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In this paper, we prove a Ros–Rosenberg theorem in the setting of Special Weingarten surfaces. We show that a compact, connected, embedded, Special Weingarten surface in ℝ+3 with planar convex boundary is a topological disk under mild suitable assumptions. [ABSTRACT FROM AUTHOR]

Photoinduced charge-transfer processes play a key role for novel photovoltaic phenomena and devices. Thus, the development of ab initio methods that allow for an accurate and computationally inexpensive treatment of charge-transfer excitations is a topic that nowadays attracts a lot of scientific attention. In this paper we extend an approach recently introduced for the description of single and double excitations [M. Tassi, I. Theophilou, and S. Thanos, Int. J. Quantum Chem. 113, 690 (2013); J. Chem. Phys. 138, 124107 (2013)] to allow for the description of intermolecular chargetransfer excitations. We describe an excitation where an electron is transferred from a donor system to an acceptor one, keeping the excited state orthogonal to the ground state and avoiding variational collapse. These conditions are achieved by decomposing the space spanned by the Hartree-Fock (HF) ground state orbitals into four subspaces: The subspace spanned by the occupied orbitals that are localized in the region of the donor molecule, the corresponding for the acceptor ones and two more subspaces containing the virtual orbitals that are localized in the neighborhood of the donor and the acceptor, respectively. Next, we create a Slater determinant with a hole in the subspace of occupied orbitals of the donor and a particle in the virtual subspace of the acceptor. Subsequently we optimize both the hole and the particle by minimizing the HF energy functional in the corresponding subspaces. Finally, we test our approach by calculating the lowest charge-transfer excitation energies for a set of tetracyanoethylene-hydrocarbon complexes that have been used earlier as a test set for such kind of excitations. [ABSTRACT FROM AUTHOR]

Doubly excited states have nowadays become important in technological applications, e.g., in increasing the efficiency of solar cells and therefore, their description using ab initio methods is a great theoretical challenge as double excitations cannot be described by linear response theories based on a single Slater determinant. In the present work we extend our recently developed Hartree-Fock (HF) approximation for calculating singly excited states [M. Tassi, I. Theophilou, and S. Thanos, Int. J. Quantum Chem. 113, 690 (2013)] in order to allow for the calculation of doubly excited states. We describe the double excitation as two holes in the subspace spanned from the occupied HF orbitals and two particles in the subspace of virtual HF orbitals. A subsequent minimization of the energy results to the determination of the spin orbitals of both the holes and the particles in the occupied and virtual subspaces, respectively. We test our method, for various atoms, H2 and polyene molecules which are known to have excitations presenting a significant double excitation character. Importantly, our approach is computationally inexpensive. [ABSTRACT FROM AUTHOR]

In this work we give a characterization of pseudo-parallel surfaces in S c n × R and H c n × R , extending an analogous result by Asperti-Lobos-Mercuri for the pseudo-parallel case in space forms. Moreover, when n = 3 , we prove that any pseudo-parallel surface has flat normal bundle. We also give examples of pseudo-parallel surfaces which are neither semi-parallel nor pseudo-parallel surfaces in a slice. Finally, when n ≥ 4 we give examples of pseudo-parallel surfaces with non vanishing normal curvature. [ABSTRACT FROM AUTHOR]

We calculate the lowest ionisation and excitation energies in a variety of biologically important molecules, i.e. π-conjugated systems like DNA and RNA bases and isomers plus related heterocyclic molecules. For approximately half of these molecules, there are no experimental and theoretical/numerical data in the literature, as far as we know. These electronic transitions are mainly but not exclusively of π and π–π* character, respectively. We perform symmetry-constrained density functional theory (DFT) geometry optimisation at the B3LYP/6-311++G** level of theory. At the DFT-obtained ground-state geometries, we calculate vertical ionisation energies with ionisation potential coupled cluster with singles and doubles (IP-EOMCCSD) and vertical excitation energies with the completely renormalised equation of motion coupled cluster with singles, doubles, and non-iterative triples (CR-EOMCCSD(T)) method. We also investigate whether a simple semi-empirical Hückel-type model approach with novel parametrisation could provide reasonable estimates of the lowest π ionisation and π–π* excitation energies. Our coupled cluster (CC) results are in very good agreement with experimental data, while the Hückel-type model predictions generally follow the trends with some deviation. Finally, we investigate the effect of basis set in IP-EOMCCSD energies and we compare our CR-EOMCCSD(T) results with time-dependent DFT (TDDFT) ones. [ABSTRACT FROM AUTHOR]

