Hypophosphatemia after high-dose iron repletion with ferric carboxymaltose and ferric derisomaltose-the randomized controlled HOMe aFers study.

BACKGROUND: In patients with iron deficiency anemia, ferric carboxymaltose (FCM) and ferric derisomaltose (FDI) allow high-dose iron repletion. While FCM is reported to induce hypophosphatemia, the frequency of hypophosphatemia after an equivalent dosage of FDI had not been assessed prospectively. METHODS: In the prospective, single-center, double-blind HOMe aFers study, 26 women with iron deficiency anemia (hemoglobin < 12 g/dL plus either plasma ferritin ≤ 100 ng/mL or a plasma ferritin ≤ 300 ng/mL and transferrin saturation (TSAT) ≤ 30%) were randomized to a single intravenous infusion of 20 mg/kg body weight (up to a maximum of 1000 mg) FCM or FDI. The primary endpoint was the incidence of hypophosphatemia (plasma phosphorus levels < 2.0 mg/dL at day 1, day 7 ± 2, and/or day 35 ± 2 after the infusion). In order to investigate potential skeletal and cardiovascular implications, we assessed changes in other components of mineral and bone metabolism, left ventricular function, and arrhythmias. RESULTS: Hypophosphatemia occurred more frequently in women treated with FCM (9 out of 12 [75%]) than in those treated with FDI (1 out of 13 [8%]; p = 0.001). Within 24 h after iron supplementation, women in the FCM group had significant higher plasma intact FGF23 (p < 0.001) and lower plasma 1.25-dihydroxyvitamin D (p < 0.001). As an indicator of urinary phosphorus losses, urinary fractional phosphorus excretion was higher in the FCM group (p = 0.021 at day 7 ± 2 after iron supplementation). We did not observe differences in skeletal and cardiovascular markers, potentially because of the limited number of participants. CONCLUSIONS: While both FCM and FDI provide efficient iron repletion in participants with iron deficiency anemia, FCM induced hypophosphatemia more often than FDI. TRIAL REGISTRATION: Clinical Trials.gov NCT02905539. Registered on 8 September 2016. 2015-004808-36 (EudraCT Number) U1111-1176-4563 (WHO Universal Trial Number) DRKS00010766 (Deutsches Register Klinischer Studien).

Universal Landau pole.

Our understanding of quantum gravity suggests that at the Planck scale the usual geometry loses its meaning. If so, the quest for grand unification in a large non-Abelian group naturally endowed with the property of asymptotic freedom may also lose its motivation. Instead, we propose a unification of all fundamental interactions at the Planck scale in the form of a universal Landau pole, at which all gauge couplings diverge. The Higgs quartic coupling also diverges while the Yukawa couplings vanish. The unification is achieved with the addition of fermions with vector gauge couplings coming in multiplets and with hypercharges identical to those of the standard model. The presence of these particles also prevents the Higgs quartic coupling from becoming negative, thus avoiding the instability (or metastability) of the standard model vacuum.

Mechanical characteristic and biological behaviour of implanted and restorative bioglasses used in medicine and dentistry: A systematic review.

OBJECTIVE: Nowadays bioactive glasses are finding increasing applications in medical practice due to their ability to stimulate re-mineralisation. However, they are intrinsically brittle materials and the study of new compositions will open up new scenarios enhancing their mechanical properties and maintaining the high bioactivity for a broader range of applications. This systematic review aims to identify the relationship between the composition of bioactive glasses used in medical applications and their influence on the mechanical and biological properties. METHODS: Various electronic databases (PubMed, Science Direct) were used for collecting articles on this subject. This research includes papers from January 2011 to March 2016. PRISMA guidelines for systematic review and meta-analysis have been used. 109 abstracts were collected and screened, 68 articles were read as relevant articles and a total of 22 papers were finally selected for this study. RESULTS: Most of the studies obtained enhanced mechanical properties and the conservation of bioactivity behaviours; although a lack of homogeneity in the characterization methods makes it difficult to compare data. SIGNIFICANCE: New compositions of bioactive glasses incorporating specific ions and the addition in polymers will be the most important direction for future researches in developing new materials for medical applications and especially for dentistry.

