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Leukemic stem cells (LSCs) can acquire non-mutational resistance following drug treatment leading to therapeutic failure and relapse. However, oncogene-independent mechanisms of drug persistence in LSCs are incompletely understood, which is the primary focus of this study. We integrated proteomics, transcriptomics, and metabolomics to determine the contribution of STAT3 in promoting metabolic changes in tyrosine kinase inhibitor (TKI) persistent chronic myeloid leukemia (CML) cells. Proteomic and transcriptional differences in TKI persistent CML cells revealed BCR-ABL-independent STAT3 activation in these cells. While knockout of STAT3 inhibited the CML cells from developing drug-persistence, inhibition of STAT3 using a small molecule inhibitor sensitized the persistent CML cells to TKI treatment. Interestingly, given the role of phosphorylated STAT3 as a transcription factor, it localized uniquely to genes regulating metabolic pathways in the TKI-persistent CML stem and progenitor cells. Subsequently, we observed that STAT3 dysregulated mitochondrial metabolism forcing the TKI-persistent CML cells to depend on glycolysis, unlike TKI-sensitive CML cells, which are more reliant on oxidative phosphorylation. Finally, targeting pyruvate kinase M2, a rate-limiting glycolytic enzyme, specifically eradicated the TKI-persistent CML cells. By exploring the role of STAT3 in altering metabolism, we provide critical insight into identifying potential therapeutic targets for eliminating TKI-persistent LSCs.

Background: High sugar and fat intakes are known to increase intrahepatocellular lipids (IHCLs) and to cause insulin resistance. High protein intake may facilitate weight loss and improve glucose homeostasis in insulin-resistant patients, but its effects on IHCLs remain unknown. Objective: The aim was to assess the effect of high protein intake on high-fat diet--induced IHCL accumulation and insulin sensitivity in healthy young men. Design: Ten volunteers were studied in a crossover design after 4 d of either a hypercaloric high-fat (HF) diet; a hypercaloric high-fat, high-protein (HFHP) diet; or a control, isocaloric (control) diet. IHCLs were measured by [sup.1]H-magnetic resonance spectroscopy, fasting metabolism was measured by indirect calorimetry, insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and plasma concentrations were measured by enzyme-linked immunosorbent assay and gas chromatography--mass spectrometry; expression of key lipogenic genes was assessed in subcutaneous adipose tissue biopsy specimens. Results: The HF diet increased IHCLs by 90 [+ or -] 26% and plasma tissue-type plasminogen activator inhibitor-1 (tPAI-1) by 54 [+ or -] 11% (P < 0.02 for both) and inhibited plasma free fatty acids by 26 [+ or -] 11% and [beta]-hydroxybutyrate by 61 [+ or -] 27% (P < 0.05 for both). The HFHP diet blunted the increase in IHCLs and normalized plasma [beta]-hydroxybutyrate and tPAI-I concentrations. Insulin sensitivity was not altered, whereas the expression of sterol regulatory element-binding protein-1c and key lipogenic genes increased with the HF and HFHP diets (P < 0.02). Bile acid concentrations remained unchanged after the HF diet but increased by 50 [+ or -] 24% after the HFHP diet (P = 0.14). Conclusions: Protein intake significantly blunts the effects of an HF diet on IHCLs and tPAI-1 through effects presumably exerted at the level of the liver. Protein-induced increases in bile acid concentrations may be involved. This trial was registered at www.clinicaltrials.gov as NCT00523562.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

