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1.  Characterisation of weak magnetic field effects in an aqueous glutamic acid solution by nonlinear dielectric spectroscopy and voltammetry 
Background
Previous reports indicate altered metabolism and enzyme kinetics for various organisms, as well as changes of neuronal functions and behaviour of higher animals, when they were exposed to specific combinations of weak static and alternating low frequency electromagnetic fields. Field strengths and frequencies, as well as properties of involved ions were related by a linear equation, known as the formula of ion cyclotron resonance (ICR, abbreviation mentioned first by Liboff). Under certain conditions already a aqueous solution of the amino acid and neurotransmitter glutamate shows this effect.
Methods
An aqueous solution of glutamate was exposed to a combination of a static magnetic field of 40 μT and a sinusoidal electromagnetic magnetic field (EMF) with variable frequency (2–7 Hz) and an amplitude of 50 nT. The electric conductivity and dielectric properties of the solution were investigated by voltammetric techniques in combination with non linear dielectric spectroscopy (NLDS), which allow the examination of the dielectric properties of macromolecules and molecular aggregates in water. The experiments target to elucidate the biological relevance of the observed EMF effect on molecular level.
Results
An ion cyclotron resonance (ICR) effect of glutamate previously reported by the Fesenko laboratory 1998 could be confirmed. Frequency resolution of the sample currents was possible by NLDS techniques. The spectrum peaks when the conditions for ion cyclotron resonance (ICR) of glutamate are matched. Furthermore, the NLDS spectra are different under ICR- and non-ICR conditions: NLDS measurements with rising control voltages from 100–1100 mV show different courses of the intensities of the low order harmonics, which could possibly indicate "intensity windows". Furthermore, the observed magnetic field effects are pH dependent with a narrow optimum around pH 2.85.
Conclusions
Data will be discussed in the context with recent published models for the interaction of weak EMF with biological matter including ICR. A medical and health relevant aspect of such sensitive effects might be given insofar, because electromagnetic conditions for it occur at many occasions in our electromagnetic all day environment, concerning ion involvement of different biochemical pathways.
doi:10.1186/1477-044X-2-8
PMCID: PMC538269  PMID: 15571630
2.  The Complex Behaviour of High-Frequency Currents in Simple Circuits 
The fact that standing wave phenomena exist along transmission lines and loops conducting high-frequency electrical energy is responsible for effects of which therapeutic use can be made.
A. Power measurements are made possible because parallel transmission lines behave as power transformers of which the ratio varies with the length of these lines. In a generator designed by the G.E.C. the dimensions of the lines are such that after a preliminary estimation of the impedance of the load in the treatment field, the sensitivity of the meter can be adjusted so that the meter subsequently registers in watts the power absorbed in this load.
B. When using cable electrodes, in practice, the presence of strong electric fields between the antinodal portions of the loop as well as strong oscillating magnetic fields around the nodal portion gives rise to two distinct phenomena (fig. 6).
Search for currents resulting from the electric field on the one hand, and for eddy currents due to the magnetic field on the other, was carried out at St. Thomas's Hospital, in liquid phantoms by means of a probe (fig. 5a) incorporating a small lamp capable of being rotated in every direction. Voltage measurements were recorded by matching its light intensity with that of a similar lamp in circuit with a variable resistance and a voltmeter (fig. 5b).
When a portion of a cable electrode was coiled around a cylindrical vessel containing an electrolyte, the effects due to the two conditions could be dissociated. The following observations were made (fig. 7):
(a) By using the nodal portions of the loop only, it was shown that only eddy currents are produced and that the lower the resistance of the electrolyte the more easily they are produced. They are strongest at the periphery and rapidly fall off away from it, as shown by the curves of the graph in fig. 8.
(b) By using only the antinodal portions of the loop, coiled around the same vessel, coaxial or longitudinal currents can be demonstrated. It is interesting to note that these exist both at the periphery and at the centre.
(c) When the whole cable is wound around the vessel, the concentration of the electrolyte becomes the factor determining the way in which the energy will be dissipated: (1) with tap-water, it is found that no eddy currents can be demonstrated whereas coaxial currents exist; (2) with strong saline solutions the converse holds good; (3) with electrolytes of intermediate concentration both types of currents can be shown to coexist at the periphery while at the centre only coaxial currents can be demonstrated.
The fact that eddy currents and coaxial currents could be detected simultaneously and did not, as might be expected, give rise to a resultant, could only be explained by assuming that although eddy currents and coaxial currents coexisted as far as their effects on the pilot lamp were concerned, these two phenomena were not coincident as regards their phase relations. On examining the system more closely it became clear that the coaxial currents must be approximately 90 degrees out of phase with the eddy currents.
By means of another type of probe (fig. 5c) for surface work, consisting of two metallic buttons mounted on an insulating strip and bridged by a small lamp, P3, similar to the one used throughout the investigations, it was possible to show that the same conditions existed in the body. It could be demonstrated that both coaxial and eddy currents occurred and that the predominance of one or the other type was dictated by conditions related to impedance. In the thigh just above the knee-joint, in most cases both currents could be demonstrated. It could also be shown that when half the cable was wound clockwise and the other half anticlockwise, so as to cancel the magnetic field between the two halves, no eddy currents existed.
C. Present therapeutic applications of high-frequency currents involve the continuous dissipation of electrical energy in the load under treatment. Under these conditions the only detectable effect to which therapeutic value may be ascribed is the rise in temperature which results from heat production. This rise in temperature sets a limit to the power which can be used without risk of burns. Consequently effects other than thermal ones which might manifest themselves under higher intensities remain undetected.
It is not possible to predict what would happen if, instead of treating tissues by means of sustained high-frequency electrical energy, tissues were subjected to intermittent radio-frequency pulses of very high intensity separated by silent periods of sufficient length to allow for the dissipation of heat. Those who have some technical knowledge of such matters will readily recognize an application of “Radar” technique in this.
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PMCID: PMC2184441  PMID: 19993665
3.  Cyclotron production of 68Ga via the 68Zn(p,n)68Ga reaction in aqueous solution 
The objective of the present work is to extend the applicability of the solution target approach to the production of 68Ga using a low energy cyclotron. Since the developed method does not require solid target infrastructure, it offers a convenient alternative to 68Ge/68Ga generators for the routine production of 68Ga. A new solution target with enhanced heat exchange capacity was designed and utilized with dual foils of Al (0.20 mm) and Havar (0.038 mm) separated by helium cooling to degrade the proton energy to ~14 MeV. The water-cooled solution target insert was made of Ta and its solution holding capacity (1.6 mL) was reduced to enhance heat transfer. An isotopically enriched (99.23%) 1.7 M solution of 68Zn nitrate in 0.2 N nitric acid was utilized in a closed target system. After a 30 min irradiation at 20 μA, the target solution was unloaded to a receiving vessel and the target was rinsed with 1.6 mL water, which was combined with the target solution. An automated module was used to pass the solution through a cation-exchange column (AG-50W-X8, 200-400 mesh, hydrogen form) which efficiently trapped zinc and gallium isotopes. 68Zn was subsequently eluted with 30 mL of 0.5 N HBr formulated in 80% acetone without any measurable loss of 68Ga. 68Ga was eluted with 7 mL of 3 N HCl solution with 92-96% elution efficiency. The radionuclidic purity was determined using an HPGe detector. Additionally, ICP-MS was employed to analyze for non-radioactive metal contaminants. The product yield was 192.5 ± 11.0 MBq/μ·h decay-corrected to EOB with a total processing time of 60-80 min. The radionuclidic purity of 68Ga was found to be >99.9%, with the predominant contaminant being 67Ga. The ICP-MS analysis showed small quantities of Ga, Fe, Cu, Ni and Zn in the final product, with 68Ga specific activity of 5.20-6.27 GBq/μg. Depending upon the user requirements, 68Ga production yield can be further enhanced by increasing the 68Zn concentration in the target solution and extending the irradiation time. In summary, a simple and efficient method of 68Ga production was developed using low energy cyclotron and a solution target. The developed methodology offers a cost-effective alternative to the 68Ge/68Ga generators for the production of 68Ga.
