different divisions of the lateral, basal, accessory basal, and central nuclei of the amygdala to the cholinergic basal forebrain in rat using a sensitive anterograde tracer, Phaseolus vulgaris leucoagglutinin. The most substantial projections from the amygdala to the basal forebrain are directed to the ventrolateral and dorsomedial aspects of the substantia innominata and the fundus of the striatum. The heaviest projections originate in the capsular, lateral, and intermediate divisions of the central nucleus as well as in the magnocellular and parvicellular divisions of the basal nucleus. Light microscopic analysis of double-stained preparations revealed that the distribution of amygdaloid efferents and cholinergic neurons overlaps most prominently in the ventrolateral substantia innominata. Despite the fact that the central nucleus efferents and cholinergic elements overlap in the ventrolateral substantia innominata, electron microscopic analysis revealed, first, that the postsynaptic targets of the central nucleus efferents are non-cholinergic, probably GABAergic, neurons. Second, 80% of the synaptic contacts were symmetric. The present data extend previous observations showing that the different amygdaloid nuclei provide projections to the selective basal forebrain areas. Further, the central nucleus efferents modulate cholinergic neurons in the basal forebrain indirectly via the GABAergic interneurons.


Mechanics dictate where and how freshwater planarians fission.
Asexual freshwater planarians reproduce by tearing themselves into two pieces by a process called binary fission. The resulting head and tail pieces regenerate within about a week, forming two new worms. Understanding this process of ripping oneself into two parts poses a challenging biomechanical problem. Because planarians stop "doing it" at the slightest disturbance, this remained a centuries-old puzzle. We focus on Dugesia japonica fission and show that it proceeds in three stages: a local constriction ("waist formation"), pulsation-which increases waist longitudinal stresses-and transverse rupture. We developed a linear mechanical model with a planarian represented by a thin shell. The model fully captures the pulsation dynamics leading to rupture and reproduces empirical time scales and stresses. It asserts that fission execution is a mechanical process. Furthermore, we show that the location of waist formation, and thus fission, is determined by physical constraints. Together, our results demonstrate that where and how a planarian rips itself apart during asexual reproduction can be fully explained through biomechanics.


As main meal for sperm whales: plastics debris.
Marine debris has been found in marine animals since the early 20th century, but little is known about the impacts of the ingestion of debris in large marine mammals. In this study we describe a case of mortality of a sperm whale related to the ingestion of large amounts of marine debris in the Mediterranean Sea (4th published case worldwide to our knowledge), and discuss it within the context of the spatial distribution of the species and the presence of anthropogenic activities in the area that could be the source of the plastic debris found inside the sperm whale. The spatial distribution modelled for the species in the region shows that these animals can be seen in two distinct areas: near the waters of Almería, Granada and Murcia and in waters near the Strait of Gibraltar. The results shows how these animals feed in waters near an area completely flooded by the greenhouse industry, making them vulnerable to its waste products if adequate treatment of this industry's debris is not in place. Most types of these plastic materials have been found in the individual examined and cause of death was presumed to be gastric rupture following impaction with debris, which added to a previous problem of starvation. The problem of plastics arising from greenhouse agriculture should have a relevant section in the conservation plans and should be a recommendation from ACCOBAMS due to these plastics' and sperm whales' high mobility in the Mediterranean Sea.


No radiographic sacroiliitis progression was observed in patients with early spondyloarthritis at 6 years: results of the Esperanza multicentric prospective cohort.
To estimate the 6-year radiographic progression of sacroiliitis in patients with early spondyloarthritis (SpA). Sacroiliac joint (SIJ) radiographs (baseline and 6 years) of 94 patients with recent-onset SpA from the Esperanza cohort were scored, blindly and in a random order, by nine readers. The modified New York criteria were used to define the presence of sacroiliitis. As the gold standard for radiographic (r) sacroiliitis, the categorical opinion of at least five readers was used. Progression was defined as the shift from non-radiographic (nr) to r-sacroiliitis. In the 94 SIJ radiographs (baseline and 6 years), 78/94 (83%) pairs of radiographs had not changed from baseline to 6 years. Sacroiliitis was present in 20 patients at baseline (21.3%) and in 18 (19.2%) patients at 6 years; 11 patients had sacroiliitis at both the baseline and final visits; 9 patients changed from baseline r-sacroiliitis to nr-sacroiliitis at 6 years, and 7 changed from baseline nr-sacroiliitis to r-sacroiliitis at 6 years. The mean continuous change score (range: -8 to +8) was 2.80 at baseline and 2.55 at 6 years (mean net progression of -0.25). The reliability of the readers was fair (mean inter-reader kappa of 0.375 (0.146-0.652) and mean agreement of 73.7% (58.7-90%)). In the early SpA Esperanza cohort, progression from nr-axSpA to r-axSpA over 6 years was not observed, although the SIJ radiographs scoring has limitations to detect low levels of radiographic progression.


Surgical treatment of arrhythmias.
Surgical treatment of arrhythmias is often more expeditious and more cost-effective in the long run than pharmacologic therapy. In the past, surgical treatment of arrhythmias has been reserved for patients with disabling paroxysmal or incessant tachycardia refractory to medical management, severe life-threatening arrhythmia or aborted episodes of sudden death. However, tachyarrhythmias that are refractory to pharmacologic therapy because of drug inefficacy, noncompliance or limiting side effects are not uncommon. Although nonpharmacologic treatment of arrhythmias carries with it a one-time period of higher risk (i.e., when the patient undergoes surgery), it is curative and often preferable to the uncertainty and possibly higher cumulative risk associated with medical management.


Corrigendum: Melatonin ameliorates serobiochemical alterations and restores the cardio-nephro diabetic vascular and cellular alterations in streptozotocin-induced diabetic rats.
[This corrects the article DOI: 10.3389/fvets.2023.1089733.].


'Modest' boost in training places is not enough - RCN.
Poor workforce planning has been blamed for almost one in ten nursing posts in England, Wales and Northern Ireland remaining vacant.


Plasma extracellular vesicle test sample to standardize flow cytometry measurements.
Extracellular vesicles (EVs) in body fluids are explored as disease biomarkers, but EV concentrations measured by flow cytometers (FCMs) are incomparable. To improve data comparability, new reference materials with physical properties resembling EVs and reference procedures are being developed. The validation of new reference materials and procedures requires biological test samples. We developed a human plasma EV test sample (PEVTES) that i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. The PEVTES was prepared from human plasma of 3 fasting donors. EVs were immunofluorescently stained with antibodies against platelet-specific (CD61) and erythrocyte-specific (CD235a) antigens or lactadherin. To reduce the concentration of soluble proteins, lipoproteins, and unbound reagents, stained EVs were isolated from plasma by size-exclusion chromatography. After isolation, the PEVTES was filtered to remove remnant platelets. PEVTESs were diluted in cryopreservation agents, dimethyl sulfoxide, glycerol, or trehalose and stored at -80 °C for 12 months. After thawing, stained EV concentrations were measured with a calibrated FCM (Apogee A60-Micro). We demonstrate that the developed PEVTES resembles subcellular particles in human plasma when measured using FCM and that the concentrations of prestained platelet-derived, erythrocyte-derived, and lactadherin+ EVs in the PEVTES are stable during storage at -80 °C for 12 months when stored in trehalose. The PEVTES i) resembles subcellular particles in plasma, ii) is ready-to-use, iii) is flow cytometry-compatible, and iv) is stable. Therefore, the developed PEVTES is an ideal candidate to validate newly developed reference materials and procedures.


Impact of prescription size on statin adherence and cholesterol levels.
Therapy with 3-Hydroxy-3-methylglutaryl Co-enzyme A reductase inhibitors (statins) improve outcomes in a broad spectrum of patients with hyperlipidemia. However, effective therapy requires ongoing medication adherence; restrictive pharmacy policies may represent a barrier to successful adherence, particularly among vulnerable patients. In this study we sought to assess the relationship between the quantity of statin dispensed by the pharmacy with patient adherence and total cholesterol. We analyzed a cohort of 3,386 patients receiving more than one fill of statin medications through an integrated, inner-city health care system between January 1, 2000 and December 31, 2002. Our measure of adherence was days of drug acquisition divided by days in the study for each patient, with adequate adherence defined as > or = 80%. Log-binomial regression was used to determine the relative risk of various factors, including prescription size, on adherence. We also assessed the relationship between adherence and total cholesterol using multiple linear regression. After controlling for age, gender, race, co-payment, comorbidities, and insurance status, patients who obtained a majority of fills as 60-day supply compared with 30-day supply were more likely to be adherent to their statin medications (RR 1.41, 95% CI 1.28-1.55, P < 0.01). We found that statin non-adherence less than 80% was predictive of higher total serum cholesterol by 17.23 +/- 1.64 mg/dL (0.45 +/- 0.04 mmol/L). In a healthcare system serving predominantly indigent patients, the provision of a greater quantity of statin medication at each prescription fill contributes to improved adherence and greater drug effectiveness.