The SARS-CoV-2 beta coronavirus is the etiological driver of COVID-19 disease, which is primarily characterized by shortness of breath, persistent dry cough, and fever. Because they transport oxygen, red blood cells (RBCs) may play a role in the severity of hypoxemia in COVID-19 patients. The present study combines state-of-the-art metabolomics, proteomics, and lipidomics approaches to investigate the impact of COVID-19 on RBCs from 23 healthy subjects and 29 molecularly diagnosed COVID-19 patients. RBCs from COVID-19 patients had increased levels of glycolytic intermediates, accompanied by oxidation and fragmentation of ankyrin, spectrin beta, and the N-terminal cytosolic domain of band 3 (AE1). Significantly altered lipid metabolism was also observed, in particular, short- and medium-chain saturated fatty acids, acyl-carnitines, and sphingolipids. Nonetheless, there were no alterations of clinical hematological parameters, such as RBC count, hematocrit, or mean corpuscular hemoglobin concentration, with only minor increases in mean corpuscular volume. Taken together, these results suggest a significant impact of SARS-CoV-2 infection on RBC structural membrane homeostasis at the protein and lipid levels. Increases in RBC glycolytic metabolites are consistent with a theoretically improved capacity of hemoglobin to off-load oxygen as a function of allosteric modulation by high-energy phosphate compounds, perhaps to counteract COVID-19-induced hypoxia. Conversely, because the N-terminus of AE1 stabilizes deoxyhemoglobin and finely tunes oxygen off-loading and metabolic rewiring toward the hexose monophosphate shunt, RBCs from COVID-19 patients may be less capable of responding to environmental variations in hemoglobin oxygen saturation/oxidant stress when traveling from the lungs to peripheral capillaries and vice versa.

Obesity results from a complex interplay of diet, behavior, and genetic background. Our genes are out of our control, but it may be possible to customize our diet to match changes in metabolism resulting from...Obesity and its comorbidities are a growing health epidemic. Interactions between genetic background, the environment, and behavior (i.e., diet) greatly influence organismal energy balance. Previously, we described obesogenic mutations in the gene Split ends(Spen) in Drosophila melanogaster, and roles for Spen in fat storage and metabolic state. Lipid catabolism is impaired in Spen-deficient fat storage cells, accompanied by a compensatory increase in glycolytic flux and protein catabolism. Here, we investigate gene–diet interactions to determine if diets supplemented with specific macronutrients can rescue metabolic dysfunction in Spen-depleted animals. We show that a high-yeast diet partially rescues adiposity and developmental defects. High sugar partially improves developmental timing as well as longevity of mated females. Gene–diet interactions were heavily influenced by developmental-stage-specific organismal needs: extra yeast provides benefits early in development (larval stages) but becomes detrimental in adulthood. High sugar confers benefits to Spen-depleted animals at both larval and adult stages, with the caveat of increased adiposity. A high-fat diet is detrimental according to all tested criteria, regardless of genotype. Whereas Spen depletion influenced phenotypic responses to supplemented diets, diet was the dominant factor in directing the whole-organism steady-state metabolome. Obesity is a complex disease of genetic, environmental, and behavioral inputs. Our results show that diet customization can ameliorate metabolic dysfunction underpinned by a genetic factor.

Metals embedded in porous media interact electrochemically with the liquid phase contained in the pores. A widespread form of this, adversely affecting the integrity of engineered structures, is corrosion of steel in porous media or in natural environments. While it is well documented that the rate of this electrochemical dissolution process can vary over several orders of magnitude, understanding the underlying mechanisms remains a critical challenge hampering the development of reliable predictive models. Here we study the electrochemical dissolution kinetics of steel in meso-to-macro-porous media, using cement-based materials, wood and artificial soil as model systems. Our results reveal the dual role of the pore structure (that is, the influence on the electrochemical behaviour through transport limitations and an area effect, which is ultimately due to microscopic inhomogeneity of the metal/porous material interface). We rationalize the observations with the theory of capillary condensation and propose a material-independent model to predict the corrosion rate. A model is proposed to predict the corrosion rate of steels embedded in different porous media including concrete, wood and soil. It relies on the moisture state and the pore structure, which affect the electrochemical dissolution kinetics.