We investigated the renal effects of a high-intensity exercise (HIE) program based on strength training. 20 Wistar rats were randomly assigned to 2 experimental groups performing HIE or control over 12 weeks. Urinary volume, pH, citrate and calcium, and plasma urea, total proteins, creatinine, albumin, lactate dehydrogenase, creatine kinase (CK), calcium, magnesium, corticosterone and testosterone were measured. We also studied renal morphology with the Fibrosis HR ® software. Plasma urea and CK concentrations were higher in the HIE compared to the control group (p < 0.05), whereas plasma creatinine was lower (p < 0.01). Plasma corticosterone was higher (p < 0.05) and testosterone lower (p < 0.01) in the HIE group. Except for the higher urinary volume found in the HIE group (p < 0.05), no differences between groups were observed in the rest of urinary parameters analyzed. Renal interstitial connective tissue was ~30 % higher in the HIE group (p < 0.05). Glomerular tufts and mesangial areas were also higher in the HIE group (all, p < 0.05). No differences between groups were observed in the glomerular area. Overall, HIE promoted a worse morphological renal profile that might be associated with a higher risk for incidence of kidney disease in the long-term. The stress induced by the type of exercise performed could be on the basis of this worse morphological renal status. [ABSTRACT FROM AUTHOR]

The Hartree-Fock (HF) method, widely used for the calculation of ground state properties, in recent years has been extended for calculating excited states. In this article, we develop an approach, which does not require time consuming calculations and can give a good approximation for the excitation energies. The method is based on the fact that the subspaces of the occupied and virtual orbitals are mutually orthogonal. We test the accuracy of our method by evaluating the excited state wavefunctions and the corresponding energies for the Li, N, F, Ne, and Na atoms and for the BeH and CH molecules, and we found good agreement with configuration interaction and experimental results. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Calcaneal fractures are difficult to treat because of their often-related sequelae. The authors present a simple, rapid, economic, and easy-to-perform technique that uses percutaneously positioned Kirschner wires plus a plaster cast for the reduction and stabilization of certain calcaneal fractures. A review of the relevant literature is also provided. [ABSTRACT FROM AUTHOR]

Presents an algorithm devised to select compact groups of galaxies from digitized catalogues. Properties of the groups.

We employ Real-Time Time-Dependent Density Functional Theory to study hole oscillations within a B-DNA monomer (one base pair) or dimer (two base pairs). Placing the hole initially at any of the bases which make up a base pair, results in THz oscillations, albeit of negligible amplitude. Placing the hole initially at any of the base pairs which make up a dimer is more interesting: For dimers made of identical monomers, we predict oscillations with frequencies in the range20–40 THz, with a maximum transfer percentage close to 1. For dimers made of different monomers,80–400 THz, but with very small or small maximum transfer percentage. We compare our results with those obtained recently via our Tight-Binding approaches and find that they are in good agreement. [ABSTRACT FROM PUBLISHER]

We employ two tight-binding (TB) approaches to systematically study the electronic structure and hole or electron transfer in B-DNA monomer polymers and dimer polymers made up of N monomers (base pairs): (I) at the base-pair level, using the onsite energies of base pairs and the hopping integrals between successive base pairs, i.e., a wire model and (II) at the single-base level, using the onsite energies of the bases and the hopping integrals between neighboring bases, i.e., an extended ladder model since we also include diagonal hoppings. We solve a system of M (matrix dimension) coupled equations [(I) M=N, (II) M=2N] for the time-independent problem, and a system of M coupled first order differential equations for the time-dependent problem. We perform a comparative study of stationary and time-dependent aspects of the two TB variants, using realistic sets of parameters. The studied properties include HOMO and LUMO eigenspectra, occupation probabilities, density of states and HOMO-LUMO gaps as well as mean over time probabilities to find the carrier at each site [(I) base pair or (II) base], Fourier spectra, which reflect the frequency content of charge transfer, and pure mean transfer rates from a certain site to another. The two TB approaches give coherent, complementary aspects of electronic properties and charge transfer in B-DNA monomer polymers and dimer polymers. [ABSTRACT FROM AUTHOR]

Introduction: Patients with cancer are presumed a frail group at high risk of contracting coronavirus disease (COVID-19), and vaccination represents a cornerstone in addressing the COVID-19 pandemic. However, data on COVID-19 vaccination in cancer patients are fragmentary and poor., Methods: An observational study was conducted to evaluate the seropositivity rate and safety of a two-dose regimen of the BNT162b2 or messenger RNA-1273 vaccine in adult patients with solid cancer undergoing active anticancer treatment or whose treatment had been terminated within 6 months of the start of the study. The control group was composed of healthy volunteers. Serum samples were evaluated for SARS-COV-2 antibodies before vaccinations and 2-6 weeks after the administration of the second vaccine dose. Primary end-point: seropositivity rate. Secondary end-points: safety, factors influencing seroconversion, IgG titers of patients versus healthy volunteers, COVID-19 infection., Results: Between 20th March 2021 and 12th June 2021, 293 consecutive patients with cancer-solid tumours underwent a program of COVID-19 vaccinations; of these, 2 patients refused vaccination, 13 patients did not receive the second dose of the vaccine because of cancer progression, and 21 patients had COVID-19 antibodies at baseline and were excluded. The 257 evaluable patients had a median age of 65 years (range 28-86), 66.15% with metastatic disease. Primary end-point: seropositivity rate in patients was 75.88% versus 100% in the control group. Secondary end-points: no Grade 3-4 side-effects, no COVID-19 infections were reported. Patients median IgG titer was significantly lower than in the control group; male sex and active anticancer therapy influenced negative seroconversion. BNT162b2 or messenger RNA-1273 vaccines were immunogenic in cancer patients, showing good safety profile., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luigi Cavanna: Consulting or Advisory Role for AstraZeneca; Travel, Accommodations, Expenses from Pfizer, Ipsen And Celgene. Other authors: No Relationships to Disclose., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In recent years, isotopic analysis has been proven a valuable tool for the determination of the origin of various materials. In this article, we studied the 18 O and 13 C isotopic values of 210 olive oil samples that were originated from different regions in Greece in order to verify how these values are affected by the climate regime. We observed that the δ 18 O isotopic values range from 19.2 ‱ to 25.2 ‱ and the δ 13 C values range from -32.7 ‱ to -28.3 ‱. These differences between the olive oils' isotopic values depended on the regional temperature, the meteoric water, and the distance from the sea. Furthermore, we studied the 13 C isotopic values of biophenolic extracts, and we observed that they have same capability to differentiate the geographic origin. Finally, we compared the isotopic values of Greek olive oils with samples from Italy, and we concluded that there is a great dependence of oxygen isotopes on the climatic characteristics of the different geographical areas.

Obesity and associated diabetes (diabesity) impair kidney mitochondrial dynamics by augmenting fission and diminishing fusion, which results in mitochondrial and renal dysfunction. Based on available evidence, the antioxidant activities of melatonin may improve impaired renal mitochondrial function in obese diabetic animals by restoring the imbalanced dynamics through inhibiting fission and promoting fusion. Male Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally treated either with melatonin (10 mg/kg BW/day) (M-ZDF and M-ZL) or vehicle (C-ZDF and C-ZL) for 17 weeks. Kidney function was evaluated by measurement of total urine volume, proteinuria, creatinine clearance, and assessment of kidney mitochondrial dynamics and function. C-ZDF exhibited impaired dynamics and function of kidney mitochondria in comparison to C-ZL. Melatonin improved nephropathy of ZDF rats and modulated their mitochondrial dynamics by reducing expression of Drp1 fission marker and increasing that of fusion markers, Mfn2 and Opa1. Furthermore, melatonin ameliorated mitochondrial dysfunction by increasing respiratory control index and electron transfer chain complex IV activity. In addition, it lowered mitochondrial oxidative status. Our findings show that melatonin supplementation improves nephropathy likely via modulation of the mitochondrial fission/fusion balance and function in ZDF rats.

Background: Acute ischemic stroke (AIS) is associated with autonomic dysfunction. We evaluated the prognostic value of heart rate variability (HRV) and the role of stroke localization and reperfusion treatment (RT) on autonomic control., Methods: Patients with AIS and sinus rhythm were enrolled in the emergency department. Autonomic parameters were recorded at the onset and after a potential RT. Neurological deficit was assessed using the National Institute of Health Stroke Scale (NIHSS) at the onset and residual disability with modified Rankin Scale (mRS) at 3 months. Two analyses were used to assess HRV. Low frequency (LF) and high frequency (HF) are, respectively, markers of sympathetic and respiratory vagal modulation in spectral analysis. Symbolic analysis provides pattern with no variation (0V%) as an index of sympathetic modulation and pattern with two like variations (2LV%) and pattern with two unlike variations (2UV%) as markers of vagal modulation., Results: We enrolled 41 patients. Twenty-seven underwent RT. A prevalent parasympathetic modulation was found in patients with NIHSS ≥14. The group with mRS 3-6 exhibited a higher 2UV% and lower 0V%. Right-sided strokes were associated with a higher respiratory vagal control. RT had no effects on HRV parameters., Conclusions: In the very early phases of AIS, a decreased 0V% and an increased 2UV% may reflect a loss of sympathetic oscillation, predicting a poorer 3 month-outcome., Competing Interests: The authors declare no conflict of interests.

Background: Cannabinoid receptors have been detected in human gliomas and cannabinoids have been proposed as novel drug candidates in the treatment of brain tumors., Aims: To test the in vitro antitumor activity of COR167, a novel cannabinoid CB2-selective agonist displaying a high binding affinity for human CB2 receptors, on tumor cells isolated from human glioblastoma multiforme and anaplastic astrocytoma., Methods: Glioma cell cultures were established from two glioblastoma multiforme and two anaplastic astrocytomas. Proliferation was measured in the presence or absence of COR167 with a bromodeoxyuridine (BrdU) cell proliferation ELISA assay. CB2 receptor expression was detected by western blotting. Apoptosis was assessed with phycoerythrin (PE) annexin V flow cytometry kit. TGF-beta 1 and 2 levels were analyzed in culture supernatants with commercial ELISAs., Results: COR167 was found to significantly reduce the proliferation of both glioblastoma and anaplastic astrocytoma in a dose-dependent manner at lower doses than other known, less specific CB2 agonists. This activity is independent of apoptosis and is associated with a significant reduction of TGF-beta 1 and 2 levels in supernatants of glioma cell cultures., Conclusion: These findings add to the role of cannabinoid CB2 receptor as a possible pharmacological target to counteract glial tumor growth and encourage further work to explore any other pharmacological effect of this novel CB2 agonist useful in the treatment of human gliomas., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

There are no data on the effects of fingolimod, an immunomodulatory drug used in treatment of multiple sclerosis (MS), on circulating tight-junction (TJ) protein levels as well as on peripheral blood mononuclear cells (PBMC) migration. Serum TJ protein [occludin (OCLN), claudin-5 (CLN-5) and zonula occludens-1 (ZO-1)] levels, sphingosine-1 phosphate 1 (S1P 1 ) receptor expression on circulating leukocyte populations as well as in vitro PBMC migration were longitudinally assessed in 20 MS patients under 12-months fingolimod treatment and correlated with clinical and magnetic resonance imaging (MRI) parameters. After 12 months of treatment, a significant reduction of mean relapse rate as well as number of active lesions at MRI was found. TJ protein levels significantly decreased and were associated with reduction of S1P 1 expression as well as of PBMC in vitro migratory activity. A significant correlation of CLN-5/OCLN ratio with new T 2 MRI lesions and a significant inverse correlation of CLN-5/ZO-1 ratio with disability scores were found. These findings support possible in vivo effects of fingolimod on the blood-brain barrier (BBB) functional activity as well as on peripheral cell trafficking that could result in avoiding passage of circulating autoreactive cells into brain parenchyma. Circulating TJ protein levels and respective ratios could be further studied as a novel candidate biomarker of BBB functional status to be monitored in course of fingolimod as well as of other immunomodulatory treatments in MS.

We describe a liquid chromatography method development approach for the separation of intact proteins using hydrophobic interaction chromatography. First, protein retention was determined as function of the salt concentration by isocratic measurements and modeled using linear regression. The error between measured and predicted retention factors was studied while varying gradient time (between 15 and 120 min) and gradient starting conditions, and ranged between 2 and 15%. To reduce the time needed to develop optimized gradient methods for hydrophobic interaction chromatography separations, retention-time estimations were also assessed based on two gradient scouting runs, resulting in significantly improved retention-time predictions (average error < 2.5%) when varying gradient time. When starting the scouting gradient at lower salt concentrations (stronger eluent), retention time prediction became inaccurate in contrast to predictions based on isocratic runs. Application of three scouting runs and a nonlinear model, incorporating the effects of gradient duration and mobile-phase composition at the start of the gradient, provides accurate results (improved fitting compared to the linear solvent-strength model) with an average error of 1.0% and maximum deviation of -8.3%. Finally, gradient scouting runs and retention-time modeling have been applied for the optimization of a critical-pair protein isoform separation encountered in a biotechnological sample., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The characterization of biotherapeutics represents a major analytical challenge. This review discusses the current state-of-the-art in analytical technologies to profile biopharma products under native conditions, i.e., the protein three dimensional conformation is maintained during liquid chromatographic analysis. Native liquid-chromatographic modes that are discussed include aqueous size-exclusion chromatography, hydrophobic interaction chromatography, and ion-exchange chromatography. Infusion conditions and the possibilities and limitations to hyphenate native liquid chromatography to mass spectrometry are discussed. Furthermore, the applicability of native liquid-chromatography methods and intact mass spectrometry analysis for the characterization of monoclonal antibodies and antibody-drug conjugates is discussed., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We call monomer a B-DNA base pair and study, analytically and numerically, electron or hole oscillations in monomers, dimers and trimers. We employ two tight binding (TB) approaches: (I) at the base-pair level, using the on-site energies of the base pairs and the hopping parameters between successive base pairs i.e. a wire model, and (II) at the single-base level, using the on-site energies of the bases and the hopping parameters between neighbouring bases, specifically between (a) two successive bases in the same strand, (b) complementary bases that define a base pair, and (c) diagonally located bases of successive base pairs, i.e. an extended ladder model since it also includes the diagonal hoppings (c). For monomers, with TB II, we predict periodic carrier oscillations with frequency [Formula: see text]-550 THz. For dimers, with TB I, we predict periodic carrier oscillations with [Formula: see text]-100 THz. For trimers made of identical monomers, with TB I, we predict periodic carrier oscillations with [Formula: see text]-33 THz. In other cases, either with TB I or TB II, the oscillations may be not strictly periodic, but Fourier analysis shows similar frequency content. For dimers and trimers, TB I and TB II are successfully compared giving complementary aspects of the oscillations.