Effect of Using Hybrid Polypropylene and Glass Fibre on the Mechanical Properties and Permeability of Concrete.
A comprehensive program of experiments consisting of compression, uniaxial compression, direct shear, flexural as well as splitting tensile and air permeability tests were performed to analyse the effect of the level of fibre dosage and the water-cement ratio on the physical properties of hybrid fibre-reinforced concrete (HFRC). Two types of fibres were studied in terms of their effect on the properties of HFRC. The results indicated that the mechanical properties of concrete were significantly improved by increasing the fibre content. However, increasing the percentage fibre content past a certain peak performance limit (0.9% glass fibre (GF) and 0.45% polypropylene fibre (PPF)) led to a decrease in strength compared to reference mixes. Additionally, the incorporation of hybrid fibres yielded an increase in air permeability in the tested specimens. The results showed that the strength-related properties of HFRC were superior to the properties of single fibre-reinforced concrete.


Neoadjuvant chemoradiation (modified Eilber protocol) versus adjuvant radiotherapy in the treatment of extremity soft tissue sarcoma.
Local control for extremity soft tissue sarcomas (STS) requires surgery combined with radiotherapy, usually given pre-operatively or post-operatively. The modified Eilber protocol, a neoadjuvant chemoradiation regimen, has been reported with excellent local control rates. This retrospective single-centre study compared outcomes for patients treated with the modified Eilber protocol with those treated with standard adjuvant radiotherapy. Patients with a diagnosis of extremity STS were retrospectively reviewed from the Prince of Wales Hospital Sarcoma Database from 1995 to 2012. Sixty-three patients underwent curative surgery with either neoadjuvant Eilber chemoradiotherapy (Eilber) or adjuvant radiotherapy (Adjuvant). Twenty-nine patients were treated with modified Eilber protocol. Thirty-four patients received adjuvant radiotherapy. Three patients (10%) in the Eilber group and five patients (15%) in the Adjuvant group developed local recurrence (P = 0.87). Major acute wound complications were noted in four patients in each group (P = 0.55). One patient (3.4%) in the Eilber group developed Grade 3 or 4 late toxicities after 1 year compared with nine patients (27%) in the Adjuvant group (P = 0.02). Neoadjuvant chemoradiation (Eilber protocol) provided similar rates of local control when compared with adjuvant radiotherapy. Acute wound complication rates were similar but there was less severe late toxicity in the Eilber group.


DNA damaging agents in ovarian cancer.
Epithelial ovarian cancer (EOC) is very sensitive to upfront chemotherapy. This condition is attributable to defects in the DNA damage repair system. Agents that damage DNA are the main drugs used for its treatment. Many EOC cells have DNA repair deficiencies that confer susceptibility to these agents. Platinum is the most important agent for first-line and also for relapses, together with other drugs that can be given as monotherapy or along with platinum or other drugs. Lately, the emerging role of PARP inhibitors has changed the landscape of opportunities for patients with EOC. All these strategies will be reviewed in this article.


First results of GEN-AU: Cloning of Deoxynivalenol- and Zearalenone-inactivating UDP-glucosyltransferase genes fromArabidopsis thaliana and expression in yeast for production of mycotoxin-glucosides.
First results of the GEN-AU pilot project "Fusarium virulence and plant resistance mechanisms" are reported. Employing genetically engineered yeast strains we have been able to clone genes from the model plantArabidopsis thaliana encoding UDP-glucosyltransferases which can inactivate deoxynivalenol (DON) and zearalenone (ZON). The structure of the metabolites produced by the transformed yeast strains were determined by LC-MS/MS as DON-3O-glucoside and ZON-4O-glucoside, respectively. ZON and derivatives added to glucosyltransferase expressing yeast cultures are converted into the corresponding glucosides in very high yield, opening an efficient way to produce reference materials for these masked mycotoxins.


Analysis of IgG4-positive clones in affected organs of IgG4-related disease.
We investigated class switch reaction (CSR) in affected organs and evaluated whether the same or genetically related clones exist in IgG4-RD. We studied three patients with IgG4-RD. Total cellular RNA was extracted from salivary glands and peripheral blood and lung tissue. Activation-induced cytidine deaminase (AID) and immunoglobulin heavy chain third complementarity determining region (IgVH-CDR3) of IgM and IgG4 were detected by reverse transcription polymerase chain reaction (RT-PCR). We analyzed the clonal relationship of infiltrating IgG4-positive cells, as compared with IgM. We determined the existence of common clones among organs and patients. AID was expressed in salivary glands of all patients and lung tissue in one. Closely related IgVH-CDR3 sequences in infiltrating IgG4-positive cells were detected in salivary glands and lung tissue. Identical IgVH-CDR3 sequence between IgM and IgG4 in salivary glands was detected in one patient, indicating CSR in salivary glands. Identical IgVH-CDR3 sequences of IgG4-positive cells were detected between salivary glands and peripheral blood in two patients. Four identical sequences of IgVH-CDR3 existed between patients. Interestingly, one of the four sequences was detected in all patients. Our results demonstrate the existence of common antigen(s) shared by patients with IgG4-RD.


Cardiac Imaging Integration in 2009 and Beyond: Cardiovascular magnetic resonance.
Cardiovascular magnetic resonance (CMR) is currently well recognized in clinical practice for the diagnosis and management of cardiovascular diseases. CMR is helpful in the diagnosis and prognosis of patients with myocardial infarction. The high spatial resolution of CMR enables accurate assessment of tissue characterization in various types of cardiomyopathy. In addition, CMR may play a complementary role with echocardiography in clinical evaluation of patients with valvular and congenital heart disease.


KMUP-1 inhibits H441 lung epithelial cell growth, migration and proinflammation via increased NO/CGMP and inhibited RHO kinase/VEGF signaling pathways.
This study investigates whether KMUP-1 protects soluble guanylate cyclase (sGC) and inhibits vascular endothelial growth factor (VEGF) expression in lung epithelial cells in hypoxia, therapeutically targeting epithelial proinflammation. H441 cells were used as a representative epithelial cell line to examine the role of sGC and VEGF in hypoxia and the anti-proinflammatory activity of KMUP-1 in normoxia. Human H441 cells were grown in hypoxia for 24-72 h. KMUP-1 (1, 10, 100 microM) arrested cells at the G0/G1 phase of the cell cycle, reduced cell survival and migration, increased p21/p27, restored eNOS, increased soluble guanylate cyclase (sGC) and PKG and inhibited Rho kinase II (ROCK-II). KMUP-1 (0.001-0.1 microM) concentration dependently increased eNOS in normoxia and did not inhibit phosphodiesterase-5A (PDE-5A) in hypoxic cells. Hypoxia-induced factor-1alpha (HIF-1alpha) and VEGF were suppressed by KMUP-1 but not by L-NAME (100 microM). The PKG inhibitor Rp-8-CPT-cGMPS (10 microM) blunted the inhibition of ROCK-II by KMUP-1. KMUP-1 inhibited thromboxane A2-mimetic agonist U46619-induced PDE-5A, TNF-alpha (100 ng/ml)-induced iNOS, and ROCK-II and associated phospho-p38 MAPK, suggesting multiple anti-proinflammatory activities. In addition, increased p21/p27 by KMUP-1 at higher concentrations might contribute to an increased Bax/Bcl-2 and active caspase-3/procaspase-3 ratio, concomitantly causing apoptosis. KMUP-1 inhibited ROCK-II/VEGF in hypoxia, indicating its anti-neoplastic and anti-inflammatory properties. KMUP-1 inhibited TNF-alpha-induced iNOS and U46619-induced PDE-5A and phospho-p38 MAPK in normoxia, confirming its anti-proinflammatory action. KMUP-1 could be used as an anti-proinflammatory to reduce epithelial inflammation.


Organ perfusion during partial REBOA in haemorrhagic shock: dynamic 4D-CT analyses in swine.
Resuscitative endovascular balloon occlusion of the aorta (REBOA) increases proximal blood pressure while inducing distal ischemia of visceral organs. The evaluation of distal ischemia severity during REBOA is a prerequisite for safe resuscitation of haemorrhagic shock patients with REBOA. We evaluated changes in blood flow and organ perfusion due to the degree of occlusion using dynamic 4D-computed tomography (CT). We compared the results with those of a previous study on euvolemic status. Delayed enhancement of the inferior vena cava (IVC) without retrograde flow was observed in the 4D-volume rendering images in the high-degree occlusion. The time-density curve (TDC) of the liver parenchyma (liver perfusion) and superior mesenteric vein (SMV) demonstrated a decreased peak density and a delayed peak in high-degree occlusion. The change rate of the area under the TDC of the liver and SMV decreased linearly as the degree of occlusion increased (PV, Y = -1.071*X + 106.8, r2 = 0.972, P = 0.0003; liver, Y = -1.050*X + 101.8, r2 = 0.933, P = 0.0017; SMV, Y = -0.985*X + 100.3, r2 = 0.952, P = 0.0009). Dynamic 4D-CT revealed less severe IVC congestion during P-REBOA in haemorrhagic shock than in euvolemia. Analyses of TDC of the liver and SMV revealed a linear change in organ perfusion, regardless of intravascular volume.


LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer.
Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.


Distribution, toxicity and bioaccumulation of trace metals in environmental matrices of an estuary in a protected area.
Mangroves are productive ecosystems that are highly threatened by anthropogenic activities. We investigated the environmental quality of the Serinhaém river estuary located in a legally protected area. Through chemical analysis of sediments and tissues of Cardisoma guanhumi, in addition to bioassays with elutriate involving Nitokra sp. and Thalassiosira pseudonana, we determined the contamination status and risk factors related to trace metals in the estuary. For the sediment, the concentrations of Cr and Ni were above the limit established by CONAMA n° 454/2012 in the "City" site, and Cr above the TEL in all sampling sites. Ecotoxicological tests showed high toxicity in samples from "City" and "Tributary". The elements Cr, Mn, Ni and Zn were also higher in crabs from these sites. Cr levels exceeded the Brazilian limit for food consumption. The bioaccumulation factor was not significant. However, the overall analysis proved that this estuary is increasingly impacted by anthropogenic pressure.