Arctic ground squirrels provide a unique model to investigate metabolic responses to hibernation in mammals. During winter months these rodents are exposed to severe hypothermia, prolonged fasting, and hypoxemia. In the light of their role in oxygen transport/off-loading and owing to the absence of nuclei and organelles (and thus de novo protein synthesis capacity), mature red blood cells have evolved metabolic programs to counteract physiological or pathological hypoxemia. However, red blood cell metabolism in hibernation has not yet been investigated. Here we employed targeted and untargeted metabolomics approaches to investigate erythrocyte metabolism during entrance to torpor to arousal, with a high resolution of the intermediate time points. We report that torpor and arousal promote metabolism through glycolysis and pentose phosphate pathway, respectively, consistent with previous models of oxygen-dependent metabolic modulation in mature erythrocytes. Erythrocytes from hibernating squirrels showed up to 100-fold lower levels of biomarkers of reperfusion injury, such as the pro-inflammatory dicarboxylate succinate. Altered tryptophan metabolism during torpor was here correlated to the accumulation of potentially neurotoxic catabolites kynurenine, quinolinate, and picolinate. Arousal was accompanied by alterations of sulfur metabolism, including sudden spikes in a metabolite putatively identified as thiorphan (level 1 confidence)—a potent inhibitor of several metalloproteases that play a crucial role in nociception and inflammatory complication to reperfusion secondary to ischemia or hemorrhage. Preliminary studies in rats showed that intravenous injection of thiorphan prior to resuscitation mitigates metabolic and cytokine markers of reperfusion injury, etiological contributors to inflammatory complications after shock.

Background and Rationale

Background:Salvage autologous stem cell transplant (sASCT) has been indicated as possible therapeutic option at first (1 st) relapse, alternative to continuous treatment with novel agent combinations in selected Multiple Myeloma (MM) patients (pts). Particularly, MM pts who are eligible for a transplant procedure at the time of relapse and who have prolonged progression free survival (PFS) after the 1 stASCT - i.e. at least 36 or 18 months, respectively, with or without Lenalidomide (Len) maintenance - are those who could benefit most from sASCT. There are limited data regarding the frequency of choice for sASCT in the current therapeutic scenario and the outcome of sASCT when incorporating novel Len-based triplets KRd (Carfilzomib-Lenalidomide-Dexamethasone) and DaraRd (Daratumumab-Lenalidomide-Dexamethasone) as induction regimens before sASCT.

Background

A growing number of retail chains in Europe are adopting the concept of central purchasing, giving rise to the establishment of more purchasing supercenters in the region. Leading the market is European Marketing Distribution, which boasts of a turnover double that of Fiat. Central purchasing was first adopted by large discount houses, which realized that the practice translates to lower costs and lower prices for consumers. Small European discount stores have caught on the idea, as they have established their own purchasing groups at the regional level., Central purchasing is a major element of competition among discount stores. European purchasing supercentres are on the increase. The continental European market leader, European Marketing Distribution (Emd), has a turnover [...]

•Fluorescently tagged 3DNA can be visualized in vivonon-invasively•Folic acid or transferrin conjugated 3DNA increases delivery to pancreatic tumors•Non-tumor-bearing organs have significantly less 3DNA detection•Folic acid conjugated 3DNA effectively delivers siRNA with high durability

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Land-use change occurs nowhere more rapidly than in the tropics, where the imbalance between deforestation and forest regrowth has large consequences for the global carbon cycle. However, considerable uncertainty remains about the rate of biomass recovery in secondary forests, and how these rates are influenced by climate, landscape, and prior land use. Here we analyse aboveground biomass recovery during secondary succession in 45 forest sites and about 1,500 forest plots covering the major environmental gradients in the Neotropics. The studied secondary forests are highly productive and resilient. Aboveground biomass recovery after 20 years was on average 122 megagrams per hectare (Mg ha−1), corresponding to a net carbon uptake of 3.05 Mg C ha−1yr−1, 11 times the uptake rate of old-growth forests. Aboveground biomass stocks took a median time of 66 years to recover to 90% of old-growth values. Aboveground biomass recovery after 20 years varied 11.3-fold (from 20 to 225 Mg ha−1) across sites, and this recovery increased with water availability (higher local rainfall and lower climatic water deficit). We present a biomass recovery map of Latin America, which illustrates geographical and climatic variation in carbon sequestration potential during forest regrowth. The map will support policies to minimize forest loss in areas where biomass resilience is naturally low (such as seasonally dry forest regions) and promote forest regeneration and restoration in humid tropical lowland areas with high biomass resilience.

L’obiettivo di questo articolo è segnalare l’importanza di mantenere frequenti controlli nei pazienti con plasmocitoma dei mascellari: seppur rara, tale patologia può presentare una progressione da plasmocitoma solitario a mieloma multiplo.