PMCID: PMC4074496  PMID: 24982816
68Ga; cyclotron targetry; solution target
4.  Investigating the Icr Effect in a Zhadin’s Cell 
Investigations into the ion cyclotronic resonance (ICR) in living matter confront the so called Zhadin effect (12), whose explanation is not fully achieved. Several attempts have been done to explain this phenomenon, the most interesting of which is based on Quantum Electrodynamics (18): the molecules of water, the ions and the biomolecules form extended mesoscopic regions, called Coherence Domains (CD), where they oscillate in unison between two selected levels of their spectra in tune with a self-produced coherent E.M. field having a well defined frequency, dynamically trapped within the CD. Moreover, it is possible, to induce, by an external applied field (either hydrodynamical or EM) or also by a chemical stimulation, coherent excitations of CD’s that give rise to electric currents circulating without friction within the CD’s: as a consequence magnetic fields are produced. A resonating magnetic field thus is able to extract the ions from the orbit and push them in the flowing current. Electrochemical investigation of the system suggested that the observed phenomenon involves the transitory activation of the anode due to ICR, followed by anode passivation due to the adsorption of amino acid and its oxidation products (18). This hypothesis induced us to investigate an alternate configuration of the experiment, removing the electrolytic cell and submitting a flask containing the solution into a condenser to be exposed to the proper ICR. Temperature and variable parameters involved in the effect have been investigated in order to overcome the randomness of the effect.
PMCID: PMC3614765  PMID: 23675133
iono-cyclotronic resonance (ICR); BLZ; Zhadin’s cell
5.  Simulating Magnetic Nanoparticle Behavior in Low-field MRI under Transverse Rotating Fields and Imposed Fluid Flow 
In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle’s time constant, τ. As the magnetic field frequency is increased, the nanoparticle’s magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid’s temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid’s temperature in the MRI environment which is characterized by a large DC field, B0. Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B0. Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful The goal of this work is to examine, by means of analysis and simulation, the concept of interactive fluid magnetization using the dynamic behavior of superparamagnetic iron oxide nanoparticle suspensions in the MRI environment. In addition to the usual magnetic fields associated with MRI, a rotating magnetic field is applied transverse to the main B0 field of the MRI. Additional or modified magnetic fields have been previously proposed for hyperthermia and targeted drug delivery within MRI. Analytical predictions and numerical simulations of the transverse rotating magnetic field in the presence of B0 are investigated to demonstrate the effect of Ω, the rotating field frequency, and the magnetic field amplitude on the fluid suspension magnetization. The transverse magnetization due to the rotating transverse field shows strong dependence on the characteristic time constant of the fluid suspension, τ. The analysis shows that as the rotating field frequency increases so that Ωτ approaches unity, the transverse fluid magnetization vector is significantly non-aligned with the applied rotating field and the magnetization’s magnitude is a strong function of the field frequency. In this frequency range, the fluid’s transverse magnetization is controlled by the applied field which is determined by the operator. The phenomenon, which is due to the physical rotation of the magnetic nanoparticles in the suspension, is demonstrated analytically when the nanoparticles are present in high concentrations (1 to 3% solid volume fractions) more typical of hyperthermia rather than in clinical imaging applications, and in low MRI field strengths (such as open MRI systems), where the magnetic nanoparticles are not magnetically saturated. The effect of imposed Poiseuille flow in a planar channel geometry and changing nanoparticle concentration is examined. The work represents the first known attempt to analyze the dynamic behavior of magnetic nanoparticles in the MRI environment including the effects of the magnetic nanoparticle spin-velocity. It is shown that the magnitude of the transverse magnetization is a strong function of the rotating transverse field frequency. Interactive fluid magnetization effects are predicted due to non-uniform fluid magnetization in planar Poiseuille flow with high nanoparticle concentrations.
doi:10.1016/j.jmmm.2010.03.029
PMCID: PMC2901184  PMID: 20625540
Magnetic nanoparticles; MRI; rotating magnetic field; interactive magnetization; magnetic particle imaging
6.  Transient effect of weak electromagnetic fields on calcium ion concentration in Arabidopsis thaliana 
BMC Plant Biology  2009;9:47.
Background
Weak magnetic and electromagnetic fields can influence physiological processes in animals, plants and microorganisms, but the underlying way of perception is poorly understood. The ion cyclotron resonance is one of the discussed mechanisms, predicting biological effects for definite frequencies and intensities of electromagnetic fields possibly by affecting the physiological availability of small ions. Above all an influence on Calcium, which is crucial for many life processes, is in the focus of interest. We show that in Arabidopsis thaliana, changes in Ca2+-concentrations can be induced by combinations of magnetic and electromagnetic fields that match Ca2+-ion cyclotron resonance conditions.
Results
An aequorin expressing Arabidopsis thaliana mutant (Col0-1 Aeq Cy+) was subjected to a magnetic field around 65 microtesla (0.65 Gauss) and an electromagnetic field with the corresponding Ca2+ cyclotron frequency of 50 Hz. The resulting changes in free Ca2+ were monitored by aequorin bioluminescence, using a high sensitive photomultiplier unit. The experiments were referenced by the additional use of wild type plants. Transient increases of cytosolic Ca2+ were observed both after switching the electromagnetic field on and off, with the latter effect decreasing with increasing duration of the electromagnetic impact. Compared with this the uninfluenced long-term loss of bioluminescence activity without any exogenic impact was negligible. The magnetic field effect rapidly decreased if ion cyclotron resonance conditions were mismatched by varying the magnetic fieldstrength, also a dependence on the amplitude of the electromagnetic component was seen.
Conclusion
Considering the various functions of Ca2+ as a second messenger in plants, this mechanism may be relevant for perception of these combined fields. The applicability of recently hypothesized mechanisms for the ion cyclotron resonance effect in biological systems is discussed considering it's operating at magnetic field strengths weak enough, to occur occasionally in our all day environment.
doi:10.1186/1471-2229-9-47
PMCID: PMC2681476  PMID: 19405943
7.  Dynamic and Inherent B0 Correction for DTI Using Stimulated Echo Spiral Imaging 
Purpose
To present a novel technique for high-resolution stimulated echo (STE) diffusion tensor imaging (DTI) with self-navigated interleaved spirals (SNAILS) readout trajectories that can inherently and dynamically correct for image artifacts due to spatial and temporal variations in the static magnetic field (B0) resulting from eddy currents, tissue susceptibilities, subject/physiological motion, and hardware instabilities.
Methods
The Hahn spin echo formed by the first two 90° radio-frequency pulses is balanced to consecutively acquire two additional images with different echo times (TE) and generate an inherent field map, while the diffusion-prepared STE signal remains unaffected. For every diffusion-encoding direction, an intrinsically registered field map is estimated dynamically and used to effectively and inherently correct for off-resonance artifacts in the reconstruction of the corresponding diffusion-weighted image (DWI).
