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In this paper, we study Lebesgue differentiation processes along rectangles R k shrinking to the origin in the Euclidean plane, and the question of their almost everywhere convergence in L p spaces. In particular, classes of examples of such processes failing to converge a.e., in L ∞ are provided, for which R k is known to be oriented along the slope k - s for s > 0 , yielding an interesting counterpart to the fact that the directional maximal operator associated to the set { k - s : k ∈ N ∗ } fails to be bounded in L p for any 1 ⩽ p < ∞ . [ABSTRACT FROM AUTHOR]

Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions. [ABSTRACT FROM AUTHOR]

Microbiologically influenced corrosion (MIC), also known as biocorrosion, is caused by corrosive biofilms. MIC is a growing problem, especially in the oil and gas industry. Among various corrosive microbes, sulfate reducing bacteria (SRB) are often the leading culprit. Biofilm mitigation is the key to MIC mitigation. Biocide applications against biofilms promote resistance over time. Thus, it is imperative to develop new biodegradable and cost-effective biocides for large-scale field applications. Using the corrosive Desulfovibrio vulgaris (an SRB) biofilm as a model biofilm, this work demonstrated that a cocktail of glyceryl trinitrate (GTN) and caprylic acid (CA) was very effective for biofilm prevention and mitigation of established biofilms on C1018 carbon steel coupons. The most probable number sessile cell count data and confocal laser scanning microscope biofilm images proved that the biocide cocktail of 25 ppm (w/w) GTN + 0.1 % (w/w) CA successfully prevented the D. vulgaris biofilm establishment on C1018 carbon steel coupons while 100 ppm GTN + 0.1 % CA effectively mitigated pre-established D. vulgaris biofilms on C1018 carbon steel coupons. In both cases, the cocktails were able to reduce the sessile cell count from 10 cells/cm to an undetectable level. [ABSTRACT FROM AUTHOR]

Purpose: Brentuximab vedotin (ADCETRIS), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. Methods: Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). Results: There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. Conclusion: There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies. [ABSTRACT FROM AUTHOR]

Vitamin D, a hormone involved in bone and calcium homeostasis, has been shown to have potent immunomodulatory effects. We performed a retrospective cohort analysis to evaluate whether monohydroxyvitamin D levels before allogeneic hematopoietic SCT (HSCT) correlate with the risk of GVHD. Fifty-three patients who underwent myeloablative HSCT were studied. Vitamin D levels were measured in serum samples obtained before HSCT. The median 25-hydroxyvitamin vitamin D level was 21.9 ng/mL (7.8-45.7). The cumulative incidence (CI) of grades II-IV acute GVHD at 100 days was 53.1% in patients with vitamin D<25, versus 33.3% in patients with vitamin D25 ng/mL (P=0.13). The CI of chronic GVHD (cGVHD) at 2 years in patients with vitamin D<25 was 63.8%, compared with 23.8% in patients with vitamin D25 ng/mL (P=0.009). Similarly, the 2 year CI of extensive cGVHD was significantly greater in patients with vitamin D<25 compared with those with vitamin D25 ng/mL (54.5% versus 14.3%, P=0.005). In a multivariable competing risk model, low pre-transplant vitamin D levels remained a significant factor associated with cGVHD (hazard ratio=5.26, P=0.02). Our results demonstrate that vitamin D deficiency before HSCT is associated with an increased risk of cGVHD. [ABSTRACT FROM AUTHOR]

GVHD remains a major source of morbidity and mortality after allogeneic BMT. GVHD is mediated by alloreactive T cells derived from the hematopoietic graft that target host tissues. Pre-clinical models have shown that presentation of alloantigens by host DCs results in the activation of donor-derived T cells that mediate GVHD. Strategies that interfere with the Ag-presenting capacity of DCs after allogeneic transplantation may decrease the risk of developing GVHD. Vitamin D is a hormone essential for calcium metabolism that shows immunomodulatory properties. We showed that correction of vitamin D deficiency appeared to mitigate manifestations of GVHD. In pre-clinical studies, we have shown that vitamin D inhibits DC maturation, polarizes T-cell populations toward the expression of Th2 as compared with Th1 cytokines, and blunts allogeneic T-cell proliferation in response to DC stimulation. Exposure to vitamin D resulted in increased expression of IDO, an enzyme responsible for tryptophan metabolism that is upregulated in tolerizing DCs. These data suggest that exposure to vitamin D results in immature DC populations that bias toward tolerizing rather than stimulatory T-cell populations. Vitamin D may therefore have a role in the prevention of GVHD. [ABSTRACT FROM AUTHOR]