Families and schizophrenia: the view from advocacy.
Historically, families of persons who have schizophrenia often were blamed for the development of the condition and subsequently might have been excluded from care. Now these notions, which never had much systematic empiric support, have been abandoned. Family involvement often is critical to the recovery process and must be engaged actively whenever possible. This article calls for the inclusion of patients who have schizophrenia and their families in a redesigned model of care that is explicitly collaborative in its orientation and routinely includes evidence-based treatments that are informed by a vision of recovery.


Recent Trends and In-Hospital Mortality of Transarterial Chemoembolization (TACE) in Germany: A Systematic Analysis of Hospital Discharge Data between 2010 and 2019.
(1) Background: Transarterial chemoembolization (TACE) is a minimally invasive procedure, characterized by the selective occlusion of tumor-feeding hepatic arteries, via injection of an embolizing agent and an anticancer drug. It represents a standard of care for intermediate-stage hepatocellular carcinoma (HCC), and it is also increasingly performed in cholangiocarcinoma (CCA), as well as in liver metastases. Apart from the original method, based on intra-arterial infusion of a liquid drug followed by embolization, newer particle-based TACE procedures have been introduced recently. As yet, comprehensive data on current trends of TACE, as well as its in-hospital mortality in Germany, which could help to further improve outcome following TACE, are missing. (2) Methods: Based on standardized hospital discharge data, provided by the German Federal Statistical Office from 2010 to 2019, we aimed at systematically evaluating current clinical developments and in-hospital mortality related to TACE in Germany. (3) Results: A total of 49,595 individual cases undergoing TACE were identified within the observation period. The overall in-hospital mortality was 1.00% and significantly higher in females compared to males (1.12 vs. 0.93%; p < 0.001). We identified several post-interventional complications, such as liver failure (51.49%), sepsis (33.87%), renal failure (23.9%), and liver abscess (15.87%), which were associated with a significantly increased in-hospital mortality. Moreover, in-hospital mortality significantly differed between the underlying indications for TACE (HCC: 0.83%, liver metastases: 1.22%, and CCA: 1.40%), as well as between different embolization agents (liquid embolization: 0.80%, loaded microspheres: 0.92%, spherical particles: 1.54%, and non-spherical particles: 2.84%), for which we observed large geographic differences in their frequency of use. Finally, in-hospital mortality was significantly increased in centers with a low annual TACE case volume (<15 TACE/year: 2.08% vs. >275 TACE/year: 0.45%). (4) Conclusion: Our data provide a systematic overview of indications and embolization methods for TACE in Germany. We identified a variety of factors, such as post-interventional complications, the embolization method used, and the hospitals' annual case volume, which are associated with an increased in-hospital mortality following TACE. These data might help to further reduce the mortality of this routinely performed local-ablative procedure in the future.


Novel indanyl-substituted imidazo[1,2-a]pyridines as potent reversible inhibitors of the gastric H+/K+-ATPase.
A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2-a]pyridines with reduced lipophilicity was synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a competitive binding assay against H(+)/K(+)-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump.


The role of family in supporting adherence to diabetes self-care management practices: An umbrella review.
Synthesize a review of reviews of the family's role in supporting adherence to diabetes self-care management practices (DSMP) for adults with type 2 diabetes (DM2). An umbrella review. Scopus, Web of Science including MEDLINE, CINAHL via EBSCO, PubMed and Science Direct were searched for systematic reviews from their year of establishment until June 2021. The review followed the Joanna Briggs Institute (JBI) guidelines for umbrella reviews. The JBI data extraction form for systematic reviews and research syntheses was used for data extraction. Methodological quality was assessed using the JBI Critical Appraisal Checklist for Systematic reviews and Research Syntheses. Nineteen reviews met the inclusion criteria. The key findings were summarized using a narrative and thematic analysis methods. Four main themes were identified: family interactions and diabetes self-management, family support as informal social support, factors affecting families' roles, and tailoring culturally sensitive family-based interventions. There appears to be a consensus regarding the impact of family on adults' self-management of DM2. Additional research is needed to comprehend the role of the family in underrepresented populations and examine what constitutes a family and the diverse family functions in different groups. Enhancing adherence to self-care management practices is crucial for the well-being of adults with DM2. Family support is a key to successful self-care management at home. However, understanding the unique needs of adults with DM2 and their families can help healthcare professionals plan appropriate support strategies and sustainable family-based interventions. This review did not incorporate direct patients or public input as it summarizes evidence from previously published systematic reviews.


Enhancing anaerobic digestion of food waste with granular activated carbon immobilized with riboflavin.
Previous studies have shown that anaerobic digestion of food waste can be enhanced by addition of conductive materials that stimulate direct interspecies electron transfer (DIET) between bacteria and methanogens. However, at extremely high organic loading rates (OLRs), volatile fatty acids (VFAs) still tend to accumulate even in the presence of conductive materials because of an imbalance between the formation of fermentation products and the rate of methanogenesis. In this study, granular activated carbon (GAC) immobilized with riboflavin (GAC-riboflavin) was added to an anaerobic digester treating food waste. The GAC-riboflavin reactor operated stably at OLRs as high as 11.5 kgCOD/ (m3·d) and kept VFA concentrations below 69.4 mM, COD removal efficiencies, methane production rates, and biogas methane concentrations were much higher in the GAC-riboflavin reactor than the GAC- and non-amended reactors. Transcripts associated with genes that code for proteins involved in DIET based metabolism were somewhat more highly expressed by Methanothrix in the GAC-riboflavin reactor. However, it is unlikely that riboflavin acted as an electron shuttle to stimulate DIET. Rather, it seemed to provide nutrients that enhanced the growth of microorganisms involved in the anaerobic digestion process, including those that are capable of DIET.


Prevalence and timeline of nonmotor symptoms in idiopathic rapid eye movement sleep behavior disorder.
Parkinson disease (PD) patients may experience nonmotor symptoms (NMS) before Parkinsonism onset. Patients with idiopathic REM sleep behavior disorder (IRBD) eventually develop PD and may represent premotor PD. We aimed to evaluate the prevalence and perceived timeline of NMS in IRBD through validated scales and questionnaires used in PD research. In 44 IRBD patients and 40 matched controls, overall NMS evaluation was assessed by NMS questionnaire for Parkinson disease, olfaction by University of Pennsylvania Smell Identification Test, dysautonomia by scales for outcomes in Parkinson's disease-autonomic, constipation by Rome III criteria, depression by Hospital Anxiety and Depression Scale, cognitive impairment by Montreal cognitive assessment (MoCA) and hypersomnia by Epworth Sleepiness Scale. Patients were asked to report the perceived time of onset of hyposmia, constipation, and depression. Hyposmia (52.3 vs. 20.0 %, p = 0.002) and constipation (56.8 vs. 20.0 %, p = 0.001) were more frequent in patients than in controls. Patients reported more memory problems and showed a trend toward lower score in MoCA. Depression and hypersomnia were not more frequent in patients. The first symptom perceived was RBD in 38.6 % patients, hyposmia in 15.9 %, constipation in 11.4 %, and depression in 6.8 %. The temporal course of the NMS studied was heterogeneous. The three most common presentations were RBD followed by hyposmia; hyposmia followed by RBD; and hyposmia followed by RBD and constipation occurring at the same time span. IRBD patients frequently exhibit NMS that occur in premotor PD, particularly hyposmia and constipation. In IRBD, the perceived timeline of NMS is highly variable. This variability may suggest that pathological changes occurring in IRBD subjects are also heterogeneous and not restricted to the structures that regulate REM sleep.


Teratogenic effects of the Zika virus and the role of the placenta.
The mechanism by which the Zika virus can cause fetal microcephaly is not known. Reports indicate that Zika is able to evade the normal immunoprotective responses of the placenta. Microcephaly has genetic causes, some associated with maternal exposures including radiation, tobacco smoke, alcohol, and viruses. Two hypotheses regarding the role of the placenta are possible: one is that the placenta directly conveys the Zika virus to the early embryo or fetus. Alternatively, the placenta itself might be mounting a response to the exposure; this response might be contributing to or causing the brain defect. This distinction is crucial to the diagnosis of fetuses at risk and the design of therapeutic strategies to prevent Zika-induced teratogenesis.


Long-term effects of non-retrieved inferior vena cava filters on recurrences of venous thromboembolism in cancer and non-cancer patients: From the COMMAND VTE registry.
There is a paucity of data comparing the long-term outcomes after inferior vena cava (IVC) filters placement for patients with acute venous thromboembolism (VTE) between those with and without active cancer. In the COMMAND VTE Registry, we evaluated the effects of IVC filter use on the long-term clinical outcomes stratified by the presence and absence of active cancer. Among 2,626 patients with acute symptomatic VTE, there were 604 patients with active cancer, and 2022 patients without active cancer. IVC filters were placed and not retrieved in 455 patients (17%) in the entire cohort, in 150 patients (24.8%) in the active cancer stratum, and in 305 patients (15.1%) in the non-cancer stratum. In the entire cohort, non-retrieved IVC filter placement was not associated with a lower adjusted risk for PE recurrence (HR 0.59, 95% CI 0.30-1.15, P = 0.122), but with an increased adjusted risk for DVT recurrence (HR 2.27, 95% CI 1.43-3.60, P<0.001). In the non-cancer stratum, the non-retrieved IVC filter placement was associated with a decreased risk for PE (HR 0.29, 95% CI 0.09-0.93, P = 0.037), but not with an increased risk for DVT (HR 1.73, 95% CI 0.89-3.38, P = 0.108), while in the active cancer stratum, it was associated with an increased risk for DVT (HR 2.47, 95% CI 1.24-4.91, P = 0.010), but not with a decreased risk for PE (HR 0.82, 95% CI 0.34--1.96, P = 0.650). There were some differences in the risk-benefit balance between VTE patients with and without active cancer.