Results
After correction with the dynamically acquired field maps, local blurring artifacts are specifically removed from individual STE DWIs and the estimated diffusion tensors have significantly improved spatial accuracy and larger fractional anisotropy.
Conclusion
Combined with the SNAILS acquisition scheme, our new method provides an integrated high-resolution short-TE DTI solution with inherent and dynamic correction for both motion-induced phase errors and off-resonance effects.
doi:10.1002/mrm.24767
PMCID: PMC3760972  PMID: 23630029
DTI - diffusion tensor imaging; STE - stimulated echo; off-resonance correction; eddy current correction; magnetic field inhomogeneities
8.  Influence of constant, alternating and cyclotron low-intensity electromagnetic fields on fibroblast proliferative activity in vitro 
Available data allow assuming the presence of stimulation of reparative processes under influence of low-intensity electromagnetic field, commensurable with a magnetic field of the Earth. Research of effects of low-intensity electromagnetic fields on fibroblast proliferative activity in human lungs in cell culture was performed.
The influence of a constant electromagnetic field, an alternating electromagnetic field by frequency of 50 Hz and cyclotron electromagnetic field with identical intensity for all kinds of fields – 80 mcTl – on value of cellular mass and a correlation of live and dead cells in culture is investigated in three series of experiments. We used the universal electromagnetic radiator generating all three kinds of fields and supplied by a magnetometer which allows measuring the intensity of accurate within 0.1 mcTl including taking into account the Earth’s magnetic field intensity.
The peak value for stimulation cellular proliferation in the present experiences was two-hour influence by any of the specified kinds of electromagnetic fields. The irradiation by cyclotron electromagnetic field conducts positive dynamics in growth of live cells (up to 206±22%) and decreases the number of dead cells (down to 31±6%). Application of cyclotron magnetic fields promoted creation of optimum conditions for proliferation. As a result of researches we observed the reliable 30% increase of nitro-tetrazolium index (in nitro-tetrazolium blue test) after irradiation by cyclotron electromagnetic field in experience that testifies to strengthening of the cell breathing of living cells.
In our opinion, it is necessary to pay attention not only to a pure gain of cells, but also to reduction of number dead cells that can be criterion of creation of optimum conditions for their specific development and valuable functioning.
doi:10.3205/dgkh000132
PMCID: PMC2831248  PMID: 20204088
electromagnetic field; human lung fibroblasts; cell culture; stimulation of growth; decrease of number of dead cells
9.  Functional investigations on human mesenchymal stem cells exposed to magnetic fields and labeled with clinically approved iron nanoparticles 
BMC Cell Biology  2010;11:22.
Background
For clinical applications of mesenchymal stem cells (MSCs), labeling and tracking is crucial to evaluate cell distribution and homing. Magnetic resonance imaging (MRI) has been successfully established detecting MSCs labeled with superparamagnetic particles of iron oxide (SPIO). Despite initial reports that labeling of MSCs with SPIO is safe without affecting the MSC's biology, recent studies report on influences of SPIO-labeling on metabolism and function of MSCs. Exposition of cells and tissues to high magnetic fields is the functional principle of MRI. In this study we established innovative labeling protocols for human MSCs using clinically established SPIO in combination with magnetic fields and investigated on functional effects (migration assays, quantification of colony forming units, analyses of gene and protein expression and analyses on the proliferation capacity, the viability and the differentiation potential) of magnetic fields on unlabeled and labeled human MSCs. To evaluate the imaging properties, quantification of the total iron load per cell (TIL), electron microscopy, and MRI at 3.0 T were performed.
Results
Human MSCs labeled with SPIO permanently exposed to magnetic fields arranged and grew according to the magnetic flux lines. Exposure of MSCs to magnetic fields after labeling with SPIO significantly enhanced the TIL compared to SPIO labeled MSCs without exposure to magnetic fields resulting in optimized imaging properties (detection limit: 1,000 MSCs). Concerning the TIL and the imaging properties, immediate exposition to magnetic fields after labeling was superior to exposition after 24 h. On functional level, exposition to magnetic fields inhibited the ability of colony formation of labeled MSCs and led to an enhanced expression of lipoprotein lipase and peroxisome proliferator-activated receptor-γ in labeled MSCs under adipogenic differentiation, and to a reduced expression of alkaline phosphatase in unlabeled MSCs under osteogenic differentiation as detected by qRT-PCR. Moreover, microarray analyses revealed that exposition of labeled MSCs to magnetic fields led to an up regulation of CD93 mRNA and cadherin 7 mRNA and to a down regulation of Zinc finger FYVE domain mRNA. Exposition of unlabeled MSCs to magnetic fields led to an up regulation of CD93 mRNA, lipocalin 6 mRNA, sialic acid acetylesterase mRNA, and olfactory receptor mRNA and to a down regulation of ubiquilin 1 mRNA. No influence of the exposition to magnetic fields could be observed on the migration capacity, the viability, the proliferation rate and the chondrogenic differentiation capacity of labeled or unlabeled MSCs.
Conclusions
In our study an innovative labeling protocol for tracking MSCs by MRI using SPIO in combination with magnetic fields was established. Both, SPIO and the static magnetic field were identified as independent factors which affect the functional biology of human MSCs. Further in vivo investigations are needed to elucidate the molecular mechanisms of the interaction of magnetic fields with stem cell biology.
doi:10.1186/1471-2121-11-22
PMCID: PMC2871263  PMID: 20370915
10.  Growth of etiolated barley plants in weak static and 50 Hz electromagnetic fields tuned to calcium ion cyclotron resonance 
Background
The effects of weak magnetic and electromagnetic fields in biology have been intensively studied on animals, microorganisms and humans, but comparably less on plants. Perception mechanisms were attributed originally to ferrimagnetism, but later discoveries required additional explanations like the "radical pair mechanism" and the "Ion cyclotron resonance" (ICR), primarily considered by Liboff. The latter predicts effects by small ions involved in biological processes, that occur in definite frequency- and intensity ranges ("windows") of simultaneously impacting magnetic and electromagnetic fields related by a linear equation, which meanwhile is proven by a number of in vivo and in vitro experiments.
Methods
Barley seedlings (Hordeum vulgare, L. var. Steffi) were grown in the dark for 5 and 6 days under static magnetic and 50 Hz electromagnetic fields matching the ICR conditions of Ca2+. Control cultures were grown under normal geomagnetic conditions, not matching this ICR. Morphology, pigmentation and long-term development of the adult plants were subsequently investigated.
Results
The shoots of plants exposed to Ca2+-ICR exposed grew 15–20% shorter compared to the controls, the plant weight was 10–12% lower, and they had longer coleoptiles that were adhering stronger to the primary leaf tissue. The total pigment contents of protochlorophyllide (PChlide) and carotenoids were significantly decreased. The rate of PChlide regeneration after light irradiation was reduced for the Ca2+-ICR exposed plants, also the Shibata shift was slightly delayed. Even a longer subsequent natural growing phase without any additional fields could only partially eliminate these effects: the plants initially exposed to Ca2+-ICR were still significantly shorter and had a lower chlorophyll (a+b) content compared to the controls. A continued cultivation and observation of the adult plants under natural conditions without any artificial electromagnetic fields showed a retardation of the originally Ca2+-ICR exposed plants compared to control cultures lasting several weeks, with an increased tendency for dehydration.
