Hypoxia and inflammation as a consequence of β-fibril accumulation. A perspective view for new potential therapeutic targets

Amyloidoses are heterogeneous diseases that result from the deposition of toxic insoluble β-sheet fibrillar protein aggregates in different tissues. The cascade of molecular events leading to amyloidoses and to the related clinical manifestations is not completely understood. Nevertheless, it is known that tissue damage associated to this disease involves alteration of tissue architecture, interaction with cell surface receptors, inflammation elicited by the amyloid protein deposition, oxidative stress, and apoptosis. However, another important aspect to consider is that systemic protein massive deposition not only subverts tissue architecture but also determines a progressive cellular hypertrophy and dilation of the extracellular space enlarging the volume of the organ. Such an alteration increases the distance between cells and vessels with a drop in pO2 that, in turn, causes both necrotic cell death and activation of the hypoxia transcription factor HIF-1α. Herewith, we propose the hypothesis that both cell death and hypoxia represent two important events for the pathogenesis of damage and progression of amyloidoses. In fact, molecules released by necrotic cells activate inflammatory cells from one side while binding to HIF-1α-dependent membrane receptors expressed on hypoxic parenchymal cells on the other side. This latter event generates a signaling cascade triggering NFκB activation and chronic inflammation. Finally, we also suggest that this scenario, once proved and detailed, might suggest important targets for new therapeutic interventions

One-Loop Effect of Null-Like Cosmology's Holographic Dual Super-Yang-Mills

We calculate the 1-loop effect in super-Yang-Mills which preserves 1/4-supersymmetries and is holographically dual to the null-like cosmology with a big-bang singularity. Though the bosonic and fermionic spectra do not agree precisely, we do obtain vanishing 1-loop vacuum energy for generic warped plane-wave type backgrounds with a big-bang singularity. Moreover, we find that the cosmological "constant" contributed either by bosons or fermions is time-dependent. The issues about the particle production of some background and about the UV structure are also commented. We argue that the effective higher derivative interactions are suppressed as long as the Fourier transform of the time-dependent coupling is UV-finite. Our result holds for scalar configurations that are BPS but with arbitrary time-dependence. This suggests the existence of non-renormalization theorem for such a new class of time-dependent theories. Altogether, it implies that such a super-Yang-Mills is scale-invariant, and that its dual bulk quantum gravity might behave regularly near the big bang.Comment: 20 pages, v2 add comments and references, v3 clarify BPS condition & add new discussion on particle production and UV structure, v4&v5 minor changes, final to JHE

Hagedorn Strings and Correspondence Principle in AdS(3)

Motivated by the possibility of formulating a strings/black hole correspondence in AdS space, we extract the Hagedorn behavior of thermal AdS_3 bosonic string from 1-loop partition function of SL(2,R) WZW model. We find that the Hagedorn temperature is monotonically increasing as the AdS radius shrinks, reaches a maximum of order of string scale set by the unitarity bound of the CFT for internal space. The resulting density of states near the Hagedorn temperature resembles the form as for strings in flat space and is dominated by the space-like long string configurations. We then argue a conjectured strings/black hole correspondence in AdS space by applying the Hagedorn thermodynamics. We find the size of the corresponding black hole is a function of the AdS radius. For large AdS radius a black hole far bigger than the string scale will form. On the contrary, when the AdS and string scales are comparable a string size black hole will form. We also examine strings on BTZ background obtained through SL(2,Z) transformation. We find a tachyonic divergence for a BTZ black hole of string scale size.Comment: 28 pages, 4 figures;v2 references added & appear on JHE

Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry

AbstractBackground and aimsIn Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.Methods and resultsFrom February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m2, n = 22,015), and metabolic control (HbA1c ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21–26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27–40% of all discontinuations, after excluding lost to follow-up. HbA1c decreased on average by 0.9–1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0–1.5% with DPP-4 inhibitors.ConclusionsIn the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials

A Panel of Serum Biomarkers Differentiates IgA Nephropathy from Other Renal Diseases