First-in-Human Implantation of a New Transcatheter Tricuspid Valve Replacement System.
Therapeutic options for patients with isolated severe to torrential tricuspid regurgitation have been limited. Because a surgical option is often not attractive, new catheter-based therapies are emerging. We report the first-in-human percutaneous transcatheter tricuspid valve replacement with the MonarQ system in a 75-year-old female patient with severely symptomatic torrential tricuspid regurgitation. (Level of Difficulty: Advanced.).


A Syndrome-Based Surveillance System for Infectious Diseases Among Asylum Seekers in Austrian Reception Centers, 2015-2018: Analysis of Reported Data.
Austria has been among the main European countries hosting incoming asylum seekers since 2015. Consequently, there was an urgent need to predict any public health threats associated with the arriving asylum seekers. The Department of Surveillance and Infectious Disease Epidemiology at the Austrian Agency for Health and Food Safety (AGES) was mandated to implement a national syndrome-based surveillance system in the 7 reception centers by the Austrian Ministry of Interior and Ministry of Health. We aimed to analyze the occurrence and spread of infectious diseases among asylum seekers using data reported by reception centers through the syndrome-based surveillance system from September 2015 through February 2018. We deployed a daily data collection system for 13 syndromes: rash with fever; rash without fever; acute upper respiratory tract infection; acute lower respiratory tract infection; meningitis or encephalitis; fever and bleeding; nonbloody gastroenteritis or watery diarrhea; bloody diarrhea; acute jaundice; skin, soft tissue, or bone abnormalities; acute flaccid paralysis; high fever with no other signs; and unexplained death. General practitioners, the first professionals to consult for health problems at reception centers in Austria, sent the tally sheets on identified syndromes daily to the AGES. We identified a total of 2914 cases, presenting 8 of the 13 syndromes. A total of 405 signals were triggered, and 6.4% (26/405) of them generated alerts. Suspected acute upper respiratory tract infection (1470/2914, 50.45% of cases), rash without fever (1174/2914, 40.29% of cases), suspected acute lower respiratory tract infection (159/2914, 5.46% of cases), watery diarrhea (73/2914, 2.51% of cases), and skin, soft tissue, or bone abnormalities (32/2914, 1.10% of cases) were the top 5 syndromes. The cooperation of the AGES with reception center health care staff, supported by the 2 involved ministries, was shown to be useful for syndromic surveillance of infectious diseases among asylum seekers. None of the identified alerts escalated to an outbreak.


Performance of various catalysts on treatment of refractory pollutants in industrial wastewater by catalytic wet air oxidation: A review.
The tremendous increase of industrialization and urbanization worldwide causes the depletion of natural resources such as water and air which urges the necessity to follow the environmental sustainability across the globe. This requires eco-friendly and economical technologies for depollution of wastewater and gases or zero emission approach. Therefore, in this context the treatment and reuse of wastewater is an environmental friendly approach due to shortage of fresh water. Catalytic wet air oxidation (CWAO) is a promising technology for the treatment of toxic and non-biodegradable organic pollutants in the wastewater generated from various industries. Various heterogeneous catalysts have been extensively used for treatment of various model pollutants such as phenols, carboxylic acids, nitrogenous compounds and different types of industrial effluents. The present review focuses on the literature published on the performances of various noble and non-noble metal catalysts for the treatment of various pollutants by CWAO. Reports on biodegradability enhancement of industrial wastewater containing toxic contaminants by CWAO are reviewed. Detailed discussion is made on catalyst deactivation and their mitigation study and also on the various factors which affects the CWAO reaction.


Venous thromboembolism GWAS reported genetic makeup and the hallmarks of cancer: Linkage to ovarian tumour behaviour.
Venous thromboembolism (VTE) is a common cardiovascular disease thought to be the outcome of an intricate interplay between acquired and inherited factors that act together to modify disease risk. Over the years, several single-nucleotide polymorphisms (SNPs) in candidate genes have been associated with disease risk, including F5 rs6025, F2 rs1799963, FGG rs2066865, ABO genetic variants, among others less common. More recently, genome-wide association studies (GWAS) have contributed to the identification of novel VTE-associated SNPs, some of them located in novel genes with no clear role in the haemostatic system, such as SLC44A2 rs2288904 and TSPAN15 rs78707713. Given the existence of a tight relationship between VTE and cancer, with both pathologies sharing biological pathways that allow one to promote the other, these SNPs constitute potential prognostic and predictive biomarkers currently needed for better management of cancer patients. Among solid tumours, ovarian cancer (OC) is one of the most frequently associated with VTE. Indeed, haemostatic components might have a significant impact in OC progression, and therefore, the clinical and biological implications of VTE-associated SNPs should be assessed in patients with this neoplasia.


Ex situ remediation of sediment from Serbia using a combination of electrokinetic and stabilization/solidification with accelerated carbonation treatments.
The application of three simple and cost-effective technologies for ex situ remediation of the sediment of Begej River in Serbia is presented in this paper. In the first step, conventional electrokinetic treatment (EK) was carried out to reduce the amount of contaminated sediment and enhance the accumulation of metals. Subsequently, stabilization/solidification (S/S) treatment was applied to the remaining portion of polluted sediment to immobilize the accumulated metals. At the same time, the influence of accelerated carbonation on the effectiveness of the treatment was evaluated. The immobilizing agents used in this study included bio ash produced by combustion of wheat and soy straw mixture and bio ash derived from molasses incineration. After the treatments, the risk assessment was performed by using the sequential extraction procedure (SEP) and TCLP and DIN 3841-4 S4 leaching tests. The results obtained after the EK treatment revealed a reduction in the amount of polluted sediment to a half. Leaching tests and SEP performed on S/S mixtures after a 28-day maturation period indicated that accelerated carbonation decreased the mobility of critical metals, especially in wheat and soy straw mixtures. Moreover, based on the leaching tests, all prepared mixtures were categorized as non-hazardous and safe for disposal according to the relevant Serbian regulations. The newly developed method that combines EK and S/S treatments with the addition of accelerated carbonation produced reduced volumes of stabilized sediment which is safe for disposal.


A hyperlipidemic rabbit model provides new insights into pulmonary zinc exposure effects on cardiovascular health.
This study ascertains the effects of zinc, a major component of particulate matter, on pulmonary and systemic endpoints using hyperlipidemic rabbits to model diet-induced human atherosclerosis. New Zealand White rabbits were fed a normal or cholesterol-enriched diet and then were intratracheally instilled 1x/week for 4 weeks with saline or 16 microg/kg of zinc, equal parts sulfate and oxide. Physiologic responses, blood after each exposure, and terminal bronchoalveolar lavage (BAL) were assessed. Rabbits fed a cholesterol-rich diet developed hyperlipidemia and had consistently higher circulating leukocyte counts than rabbits fed normal chow. Within minutes after zinc instillation, saturation of peripheral oxygen was decreased in hyperlipidemic rabbits and heart rate was increased in hyperlipidemic rabbits with total serum cholesterol levels greater than 200 mg/dl. Total circulating leukocytes levels were increased 24 h after the first zinc instillation, but upon repeated exposures this effect was attenuated. After repeated zinc exposures, BAL fluid (BALF) N-acetylglucosaminidase activity was increased regardless of hyperlipidemic state. Hyperlipidemic rabbits had an increase in BALF-oxidized glutathione and a decrease in serum nitrite. The study elucidates mechanisms by which the zinc metal component of PM drives cardiovascular health effects, as well as the possible susceptibility induced by hyperlipidemia. Furthermore, the study exemplifies the benefits of monitoring circulatory physiology during exposure as well as after exposure.


Cannula provoked upper extremity superficial vein thrombophlebitis: are we overtreating?
Cannula provoked upper extremity superficial vein thrombophlebitis (UESVT) is common. Retrospective audit of 93 consecutive patients, 51% male, median age 57 years (range 20-91), with symptomatic UESVT revealed varied management including symptomatic management (37%), prophylactic (37%) and higher dose anticoagulation (27%). There was 2% (95% confidence interval (CI) 0-7.6) thrombus extension and 1% (95% CI 0-5.9) major bleeding, both limited to cancer. We argue anticoagulation is unnecessary in most UESVT patients.