Monocyte nonspecific esterase. Enzymologic characterization of a neutral serine esterase associated with myeloid cells.

Monocytes contain a characteristic, prominent set of membrane-bound nonspecific esterases with a slightly acid isoelectric point. These esterases are also detected at modest levels in some granulocyte preparations. They are not apparent in lymphocytes. Among 18 fresh myeloid leukemias and myeloid leukemia cell lines, those of subtypes M4 (myelomonocytic) and M5 (monocytic) were strongly positive; some of subtypes M1-M3 (granulocytic) were moderately positive. The esterases were not detected among 32 fresh lymphoid leukemias and lymphoid leukemia and lymphoblast cell lines. The membrane-bound monocyte esterases, solubilized by treatment of monocyte preparations with nonionic detergent, were resolved by ion-exchange chromatography. The monocyte species account for 80-95% of the total nonspecific esterase activity of monocytes. The resolved enzymes behave as neutral serine carboxyl esterases and are highly sensitive to inhibition by diisopropylfluorophosphate (DFP) and also by sodium fluoride. Similar analysis of a lymphocyte preparation yielded no detectable monocyte esterases, but yielded numerous other forms which were generally resistant to inhibition by DFP and NaF. These nonspecific esterases are also present at background levels in monocytes. The resolution and characterization of the membrane-bound serine esterases from monocytes demonstrates the basis for the well-known cytochemistry of monocytes. The results are also crucial to the development of an immunologic surface marker test for myeloid cells and the study of monocyte membrane physiology.

Histologic effects of contact ultrasound for the treatment of glaucoma.

The histologic effects of a contact ultrasound applicator were compared with those of the immersion applicator that is currently used clinically for the treatment of glaucoma. The applicator coupling cone uses a distensible rubber membrane that can be inflated to control stand-off distance relative to the surface of the eye. This feature allows the focal point of the therapeutic beam to be placed at selective depths. Histologic comparisons of lesions in rabbit and pig eyes showed lesions in the sclera and ciliary body that were similar to those produced by the immersion transducer when the same focal position was used. Moving the focal point to a greater depth resulted in less superficial damage, yet still produced ciliodestruction. Damage to the blood supply of the ciliary body, as found in human cadaver eyes, may be an additional mechanism of action of therapeutic ultrasound, and perhaps of other transscleral high-energy modalities.

Experimental, ultrasonically induced lesions in the retina, choroid, and sclera.

Lesions of the retina, choroid, and sclera were created in the proptosed eye of the rabbit with the use of focused ultrasound at 9.8 MHz. Exposure levels greatly exceeding those encountered in diagnostic systems were required. Histological examination of selected tissue samples, analysis of lesion-producing exposures, and lesion size variations suggest that thermal mechanisms are the principal cause of permanent tissue alterations. Subthreshold lesions, which consist of transitory effects, were observed. 'Threshold" lesions first manifested tansitory effects followed by permanent alterations which appeared within 24 hr. Suprathreshold lesions were evidenced by the immediate appearance of a highly blanched area with an overlying edema and occasional hemorrhage, appearing within 24 hr. The edema in these cases was resorbed within a few days, leaving behind a permanently blanched region. The threshold curve developed from these data is similar in shape to the threshold curve for light-induced lesions created with a commensurate focal spot.

A model for acoustic characterization of intraocular tumors.