Although much less investigated than that induced by chlorides, the corrosion of steel reinforcing bars due to bacteria metabolic products is recognised as a serious issue, primarily for concrete pipes in sewer network. In order to overcome the complications due to the preparation of concrete samples the investigation was performed using simulating solutions. The passivation of the metallic specimens was obtained by immersion in Ca (OH)2 sat and monitored through several different electrochemical techniques. The depassivation was induced by either sulphuric acid or sulphides in order to simulate different bacterial metabolites. Anodic polarization curves and optical microscopy examination revealed a significant corrosion in the former case, while a competitive interaction among the sulphide and the alkalinity was hypothesized in sulphide-containing solutions.

The unquestionable advantages provided by modern neuroimaging techniques have recently led some to question the duty of the neurologist, traditionally struggling first and foremost to establish the semeiotic localization of brain lesions and only then to interpret them. The present brief report of six clinical patients who came recently to our attention aims to emphasize that the interpretation of neuroimaging results always requires integration with anamnestic, clinical and laboratory data, together with knowledge of nosography and the literature. The solutions of the reported cases always originated from close interaction between the neurologist and the neuroradiologist, based on the initial diagnostic uncertainty linked to the finding of isolated or multiple brain target or ring lesions, too often considered paradigmatic examples of the pathognomonic role of neuroimaging.

A 1993 worldwide opinion poll showcased the strengths and weaknesses of brand names in different countries. In Italy, the survey was conducted by Young and Rubicam and Doxa to evaluate the brand consciousness of 1,500 consumers with respect to 917 brands in different product categories. The results showed that the best-known brands are Rai Uno, Barilla, Lavazza and Fiat, while the most respected names are Ferrari, Rolex, and Mercedes Benz., Coca-Cola, Barilla, Lavazza, Fiat: these are names with powerful appeal in Italy. So are their positions unassailable? Which brands are untouchable? Which others are growing fast? Which names are losing [...]

Merkel cell carcinoma (MCC) is a rare neuroendocrine tumour of the skin, characterised by an aggressive clinical course. The incidence of this rare neoplasia is rapidly increasing. Herein we report our experience with a patient who developed a MCC of the inguinal region.

The aim was to evaluate the differences between labial and lingual application of an orthodontic force. This was achieved using a three-dimensional CAD design software model of a real lower incisor surrounded by a prismatic representation of the mandibular bone. This model was subjected to various loading conditions, with finite-element analysis.

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We present an innovative and simple, soft UV lithographic method “FIll‐Molding In Capillaries” (FIMIC) that combines soft lithography with capillary force driven filling of micro‐channels to create smooth hydrogel substrates with a 2D micro‐pattern on the surface. The lithographic procedure involves the molding of a polymer; in our case a bulk PEG‐based hydrogel, via UV‐curing from a microfabricated silicon master. The grooves of the created regular line pattern are consequently filled with a second hydrogel by capillary action. As a result, a smooth surface is obtained with a well‐defined pattern design of the two different polymers on its surface. The FIMIC method is very versatile; the only prerequisite is that the second material is liquid before curing in order to enable the filling process. In this specific case we present the proof of principle of this method by applying two hydrogels which differ in their crosslinking density and therefore in their elasticity. Preliminary cell culture studies on the fabricated elasticity patterned hydrogels indicate the preferred adhesion of the cells to the stiffer regions of the substrates, which implies that the novel substrates are a very useful platform for systematic cell migration studies, e.g. more fundamental investigation of the concept of “durotaxis”.