Ether lipids and analogs in experimental cancer therapy. A brief review of the Munich experience.
This review covers the work of our laboratory on the antineoplastic activity of some ether lipids and derivatives that are related to platelet-activating factor (PAF). Various 1-O-alkyl lysophospholipid derivatives (ALP) show therapeutic activity in mouse transplant tumor models and in metastatic 3-Lewis lung carcinoma in vivo. However, certain autochthonous mouse leukemias and radiation-induced lymphomas are resistant to ALP treatment. The therapeutic effects of these compounds are partially due to the activation of cytotoxic macrophages and direct cytotoxicity. Approximately 20 ether lipids and derivatives were tested for direct cytotoxicity in cells from human solid tumors and leukemias using [3H]thymidine uptake, trypan blue dye exclusion, human tumor clonogenic assays (HTCA) and cell morphology as criteria. Certain ALP, thioether lysophospholipid-derivatives (TLP), ether-linked lipoidal amines, sn-2 analogs of PAF, and conjugates of ether lipids and cytosine arabinoside were found cytotoxic in a dose- and time-dependent fashion. Cytotoxicity of some of the ether lipids tested is based on destruction of cell membranes. Structure-activity studies were performed to better understand the mechanisms leading to accumulation and cytotoxicity of ALP. Comparative studies with normal bone marrow cells and leukemic blasts from humans revealed preferential anti-leukemic cytotoxicity of three ether lipids.


Lipid-dependent protein sorting at the trans-Golgi network.
In eukaryotic cells, the trans-Golgi network serves as a sorting station for post-Golgi traffic. In addition to coat- and adaptor-mediated mechanisms, studies in mammalian epithelial cells and yeast have provided evidence for lipid-dependent protein sorting as a major delivery mechanism for cargo sorting to the cell surface. The mechanism for lipid-mediated sorting is the generation of raft platforms of sphingolipids, sterols and specific sets of cargo proteins by phase segregation in the TGN. Here, we review the evidence for such lipid-raft-based sorting at the TGN, as well as their involvement in the formation of TGN-to-PM transport carriers. This article is part of a Special Issue entitled Lipids and Vesicular Transport.


Genomic instability in myeloid malignancies: increased reactive oxygen species (ROS), DNA double strand breaks (DSBs) and error-prone repair.
Disease progression in myeloid malignancies results from the accumulation of "mutations" in genes that control cellular growth and differentiation. Many types of genetic alterations have been identified in myeloid diseases. However, the mechanism(s) by which these cells acquire genetic alterations or "Genomic instability", is less well understood. Increasing evidence suggests that the genetic changes in myeloid malignancies lead to increased production of endogenous sources of DNA damage, such as, reactive oxygen species (ROS). The fusion gene BCR-ABL in chronic myeloid leukemia (CML), FLT3/ITD in acute myeloid leukemia (AML), and RAS mutations in myelodysplastic syndromes (MDS)/myeloproliferative diseases (MPD) result in ROS production. Increased ROS can drive a cycle of genomic instability leading to DNA double strand breaks (DSBs) and altered repair that can lead to acquisition of genomic changes. Evidence is coming to light that defects in a main repair pathway for DSBs, non-homologous end-joining (NHEJ), lead to up-regulation of alternative or "back-up" repair that can create chromosomal deletions and translocations. This article will review evidence for activation of RAS/PI3K/STAT pathways, that lead to increased ROS, DNA damage and defective repair in myeloid diseases, a mechanism for acquisition of additional mutations that can drive disease progression.


Can receipt of a regular postcard reduce suicide-related behaviour in young help seekers? A randomized controlled trial.
Suicide attempt, ideation and deliberate self-harm are common among adolescents. Limited evidence exists regarding interventions that can reduce risk; however, research indicates that maintaining contact with at-risk adults following discharge from services via letter or postcard can reduce risk. The aim of the study was to test a postcard intervention among people aged 15-24 who presented to mental health services but were not accepted, yet were at risk of suicide. A randomized controlled trial of 3 years in duration was used. The intervention consisted of 12 postcards sent once a month for 12 months following presentation to the service. Key outcomes of interest were reduced rates of suicide attempt, suicidal ideation and deliberate self-harm, assessed at 12 and 18 months. Participants reported that they liked receiving the postcard and that they used the strategies recommended. However, no significant effect of the postcard intervention was found on suicide risk, although participants in both groups improved on measures of mental health over the course of the study. There remains a need for further research into youth-friendly interventions for young people at risk of suicide.


Characterisation of the large-scale production process of oyster mushroom (Pleurotus ostreatus) with the analysis of succession and spatial heterogeneity of lignocellulolytic enzyme activities.
Oyster mushroom (Pleurotus ostreatus) lignocellulolytic enzyme activity pattern and variation was investigated in a large-scale facility from spawning until the end of the second flush. In the first cultivation cycle laccase production reached its peak during vegetative growth stage, while manganese-peroxidase showed the highest activity during fruiting body induction. Cellulose and hemicellulose degrading enzymes had maximal activity at the beginning of flush and harvest stage. The enzyme activities showed similar tendencies among five different mushroom substrate blocks representing a production house. The spatial variability analysis of enzyme activities pointed out the within substrate block heterogeneity as the main source if variation. This result was confirmed by Combined Cluster and Discriminant Analysis (CCDA) method showing minimal among block heterogeneity considering the whole investigation period; furthermore in the first cultivation cycle all blocks were grouped into one cluster.


Large scale purification and characterization of TraI endonuclease encoded by sex factor plasmid R100.
The TraI protein encoded by plasmid R100 was purified in a large scale by monitoring the strand- and site-specific nicking activity at the origin of transfer, oriT. The N-terminal amino acid sequence of the purified protein was identical to that deduced from the DNA sequence of an open reading frame encoding TraI. The TraI protein is a DNA helicase which is highly processive and unwinds DNA in the 5' to 3' direction. The Stokes radius and the sedimentation coefficient for the TraI protein in 200 mM NaCl indicate that the protein is a rod-shaped monomer, whose native molecular weight is 186,000. Chemical cross-linking analysis revealed that there exist more dimers of TraI under the low salt conditions, under which both nicking and unwinding reactions catalyzed by TraI are the most efficient, indicating that the TraI protein is functionally active in a dimer form. TraI hardly introduced a nick into the linearized plasmid DNA and only slightly into the relaxed closed circular DNA, indicating that TraI requires superhelical structure of substrate DNA for the nicking reaction. Deletion analysis in the oriT region revealed that a particular region of 54 base pairs containing oriT is required for the nicking reaction.


Relief from chronic pain by low power laser irradiation.
In a double blind study, repeated irradiation with a low-power (1 mW) helium-neon laser produced relief in subjects with chronic pain. Analgesia was observed after exposure of the skin overlying the radial, medial and saphenous nerves and in some cases, irradiation of the appropriate painful nerve. Exposure of areas of skin not innervated by these nerves did not result in pain relief. Of the patients with trigeminal neuralgia, post-herpetic neuralgia, sciatica and ostearthritis, 19 of 26 experienced pain relief without the use of drugs. Patients who received sham stimulation reported no analgesia. Subjects who were exposed to laser irradiation had a large increase in the urinary excretion of 5-hydroxyindoleacetic acid, the degradation product of serotonin.


Influence of diet based on bread supplemented with raw and roasted cocoa bean extracts on physiological indices of laboratory rats.
The aim of the study was to determine the physiological indices of laboratory rats as a response to a diet consisting of a bread supplemented with freeze-dried water extracts of raw and roasted cocoa beans of Forastero variety. The influence of different cocoa extracts on oxidative stress, hyperglycemia, and lipid metabolism was studied during long-term feeding of laboratory rats with bread supplemented with cocoa extracts. During the 4-week experimental feeding samples of rats feces were subjected to analysis and after its completion, biological samples were collected i.e. intestines content, blood, and organs retrieved individually from each rat. The observed changes indicate the biological activity of polyphenol extracts and other components of cocoa beans present in the prepared extracts. The differences in the results obtained for the analyzed parameters of the gastrointestinal tract revealed that the cocoa bean extracts being the subject of this investigation differently affected the physicochemical properties of rats' intestines, including intestinal microflora. The results show the influence of the diet on the activity of both fecal and cecal enzymes. Applied nutrition treatment varied the concentration and total production of volatile fatty acids in the cecum. Furthermore, the diverse composition of the applied diet affected the level of some biochemical indicators of blood serum of rats. Additionally, to a small extent influenced the analyzed indicators of the antioxidative status of rats as characterized by the concentration of substances reacting with thiobarbituric acid in internal organs.


A novel F8 variant in a Chinese hemophilia A family and involvement of X-chromosome inactivation: A case report.
Hemophilia A (HA) is an X-linked recessive bleeding disorder, which shows factor VIII (FVIII) deficiency caused by genetic variant in F8 gene. Males with F8 variants are affected, whereas female carriers with a wide range of FVIII levels are usually asymptomatic, it is possible that different X-chromosome inactivation (XCI) may effect the FVIII activity. We identified a novel variant F8: c.6193T > G in a Chinese HA proband, it was inherited from the mother and grandmother with different FVIII levels. We performed Androgen receptor gene (AR) assays and RT-PCR. AR assays revealed that the X chromosome with the F8 variant was severely skewed inactivated in the grandmother with higher FVIII levels, but not in the mother with lower FVIII levels. Further, RT-PCR of mRNA confirmed that only the wild allele of F8 was expressed in the grandmother, with lower expression in the wild allele of the mother. Our findings suggest that F8: c.6193T > G could be the cause of HA and that XCI affected the FVIII plasma levels in female carriers.