For the first time, an absolute quantification of hybrid materials obtained from the reaction of phenylphosphonic acid (PPA) with TiO2 nanoparticles under different reaction conditions is reported. Next to the amount of PPA involved in grafting to the TiO2 nanoparticles, also the PPA included in titaniumphenylphosphonate crystallites is described quantitatively. The quantitative analysis is based on solid state (31)P MAS NMR and is further applied to evaluate the stability of the resulting hybrid materials towards hydrolysis and organic solvent exposure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hepatic mitochondrial dysfunction is thought to play a role in the development of liver steatosis and insulin resistance, which are both common characteristics of obesity and type 2 diabetes mellitus (T2DM). It was hypothesized that the antioxidant properties of melatonin could potentially improve the impaired functions of hepatic mitochondria in diabetic obese animals. Male Zucker diabetic fatty (ZDF) rats and lean littermates (ZL) were given either melatonin (10 mg/kg BW/day) orally for 6 wk (M-ZDF and M-ZL) or vehicle as control groups (C-ZDF and C-ZL). Hepatic function was evaluated by measurement of serum alanine transaminase and aspartate transaminase levels, liver histopathology and electron microscopy, and hepatic mitochondrial functions. Several impaired functions of hepatic mitochondria were observed in C-ZDF in comparison with C-ZL rats. Melatonin treatment to ZDF rats decreases serum levels of ALT (P < 0.001), alleviates liver steatosis and vacuolation, and also mitigates diabetic-induced mitochondrial abnormalities, glycogen, and lipid accumulation. Melatonin improves mitochondrial dysfunction in M-ZDF rats by increasing activities of mitochondrial citrate synthase (P < 0.001) and complex IV of electron transfer chain (P < 0.05) and enhances state 3 respiration (P < 0.001), respiratory control index (RCR) (P < 0.01), and phosphorylation coefficient (ADP/O ratio) (P < 0.05). Also melatonin augments ATP production (P < 0.05) and diminishes uncoupling protein 2 levels (P < 0.001). These results demonstrate that chronic oral melatonin reduces liver steatosis and mitochondria dysfunction in ZDF rats. Therefore, it may be beneficial in the treatment of diabesity., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Different dietary protein sources can promote different renal statuses. We examined the effects of whey protein (WP) and soy protein (SP) intake on plasma, urinary, and morphological renal parameters in rats. One hundred and twenty Wistar rats were randomly distributed into 2 experimental groups fed with either WP or SP diets over 12 weeks. These diets were based on commercial WP or SP isolates. The urinary calcium content was higher in the WP diet compared to the SP diet group (P<.001) whereas the urinary citrate level was lower (P<.001). The urinary pH was more acidic in the WP diet group compared to the SP diet group (P<.001); however, no differences were observed between the groups for any of the renal morphological parameters analyzed (all, P>.05) or other plasma renal markers such as albumin or urea concentrations. The increase of acid and urinary calcium and the lower urinary citrate level observed in the WP diet group could increase the incidence of nephrolithiasis compared to the SP diet group. Despite the WP showed poorer acid-base profile, no significant morphological renal changes were observed. These results suggest that the use of SP instead of WP appears to promote a more alkaline plasma and urinary profile, with their consequent renal advantages.

Melatonin limits obesity in rodents without affecting food intake and activity, suggesting a thermogenic effect. Identification of brown fat (beige/brite) in white adipose tissue (WAT) prompted us to investigate whether melatonin is a brown-fat inducer. We used Zücker diabetic fatty (ZDF) rats, a model of obesity-related type 2 diabetes and a strain in which melatonin reduces obesity and improves their metabolic profiles. At 5 wk of age, ZDF rats and lean littermates (ZL) were subdivided into two groups, each composed of four rats: control and those treated with oral melatonin in the drinking water (10 mg/kg/day) for 6 wk. Melatonin induced browning of inguinal WAT in both ZDF and ZL rats. Hematoxylin-eosin staining showed patches of brown-like adipocytes in inguinal WAT in ZDF rats and also increased the amounts in ZL animals. Inguinal skin temperature was similar in untreated lean and obese rats. Melatonin increased inguinal temperature by 1.36 ± 0.02°C in ZL and by 0.55 ± 0.04°C in ZDF rats and sensitized the thermogenic effect of acute cold exposure in both groups. Melatonin increased the amounts of thermogenic proteins, uncoupling protein 1 (UCP1) (by ~2-fold, P < 0.01) and PGC-1α (by 25%, P < 0.05) in extracts from beige inguinal areas in ZL rats. Melatonin also induced measurable amounts of UCP1 and stimulated by ~2-fold the levels of PGC-1α in ZDF animals. Locomotor activity and circulating irisin levels were not affected by melatonin. These results demonstrate that chronic oral melatonin drives WAT into a brown-fat-like function in ZDF rats. This may contribute to melatonin's control of body weight and its metabolic benefits., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study assessed salt sensitivity, analyzing the effects of an increased saline intake on hemodynamic, morphological, and oxidative stress and renal variables in experimental thyroid disorders. Six groups of male Wistar rats were used: control, hypothyroid, hyperthyroid, and the same groups treated with salt (8% via food intake). Body weight, blood pressure (BP), and heart rate (HR) were recorded weekly for 6 wk. Finally, BP and HR were recorded directly, and morphological, metabolic, plasma, and renal variables were measured. High-salt intake increased BP in thyroxine-treated rats but not in control or hypothyroid rats. High-salt intake increased cardiac mass in all groups, with a greater increase in hyperthyroid rats. Urinary isoprostanes and H(2)O(2) were higher in hyperthyroid rats and were augmented by high-salt intake in all groups, especially in hyperthyroid rats. High-salt intake reduced plasma thyroid hormone levels in hyperthyroid rats. Proteinuria was increased in hyperthyroid rats and aggravated by high-salt intake. Urinary levels of aminopeptidases (glutamyl-, alanyl-, aspartyl-, and cystinylaminopeptidase) were increased in hyperthyroid rats. All aminopeptidases were increased by salt intake in hyperthyroid rats but not in hypothyroid rats. In summary, hyperthyroid rats have enhanced salt sensitivity, and high-salt intake produces increased BP, cardiac hypertrophy, oxidative stress, and signs of renal injury. In contrast, hypothyroid rats are resistant to salt-induced BP elevation and renal injury signs. Urinary aminopeptidases are suitable biomarkers of renal injury.