The importance of space as an ecological factor is an emerging paradigm in community ecology, particularly as a driving force of biodiversity patterns. We analysed β-diversity linked to spatial structure in four communities (tropical dry forest, savanna, xerophytic vegetation, subdeciduous forest) that occur in a tropical complex landscape of southern Mexico. The landscape was described through an object-oriented classification of a Quickbird satellite image. The classification revealed a highly heterogeneous spatial arrangement of the four communities. Global (landscape-level) β-diversity was 0.12 (mean Sørensen index), a value smaller than those observed for the individual communities (0.20–0.41). By using multivariate classic and partial Mantel tests, and Mantel correlograms based on two distance classes, we analysed β-diversity spatial variation related to landscape configuration. The Mantel statistic values for the four communities combined were negative and very similar both for the classic Mantel (rM= −0.23) and the partial Mantel test (rM= −0.19). Correlograms proved significant spatial autocorrelation across most of the analysed distance classes, except in the case of riparian subdeciduous forest. Tropical dry forest and savanna occupy large, highly connected areas in the landscape. Correlograms for these two communities showed decreasing trends, starting at positive, significant autocorrelation values at short distances. The loss of floristic autocorrelation beyond a 5000 m distance for the tropical dry forest may reflect spatially autocorrelated dispersal, and thus a dispersal-limited community. Xerophytic vegetation displayed a distinctly different correlogram, with a wavy shape showing an alternation of positive and negative values, in agreement with the insular configuration of this community in the landscape. We suggest that the routinely incorporation of a spatial approach in community ecology research will help in furthering our understanding of the elusive issues of species turnover across space.

The importance of space as an ecological factor is an emerging paradigm in community ecology, particularly as a driving force of biodiversity patterns. We analysed ß-diversity linked to spatial structure in four communities (tropical dry forest, savanna, xerophytic vegetation, subdeciduous forest) that occur in a tropical complex landscape of southern Mexico. The landscape was described through an object-oriented classification of a Quickbird satellite image. The classification revealed a highly heterogeneous spatial arrangement of the four communities. Global (landscape-level) P-diversity was 0.12 (mean Sørensen index), a value smaller than those observed for the individual communities (0.20-0.41). By using multivariate classic and partial Mantel tests, and Mantel correlograms based on two distance classes, we analysed P-diversity spatial variation related to landscape configuration. The Mantel statistic values for the four communities combined were negative and very similar both for the classic Mantel (rM = -0.23) and the partial Mantel test (rM = -0.19). Correlograms proved significant spatial autocorrelation across most of the analysed distance classes, except in the case of riparian subdeciduous forest. Tropical dry forest and savanna occupy large, highly connected areas in the landscape. Correlograms for these two communities showed decreasing trends, starting at positive, significant autocorrelation values at short distances. The loss of floristic autocorrelation beyond a 5000 m distance for the tropical dry forest may reflect spatially autocorrelated dispersal, and thus a dispersal-limited community. Xerophytic vegetation displayed a distinctly different correlogram, with a wavy shape showing an alternation of positive and negative values, in agreement with the insular configuration of this community in the landscape. We suggest that the routinely incorporation of a spatial approach in community ecology research will help in furthering our understanding of the elusive issues of species turnover across space.

Copyright of Nueva Sociedad is the property of Nueva Sociedad and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Rhenium does the job!A readily available rhenium complex efficiently catalyzed the direct Meyer–Schuster‐like rearrangement of different alkyl‐ and aryl‐substituted propargylic secondary and tertiary alcohols to the corresponding α,β‐unsaturated compounds, which were produced with virtually complete Estereoselectivity. The reaction proceeded under neutral conditions and no racemization of potentially enolizable stereocenters was observed.

Abstract: Background: Laparoscopic hernia repair is not as popular as cholecystectomy. We have performed more than 3,000 laparoscopic herniorrhaphies using the trans-abdominal (TAPP) technique. To prevent recurrences we fix the polypropylene mesh with staples. The use of fibrin glue for graft fixation is a possible alternative. Methods: We have performed 3,130 laparoscopic hernia repairs over 14 years. For mesh fixation we used titanium clips and observed a small number of complications. In July 2003 we started using fibrin glue (Tissucol®). The purpose of this retrospective longitudinal study was to evaluate if the use of fibrin sealant was as safe and effective as conventional stapling and if there were differences in post-operative pain, complications and recurrences. Results: From July 2003 to June 2006 we performed 823 laparoscopic herniorrhaphies. Fibrin glue (Tissucol®) was used in 88 cases. Two homogeneous groups of 68 patients (83 cases) treated with fibrin glue and 68 patients (87 cases) where the mesh was fixed with staples, were compared. Patients with relevant associated diseases or large inguino-scrotal hernias were excluded. Operative times were longer in the group treated with fibrin glue with a mean of 35 minutes (range 22–65 mins) compared to the group treated with staples (25 minutes, range 14–50 mins). The time of hospital stay was the same (24 hours). Post-operative complications, that were more frequent in the stapled group, included trocar site pain, hematomas, intra-operative bleedings and incisional hernias. No significant difference was observed concerning seromas, chronic pain and recurrence rate. Conclusions: Less post-operative pain, and a faster return to usual activities are the main advantages of laparoscopic repair compared to the traditional approach. The use of fibrin sealant reduces in our experience the risk of post- and intra-operative complications such as bleeding and incisional hernia; recurrence rates are similar, but the operative time is longer.