Weight estimation in two groups of Ghanaian children with chronic diseases using Broselow, Mercy, PAWPER XL and PAWPER XL-MAC tapes.
The performance of various weight estimation methods in children with sickle cell disease (SCD) and heart disease (HD) has not been studied. We aimed to determine and compare the accuracies of the Broselow, Mercy, PAWPER XL and PAWPER XL-MAC tapes in Ghanaian children with no known chronic diseases (controls), SCD and HD. We prospectively recruited 631 children (199 with HD, 209 SCD and 223 controls) from the Komfo Anokye Teaching Hospital (KATH). Their weights were estimated using the Broselow, Mercy, PAWPER XL and PAWPER XL-MAC tapes. These estimated weights were compared to measured weight using mean percentage error (MPE), the proportion of weight estimates within ±10% (P10) and ±20% (P20) of measured weight. Bland-Altman limits of agreement (LOA) were determined to assess the precision of weight estimation and agreement with measured weight. The PAWPER XL, Mercy and PAWPER XL-MAC were the most accurate in all groups of children studied. All methods except the Broselow tape (BT), which performed best in the control group, had their best performance among children with SCD with negligible critical error rates (proportion of children with weight estimates > 20% of their actual weight). The P20 in the various groups of children using the BT were 88.36%, 80.21% and 51.10% respectively in the control, SCD and HD groups. The Mercy, PAWPER XL and PAWPER XL MAC tapes were generally above 90% in all groups. The Mercy, PAWPER XL and PAWPER XL-MAC tapes performed significantly better than the BT in all groups of children studied. These methods of weight estimation performed best in children with SCD with very little critical error.


[Transfusion in elderly patients].
The frequency of anemia is responsible of a frequent use of transfusion in elderly patients. However, transfusion in elderly patients requires several warnings. First, semiology of elderly patients is characterized with atypical clinical signs, and anemia tolerance is often difficult to appreciate. Second, numerous comorbidities make of elderly patients an heterogeneous population, in which guidelines are poorly applicable. Last, elderly patients are particularly sensitive to iatrogenic events, and the haemodynamic overload related to transfusion has to be carefully managed. All these difficulties raise the need of prospective studies on transfusion in elderly patients to validate clinical practice.


Connecting with others in the midst of stressful upheaval on September 11, 2001.
This study was originally planned from September tenth through twelfth to assess concurrent use of three real-time data sources during a usual day. When the World Trade Center towers collapsed, the plan expanded to describe 24-hour blood pressure and heart rate, natural environment word use, television viewing/radio listening, and self-reported diary feelings for six undergraduate students in the midst of stressful upheaval. Heart rate, "we" word-use and television viewing/radio listening increased over time. Higher negative and lower positive feelings/emotions occurred during morning hours on September 11. Students connected with others and shared good thoughts. Measurement with real-time data sources was informative.


Effects of intravascular, intrauterine transfusion on prenatal and postnatal hemolysis and erythropoiesis in severe fetal isoimmunization.
In an investigation of the effects of intrauterine, intravascular transfusions (IUT) on fetal and neonatal hemolysis and erythropoiesis, 12 fetuses who received IUT for treatment of severe isoimmunization had serial measurements of hemoglobin concentration, Kleihauer-Betke stains to detect fetal hemoglobin-containing erythrocytes, and determination of plasma erythropoietin (EPO) concentration before each IUT, at birth, and postnatally. Reticulocyte counts and sensitizing antibody titers were measured in five fetuses. Mean values before the first IUT, before the final IUT, and at birth were as follows: hemoglobin level, 6.1, 9.1, and 11.3 gm/dl; reticulocyte count, 22.7%, 0.5%, and 0.9%; fetal hemoglobin-containing erythrocytes, 100%, 1.6%, and 1.5%; and EPO level, 12, 56, and 756 mU/ml, respectively. Only one neonate required exchange transfusion. In the first month postnatally, all infants had a profound anemia. All but one infant required simple blood transfusions postnatally. Before the first postnatal transfusion, mean hemoglobin concentration was 6.2 gm/dl, mean reticulocyte count was 0.8%, mean erythropoietin concentration was 23 mU/ml, and the sensitizing antibody titer remained markedly elevated. Except for the surge of EPO at birth, EPO levels did not rise prenatally or postnatally unless marked anemia (hemoglobin level less than 5 gm/dl) occurred. These observations suggest that the intrauterine and postnatal anemia in fetuses who receive IUTs may be explained both by hemolysis of newly formed erythrocytes by circulating antibody, which typically persisted for more than a month after birth, and by suppressed erythropoiesis.


In vitro trials of some antimicrobial combinations against Staphylococcus aureus and Pseudomonas aeruginosa.
Staphylococcus aureus and Pseudomonas aeruginosa are rapidly increasing as multidrug resistant strains worldwide. In nosocomial settings because of heavy exposure of different antimicrobials, resistance in these pathogens turned into a grave issue in both developed and developing countries. The aim of this study was to investigate in vitro antibiotic synergism of combinations of β-lactam-β-lactam and β-lactam-aminoglycoside against clinical isolates of S. aureus and P. aeruginosa. Synergy was determined by checkerboard double dilution method. The combination of amoxicillin and cefadroxil was found to be synergistic against 47 S. aureus isolates, in the FICI range of 0.14-0.50 (81.03%) followed by the combination of streptomycin and cefadroxil synergistic against 44 S. aureus isolates in the FICI range of 0.03-0.50 (75.86%). The combination of streptomycin and cefadroxil was observed to be synergistic against 39 P. aeruginosa isolates in the FICI range of 0.16-0.50 (81.28%). Further actions are needed to characterize the possible interaction mechanism between these antibiotics. Moreover, the combination of streptomycin and cefadroxil may lead to the development of a new and vital antimicrobial against simultaneous infections of S. aureus and P. aeruginosa.


GLUT4 translocation is not impaired after acute exercise in skeletal muscle of women with obesity and polycystic ovary syndrome.
The aim of this study was to examine the effects of acute exercise on insulin signaling in skeletal muscle of women with polycystic ovary syndrome (PCOS) and controls (CTRL). Fifteen women with obesity and PCOS and 12 body mass index-matched CTRL participated in this study. Subjects performed a 40-min single bout of exercise. Muscle biopsies were performed before and 60 min after exercise. Selected proteins were assessed by Western blotting. CTRL, but not PCOS, showed a significant increase in PI3-k p85 and AS160 Thr 642 after a single bout of exercise (P = 0.018 and P = 0.018, respectively). Only PCOS showed an increase in Akt Thr 308 and AMPK phosphorylation after exercise (P = 0.018 and P = 0.018, respectively). Total GLUT4 expression was comparable between groups (P > 0.05). GLUT4 translocation tended to be significantly higher in both groups after exercise (PCOS: P = 0.093; CTRL: P = 0.091), with no significant difference between them (P > 0.05). A single bout of exercise elicited similar GLUT4 translocation in skeletal muscle of PCOS and CTRL, despite a slightly differential pattern of protein phosphorylation. The absence of impairment in GLUT4 translocation suggests that PCOS patients with obesity and insulin resistance may benefit from exercise training.


Ventilator autotriggering : An underestimated phenomenon in the determination of brain death.
Ventilator autotriggering (VAT) may induce uncertainty in diagnosing brain death because it may falsely suggest a central respiratory drive in brain-dead patients where no intrinsic respiratory efforts exist. Since the lack of international standardization of brain death criteria contributes to the loss of potential donor organs, it is important to be aware of this phenomenon, which is a not well-known confounder in the process of diagnosing brain death. The national official recommendations or guidelines for the determination of brain death and organ transplantation of 15 selected European countries (including all 8 member states of the Eurotransplant network) were evaluated with respect to VAT. In addition, a literature search (PubMed, Google Scholar) using the term "ventilator autotriggering", synonyms or similar content-related wording was carried out. The VAT phenomenon was mentioned in 3 of the 15 official recommendations and guidelines on diagnosing brain death. The causes and management of VAT are presented in different ways in the reviewed official recommendations and guidelines. The phenomenon of VAT is inconsistently addressed in the national guidelines and recommendations for the determination of brain death and should, therefore, be included in future harmonized brain death codes. Detection and correction of VAT should be implemented as early as possible by a structured procedure. Additional training and information on this phenomenon should be made available to the entire intensive care unit staff.


Rotavirus VP6 modified for expression on the plasma membrane forms arrays and exhibits enhanced immunogenicity.
The major inner capsid protein of rotavirus is VP6, a 42-kDa polypeptide that forms the icosahedral surface of the rotavirus single-shelled particle. A chimeric form of VP6 (VP6sc) was constructed containing an upstream leader sequence derived from the influenza virus hemagglutinin and a downstream membrane-spanning (anchor) domain from a mouse immunoglobulin gene. When VP6sc was expressed in cells using a recombinant vaccinia virus, the protein was transported, glycosylated, and anchored in the plasma membrane as a trimer with the major domains of the protein orientated externally. Immunofluorescence and immunolabeling with colloidal gold indicated that VP6sc also localized in patches on the cell surface; electron microscopy revealed that the protein assembled into two-dimensional arrays which exhibited the same periodicity as the paracrystalline arrays formed by purified (viral) VP6. Mice inoculated with a recombinant vaccinia virus that expressed VP6sc produced rotavirus-specific antibodies at a titer 10 times higher than that achieved when wild-type, intracellular VP6 was delivered in the same way. Presentation at the cell surface therefore may represent a general method for enhancing the immunogenicity of rotavirus proteins.


Novel ester tethered dihydroartemisinin-3-(oxime/thiosemicarbazide)isatin hybrids as potential anti-breast cancer agents: Synthesis, in vitro cytotoxicity and structure-activity relationship.
A series of ester tethered dihydroartemisinin-3-(oxime/thiosemicarbazide)isatin hybrids 7a-p were designed, synthesized, and assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR, and MDA-MB-231/ADR breast cancer cell lines. Among them, hybrids 7a,f (IC50 : 1.33-3.84 µM) showed potent activity against triple-negative (MDA-MB-231 and MDA-MB-231/ADR) breast cancer cell lines, and hybrid 7f (IC50 : 3.90 and 10.18 µM) also demonstrated promising activity against estrogen receptor-positive breast cancer cells (MCF-7 and MCF-7/ADR), and the activity was superior to these of artemisinin, dihydroartemisinin, and ADR, revealing their potential to fight against both drug-sensitive and drug-resistant breast cancers. The enriched structure-activity relationships may facilitate further design of more active candidates.


[Genetic study of stable inheritable cell resistance to colchicine. Chromosomal and hybridization analysis].
The karyotype of mouse B-82CH-9 and B-82CH-9/CAP cell lines as well as the inheritance of their colchicine resistance in somatic cell hybrids were studied. We found earlier that these cell lines differ from other colchicine-resistant mouse and Djungarian hamster cell lines in stability of drug resistance and the lack of overproduction of the p22 polypeptide. The analysis of chromosomes stained by trypsin G-banding technique showed that, unlike mouse L-53 cells possessing unstable colchicine resistance, the B-82CH-9 and its B-82CH-9/CAP derivative had neither chromosomes with long homogeneously staining regions (HSRs) nor other cytological manifestations of gene amplification, such as double-minute chromosomes and small chromatin bodies. The hybrids of B-82CH-9/CAP and sensitive to colchicine Djungarian hamster DM-15 cells appeared in the HAT medium 10-fold more frequently than in the HAT medium containing colchicine. The hybrids grown in the HAT medium had complete chromosome complements of parent cells, while hybrids isolated from the medium with colchicine lacked some Djungarian hamster and mouse chromosomes. 4 independent clones and the cell line originated from the mixture of about 100 clones grown in HAT medium were sensitive to colchicine. We failed to transfer colchicine resistance with B-82CH-9/CAP microcells, while they were able to transfer HPRT+. At the same time, microcells of DM2/1 cells, possessing unstable colchicine resistance connected with gene amplification, could transfer both TK+ and resistance to colchicine. These results indicate that colchicine resistance of B-82CH-9 is suppressed in somatic cell hybrids. Stability of the trait, the absence of cytological manifestations of gene amplification, the lack of overproduction of p22 polypeptide and recessive inheritance suggest that colchicine resistance in these cells is not connected with gene amplification but rather results from another genetic alteration, possibly, gene mutation.


Mechanisms of Infection in Zika Virus.
Zika virus (ZIKV) is a mosquito-borne flavivirus that was first identified in Uganda in 1947, then was essentially neglected for six decades [...].


Chromatographic analysis, isolation and partial characterization of two photocatalysed reaction products of haem and quinone.
Quinone was reacted in vitro with free haem under ultraviolet light. Two principal products were detected by liquid chromatography and purified by column chromatography. Mass spectral and Fourier transform infrared analyses showed that both products contained pyrroles and that the first product was probably an ether formed after reaction with the haem vinyl moieties. This product was entirely different from the known N-alkyl intermediates in the haem-catalysed epoxidation reactions of porphyrin dimerization by quinone.


Passing the Turing Test Does Not Mean the End of Humanity.
In this paper we look at the phenomenon that is the Turing test. We consider how Turing originally introduced his imitation game and discuss what this means in a practical scenario. Due to its popular appeal we also look into different representations of the test as indicated by numerous reviewers. The main emphasis here, however, is to consider what it actually means for a machine to pass the Turing test and what importance this has, if any. In particular does it mean that, as Turing put it, a machine can "think". Specifically we consider claims that passing the Turing test means that machines will have achieved human-like intelligence and as a consequence the singularity will be upon us in the blink of an eye.


Oxide-Derived Core-Shell Cu@Zn Nanowires for Urea Electrosynthesis from Carbon Dioxide and Nitrate in Water.
Urea electrosynthesis provides an intriguing strategy to improve upon the conventional urea manufacturing technique, which is associated with high energy requirements and environmental pollution. However, the electrochemical coupling of NO3- and CO2 in H2O to prepare urea under ambient conditions is still a major challenge. Herein, self-supported core-shell Cu@Zn nanowires are constructed through an electroreduction method and exhibit superior performance toward urea electrosynthesis via CO2 and NO3- contaminants as feedstocks. Both 1H NMR spectra and liquid chromatography identify urea production. The optimized urea yield rate and Faradaic efficiency over Cu@Zn can reach 7.29 μmol cm-2 h-1 and 9.28% at -1.02 V vs RHE, respectively. The reaction pathway is revealed based on the intermediates detected through in situ attenuated total reflection Fourier transform infrared spectroscopy and online differential electrochemical mass spectrometry. The combined results of theoretical calculations and experiments prove that the electron transfer from the Zn shell to the Cu core can not only facilitate the formation of *CO and *NH2 intermediates but also promote the coupling of these intermediates to form C-N bonds, leading to a high faradaic efficiency and yield of the urea product.


Predictive (subtle or overlooked) initial head CT findings in patients who develop delayed chronic subdural hematoma.
With the aging population, the incidence of chronic subdural hematoma (CSDH) is expected to rise. Once symptomatic the morbidity from CSDH is not insignificant. We studied patients who had a minor head injury and CT brain scan prior to developing CSDH to determine if there were any predictors on these scans for subsequent development of a CSDH. A retrospective review was performed on all patients operated for CSDH over a 3-year period and a review performed on those who had imaging studies at the time of a preceding minor head injury. Seven of 37 patients had CT scans prior to developing CSDH. All had evidence of small increases in CSF intensity on the side or sides of the subsequent CSDH. In conclusion, in those patients with a history of minor head injury prior to developing a CSDH, CT brain demonstrated small increases in cerebral spinal fluid (CSF) intensity on the side or sides of the subsequent CSDH. Recognizing this finding may be helpful in monitoring these patients or initiating medical therapy.


Relationship between schistosomicidal drug efficacy, gonadal steroid hormonal changes and state of disease immunopathology in murine schistosomiasis mansoni.
The schistosomicidal efficacy of praziquantel (2 x 500 mg/kg), oxamniquine (1 x 100 mg/kg) and combined one-third the curative dose of each of them (333 mg/kg praziquantel + 33 mg/kg oxamniquine), were correlated to gonadal steroid hormonal changes and state of disease immunopathology, in mice infected with 100 Schistosoma mansoni (S. mansoni) cercariae. Maximum efficacy recorded with combination regimen particularly 4 weeks after treatment, was accompanied by maximum reduction in granuloma volume (65%), least fall in testosterone level (-56.2 and -60.2% in male and female mice respectively) and increased progesterone level (+33.9 and +81.5% in male and female mice respectively). These findings revealed a potentiated effect of combination therapy on mature infection and the possible involvement of gonadal steroid hormones in affecting the efficacy of schistosomicidal drugs and state of disease immunopathology.


Motoneuron loss in the abducens nucleus of wobbler mice.
The 'wobbler' mutant mouse can be recognized at about 4 weeks of age by its tremor and atrophy of forelimb muscles. In addition to degeneration of spinal motoneurons, especially in cervical spinal cord, selected bulbar motoneurons have also been reported to degenerate in the mutant. We examined a cranial motor nucleus and found a 31% loss of abducens motoneurons in 4-5-week-old wobbler mice as compared to age-matched control mice.


Formation of the neurotransmitter glycine from the anticonvulsant milacemide is mediated by brain monoamine oxidase B.
Milacemide (2-n-pentylaminoacetamide) is a secondary monoamine that in the brain is converted to glycinamide and glycine. This oxidative reaction was suspected to involve the reaction of monoamine oxidase (MAO). Using mitochondrial preparations from tissues that contain MAO-A and -B (rat brain and liver), MAO-A (human placenta), and MAO-B (human platelet and bovine adrenal chromaffin cell), it has been established that mitochondria containing MAO-B rather than MAO-A oxidize (H2O2 production and glycinamide formation) milacemide. The apparent Km (30-90 microM) for milacemide oxidation by mitochondrial MAO-B preparations is significantly lower than that for milacemide oxidation by mitochondrial MAO-A (approximately 1,300 microM). In vitro MAO-B (l-deprenyl and AGN 1135) rather than MAO-A (clorgyline) selectively inhibited the oxidation of milacemide. These in vitro data are matched by ex vivo experiments where milacemide oxidation was compared to oxidation of serotonin (MAO-A) and beta-phenylethylamine (MAO-B) by brain mitochondria prepared from rats pretreated with clorgyline (0.5-10 mg/kg) and l-deprenyl (0.5-10 mg/kg). Furthermore, in vivo experiment demonstrated that l-deprenyl selectively increased the urinary excretion of [14C]milacemide and the total radioactivity with a concomitant decrease of [14C]glycinamide. Such changes were not observed after clorgyline treatment, but were evident only at doses beyond clorgyline selectivity. The present data therefore demonstrate that milacemide is a substrate for brain MAO-B, and its conversion to glycinamide, further transformed to the inhibitory neurotransmitter, glycine, mediated by this enzyme may contribute to its pharmacological activities.


A matching-adjusted indirect treatment comparison (MAIC) of daratumumab-bortezomib-melphalan-prednisone (D-VMP) versus lenalidomide-dexamethasone continuous (Rd continuous), lenalidomide-dexamethasone 18 months (Rd 18), and melphalan-prednisone-thalidomide (MPT).
D-VMP is a novel treatment for transplant-ineligible newly diagnosed multiple myeloma (TIE NDMM). D-VMP significantly prolonged PFS versus VMP in the ALCYONE trial. The FIRST trial investigated Rd given in 28-day cycles until disease progression, Rd for 18 cycles, and MPT for 12 cycles for TIE NDMM. As no randomized controlled trials comparing D-VMP to standard-of-care regimens such as those in FIRST are available, an MAIC was performed to assess relative OS and PFS for D-VMP from ALYCONE and Rd continuous, Rd 18, and MPT from FIRST. Individual patient data for D-VMP in ALCYONE were weighted to match aggregated baseline patient characteristics for each arm of FIRST. D-VMP significantly improved OS versus MPT and Rd 18, with a trend favoring D-VMP versus Rd continuous. D-VMP performed significantly better than all FIRST comparators for PFS. This MAIC demonstrates OS and PFS benefits for D-VMP versus Rd continuous, Rd 18, and MPT.


Role of natriuretic peptide to predict cardiac abnormalities in patients with hereditary transthyretin amyloidosis.
Familial amyloid polyneuropathy (FAP) mainly targets the peripheral nervous system and heart. Early noninvasive detection of cardiac impairment is critical for therapeutic management. To assess if amino-terminal pro-brain natriuretic peptide (NT-proBNP) or troponin T (cTnT) can predict echocardiographic left-ventricle (LV) impairment in FAP. Thirty-six asymptomatic carriers and patients with FAP had echocardiographic measurement of left-ventricular (LV) systolic function, hypertrophy (LVH) and estimation of filling pressure (FP). Overall, median age, NT-proBNP, and LV ejection fraction were, respectively, 59 years (41-74), 323 pg/ml (58-1960), and 60% (51-66). Twelve patients had increased cTnT. Prevalence of ATTR gene mutations was 53% for Val30Met. Four individuals were asymptomatic, 6 patients had isolated neurological clinical signs, and 26 had echo-LV abnormalities. The ROC curve identified NT-proBNP patients with echo-LV abnormalities (area: 0.92; (0.83-0.99), p = 0.001) at a threshold >82 pg/ml with a sensitivity of 92%, and a specificity of 90%. Increased in NT-proBNP occurred in patients with SD and/or LVH with or without increase in FP. Elevated cTnT (>0.01 ng/ml) was only observed in patients with LVH and systolic dysfunction, with or without FP. In FAP, NT-proBNP was associated with cardiac impairment suggesting that NT-proBNP could be used in carriers or in FAP patients with only neurologic symptoms for identifying the appropriate time to start cardiac echocardiographic assessment and follow-up. cTnT identified patients with severe cardiac disease.


Identifying women at risk of delayed breast cancer diagnosis.
Delays in breast cancer diagnosis contribute to increased morbidity and mortality. Factors related to the occurrence of delayed diagnosis have not been well studied. A retrospective cohort study of 5,464 women newly diagnosed with breast cancer from 1999 through 2006 was conducted at a comprehensive cancer center in Boston. A delayed diagnosis was defined as an interval greater than 90 days between the patient's first breast-related problem that prompted seeking of medical care and the breast cancer diagnosis based on biopsy. 938 (17%) patients had a delayed breast cancer diagnosis. Non-white race or Hispanic ethnicity (adjusted odds ratio [OR] = 1.46, 95% confidence interval [CI] = 1.13-1.90), living more than 26 miles from Boston (OR 1.46, 95% CI = 1.25-1.71), and initial presentation with a lump found by the patient herself (OR = 2.89, 95% CI = 2.36-3.55) or another breast symptom (OR = 0.25, 95% CI = 1.79-2.82) compared to an abnormal mammogram were significantly associated with a delay in diagnosis. In contrast, the odds of a delay were lower for women who were older than 18-39 years of age and for women living with two or more household members (OR = 0.72, 95% CI = 0.59-0.87). The likelihood of experiencing a delayed breast cancer diagnosis increased markedly if a woman had multiple risk factors, with a nearly 12-fold increase among women with five or more risk factors (OR = 11.96, 95% CI = 6.32-22.61). Younger age, minority race, and self-identification of breast symptom affect the likelihood of delayed breast cancer diagnosis. Awareness of these issues could help focus efforts to develop algorithms that identify women at risk for a delay and build programs that facilitate their timely access to care.


Emphysema in an adult with galactosialidosis linked to a defect in primary elastic fiber assembly.
Galactosialidosis is a lysosomal storage disorder caused by loss of function of protective protein cathepsin A, which leads to secondary deficiencies of β-galactosidase and neuraminidase-1. Emphysema has not been previously reported as a possible complication of this disorder, but we now describe this condition in a 41-year-old, non-smoking male. Our patient did not display deficiency in α-1-antitrypsin, the most common cause of emphysema in non-smokers, which brings about disseminated elastolysis. We therefore hypothesized that loss of cathepsin A activity was responsible because of previously published evidence showing it is prerequisite for normal elastogenesis. We now present experimental evidence to support this theory by demonstrating impaired primary elastogenesis in cultures of dermal fibroblasts from our patient. The obtained data further endorse our previous finding that functional integrity of the cell surface-targeted molecular complex of cathepsin A, neuraminidase-1 and the elastin-binding protein (spliced variant of β-galactosidase) is prerequisite for the normal assembly of elastic fibers. Importantly, we also found that elastic fiber production was increased after exposure either to losartan, spironolactone, or dexamethasone. Of immediate clinical relevance, our data suggest that surviving patients with galactosialidosis should have periodic assessment of their pulmonary function. We also encourage further experimental exploration of therapeutic potential of the afore-mentioned elastogenesis-stimulating drugs for the alleviation of pathological processes in galactosialidosis that could be mechanistically linked to impaired deposition of elastic fibers.


Ontogeny and homeostasis of CNS myeloid cells.
Myeloid cells in the central nervous system (CNS) represent a heterogeneous class of innate immune cells that contribute to the maintenance of tissue homeostasis differentially during development and adulthood. The subsets of CNS myeloid cells identified so far, including parenchymal microglia and non-parenchymal meningeal, perivascular and choroid-plexus macrophages, as well as disease-associated monocytes, have classically been distinguished on the basis of their surface epitope expression, localization and morphology. However, studies using cell-specific targeting, in vivo imaging, single-cell expression analysis and other sophisticated tools have now increased the depth of knowledge of this immune-cell compartment and call for reevaluation of the traditional views on the origin, fate and function of distinct CNS myeloid subsets. The concepts of CNS macrophage biology that are emerging from these new insights have broad implications for the understanding and treatment of CNS diseases.


Antibacterial effect of roselle extracts (Hibiscus sabadariffa), sodium hypochlorite and acetic acid against multidrug-resistant Salmonella strains isolated from tomatoes.
Antibiotic-resistant Salmonella strains were isolated from saladette and red round type tomatoes, and an analysis done of the antibacterial activity of roselle calyx extracts against any of the identified strains. One hundred saladette tomato samples and 100 red round tomato samples were collected from public markets. Each sample consisted of four whole tomatoes. Salmonella was isolated from the samples by conventional culture procedure. Susceptibility to 16 antibiotics was tested for the isolated Salmonella strains by standard test. The antibacterial effect of four roselle calyx extracts (water, methanol, acetone and ethyl acetate), sodium hypochlorite and acetic acid against antibiotic-resistant Salmonella isolates was evaluated on contaminated tomatoes. Twenty-four Salmonella strains were isolated from 12% of each tomato type. Identified Salmonella serotypes were Typhimurium and Typhi. All isolated strains exhibited resistance to at least three antibiotics and some to as many as 12. Over contaminated tomatoes, the roselle calyx extracts produced a greater reduction (2-2·6 log) in antibiotic-resistant Salmonella strain concentration than sodium hypochlorite and acetic acid. The presence of multidrug-resistant Salmonella in vegetables is a significant public health concern. Multidrug-resistant Salmonella strains were isolated from raw tomatoes purchased in public markets in Mexico and challenged with roselle Hibiscus sabdariffa calyx extracts, sodium hypochlorite and acetic acid. On tomatoes, the extracts caused a greater reduction in the concentration of antibiotic-resistant Salmonella strains than sodium hypochlorite and acetic acid. Roselle calyx extracts are a potentially useful addition to disinfection procedures of raw tomatoes in the field, processing plants, restaurants and homes.


Prevention by somatostatin of rise in blood pressure and plasma renin mediated by beta-receptor stimulation.
The interrelationships of increased plasma renin and elevated blood pressure following acute beta-stimulation by orcipernaline and its prevention by somatostatin was studied in normal man. During somatostatin infusion basal values of renin and blood pressure were unchanged. Following orciprenaline both variables increased significantly. Combination of somatostatin and orciprenaline reduced the rise in plasma renin activity by 49%, mean arterial blood pressure by 21% and heart rate by 19%, compared with beta-stimulation alone. The results indicate that the inhibitory action of somatostatin on plasma renin activity may be mediated via beta-receptors. The lesser increase of blood pressure under somatostatin plus orciprenaline also indicates a possible inhibitory effect of somatostatin on beta-adrenergic receptors.