Introduction: It is difficult to prevent and treat intra- and peri-neural fibrosis after peripheral nerve surgery. Many authors have attempted to develop and verify the effectiveness of substances to decrease the formation of adherences in different tissues., Material and Methods: this study aimed to assess the effectiveness of a barrier of oxidized regenerated cellulose (ORC) to reduce adherence and perineural fibrosis in a model of surgical perineural induced fibrosis in rat sciatic nerve in 40 rats. After tissue aggression, the nerve of the right rear limb was wrapped in ORC and the left limb served as control. Animals were killed at 3 and 6 weeks, and nerves and muscle mass were extracted en bloc. Connective tissue was quantified by conventional histopathological techniques and Fibrosis HR(R) automatic image analysis., Results: No significant differences were found in intra- or peri-neural induced fibrosis between control nerves (6.88% and 8.90%, respectively) and treated nerves (6.57% and 9.90%) at 3 or 6 weeks (10.41% and 12.51% in controls; 11.85% and 15.72% in treated nerves). Inflammatory phenomena and granulomatous reactions were more frequent in treated animals., Conclusions: ORC conferred no advantage in prevention of nerve fibrosis and might have interfered with healing.

The microglial response elicited by degeneration of retinal photoreceptor cells was characterized in BALB/c mice exposed to bright light for 7 hours and then kept in complete darkness for survival times ranging from 0 hours to 10 days. Photodegeneration resulted in extensive cell death in the retina, mainly in the outer nuclear layer (ONL), where the photoreceptor nuclei are located. Specific immunolabeling of microglial cells with anti-CD11b, anti-CD45, anti-F4/80, anti-SRA, and anti-CD68 antibodies revealed that microglial cells were activated in light-exposed retinas. They migrated to the ONL, changed their morphology, becoming rounded cells with short and thick processes, and, finally, showed immunophenotypic changes. Specifically, retinal microglia began to strongly express antigens recognized by anti-CD11b, anti-CD45, and anti-F4/80, coincident with cell degeneration. In contrast, upregulation of the antigen recognized by anti-SRA was not detected by immunocytochemistry until 6 hours after light exposure. Differences were also observed at 10 days after light exposure: CD11b, CD45, and F4/80 continued to be strongly expressed in retinal microglia, whereas the expression of CD68 and SRA had decreased to near-normal values. Therefore, microglia did not return to their original state after photodegeneration and continued to show a degree of activation. The accumulation of activated microglial cells in affected regions simultaneously with photoreceptor degeneration suggests that they play some role in photodegeneration., (2009 Wiley-Liss, Inc.)

Hairy cell leukemia (HCL) is generally responsive to single-agent cladribine, and only a minority of patients are refractory and with poor prognosis. HCLs generally express mutated (M) and, in a minority, unmutated (UM) IGHV. In a multicenter clinical trial in newly diagnosed HCL, we prospectively investigated clinical and molecular parameters predicting response and event-free survival after single-agent cladribine. Of 58 HCLs, 6 expressed UM-IGHV (UM-HCL) and 52 M-IGHV (M-HCL). Beneficial responses were obtained in 53 of 58 patients (91%), whereas treatment failures were observed in 5 of 58 patients (9%). Failures were associated significantly with UM-IGHV (5 of 5 failures vs 1 of 53 beneficial responses had UM-IGHV, P < .001), leukocytosis (3 of 5 vs 3 of 53, P = .006), and bulky spleen (4 of 5 vs 4 of 53, P < .001). The UM-HCL not benefiting from cladribine characteristically had bulky spleen (4 of 5, 80%), leukocytosis (3 of 5, 60%), and TP53 defects (2 of 5, 40%), and progressed rapidly after first treatment (median event-free survival, 7.5 months). Our data suggest that UM-HCLs identify the minor subgroup failing cladribine treatment and with more aggressive disease. High incidence of TP53 dysfunction indicates a potential mechanism of resistance to cladribine in the UM-HCL group. Overall, our data provide new molecular elements relevant for treatment concerns in HCL.

Monoclonal B-cell lymphocytosis (MBL) is an asymptomatic monoclonal expansion of <5.0 x 10(9)/l circulating CLL-phenotype B-cells. The relationship between MBL and Rai 0 CLL, as well as the impact of biological risk factors on MBL prognosis, are unknown. Out of 460 B-cell expansions with CLL-phenotype, 123 clinical MBL (cMBL) were compared to 154 Rai 0 CLL according to clinical and biological profile and outcome. cMBL had better humoral immune capacity and lower infection risk, lower prevalence of del11q22-q23/del17p13 and TP53 mutations, slower lymphocyte doubling time, and longer treatment-free survival. Also, cMBL diagnosis was a protective factor for treatment risk. Despite these favourable features, all cMBL were projected to progress, and lymphocytes <1.2 x 10(9)/l and >3.7 x 10(9)/l were the best thresholds predicting the lowest and highest risk of progression to CLL. Although IGHV status, CD38 and CD49d expression, and fluorescence in situ hybridization (FISH) karyotype individually predicted treatment-free survival, multivariate analysis identified the presence of +12 or del17p13 as the sole independent predictor of treatment requirement in cMBL (Hazard ratio: 5.39, 95% confidence interval 1.98-14.44, P = 0.001). Overall, these data showed that cMBL has a more favourable clinical course than Rai 0 CLL. Given that the biological profile can predict treatment requirement, stratification based on biological prognosticators may be helpful for cMBL management.

Conflicting data exist on expression of gp145trkB, the high affinity receptor for brain-derived neurotrophic factor (BDNF), on peripheral blood immunocompetent cells in multiple sclerosis (MS). We analyzed expression of gp145trkB by western blotting and flow cytometry in myelin basic protein (MBP)- and ovalbumin (OVA)-T cell lines prepared from 12 patients with relapsing-remitting MS and 12 normal healthy subjects (NHS) and correlated it with activation-induced apoptosis. We found a higher percentage of gp145trkB-expressing MBP-T cells in MS patients than in NHS (p=0.011). gp145trkB was mainly expressed by CD8(+) T cells to a higher extent in MS patients than in NHS (p=0.04). MBP-T cell lines from MS patients showed significantly lower apoptosis intensity than those from NHS (p=0.011). We found also a significant negative correlation between gp145trkB expression and apoptosis intensity in MS patients only (p=0.02). OVA-T cell lines showed a gp145trkB expression similar to that of MBP-T cell lines, with a higher expression in MS patients than NHS, and similar correlations with apoptosis intensity in MS. These findings suggest that gp145trkB is mainly expressed on T cell lines from MS patients and that the BDNF/gp145trkB axis is involved in the regulation of peripheral T cell apoptosis in MS.

Fludarabine plus cyclophosphamide (FC) at conventional doses is an effective treatment for chronic lymphocytic leukaemia (CLL). However, FC at standard doses may give hematological and non-hematological toxicity, predominantly in the elderly. Intravenous or oral low-dose FC regimens remain highly effective in elderly patients with Low-Grade Lymphomas other than CLL and are well tolerated. We tested efficacy and toxicity of oral FC at reduced doses in 26 elderly patients (median 71 years) with previously untreated (UT-CLL, n = 14) or relapsed/refractory CLL (R-CLL, n = 12), unfit for conventional treatments. Twentyfour-of-26 (92%) patients (14/14, 100% UT-CLL; 10/12, 83.5% R-CLL) obtained a response, with 12/26 (46%) complete responses (9/14, 64.2% in UT-CLL; 3/12, 25% in R-CLL). Non-hematological toxicity was mild and myelosuppression was documented in 8/26 (31%) patients (4/14, 28% UT-CLL; 4/12, 33% R-CLL). With a median follow-up of 24 months, median event-free survival was 48 months with no differences between UT-CLL and R-CLL and all responders were alive. Low-dose oral FC treatment showed good efficacy in both untreated and refractory/relapsed CLL. The treatment is useful in elderly patients who cannot benefit of more aggressive schedules and is easy to administer on an outpatient basis., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Macrophage/microglial cells in the mouse retina during embryonic and postnatal development were studied by immunocytochemistry with Iba1, F4/80, anti-CD45, and anti-CD68 antibodies and by tomato lectin histochemistry. These cells were already present in the retina of embryos aged 11.5 days (E11.5) in association with cell death. At E12.5 some macrophage/microglial cells also appeared in peripheral regions of the retina with no apparent relationship with cell death. Immediately before birth microglial cells were present in the neuroblastic, inner plexiform (IPL), and ganglion cell (GCL) layers, and their distribution suggested that they entered the retina from the ciliary margin and the vitreous. The density of retinal microglial cells strongly decreased at birth, increased during the first postnatal week as a consequence of the entry of microglial precursors into the retina from the vitreous, and subsequently decreased owing to the cessation of microglial entry and the increase in retina size. The mature topographical distribution pattern of microglia emerged during postnatal development of the retina, apparently by radial migration of microglial cells from the vitreal surface in a vitreal-to-scleral direction. Whereas microglial cells were only seen in the GCL and IPL at birth, they progressively appeared in more scleral layers at increasing postnatal ages. Thus, microglial cells were present within all layers of the retina except the outer nuclear layer at the beginning of the second postnatal week. Once microglial cells reached their definitive location, they progressively ramified., ((c) 2007 Wiley-Liss, Inc.)