Aim To investigate the plasma levels and prevalence of the most common antiphospholipid antibodies, as well as their relationships with several plasma markers of inflammation, in order to characterize some aspects of cancer thrombophilia.Materials and methods Eighty-three cancer patients with non-metastatic colorectal solid tumors and 94 control subjects were tested for the presence of IgG/IgM/IgA anti-cardiolipin and anti-β2-glycoprotein I antibodies and of several acute-phase reactants, i.e., fibrinogen, factor VIII:C and C4b-binding protein.Results In cancer patients the plasma levels of the acute-phase reactants and the IgA/IgG anti-cardiolipin and IgA anti-β2-glycoprotein I antibodies were significantly higher; the acute-phase reactants were significantly correlated with anti-cardiolipin antibodies; the prevalence of antiphospholipid antibodies was not significantly higher.Conclusions In patients with non-metastatic colorectal cancer the acute-phase response is associated with antiphospholipid generation. This could represent a further pathogenetic mechanism for the short-term post-surgery thrombotic complications of patients with colorectal cancer.

There is evidence that high plasma levels of factor (F) VIII, FIX, FXI and fibrinogen are independent risk factors for venous thromboembolism.Aim To determine the plasma concentrations of several coagulation factors and C4b-binding protein (C4BP) in a group of patients with non-metastatic colorectal cancer in order to investigate some aspects of cancer-acquired thrombophilia. Methods:Plasma fibrinogen, FII, FV, FVII, FVIII, FIX, FX, FXI and FXII activity levels and C4BP concentrations were determined in 73 patients with non-metastatic colorectal cancer (48 colon and 25 rectum) and in 67 matched control subjects. No one in either group had had previous thrombotic events.Results Mean plasma concentrations of fibrinogen (functional and antigen), FVIII, FIX, FV and C4BP were significantly higher in colorectal cancer patients than in control subjects, while FVII and FXII levels were significantly decreased. Several correlations were found between the increased coagulation factors and C4BP concentrations, while FVII was highly correlated with FXII.Conclusions In colorectal cancer patients high plasma fibrinogen, FVIII and FIX levels might represent further risk factors for venous thrombotic complications in the immediate post-surgery period, while decreased FVII and FXII concentrations may be an index of intravascular coagulation activation, still in a subclinical phase.

A total of 202 serum and stool samples from acute hepatitis patients attending the Fever Hospital of Alexandria, Egypt, have been studied to reveal markers of hepatitis virus infection. Anti-HAV IgM were detected in 21 out of 202 sera (10.4%), whereas 201 sera (99.5%) had anti-HAV IgG. The first age attack was in the class-age 0–9 years with 64.7% of anti-HAV IgM positive sera. Among 202 patients, anti-hepatitis E IgG (sample/over cut off > 1.0) was identified in 90 patients (44.5%). The anti-HEV seropositivity ranged from 17.6% to 60.0% in the different age groups, with the highest level in the class-age 20–29 years. Anti-hepatitis E IgM were identified in 49 patients with the first age attack in the class-age 10–19 years (39.4%). HAV RNA was identified by nested PCR in 7 samples out of 15, whereas HEV RNA was present in 4 out of 75 stool samples. Direct DNA sequence of the latter PCR products confirmed the presence of the HEV genome; comparison of the sequences of the isolates from Egypt with those in data banks revealed the highest homology to the Burma strain. Our data confirm that HAV and HEV are common causes of acute sporadic hepatitis in Alexandria but with different peak age positivity. Occasionally, but not infrequently, dual infections (HAV–HEV and HEV-enteric viruses) were also found. The risk analysis indicates that patients living in rural areas are exposed to a higher risk of hepatitis E infection compared to the urban population, whereas the presence of anti-HEV IgG was significantly associated with consumption of common village water and use of indoor dry pit and oral therapy for schistosomiasis.