Conclusion
A direct influence of the applied MF and EMF is discussed affecting Ca2+ levels via the ICR mechanism. It influences the available Ca2+ and thereby regulatory processes. Theoretical considerations on molecular level focus on ionic interactions with water related to models using quantum electrodynamics.
doi:10.1186/1477-044X-4-1
PMCID: PMC1403775  PMID: 16457719
11.  Lifetime of Ionic Vacancy Created in Redox Electrode Reaction Measured by Cyclotron MHD Electrode 
Scientific Reports  2016;6:19795.
The lifetimes of ionic vacancies created in ferricyanide-ferrocyanide redox reaction have been first measured by means of cyclotron magnetohydrodynamic electrode, which is composed of coaxial cylinders partly exposed as electrodes and placed vertically in an electrolytic solution under a vertical magnetic field, so that induced Lorentz force makes ionic vacancies circulate together with the solution along the circumferences. At low magnetic fields, due to low velocities, ionic vacancies once created become extinct on the way of returning, whereas at high magnetic fields, in enhanced velocities, they can come back to their initial birthplaces. Detecting the difference between these two states, we can measure the lifetime of ionic vacancy. As a result, the lifetimes of ionic vacancies created in the oxidation and reduction are the same, and the intrinsic lifetime is 1.25 s, and the formation time of nanobubble from the collision of ionic vacancies is 6.5 ms.
doi:10.1038/srep19795
PMCID: PMC4726188  PMID: 26791269
12.  Superparamagnetic Nanoparticle Clusters for Cancer Theranostics Combining Magnetic Resonance Imaging and Hyperthermia Treatment 
Theranostics  2013;3(6):366-376.
Superparamagnetic nanoparticles (SPIONs) could enable cancer theranostics if magnetic resonance imaging (MRI) and magnetic hyperthermia treatment (MHT) were combined. However, the particle size of SPIONs is smaller than the pores of fenestrated capillaries in normal tissues because superparamagnetism is expressed only at a particle size <10 nm. Therefore, SPIONs leak from the capillaries of normal tissues, resulting in low accumulation in tumors. Furthermore, MHT studies have been conducted in an impractical way: direct injection of magnetic materials into tumor and application of hazardous alternating current (AC) magnetic fields. To accomplish effective enhancement of MRI contrast agents in tumors and inhibition of tumor growth by MHT with intravenous injection and a safe AC magnetic field, we clustered SPIONs not only to prevent their leakage from fenestrated capillaries in normal tissues, but also for increasing their relaxivity and the specific absorption rate. We modified the clusters with folic acid (FA) and polyethylene glycol (PEG) to promote their accumulation in tumors. SPION clustering and cluster modification with FA and PEG were achieved simultaneously via the thiol-ene click reaction. Twenty-four hours after intravenous injection of FA- and PEG-modified SPION nanoclusters (FA-PEG-SPION NCs), they accumulated locally in cancer (not necrotic) tissues within the tumor and enhanced the MRI contrast. Furthermore, 24 h after intravenous injection of the NCs, the mice were placed in an AC magnetic field with H = 8 kA/m and f = 230 kHz (Hf = 1.8×109 A/m∙s) for 20 min. The tumors of the mice underwent local heating by application of an AC magnetic field. The temperature of the tumor was higher than the surrounding tissues by ≈6°C at 20 min after treatment. Thirty-five days after treatment, the tumor volume of treated mice was one-tenth that of the control mice. Furthermore, the treated mice were alive after 12 weeks; control mice died up to 8 weeks after treatment.
doi:10.7150/thno.5860
PMCID: PMC3677408  PMID: 23781284
theranostics; nanomedicine; iron oxide; MRI; hyperthermia; tumor.
13.  Microtesla MRI with dynamic nuclear polarization 
Magnetic resonance imaging at microtesla fields is a promising imaging method that combines the pre-polarization technique and broadband signal reception by superconducting quantum interference device (SQUID) sensors to enable in vivo MRI at microtesla-range magnetic fields similar in strength to the Earth magnetic field. Despite significant advances in recent years, the potential of microtesla MRI for biomedical imaging is limited by its insufficient signal-to-noise ratio due to a relatively low sample polarization. Dynamic nuclear polarization (DNP) is a widely used approach that allows polarization enhancement by two-four orders of magnitude without an increase in the polarizing field strength. In this work, the first implementation of microtesla MRI with Overhauser DNP and SQUID signal detection is described. The first measurements of carbon-13 NMR spectra at microtesla fields are also reported. The experiments were performed at the measurement field of 96 microtesla, corresponding to Larmor frequency of 4 kHz for protons and 1 kHz for carbon-13. The Overhauser DNP was carried out at 3.5 –5.7 mT field using rf irradiation at 120 MHz. Objects for imaging included water phantoms and a cactus plant. Aqueous solutions of metabolically relevant sodium bicarbonate, pyruvate, alanine, and lactate, labeled with carbon-13, were used for NMR studies. All the samples were doped with TEMPO free radicals. The Overhauser DNP enabled nuclear polarization enhancement by factor as high as −95 for protons and as high as −200 for carbon-13, corresponding to thermal polarizations at 0.33 T and 1.1 T fields, respectively. These results demonstrate that SQUID-based microtesla MRI can be naturally combined with Overhauser DNP in one system, and that its signal-to-noise performance is greatly improved in this case. They also suggest that microtesla MRI can become an efficient tool for in vivo imaging of hyperpolarized carbon-13, produced by the low-temperature dissolution DNP.
doi:10.1016/j.jmr.2010.08.015
PMCID: PMC2956831  PMID: 20843715
DNP; Overhauser; MRI; Microtesla MRI; SQUID; Carbon-13
14.  CICATRIZATION OF WOUNDS  
In the study of the action of non-antiseptic substances on the rate of cicatrization, the chief obstacle encountered is the facility with which wounds become reinfected under an aseptic dressing. At the beginning of Experiment 1 the wound was sterile. It was subjected to flushing with distilled water for 2 hours, then to flushing with 30 per cent sodium chloride solution for another 2 hours. During that time no special precaution was taken to sterilize the wound and the dressing was left intact until the following morning. It was then found that the wound contained from 30 to 50 bacteria per field. The following day, after the wound had been subjected to the same treatment, the number of bacteria had increased to 50 and 100 per field, and as an immediate consequence the surface of the wound increased from 12 to 12.6 sq. cm. in 2 days. The wound was then dressed antiseptically and was found to be sterile 3 days later. Reinfection again took place the following day in spite of antiseptic dressing with chloramine paste 4 parts per 1,000, which was applied for 20 hours. In Experiment 2 similar results were observed. After 2 days of flushing with distilled water, the number of bacteria had increased to 50 per field. The wound was thereupon sterilized, but new reinfection ensued a few days later. Another wound on the same patient became reinfected under the same conditions after 1 day of sterile dressing. In none of the patients could the wounds be kept in a sterile condition throughout the whole experiment. It was impossible to maintain the sterility of a wound under aseptic dressing. Dakin's solution was therefore injected every 4 hours, or less often, according to the degree of infection, or chloramine paste was applied during the night. If there were 3 or 4 bacteria per field, the experiment was discontinued in order that the wound might be sterilized again. The cicatrization and bacteriological curves of Experiment 4 show that by the application of chloramine paste a wound may be maintained in an appropriately bacteriological condition for carrying out an experiment. Nevertheless, in spite of the antiseptic precautions taken, it was necessary to interrupt this experiment on two occasions, on December 13 to 15 and on December 18 to 22, in order that a complete sterilization of the wound might be effected. When the sterilization was performed as soon as the bacteria were discovered, little retardation occurred in the process of cicatrization. Moreover, the reinfection from the skin was often due to fine bacilli which have but mild retarding action on the rate of healing. The use of at least six flushings in 2 hours with Dakin's solution or of 12 hours' dressing with chloramine paste 10 parts per 1,000, was necessary to keep the wound in a condition of surgical asepsis. The action of distilled water was studied in Experiments 1, 2, and 3. In Experiment 1 the wound was subjected to flushing with distilled water first for 2 hours, then 4 hours, and later for 8 hours per day. The wound was maintained in a condition of mild infection. No marked modification, either acceleration or retardation, was noted in the rate of repair during the period that the treatment was applied. From November 21 to 25 the wound was almost clean and the observed curve remained parallel to the calculated curve, showing that distilled water did not retard the rate of healing. In Experiment 2 the wound was subjected to uninterrupted flushing with distilled water, first for 2 and 8 hours, then for 24 hours. It was continued from November 24 to 30; viz., for 112 hours out of 120, without the occurrence of any marked modification of the course of healing. The bacteriological curve showed that from November 22 to 27 inclusive the wound was kept aseptic. The slight retardation which occurred afterwards was probably brought about by the infection. In Experiment 3 the wound was subjected to flushing with distilled water, first for 2, then for 4, 6, and 8 hours, a total of 20 hours in 4 days. From November 21 to 24 the wound remained surgically aseptic. No modification in the rate of healing occurred. The action of the hypertonic sodium chloride solution was studied in a similar way. In Experiment 4 the wound was flushed at first with 40 per cent sodium chloride solution, from December 4 to 9 for 12 hours a day, and from December 10 to 13 for 24 hours a day, making a total of 144 hours out of 240 hours. At the end of this time the surface area of the wound coincided exactly with the calculated area. Owing to reinfection the experiment was suspended. From December 24 to 29 the wound was kept in contact with 50 per cent sodium chloride solution for 54 hours, and after December 30 flushing with 80 per cent solution for 24 hours a day was resorted to. The total amount of time involved in the above treatments was 174 hours with 40 per cent solution, 72 hours with 50 per cent solution, and 120 hours with 80 per cent solution. On January 1, the surface measured 11 sq. cm. and the calculated surface was 11.3 sq. cm. On January 5 the. surface observed was 10 sq. cm. and the calculated surface was 9 sq. cm. It should be noticed that on January 5 the bacteria numbered 4 per field, which might account for the difference. In Experiment 5 the wound was flushed for 24 hours every day with 50 per cent sodium chloride solution from December 11 to 18, a total of 192 hours. From December 18 to 24 the wound was dressed with agar-agar cakes containing 40 per cent sodium chloride. The concentration was raised to 50 per cent from December 24 to 27. The cicatrization curve indicates only a slight retardation of the repair which can be attributed to infection when both cicatrization and infection curves are compared. The temporary acceleration on the 13th may have been due to the influence of the dressing, but as it did not occur again an experimental error is probably the cause of the change observed in the curve. In Experiment 6 two practically identical wounds at a distance of but a few centimeters from each other were located on the right thigh of Patient 721. The areas of the wounds were respectively 40 and 33 sq. cm. One of the wounds was flushed with distilled water only. The other was subjected to the action of 40 per cent sodium chloride solution. From December 20 to 25 both wounds were in a condition of surgical asepsis. However, the cicatrization curves show that in spite of the difference of treatment the rate of healing was not modified. The rate of healing of the wounds did not therefore apparently undergo any measurable modification under the influence of distilled water or hypertonic salt solution. It is well known that the osmotic changes of the medium have a marked influence on tissues deprived of circulation. But it seems that a tissue with normal circulation is protected by it against the changes of the osmotic pressure occurring at its surface. The above experiments show that apparently the conditions of the tissues of a wound are not modified by the changes of the osmotic pressure of the dressing. The beneficial effects of hypertonic sodium chloride solution on the sterilization of wounds and on the rate of healing recently described by various surgeons are possibly an illusion due to lack of precise technique.
PMCID: PMC2125649  PMID: 19868150
15.  Static field influences on transcranial magnetic stimulation: Considerations for TMS in the scanner environment 
Brain stimulation  2014;7(3):388-393.
Background:
Transcranial magnetic stimulation (TMS) can be combined with functional magnetic resonance imaging (fMRI) to simultaneously manipulate and monitor human cortical responses. Although tremendous efforts have been directed at characterizing the impact of TMS on image acquisition, the influence of the scanner’s static field on the TMS coil has received limited attention.
Objective/Hypothesis:
The aim of this study was to characterize the influence of the scanner’s static field on TMS. We hypothesized that spatial variations in the static field could account for TMS field variations in the scanner environment.
Methods:
Using a MRI-compatible TMS coil, we estimated TMS field strengths based on TMS-induced voltage changes measured in a search coil. We compared peak field strengths obtained with the TMS coil positioned at different locations (B0 field vs fringe field) and orientations in the static field. We also measured the scanner’s static field to derive a field map to account for TMS field variations.
Results:
TMS field strength scaled depending on coil location and orientation with respect to the static field. Larger TMS field variations were observed in fringe field regions near the gantry as compared to regions inside the bore or further removed from the bore. The scanner’s static field also exhibited the greatest spatial variations in fringe field regions near the gantry.
Conclusions:
The scanner’s static field influences TMS fields and spatial variations in the static field correlate with TMS field variations. TMS field variations can be minimized by delivering TMS in the bore or outside of the 0 - 70 cm region from the bore entrance.
doi:10.1016/j.brs.2014.02.007
PMCID: PMC4011976  PMID: 24656916
16.  Heating in the MRI environment due to superparamagnetic fluid suspensions in a rotating magnetic field 
In the presence of alternating-sinusoidal or rotating magnetic fields, magnetic nanoparticles will act to realign their magnetic moment with the applied magnetic field. The realignment is characterized by the nanoparticle’s time constant, τ. As the magnetic field frequency is increased, the nanoparticle’s magnetic moment lags the applied magnetic field at a constant angle for a given frequency, Ω, in rad/s. Associated with this misalignment is a power dissipation that increases the bulk magnetic fluid’s temperature which has been utilized as a method of magnetic nanoparticle hyperthermia, particularly suited for cancer in low-perfusion tissue (e.g., breast) where temperature increases of between 4°C and 7°C above the ambient in vivo temperature cause tumor hyperthermia. This work examines the rise in the magnetic fluid’s temperature in the MRI environment which is characterized by a large DC field, B0. Theoretical analysis and simulation is used to predict the effect of both alternating-sinusoidal and rotating magnetic fields transverse to B0. Results are presented for the expected temperature increase in small tumors (~1 cm radius) over an appropriate range of magnetic fluid concentrations (0.002 to 0.01 solid volume fraction) and nanoparticle radii (1 to 10 nm). The results indicate that significant heating can take place, even in low-field MRI systems where magnetic fluid saturation is not significant, with careful selection of the rotating or sinusoidal field parameters (field frequency and amplitude). The work indicates that it may be feasible to combine low-field MRI with a magnetic hyperthermia system using superparamagnetic iron oxide nanoparticles.
doi:10.1016/j.jmmm.2009.10.050
PMCID: PMC2811342  PMID: 20161608
Hyperthermia; magnetic nanoparticles; MRI; heating; superparamagnetic fluids
17.  A novel Fourier Transform Ion Cyclotron Resonance Mass Spectrometer with improved ion trapping and detection capabilities 
A novel Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer has been developed for improved biomolecule analysis. A flared metal capillary and an electrodynamic ion funnel were installed in the source region of the instrument for improved ion transmission. The transfer quadrupole is divided into 19 segments, with the capacity for independent control of DC voltage biases for each segment. Restrained Ion Population Transfer, or RIPT, is used to transfer ions from the ion accumulation region to the ICR cell. The RIPT ion guide reduces mass discrimination that occurs due to time-of-flight effects associated with gated trapping. Increasing the number of applied DC bias voltages from 8 to 18 increases the number of ions that are effectively trapped in the ICR cell. The RIPT ion guide with a novel voltage profile applied during ion transfer provides a 3-4-fold increase in the number of ions that are trapped in the ICR cell compared to gated trapping for the same ion accumulation time period. A novel ICR cell was incorporated in the instrument to reduce radial electric field variation for ions with different z-axis oscillation amplitudes. With the ICR cell, called Trapping Ring Electrode Cell or TREC, we can tailor the shape of the trapping electric fields to reduce de-phasing of coherent cyclotron motion of an excited ion packet. With TREC, nearly an order of magnitude increase in sensitivity is observed. The performance of the instrument with the combination of RIPT, TREC, flared inlet and ion funnel is presented.
doi:10.1016/j.jasms.2008.12.022
PMCID: PMC2763776  PMID: 19200753
18.  Simulation-Based Validation for Four-Dimensional Multi-Channel Ultrasound Current Source Density Imaging 
Ultrasound current source density imaging (UCSDI), which has application to the heart and brain, exploits the acoustoelectric (AE) effect and Ohm's law to detect and map an electrical current distribution. In this study, we describe 4-D UCSDI simulations of a dipole field for comparison and validation with bench-top experiments. The simulations consider the properties of the ultrasound pulse as it passes through a conductive medium, the electric field of the injected dipole, and the lead field of the detectors. In the simulation, the lead fields of detectors and electric field of the dipole were calculated by the finite element (FE) method, and the convolution and correlation in the computation of the detected AE voltage signal were accelerated using 3-D fast Fourier transforms. In the bench-top experiment, an electric dipole was produced in a bath of 0.9% NaCl solution containing two electrodes, which injected an ac pulse (200 Hz, 3 cycles) ranging from 0 to 140 mA. Stimulating and recording electrodes were placed in a custom electrode chamber made on a rapid prototype printer. Each electrode could be positioned anywhere on an x-y grid (5 mm spacing) and individually adjusted in the depth direction for precise control of the geometry of the current sources and detecting electrodes. A 1-MHz ultrasound beam was pulsed and focused through a plastic film to modulate the current distribution inside the saline-filled tank. AE signals were simultaneously detected at a sampling frequency of 15 MHz on multiple recording electrodes. A single recording electrode is sufficient to form volume images of the current flow and electric potentials. The AE potential is sensitive to the distance from the dipole, but is less sensitive to the angle between the detector and the dipole. Multi-channel UCSDI potentially improves 4-D mapping of bioelectric sources in the body at high spatial resolution, which is especially important for diagnosing and guiding treatment of cardiac and neurologic disorders, including arrhythmia and epilepsy.
doi:10.1109/TUFFC.2014.2927
PMCID: PMC4406770  PMID: 24569247
19.  Quasi-Static Magnetic Field Shielding Using Longitudinal Mu-Near-Zero Metamaterials 
Scientific Reports  2015;5:12764.
The control of quasi-static magnetic fields is of considerable interest in applications including the reduction of electromagnetic interference (EMI), wireless power transfer (WPT), and magnetic resonance imaging (MRI). The shielding of static or quasi-static magnetic fields is typically accomplished through the use of inherently magnetic materials with large magnetic permeability, such as ferrites, used sometimes in combination with metallic sheets and/or active field cancellation. Ferrite materials, however, can be expensive, heavy and brittle. Inspired by recent demonstrations of epsilon-, mu- and index-near-zero metamaterials, here we show how a longitudinal mu-near-zero (LMNZ) layer can serve as a strong frequency-selective reflector of magnetic fields when operating in the near-field region of dipole-like sources. Experimental measurements with a fabricated LMNZ sheet constructed from an artificial magnetic conductor – formed from non-magnetic, conducting, metamaterial elements – confirm that the artificial structure provides significantly improved shielding as compared with a commercially available ferrite of the same size. Furthermore, we design a structure to shield simultaneously at the fundamental and first harmonic frequencies. Such frequency-selective behavior can be potentially useful for shielding electromagnetic sources that may also generate higher order harmonics, while leaving the transmission of other frequencies unaffected.
doi:10.1038/srep12764
PMCID: PMC4522651  PMID: 26234929
20.  Comparison of a triaxial fluxgate magnetometer and Toftness sensometer for body surface EMF measurement 
Introduction
The use of magnetic fields to treat disease has intrigued mankind since the time of the ancient Greeks. More recently it has been shown that electromagnetic field (EMF) treatment aids bone healing, and repetitive transcranial magnetic stimulation (rTMS) appears to be beneficial in treating schizophrenia and depression. Since external EMFs influence internal body processes, we hypothesized that measurement of body surface EMFs might be used to detect disease states and direct the course of subsequent therapy. However, measurement of minute body surface EMFs requires use of a sensitive and well documented magnetometer. In this study we evaluated the sensitivity and frequency response of a fluxgate magnetometer with a triaxial probe for use in detecting body surface EMF and we compared the magnetometer readings with a signal from a Toftness Sensometer, operated by an experienced clinician, in the laboratory and in a clinical setting.
Methods
A Peavy Audio Amplifier and variable power output Telulex signal generator were used to develop 50 μT EMFs in a three coil Merritt coil system. A calibrated magnetometer was used to set a 60 Hz 50 μT field in the coil and an ammeter was used to measure the current required to develop the 50 μT field. At frequencies other than 60 Hz, the field strength was maintained at 50 μT by adjusting the Telulex signal output to keep the current constant. The field generated was monitored using a 10 turn coil connected to an oscilloscope. The oscilloscope reading indicated that the field strength was the same at all frequencies tested. To determine if there was a correspondence between the signals detected by a fluxgate magnetometer (FGM1) and the Toftness Sensometer both devices were placed in the Merritt coil and readings were recorded from the FGM1 and compared with the ability of a highly experienced Toftness operator to detect the 50 μT field. Subsequently, in a clinical setting, FGM1 readings made by an FGM1 technician and Sensometer readings were made by 4 Toftness Sensometer operators, having various degrees of experience with this device. Each examiner obtained instrument readings from 5 different volunteers in separate chiropractic adjusting rooms. Additionally, one of the Toftness Sensometers was equipped with an integrated fluxgate magnetometer (FGM2) and this magnetometer was used to obtain a second set of EMF readings in the clinical setting.
Results
The triaxial fluxgate magnetometer was determined to be moderately responsive to changes in magnetic field frequency below 10 Hz. At frequencies above 10 Hz the readings corresponded to that of the ambient static geofield. The practitioner operating the Toftness Sensometer was unable to detect magnetic fields at high frequencies (above 10 Hz) even at very high EMFs. The fluxgate magnetometer was shown to be essentially a DC/static magnetic field detector and like all such devices it has a limited frequency range with some low level of sensitivity at very low field frequencies. The interexaminer reliability of four Toftness practitioners using the Sensometer on 5 patients showed low to moderate correlation.
Conclusions
The fluxgate magnetometer although highly sensitive to static (DC) EMFs has only limited sensitivity to EMFs in the range of 1 to 10 Hz and is very insensitive to frequencies above 10 Hz. In laboratory comparisons of the Sensometer and the fluxgate magnetometer there was an occasional correspondence between the two instruments in detecting magnetic fields within the Merritt coil but these occasions were not reproducible. In the clinical studies there was low to moderate agreement between the clinicians using the Sensometer to diagnosing spinal conditions and there was little if any agreement between the Sensometer and the fluxgate magnetometer in detecting EMFs emanating from the volunteers body surface.
PMCID: PMC1769295  PMID: 17549105
Toftness; Magnetometer; EMF; Chiropractic
21.  Preparation of folic acid-conjugated, doxorubicin-loaded, magnetic bovine serum albumin nanospheres and their antitumor effects in vitro and in vivo 
Background
This study aimed to generate targeted folic acid-conjugated, doxorubicin-loaded, magnetic iron oxide bovine serum albumin nanospheres (FA-DOX-BSA MNPs) that lower the side effects and improve the therapeutic effect of antitumor drugs when combined with hyperthermia and targeting therapy. A new nanodrug using magnetic nanospheres for heating and addition of the folate receptor with cancer cell specificity was prepared. The characteristics of these nanospheres and their antitumor effects in nasopharyngeal carcinoma were explored.
Methods
FA-DOX-BSA MNPs comprising encapsulated magnetic iron oxide nanoparticles were prepared using a desolvation cross-linking method. Activated folic acid (N-hydroxysuccinimide ester of folic acid) was conjugated to the surface of albumin nanospheres via amino groups.
Results
Folic acid was successfully expressed on the surface of the nanospheres. Electron microscopy revealed that the FA-DOX-BSA MNPs were nearly spherical and uniform in size, with an average diameter of 180 nm. The nanomaterial could deliver doxorubicin at clinically relevant doses with an entrapment efficiency of 80%. An increasing temperature test revealed that incorporation of magnetic iron oxide into nanospheres could achieve a satisfactory heat treatment temperature at a significantly lower dose when placed in a high-frequency alternating magnetic field. FA-DOX-BSA MNPs showed greater inhibition of tumors than in the absence of folic acid in vitro and in vivo. Compared with chemotherapy alone, hyperthermia combined with chemotherapy was more effective against tumor cells.
Conclusion
Folic acid-conjugated bovine serum albumin nanospheres composed of mixed doxorubicin and magnetic iron oxide cores can enable controlled and targeted delivery of anticancer drugs and may offer a promising alternative to targeted doxorubicin therapy for nasopharyngeal carcinoma.
doi:10.2147/IJN.S67210
PMCID: PMC4160329  PMID: 25228802
doxorubicin; bovine serum albumin; folic acid; KB cells
22.  New insights into bioprotective effectiveness of disaccharides: an FTIR study of human haemoglobin aqueous solutions exposed to static magnetic fields 
Journal of Biological Physics  2011;38(1):61-74.
The aim of this study was the investigation of static magnetic field effects on haemoglobin secondary structure and the bioprotective effectiveness of two disaccharides, sucrose and trehalose. Samples of haemoglobin aqueous solutions, in the absence and in the presence of sucrose and trehalose, were exposed to a uniform magnetic field at 200 mT, which is the exposure limit established by the ICNIRP recommendation for occupational exposure. Spectral analysis by FTIR spectroscopy after 3 and 7 h of exposure revealed a decrease in the amide A vibration band for haemoglobin in bi-distilled water solution. Analogue exposures did not produce any appreciable change of amide A for haemoglobin in sucrose and trehalose solutions. Otherwise, no relative increase of \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$\upbeta $\end{document}-sheet contents in amide I and II regions was detected for haemoglobin aqueous solutions, leading us to exclude the hypothesis that static magnetic fields can induce the formation of aggregates in the protein. In addition, a decrease in CH3 stretching linkages occurred for haemoglobin in bi-distilled water solution after exposure, which was not observed for haemoglobin in sucrose and trehalose aqueous solutions, providing further evidence of a bioprotective compensatory mechanism of such disaccharides.
doi:10.1007/s10867-010-9209-1
PMCID: PMC3285734  PMID: 23277670
Haemoglobin; Static magnetic field; Electromagnetic field; Infrared spectroscopy; Disaccharides; Trehalose
23.  STUDIES ON THE BLOOD VESSELS IN THE MEMBRANES OF CHICK EMBRYOS  
When faradic stimulation was undertaken of vessels irrigated with Ringer's solution, which alternately contained and was free from carbon dioxide, it was observed that the reaction was far less when the solution contained carbon dioxide. A reversal of the effect could be obtained many times. It appears, therefore, that when Ringer's solution contained carbon dioxide in the concentration described, the irritability of the vessels to electrical stimuli decreased, although carbon dioxide by itself and in the absence of the application of the stimuli, appeared to be void of effect upon the vessels. The rare, divergent results were traced to technical errors. We attempted to discover whether the observed decrease in irritability of the vessels might not be due to the absence of oxygen. For this purpose we irrigated the vessels with Ringer's solution alternately containing nitrogen and oxygen. When nitrogen caused any change this was due to an influence on the rate of the heart and not on the irritability or reactivity of the arteries. In whatever way we tried we were unable to bring about a change in reactivity of the arteries by creating a condition of oxygen lack independently of a change in the rate of the heart beat. We attempted to study also the effect of other acids beside carbon dioxide on the changed reactivity of the arteries. Irrigation with various concentrations of lactic acid was without result. We also employed solutions buffered with potassium and sodium phosphate. When the irrigation was undertaken with these solutions having a pH range varying from 7.7 to 5.9 we observed neither a direct action nor one which modified the preparation in such a way as to change its susceptibility to faradic stimulation. Important investigations have been published recently by Atzler and Lehmann (2) on the direct influence of the hydrogen ion concentration on the behavior of blood vessels. Hammett and Zoll believed that, as the result of their experiments in which they attempted to bring about stimulation with solutions of concentrated carbon dioxide, they were able to exclude the possibility of action due to acid alone and therefore ascribed to carbon dioxide a specific effect. In our own experiments the method of irrigation does not permit an inference whether, or how far, an acid effect plays a rôle in the carbon dioxide experiments. For beside the question of hydrogen ion concentration and of buffering, the question of the penetration of substances from the surface to the contractile elements of the wall of the vessels requires to be considered. Carbon dioxide has an ability, beyond that of all other substances, to penetrate through tissues (3). It may be owing to this property that we could influence the reactivity of the blood vessels with it and it alone. This possibility must be further investigated. In these experiments, however, it was our object to show only that it was possible to influence the irritability of blood vessels experimentally. The conclusion is justified by our experiments that carbon dioxide in small concentrations reduces the threshold of irritability for electrical stimuli of the blood vessels of the embryonic membrane.
PMCID: PMC2131864  PMID: 19869753
24.  ON THE FORMATION OF PRECIPITATES AFTER THE INTRAVENOUS INJECTION OF SALVARSAN 
The results of these experiments are definite. There is, in the first place, a very striking difference with regard to precipitate formation between the acid and alkaline solutions of salvarsan when injected intravenously. Intravenous injections of alkaline solutions of salvarsan produce no precipitate in the blood, while injections of the acid solution nearly always give a precipitate. Furthermore, after injections of the acid solution, there is a striking difference between the blood from the right side of the heart and that from the left side. At the end of injections of an acid solution of salvarsan, a precipitate was seldom present in the arterial blood. Blood taken from the left ventricle at this time (at autopsy) also showed no precipitate in a large majority of cases; in eight experiments there was no precipitate, in three a doubtful trace of precipitate, and in one a definite small amount. On the other hand, blood obtained from the right ventricle and the lungs showed a very different condition. In ten out of twelve animals (rabbits and dogs), blood from the right ventricle contained a definite precipitate, and in a number of these cases the amount of precipitate was large. Blood squeezed from the lungs showed in eight out of ten cases at least as much precipitate as was found in the blood from the right ventricle. The results of injections of alkaline solutions of salvarsan, as pointed out before, are quite different from those produced by the acid solutions. In thirteen experiments upon dogs and rabbits, no trace of a precipitate was found in the arterial blood, the blood from the left ventricle, the right ventricle, or the lungs. There is no apparent difference in the process of precipitate formation whether salvarsan solutions and the blood are mixed in vivo or in vitro. In both mixtures the acid solutions produce a precipitate, while the alkaline solutions of salvarsan do not. These experiments have demonstrated the fact that a precipitate is present in the blood after an injection of an acid solution of salvarsan. One would expect that such a precipitate, consisting as it usually does of rather coarse particles, would, if brought to the medulla, cause immediate death by producing emboli. However, the freedom from such occurrences may be explained by the fact that the precipitate, which is abundantly present in the right ventricle, is only rarely seen in blood taken from the carotid or femoral arteries or even from the left ventricle itself. The fact itself, however, is quite difficult to interpret. It might perhaps be assumed that the precipitate is filtered out during its passage through the lung capillaries. If this is the case, we might expect intravenous injections of salvarsan to produce embolism in the pulmonary vessels with consequent fatal results. As a matter of fact, we have in the recent literature an instance which seems to point to such a result. Miessner (6) tried the effects of salvarsan in cattle which had foot and mouth disease. He used at first the acid solution, and though the dose was small, seven milligrams per kilo of body weight, all the animals (four) died in from ten hours to two days after the injection. They all showed labored respiration during or soon after the injection of salvarsan. He then decreased the dose to five milligrams per kilo of body weight, and repeated the experiments. He used also normal animals as controls upon those which had the foot and mouth disease. Both the sick and normal (control) animals showed labored respiration. One died after four days. At autopsy all organs except the lungs appeared to be normal. The lungs presented the following appearance: There were grayish yellow spots scattered irregularly over the surface. On the cut surface these were seen as grayish yellow spots the size of a pea, which appeared in groups and which sometimes filled a lobule completely. Other spots were surrounded by a small area of dark red lung parenchyma. The affected portion contained no air and felt solid. In adjacent parts the tissue seemed normal. A microscopic examination showed that the larger and smaller pulmonary arteries were filled with uniform, homogeneous, yellow masses. About the vessels there was a serous exudate. In brief, the changes seen indicated, he believed, that there was a thrombosis of the blood-vessels with inflammatory exudative changes of the lung parenchyma. Miessner states that a similar pathological condition was found in a normal control animal that died. He suggests that the acid solution of salvarsan might lead in man to a thrombosis of the pulmonary arteries. In support of this suggestion, he mentions a case reported to him by Ehrlich of a man who died following the injection of an acid solution. The lung picture in this case was somewhat similar to that which he had found in cattle. It may be mentioned in passing that Miessner found that alkaline solutions of salvarsan were far less toxic than the acid solutions. Animals (cattle) which received in an alkaline solution 400 milligrams of salvarsan per kilo of body weight did not show the least symptom of disturbance. In contrast to Miessner's results seem to stand my observations and those of Auer described in the introduction of this paper. Auer (5) found (in 8 rabbits) that no evident harmful effects followed the injections of very large doses of the acid solution, if they were given in a highly diluted form (one tenth per cent.). In my own experiments, it was found that a one fifth per cent. acid solution (3 rabbits) and even a one half per cent. solution (1 rabbit) produced no ill effects. The experiments described in this paper make it certain that the doses of the acid solution given to these last mentioned four animals must have produced a precipitate in the right ventricle and in the lungs, and yet the animals survived and showed no symptoms whatever of disturbance following the injection. This difference between our observations and those of Miessner might perhaps be explained by the assumption that the action of salvarsan in acid solution is more deleterious to cattle than to rabbits. Furthermore, Miessner seems to have injected the salvarsan in high concentrations. In one instance, in which figures are given, the drug was administered in a five per cent. solution. As mentioned before, Auer has shown the importance of the concentration. While in a one tenth per cent. solution twenty and thirty milligrams per kilo of body weight of the acid solution may be injected with impunity, even six or seven milligrams per kilo may prove rapidly fatal when injected in a one half per cent. solution. Our own results, however, leave us with two puzzling questions : First, if the acid solution of salvarsan causes such a coarse precipitate in the right ventricle and in the lungs, how does it happen that this precipitate does not bring about the death of the animal? Second, what is the real cause of the remarkable fact that this precipitate does not pass over into the arterial side of the circulation? Does the precipitate undergo a profound chemical or mechanical change while it passes through the lung capillaries? In future investigations we may try to answer these interesting questions. For the present, it is necessary to be content with the establishment of the bare facts as they are presented in the conclusions.
PMCID: PMC2124903  PMID: 19867454
25.  Chemical parameters, antimicrobial activities, and tissue toxicity of 0.1 and 0.5% sodium hypochlorite solutions. 
ffe chemical parameters, antimicrobial activity, and tissue toxicity of two sodium hypochlorite (NaOCl) solutions buffered to a physiologic pH were studied. Initially, a 0.5% NaOCl solution buffered with 3 g of NaH2PO4 per liter was examined. The solution had a pH of 7.49 and an osmolality of 352 mOsmol/liter. When compared with unbuffered and NaHCO3-buffered 0.5% NaOCl solutions, the NaH2PO4-buffered solution was significantly more effective in killing Staphylococcus aureus in vitro. However, the pH of the NaH2PO4-buffered solution decreased over time with a concomitant decrease in antibacterial activity. A freshly prepared solution decontaminated human cadaveric skin colonized by S. aureus, Pseudomonas aeruginosa, or Candida albicans in vitro within 10 min of exposure, whereas a 24-h-old solution cleared the skin of organisms within 15 min. When gauze soaked with 0.5% NaOCl was applied to guinea pig skin for 2 weeks, a 15% decrease in basal cell viabilities was noted. Because of the pH instability and basal cell toxicity, a 0.1% NaOCl solution buffered with NaH2PO4-Na2HPO4 was evaluated. This solution had an osmolality of 386 mOsmol/liter and a pH of 7.4 that was stable over 1 week. A freshly prepared 0.1% NaOCl solution decontaminated skin colonized with S. aureus, C. albicans, and P. aeruginosa within 10, 20, and 30 min, respectively. A 24-h-old solution did not completely decontaminate the colonized skin but significantly reduced the number of microorganisms on the skin surface (P less than 0.001). Application of this solution of guinea pig skin for 2 weeks produced no significant effect on basal cell viabilities. These solutions may serve as alternative topical agents for use in burn therapy.
Images
PMCID: PMC176321  PMID: 3929674

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