Human intraocular tumors and tumors derived from human tumor cell lines grown subcutaneously in the athymic nude mouse were scanned by diagnostic ultrasound. Radiofrequency scan data were converted to digital form and analyzed in the frequency domain. Characteristics of normalized power spectra were found to be significantly different among human spindle cell malignant melanomas, mixed/epithelioid malignant melanomas, metastatic carcinomas, and hemangiomas. Significant differences, as well, were found between implanted primary skin malignant melanomas and adenocarcinomas of the lung, colon, and stomach. Comparison of spectral properties of human intraocular and implanted tumors revealed that human spindle cell malignant melanomas and implanted melanomas exhibit similar characteristics. Human intraocular metastatic tumors from the lung were found to exhibit characteristics similar to those of implanted lung tumors. These results indicate that the implantation of human tumor cell lines in the nude mouse may provide a very useful model for application of diagnostic and therapeutic ultrasound modalities to human intraocular tumors.

High-resolution ultrasonic imaging and characterization of the ciliary body.

PURPOSE: To develop a means for noninvasive in vivo visualization of the ciliary processes using very-high-frequency (50 MHz) ultrasound and to develop quantitative morphologic descriptors that may relate to physiologic function. METHODS: The region of the ciliary body was scanned with very-high-frequency ultrasound, both in rabbits and in normal human subjects. Data were acquired in a series of planes so that the spacing between them was less than the beam width of the transducer in its focal plane. Three-dimensional perspective images were constructed, representing the anatomy of the angle region, including the ciliary processes. The automatically detected boundaries of the ciliary processes were analyzed to compute their periphery, area, shape factor, and fractal dimension. These measures were compared between the human and the rabbit eye and analyzed for periodicities related to the spacing of successive processes. RESULTS: Three-dimensional images allowed visualization of the radial arrangement of the processes. All biometric descriptors were significantly different between the rabbit and human eye and showed periodicities consistent with spacing between processes. CONCLUSIONS: The methods described in this report are sensitive descriptors of the state of the ciliary processes. These techniques may be of value in measurement of changes in the ciliary body associated with disease, medical therapy, and aging.

Isometric, three-dimensional viewing of ultrasonograms.

This report describes a system that allows amplitude information to be used as a third dimension or aspect of display on B-scan ultrasonograms. The relative strength of reflected echoes can be shown on B-scan by means of gray scale, color coding, or on A-scan with amplitude deflection. With this new technique, called isometric display, superimposition of the A-scan trace on the B-scan allows preservation of these amplitude characteristics. The three-dimensional presentation can be rotated around any azimuth to provide isometric viewing of the ultrasonogram. Tissue may then be characterized on a more reliable basis than is permitted by independent analysis of outline and amplitude features.

Proton beam irradiation and hyperthermia. Effects on experimental choroidal melanoma.

Ultrasonically induced hyperthermia (4.75 MHz) and proton irradiation (160 meV) were evaluated alone and combined to treat experimental choroidal melanoma in 58 rabbit eyes. Threshold tumoricidal doses were established for each modality. Therapy was performed combining subthreshold doses of heat and radiation. Focused ultrasonic energy via an external beam was found to deliver well-localized heat to an intraocular tumor. Ectopic temperature elevations due to soft-tissue-bone interfaces were alleviated by modifying beam alignment. The results indicate that hyperthermia (43 degrees C for one hour) potentiated the tumoricidal effects of radiation, while sparing normal ocular structures. Therefore, we believe that experimental hyperthermia is suitable as an adjuvant treatment modality. This shows that ultrasound hyperthermia has the potential to increase the efficacy of proton irradiation by lowering radiation doses and thus decreasing posttreatment ocular morbidity in human intraocular malignancies.

Computerized ultrasonic tissue characterization of ocular tumors.