Aims: Interferon-gamma (IFN-g) has been shown to upregulate MHC class I and II expression, and to promote generation of specific antitumor immune responses. We hypothesized that intratumoral administration of an IFN-γ gene transfer vector facilitates its enhanced local production and may activate effector cells locally. We conducted a phase I dose-escalation study of a replication-deficient adenovirus-interferon-gamma construct (TG1041) to determine safety and tolerability of intratumoral administration, in advanced or locally recurrent melanoma. Methods: Patients were enrolled at four successive dose levels: 10[SUP7] infectious units (iu) (n =3), 10[SUP8] iu (n =3), 10[SUP9]iu (n =3), and 10[SUP10]iu (n =2) per injection per week for 3 weeks. TG1041 was injected in the same tumor nodule weekly in each patient. Safety, toxicity, local and distant tumor responses and biologic correlates were evaluated. Results: A total of 11 patients were enrolled and received the planned three injections per cycle. One patient with stable disease received a second cycle of treatment. A maximum tolerated dose was not reached in this study. No grade 4 toxicities were observed. Two grade 3 toxicities, fever and deep venous thrombosis were observed in one patient. The most frequently reported toxicities were grade 1 pain and redness at the injected site (n =8), and grade 1 fatigue (n =5) patients. Clinical changes observed at the local injected tumor site included erythema (n =5), a minor decrease in size of the injected lesion (n =5) and significant central necrosis by histopathology (n =1). Systemic effects included stable disease in one patient. Correlative studies did not reveal evidence of immunologic activity. Conclusion: Weekly intratumoral administration of TG1041 appears to be safe and well tolerated in patients with advanced melanoma. [ABSTRACT FROM AUTHOR]

We measure the real and imaginary parts of the ac magnetic permeability of YBa2Cu3O7−δA x (A = Cl, F, H) ceramics and powders as functions of temperature and ac magnetic field amplitude H0, applying uncommonly low and widely ranged excitation fields (1 mOe ≤ Ho ≤ 200 Oe). We determine the temperature dependence of two loss peaks, Hp( T) ∼ ( Tc − T)2.7 at low fields in ceramics and Hm( T) ∼ Ts0 − T at higher fields in both powders and ceramics. The extrapolated field Hp(0) and characteristic temperature Tc depend on x and δ, whereas Hm(0) and Ts0 depend mainly on δ. The real part of the permeability indicates a two-step flux-penetration process with two threshold fields for flux penetration. The latter govern the temperature dependence of maxima in the imaginary part as well as the peaks' widths. We propose a field-dependent percolation description of this process, derived from a previous temperature-dependent percolation model. It involves two penetration depths, the classic Ginzburg–Landau one and a low-field abnormally large penetration depth due to chemical disorder. Correspondingly, two types of vortices describe high- and low-field dissipation peaks. [ABSTRACT FROM AUTHOR]

This study explored whether youth involved in joint service systems differed from single-agency users in terms of types of crimes committed and clinical functioning. Data from 4,924 youth involved in one county's public mental health and juvenile justice service systems were examined. Twenty percent of those youth receiving mental health services had recent arrest records, and 30% of youth arrested received mental health services. Of all youth arrested in the county, mental health service users had more arrests than non-mental health service users. A subsample of 94 mental health service users with arrests was matched on demographics with 94 mental health service users without arrests. Youth with arrests had a higher frequency of conduct disorder, higher Child Behavior Checklist Externalizing and Total Problem Scale scores, and more functional impairment on the Child and Adolescent Functional Assessment Scale as compared to youth without arrests. Implications for behavioral health service delivery were discussed. [ABSTRACT FROM AUTHOR]

We measure the diamagnetic response of YBa2 Cu3 Oy Ax ( A= Cl, F, H) ceramics. We obtain low-field effective penetration depths λ of a few 10 μ m, first flux-penetration field H1 distinguishable from the volume penetration field HC 1 and two characteristic temperatures Ts and Tc, Tcs, defined by the onset of the real and imaginary parts of the susceptibility, respectively. H 1(T) goes to zero as a power law H 1(T, x)=H 1( 0, x) (T−T/Tc) 2.7 near TC. From the values of λ and H 1 we infer the correlation length ξ at T= 4.2 K. A large range of values for ξ (4.2) suggests that chemical disorder plays an essential role in the phenomenology of cuprates. We find λ (4.2)∼H 1 (4.2)−1/3 . This, and the power law ξ (4.2)∼H 1 (4.2)−2/3 result from the scaling properties of a phase transition governed by disorder. [ABSTRACT FROM AUTHOR]