In the early 1970s an increased prevalence of gallstones was reported in adults and children with immunoglobulin deficiency. As the advent of ultrasonography has largely changed the diagnostic approach to gallstones, we have reevaluated the prevalence of cholelithiasis in a group including 37 patients with common variable immunodeficiency and seven patients with other forms of primary immunodeficiency. All patients were receiving intravenous gammaglobulin replacement since 1983 or, in more recent cases, soon after the diagnosis was made, and therefore had relatively few infections. All patients underwent a hepatobiliary ultrasonogram and blood sampling. Data were compared, after age and sex standardization, with those obtained by the GREPCO in a free-living population of 1239 men and 1081 women. Only two women with immunoglobulin deficiency had gallstones. One of these was obese and had had one pregnancy. Both were asymptomatic. None of the patients studied had a history of cholecystectomy or evidence of biliary sludge. Thus, the observed prevalence rates of gallstone disease were 8.7% in women and 0% in males, respectively,against expected values of 9.5% and 3.2%. Immunodeficient patients expressed several putative risk factors for gallstones in the low range (body mass index, total and HDL cholesterol, and blood glucose in both sexes, and triglycerides in men). We conclude that gallstone disease is not more frequent in patients with immunodeficiency syndromes undergoing immunoglobulin therapy than in the general population.

Abstract.: Histone genes were identified and their nucleotide sequences were determined in the polychaete marine worm Chaetopterus variopedatus. The genes are organized in about 390 clusters of 7.3 kbp. Each cluster contains one copy of the five histone genes. The H1 histone gene present in the clusters is the first ever isolated in the phylum Annelida. The cluster has the unique peculiarity that all genes contain both the replication-dependent and the replication-independent 3′ mRNA termination signals. Despite the differences in cluster organization and transcription polarity of the individual histone genes between C. variopedatus and Platynereis dumerilii, the other annelid in which histone genes have been studied, phylogenetic analysis of the encoded amino acid sequences clearly groups together those two organisms in a tree in which the other studied worms find closely related positions on the same evolutionary branch.

An uninterrupted energy supply is critical for the optimal functioning of all our organs, and in this regard the human brain is particularly energy dependent. The study of energy metabolic pathways is a major focus within neuroscience research, which is supported by genetic defects in the oxidative phosphorylation mechanism often contributing towards neurodevelopmental disorders and changes in glucose metabolism presenting as a hallmark feature in age-dependent neurodegenerative disorders. However, as recent studies have illuminated roles of cellular metabolism that span far beyond mere energetics, it would be valuable to first comprehend the physiological involvement of metabolic pathways in neural cell fate and function, and to subsequently reconstruct their impact on diseases of the brain. In this Review, we first discuss recent evidence that implies metabolism as a master regulator of cell identity during neural development. Additionally, we examine the cell type-dependent metabolic states present in the adult brain. As metabolic states have been studied extensively as crucial regulators of malignant transformation in cancer, we reveal how knowledge gained from the field of cancer has aided our understanding in how metabolism likewise controls neural fate determination and stability by directly wiring into the cellular epigenetic landscape. We further summarize research pertaining to the interplay between metabolic alterations and neurodevelopmental and psychiatric disorders, and expose how an improved understanding of metabolic cell fate control might assist in the development of new concepts to combat age-dependent neurodegenerative diseases, particularly Alzheimer's disease.

Trained immunity (TI) is a de factoinnate immune memory program induced in monocytes/macrophages by exposure to pathogens or vaccines, which evolved as protection against infections. TI is characterized by immunometabolic changes and histone post-translational modifications, which enhance production of pro-inflammatory cytokines. As aberrant activation of TI is implicated in inflammatory diseases, tight regulation is critical; however, the mechanisms responsible for this modulation remain elusive. Interleukin-37 (IL-37) is an anti-inflammatory cytokine that curbs inflammation and modulates metabolic pathways. In this study, we show that administration of recombinant IL-37 abrogates the protective effects of TI in vivo, as revealed by reduced host pro-inflammatory responses and survival to disseminated candidiasis. Mechanistically, IL-37 reverses the immunometabolic changes and histone post-translational modifications characteristic of TI in monocytes, thus suppressing cytokine production in response to infection. IL-37 thereby emerges as an inhibitor of TI and as a potential therapeutic target in immune-mediated pathologies.