Mathematical evaluation techniques to derive the calibrated power spectrum of reflected ultrasonic echoes from ocular tumors can be used with a clinical computer system to objectively classify malignant melanoma and metastatic carcinoma of the eye. Sets of spectral data provide a reproducible standard for classification that closely approximates the Callender system used in histologic classification. We used spectral data with a computer data library to separate spindle B malignant melanomas (20 tests in 17 patients) from mixed-epithelioid melanomas (17 tests in 13 patients) and to identify metastatic carcinoma (20 tests in 17 patients) with approximately 98% reliability. Tissue structures can be acoustically stained in B-mode images to define the specific anatomic and structural properties that provide the acoustic differentiation. These data are obtained under in vivo conditions and allow a noninvasive classification of tumors in a way not previously possible, aiding in the definitive diagnosis of ocular tumors, as well as in the planning and monitoring of treatment.

In vivo choroidal thickness measurement.

We developed a system that permits exceptionally accurate measurements of human choroidal thickness in vivo by means of ultrasound. With minicomputer techniques, the complementary functions of the time and spectral domains of reflected sound can be used to permit measurements accurate to less than 20 mu at 10 MHz center frequency. Even more accuracy can be obtained with higher center frequencies. Choroidal thickness has been found to exceed that previously reported, with typical values of 420 mu found at the posterior pole. Even greater values are seen in regions outside the macula.

Therapeutic ultrasound in the production of ocular lesions.

After testing high intensity focused ultrasound on ocular tissues in animals, to obtain damage threshold equations, we used ultrasound for ocular therapy in experimental animals. We developed a therapeutic system for use in conjunction with a low=energy diagnostic ultrasound visualization technique. Our system included a spherical focused transducer operated at a frequency of 9.8 MHz to produce a focal spot 9 cm from the transducer surface. This technique produced controlled ocular tissue damage similar to that produced by laser and xenon are photocoagulation. It can be used to treat any level of tissue, ocular or orbital, and does not require media clarity. Specific tissue absorption properties necessary for laser damage were not required to produce the desired damage.

Ultrasonically accelerated resorption of vitreous membranes.

A noninvasive procedure was used to treat membranes within the vitreous with controlled exposure to focused high-intensity ultrasound in rabbit eyes. Membranes were created by injecting small quantities of platelet-rich plasma into the vitreous of the intact globe of anesthetized rabbits. The average time for untreated membranes (controls and shams) to be resorbed was 34 days, whereas the average time to total resorption of membranes treated with ultrasound was 21 days. This comparison showed that high-intensity ultrasound was effective in accelerating the resorption of this type of vitreous membrane. This ultrasound technique is totally noninvasive and can be used without damage to other ocular tissues. Although this animal model departs in some respects from human vitreous membranes, eventual clinical applications are indicated in selected cases where vitrectomy must be delayed or is contraindicated. Noninvasive disruption of vitreous membranes by therapeutic ultrasound offers great promise for reducing the visual limitations produced by such membranes, and eliminating the sequence of disease leading to permanent visual loss.

Ultrasonic tissue characterization of uveal melanoma and prediction of patient survival after enucleation and brachytherapy.

We performed survival studies on 136 patients with uveal malignant melanoma who were examined with ultrasonic tissue characterization before treatment with cobalt-60 brachytherapy (74 patients) or enucleation (62 patients). Mean follow-up time was 58.7 months for the brachytherapy group and 59.0 months for the enucleated group. The maximal follow-up time was nearly ten years. Univariate survival analysis showed that patients with small tumors (less than 250 mm3, 49 patients) had a higher five-year survival when treated with brachytherapy than when treated with enucleation. No patients in this study with tumor volumes greater than 1,500 mm3 (13 patients) were treated with brachytherapy. For tumors of intermediate size (74 patients), survival analysis did not indicate appreciable differences between the treatment options. However, multivariate models including two ultrasonic tissue characterization variables, scatterer size and concentration, showed appreciable intergroup differences in the dependence of survival on these factors. Results suggest that tissue properties detectable with ultrasonic techniques are related to differences in patient survival and may be used for treatment planning for tumors of intermediate size.

Correlations of acoustic tissue typing of malignant melanoma and histopathologic features as a predictor of death.