Identification of myogenic cell targeting ligands is a critical step in the development of synthetic vectors for gene delivery to skeletal muscle. Here we describe the screening of six potential targeting ligands (insulin, insulin-like growth factor I, iron transferrin, gallium transferrin, alpha-bungarotoxin and carnitine) for their ability to bind dystrophin-deficient myotubes in vitro. Those ligands showing high levels of binding to myotubes were then tested on fully differentiated, isolated, viable myofibers. Of the ligands tested, transferrin showed the most promise based on high levels of binding to myogenic cells, high levels of receptor observed in regenerating fibers of patients with Duchenne muscular dystrophy and the ability to direct a large enzyme conjugate to the cytoplasm of myotubes. Finally, we show that incorporation of transferrin into an artificial virus consisting of poly- L-lysine-condensed DNA coated with a lipid shell (LPDII formulation) results in ligand-directed delivery of DNA to myogenic cells. This is the first report of gene transfer to myogenic cells using a ligand-directed synthetic vector. These results suggest that rational design of ligand-directed, fully synthetic, gene delivery vehicles is a viable approach to skeletal muscle vector development. [ABSTRACT FROM AUTHOR]

Conventional methods for isolating myogenic (satellite) cells are inadequate when only small quantities of muscle, the tissue in which satellite cells reside, are available. We have developed a tissue culture system that reliably permits isolation of intact, living, single muscle fibers with associated satellite cells from predominantly fast and slow muscles of rat and mouse; maintenance of the isolated fibers in vitro; dissociation, proliferation, and differentiation of satellite cells from each fiber; and removal of the fiber from culture for analysis. [ABSTRACT FROM AUTHOR]

Scaling in the transition to coherence of randomly coupled granular superconductors is described by critical exponents unexpectedly close to those reported for the spin-glass transition. We discuss a model of non-homogeneous transitions, localised in the regions of highest coupling energy in the sample. Thermal exponents are expressed in terms of percolation exponents; the numerical values thus obtained are in good agreement with the experimental ones. [ABSTRACT FROM AUTHOR]

Eighty-four anaerobic fecal isolates obtained from five healthy volunteers were tested for their ability to inhibit in vitro growth of eight species of Enterobacteriaceae, four species of faculative gram-positive cocci, and Pseudomonas aeruginosa. Forty-nine of the 84 anaerobic isolates (58 %) inhibited the growth of at least one indicator bacterium. Isolates of Bacteroides and Bifidobacterium spp. were most consistently inhibitory. Anaerobic cocci and clostridia were infrequently inhibitory; eubacteria showed no inhibitory activity. Serratia marcescens was the indicator most often inhibited; 54 % of all anaerobic isolates tested, all of nine Bifidobacterium isolates and 33 of 43 Bacteroides isolates inhibited this organism. No anaerobes inhibited the growth of Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Citrobacter freundii, Citrobacter diversus or Streptococcus faecalis. [ABSTRACT FROM AUTHOR]

The right extensor digitorum longus (EDL) muscle of growing male rats was overloaded by ablation of its synergist tibialis anterior (TA) muscle. Four weeks later, the overloaded muscle was heavier and contained larger type IIA, IIX and IIB fibres than either untreated contralateral muscle or control muscle from an untreated animal. The myonuclear-to-myoplasmic volume ratio was maintained in the overloaded muscle. Overloaded EDL muscle, previously subjected to a dose of irradiation sufficient to sterilise satellite cells, and EDL muscle which had been only irradiated, were significantly lighter and contained significantly smaller fibres than controls, though a significant amount of normal EDL muscle growth did occur following either treatment. The myonuclear-to-myoplasmic volume ratio of the irradiated muscles was smaller than in controls. Overloaded muscle, with or without prior irradiation, possessed a smaller proportion of fibres containing IIB myosin heavy chain (MHC) and a larger proportion of fibres containing IIA and IIX MHC; a significant percentage of these fibres coexpressed either type IIA and IIX MHC or type IIX and IIB MHC. Thus in the absence of satellite cell mitosis, muscles of young rats possess a limited capacity for normal growth but not for compensatory hypertrophy. Adaptations in MHC gene expression to chronic overload are completely independent of satellite cell activity. [ABSTRACT FROM AUTHOR]

Complete muscle cross sections were obtained from the proximal and distal third regions of ten rat extensor digitorum longus muscles. Electrophoretic methods were then used to quantify the various myosin isozymes and light chains in each muscle specimen. The results demonstrated that the relative distribution of the various myosin isozyme and light chain variables do not vary significantly between the two sampling regions. [ABSTRACT FROM AUTHOR]

Acute SPECT imaging with Tc-99m sestamibi is an emerging, cost-effective stratagem for selected patients arriving at the emergency department with chest pain. To date, the cohort of patients studied have included those who arrive at the emergency department with typical chest pain and a normal or nondiagnostic electrocardiogram. This application could be extended to other clinical settings. The current case demonstrates that in an outpatient setting, a severe rest SPECT perfusion defect in a symptomatic patient with a nondiagnostic electrocardiogram prompted timely hospitalization and revascularization. The resting defect was consistent with jeopardized, viable myocardium as it normalized after revascularization. [ABSTRACT FROM AUTHOR]