Platelet concentrates are currently stored at room temperature (RP) under constant agitation for up to 5–7 days depending on national regulations. However, platelet quality deteriorates during storage and room-temperature storage also increases the risk of bacterial growth. Previous studies have shown that cold-stored platelets (CPs) have higher hemostatic functions and can be stored for up to 3 weeks. While these studies have compared the metabolic phenotypes of CPs and RPs, they have neither compared the impact of storage temperature and cold agitation (CPAs) on platelet function nor identified metabolic correlates to such parameters. In vitroanalysis showed that CPAs and CPs had reduced count, faster CD62P expression, and increased lactadherin binding. Furthermore, CPAs and CPs had higher maximal aggregation and a reduced aggregation lag phase compared to RPs. Metabolomic analysis revealed that CPAs and CPs exhibited lower oxidative stress shown by preserved glutathione and pentose phosphate pools. CPAs and CPs also had reduced markers of beta-oxidation and amino acid catabolism, demonstrating reduced needs for energy. Agitation did not significantly impact in vitrofunction or metabolomic parameters of cold-stored platelets. Correlation of in vitroand metabolomic results highlighted important metabolites that may contribute to stored platelet functions. Raw data are publicly available through Metabolomics Workbench with the study identifier ST001644.

Yoshida: New Health Sciences Inc.: Employment, Equity Ownership. D'Alessandro:Hemanext, Inc.: Membership on an entity's Board of Directors or advisory committees; Omix Technologies, Inc.: Other: Founder. Nemkov:Omix Technologies, Inc.: Equity Ownership, Other: Founder. Dioguardi:Hemanext: Employment. Iselin:Hemanext: Employment. Dunham:Hemanext: Employment. Cancelas:Hemanext: Consultancy, Research Funding; Fresenius-Kabi: Research Funding; Cerus Co.: Research Funding; TerumoBCT: Consultancy, Research Funding; Macopharma Inc: Research Funding; Cytosorbents: Research Funding; Cellphire: Research Funding; Velico: Consultancy, Research Funding.

Blood transfusion is a life-saving intervention for millions of recipients worldwide every year. However, refrigerated storage of red blood cells (RBCs) for up to 42 days promotes impairments in energy and redox homeostasis, which impact RBC hemolytic propensity and post-transfusion performance of the storage-damaged RBC. Since mature RBCs are devoid of de novoprotein synthesis - owing to the lack of organelles and nuclei - they evolved metabolic mechanisms to cope with oxidative stress. Two of these involve (i) activation of the pentose phosphate pathway (PPP), which generates reducing equivalents (NADPH) to preserve glutathione homeostasis and recharge NADPH-dependent antioxidant enzymes; and (ii) recycling of oxidatively damaged proteins via methylation of dehydrated and deamidated aspartate and asparagine residues, a process that consumes methionine as the main methyl group donor. Thus, we hypothesize that the latter mechanism is relevant to routine blood bank storage, especially in glucose-6-phosphate dehydrogenase (G6PD)-deficient donors. In this routinely accepted donor population (~10% of donors of African descent), mutations of G6PD, the rate-limiting enzyme of the PPP, result in instability and decreased enzymatic activity (e.g., <1% residual activity in the Mediterranean variant).

The article offers information on the U.S. Post Office's annual breast cancer stamp sale by Sharon Clark, a breast cancer survivor, in Missouri, mentions that in October 2008 she campaign to sell stamps and money is used for cancer survivors, and presents the views of Sharon on the same.

Introduction:Despite the growing interest about the optimal treatment of older patients with cancer, only few data are available for indolent non-Hodgkin lymphomas (NHL). Aim of the study was to evaluate the impact of comorbidities on treatment choice and survival in a cohort of older indolent NHL patients.