Forty-six eyes with uveal melanoma were scanned with a computerized diagnostic ultrasound system before enucleation, and light microscope sections were obtained. Tumors were characterized by ultrasonically measured dimensions and power spectrum analysis, which provided information not available in conventional A- or B-scan ultrasonography. Histopathologic features, including cell clustering pattern, cell type, pigmentation, vascularity, and necrosis, were quantified. Statistically significant correlations were found between parameters derived from the power spectrum and histologic characteristics. Patients were followed up for up to ten years with 14 deaths occurring because of metastases. Using a Cox relative risk model with histopathologic data, a risk model comprising pigmentation and cell type (P less than .0001) was obtained. Using ultrasonic characteristics, a model comprising tumor volume and scatterer concentration (P = .0062) was obtained. The results suggest that ultrasonic tissue characterization and three-dimensional biometry may provide improved in vivo prognostic indicators for uveal melanoma.

Ultrasonic hyperthermia and radiation in the management of intraocular malignant melanoma.

Hyperthermia and radiation were used in combination to treat four patients with choroidal malignant melanoma. This technique uses ultrasonically induced hyperthermia synergistically with radiation to destroy tumor cells. The lower levels of radiation used should avoid the late vascular and inflammatory complications seen in conventional radiation therapy. Tumors were scanned by a computerized diagnostic ultrasound system before treatment and assigned an acoustic tissue type on the basis of a statistical comparison of their ultrasound backscatter spectrum with spectra of tumors of known pathologic status. During the follow-up period, the longest of which was 15 months, all tumors demonstrated regression patterns consistent with choroidal tumors of the same acoustic tissue types treated with conventional radiation therapy.

Effect of hyperthermia on experimental choroidal melanoma.

Thirty-five rabbit eyes were implanted subchoroidally with Greene's hamster melanoma. When the tumours reached a base diameter of 5 mm, they were treated with ultrasonically induced hyperthermia with a range of temperatures and exposure durations (43-67 degrees C and 75 s to 60 min). Of the 23 treated eyes examined two months after treatment eight showed complete regression of the tumour. Seven showed initial tumour regression, but there was subsequent regrowth of tumour round the margins of the original mass. In eight eyes the tumour continued to grow, though in some cases the rate of growth appeared to be slower than in the controls. In contrast, in all untreated animals the tumour grew to fill the vitreous cavity. These preliminary findings indicate that ultrasonically induced hyperthermia can be an effective local treatment of this intraocular tumour model.

Treatment of experimental lens capsular tears with intense focused ultrasound.

High-intensity focused ultrasound was employed to seal lens capsular tears in a rabbit model. Ultrasound therapy was applied either contiguously, thereby completely covering the tear, or in a discrete exposure pattern around the tear. Both methods prevented the formation of a generalised cataract. This was in contrast to results observed in a group of control (untreated) animals which all developed generalised lens opacities. Each control animal also developed a local lens opacity at the site of the capsular tear, as did half the animals treated with the discrete pattern. No animal treated with contiguous exposures developed any local or generalised traumatic-type cataract other than the small lens opacity immediately produced by the treatment. These treatment cataracts would not constitute a significant impediment to vision so long as they did not fall on the visual axis.

Ultrasonic tissue characterization of blood clots.

Ultrasonic tissue characterization based on an analysis of the power spectrum of backscattered signals obtained with ultrasound was used to distinguish morphologic components of blood clots. The three morphologic features for which discrimination was attempted were loose fibrin, red-cell, and dense fibrin clots. The UTC was able to distinguish the morphologic blood components tested. This in vitro work was based on the analysis of parameters related to ultrasound-tissue interaction and on inferences related to the physical properties of scatterer properties (scatterer size, scatterer concentration, and ratio of scatterer to medium acoustic impedances). The ability to distinguish these blood-clot components suggests that UTC may be able to distinguish red from white thrombi and to assess the structures and changes within thrombi associated with the age of the thrombus, their mechanical properties, and treatment monitoring.