Ameboid microglial cells migrate tangentially on the vitreal part of quail embryo retinas by crawling on Müller cell end-feet (MCEF) to which they adhere. These microglial cells can be cultured immediately after dissection of the eye and isolation of sheets containing the inner limiting membrane (ILM) covered by a carpet of MCEF (ILM/MCEF sheets), to which the cells remain adhered. Morphological changes of microglial cells cultured on ILM/MCEF sheets for 4 days were characterized in this study. During the first minutes in vitro, lamellipodia-bearing bipolar microglial cells became rounded in shape. From 1 to 24 h in vitro (hiv), microglial cells swept and phagocytosed the MCEF on which they were initially adhered, becoming directly adhered on the ILM. MCEF sweep was dependent on active cell motility, as shown by inhibition of sweep after cytochalasin D treatment. From 24 hiv on, after MCEF phagocytosis, microglial cells became more flattened, increasing the surface area of their adhesion to substrate, and expressed the beta1 subunit of integrins on their membrane. Morphological evidence suggested that microglial cells migrated for short distances on ILM/MCEF sheets, leaving tracks produced by their strong adhesion to the substrate. The simplicity of the isolation method, the immediate availability of cultured microglial cells, and the presence of multiple functional processes (phagocytosis, migration, upregulation of surface molecules, etc.) make cultures of microglial cells on ILM/MCEF sheets a valuable model system for in vitro experimental investigation of microglial cell functions., (2006 Wiley-Liss, Inc.)

The present study showed that the HIS-C7 monoclonal antibody, which recognizes the chick form of CD45, is a specific marker for macrophages/microglial cells in the developing and mature chick central nervous system (CNS). HIS-C7-positive cells were characterized according to their morphological features and chronotopographical distribution patterns within developing and adult CNS, similar to those of macrophages/microglial cells in the quail CNS and confirmed by their histochemical labeling with Ricinus communis agglutinin I, a lectin that recognizes chick microglial cells. Therefore, the HIS-C7 antibody is a valuable tool to identify brain macrophage and microglial cells in studies of the function, development, and pathology of the chick brain. CD45 expression differed between chick microglia (as revealed with HIS-C7 antibody) and mouse microglial cells (as revealed with an antibody against mouse form of CD45). Thus, a discontinuous label was seen on mouse microglial cells with the anti-mouse CD45 immunostaining, whereas the entire surface of chick microglial cells was labeled with the anti-chick CD45 staining. The functional relevance of these differences between species has yet to be determined.

Activation of mature (ramified) microglia in response to injury in the adult central nervous system (CNS) is well documented. However, the response of immature (ameboid) microglia to injury in the developing CNS has received little attention. In this study, a stab wound was made in embryonic quail retinas at incubation days 7 and 9, and the response of retinal microglial cells was analyzed at different times between days 1 and 37 postinjury. The appearance of microglial cells within the wound occurred at the same time as the arrival of the first migrating ameboid microglial cells at an equivalent area in control retinas. Therefore, no specific attraction of microglia toward the wound was observed. Microglial cells in the wound had phenotypic features similar to those of activated microglia in the adult CNS. Thus, their shape was more compact compared with microglial cells outside the wound, expression of the molecule recognized by the QH1 antibody was up-regulated, and their lysosomal compartment was markedly increased. Transitional forms between normal ameboid and activated-like microglial cells were seen at the wound edge, supporting the view that ameboid microglia become activated when they contact the wound during the normal course of their migration in the retina. The microglial reaction was maintained within the wound at 37 days postinjury. In addition to the stab wound, secondary damage areas were found in experimental retinas. Activated cells could still be observed in these areas at 37 days postinjury., (Copyright (c) 2005 Wiley-Liss, Inc.)