Background and Objectives: There is increasing evidence that galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complexes are important for the pathogenesis of IgA nephropathy (IgAN). In the present study, we assessed a novel noninvasive multi-biomarker approach in the diagnostic test for IgAN. Materials and Methods: We compared serum levels of IgA, IgG, Gd-IgA1, Gd-IgA1-specific IgG and Gd-IgA1-specific IgA in 135 IgAN patients, 79 patients with non-IgAN chronic kidney disease (CKD) controls and 106 healthy controls. Serum was collected at the time of kidney biopsy from all IgAN and CKD patients. Results: Each serum marker was significantly elevated in IgAN patients compared to CKD (P<0.001) and healthy controls (P<0.001). While 41% of IgAN patients had elevated serum Gd-IgA1 levels, 91% of these patients exhibited Gd-IgA1-specific IgG levels above the 90th percentile for healthy controls (sensitivity 89%, specificity 92%). Although up to 25% of CKD controls, particularly those with immune-mediated glomerular diseases including lupus nephritis, also had elevated serum levels of Gd-IgA1-specific IgG, most IgAN patients had elevated levels of Gd-IgA1-specific antibody of both isotypes. Serum levels of Gd-IgA1-specific IgG were associated with renal histological grading. Furthermore, there was a trend toward higher serum levels of Gd-IgA1-specific IgG in IgAN patients with at least moderate proteinuria (≥1.0 g/g), compared to patients with less proteinuria. Conclusions Serum levels of Gd-IgA1-specific antibodies are elevated in most IgAN patients, and their assessment, together with serum levels of Gd-IgA1, improves the specificity of the assays. Our observations suggest that a panel of serum biomarkers may be helpful in differentiating IgAN from other glomerular diseases

Branes from a non-Abelian (2,0) tensor multiplet with 3-algebra

In this paper, we study the equations of motion for non-Abelian N=(2,0) tensor multiplets in six dimensions, which were recently proposed by Lambert and Papageorgakis. Some equations are regarded as constraint equations. We employ a loop extension of the Lorentzian three-algebra (3-algebra) and examine the equations of motion around various solutions of the constraint equations. The resultant equations take forms that allow Lagrangian descriptions. We find various (5+d)-dimensional Lagrangians and investigate the relation between them from the viewpoint of M-theory duality.Comment: 44+1 pages, reference added, typos corrected, and several discussions added; v3, reference added, many typos corrected, the language improved; v4, some typos and references corrected, final version to appear in J. Phys.

Dynamical aspects of the fuzzy CP2^{2} in the large NN reduced model with a cubic term

``Fuzzy CP^2'', which is a four-dimensional fuzzy manifold extension of the well-known fuzzy analogous to the fuzzy 2-sphere (S^2), appears as a classical solution in the dimensionally reduced 8d Yang-Mills model with a cubic term involving the structure constant of the SU(3) Lie algebra. Although the fuzzy S^2, which is also a classical solution of the same model, has actually smaller free energy than the fuzzy CP^2, Monte Carlo simulation shows that the fuzzy CP^2 is stable even nonperturbatively due to the suppression of tunneling effects at large N as far as the coefficient of the cubic term ($\alpha$) is sufficiently large. As \alpha is decreased, both the fuzzy CP$^2$ and the fuzzy S^2 collapse to a solid ball and the system is essentially described by the pure Yang-Mills model (\alpha = 0). The corresponding transitions are of first order and the critical points can be understood analytically. The gauge group generated dynamically above the critical point turns out to be of rank one for both CP^2 and S^2 cases. Above the critical point, we also perform perturbative calculations for various quantities to all orders, taking advantage of the one-loop saturation of the effective action in the large-N limit. By extrapolating our Monte Carlo results to N=\infty, we find excellent agreement with the all order results.Comment: 27 pages, 7 figures, (v2) References added (v3) all order analyses added, some typos correcte

Identification of MOR-positive B cell as possible innovative biomarker (Mu lympho-marker) for chronic pain diagnosis in patients with fibromyalgia and osteoarthritis diseases

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease