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Successful integrated management of the invasive predatory sea lamprey (Petromyzon marinus) in the Laurentian Great Lakes of North America is owed largely to the long history of beneficial use of two lampricides: 3-trifluoromethyl-4-nitrophenol (TFM) and 2′,5-dichloro-4′-nitrosalicylanilide (niclosamide). Ensuring continued successful sea lamprey control necessitates consideration of possible next-generation lampricides to supplement or replace current lampricides. This review identifies fifteen hallmarks of success for current lampricides to be used as design criteria in a search for next-generation lampricides. A three-stage research approach is outlined. Targeted research using omics, computer modelling, and high-throughput technology to define molecular mechanisms and high probability molecular targets for sea lamprey selective toxic action is crucial to prioritizing chemical candidates. Targeted delivery or identifying synergists to existing or new lampricides can provide increased efficiency and reduced environmental impact. Ultimate development of next-generation lampricides will rely on traditional toxicity testing methodologies to ensure safety and regulatory compliance.

PDF file, 190K, Prophylactic vaccines enhance NK cell cytotoxicity.

Purpose: Surgical removal of solid primary tumors is an essential component of cancer treatment. Surgery-induced dysfunction in natural killer (NK) cells has been linked to the development of metastases in animal models and patients with cancer. We investigated the activation of NK cells using influenza vaccine in the perioperative period to eradicate micrometastatic disease.Experimental Design: Both the B16lacZ and 4T1 tumor models in immunocompetent mice were used to assess the in vivo efficacy of perioperative influenza vaccine administration. In healthy human donors and cancer surgery patients, we assessed NK cell function pre- and post-influenza vaccination using both in vivo and ex vivo assays.Results: Using the TLR3 agonist poly(I:C), we showed as proof-of-principle that perioperative administration of a nonspecific innate immune stimulant can inhibit surgery-induced dysfunction in NK cells and attenuate metastases. Next, we assessed a panel of prophylactic vaccines for NK cell activation and determined that inactivated influenza vaccine was the best candidate for perioperative administration. Perioperative influenza vaccine significantly reduced tumor metastases and improved NK cytotoxicity in preclinical tumor models. Significantly, IFNα is the main cytokine mediator for the therapeutic effect of influenza vaccination. In human studies, influenza vaccine significantly enhanced NK cell activity in healthy human donors and cancer surgery patients.Conclusion: These results provide the preclinical rationale to pursue future clinical trials of perioperative NK cell activation, using vaccination in cancer surgery patients. Research into perioperative immune therapy is warranted to prevent immune dysfunction following surgery and eradicate metastatic disease. Clin Cancer Res; 19(18); 5104–15. ©2013 AACR.

Summary Apparently because of mulch buildup and abstinence from pesticide use, an organically managed citrus grove in Vero Beach, Florida, can support large populations of long-legged flies (Diptera: Dolichopodidae) that impose predation pressure on inundative releases of Tamarixia radiata (Waterston) (Hymenoptera: Eulophidae) parasitoid wasps to control the Asian citrus psyllid (Hemiptera: Liviidae). During peak activity, flies on wing characteristically hawk wasps in mid-air as the wasps are sprinkled from shipment containers onto the leaves of citrus plants. Flies on leaves enter into entrained scramble competition for prey by systematically “canvassing” upper leaf surfaces in rapid, jerked movements and, albeit infrequently, attack and eat wasps when encountered during this behavior.

Objective Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. Design and results Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. Conclusions We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited.

Persuasive models of the ejection of material at high velocities from the Chicxulub asteroid impact marking the Cretaceous/Tertiary boundary have led to the conclusion that upon return, that material, heated in passage through the upper atmosphere, generated a high level of infrared energy density over the Earth’s surface. That radiant energy has been considered to be a direct source of universal wildfires, which were presumed to be a major cause of plant and animal species extinctions. The extinction of many animal species, especially the dinosaurs, has also been attributed to the immediate lethal effects of the radiation. I find that the absorption of the radiation by the atmosphere, by cloud formations, and by ejecta drifting in the lower atmosphere reduced the radiation at the surface to a level that cannot be expected to have generated universal fires. Although the reduced radiation will have likely caused severe injuries to many animals, such insults alone seem unlikely to have generated the overall...

Studies were conducted to assess population densities and phenology of the psyllid Diaphorina citri Kuwayama at two citrus groves in east-central Florida. One grove contained young, irrigated grapefruit trees and the other contained mature, nonirrigated orange trees. The two groves were sampled weekly for eggs, nymphs, and adults on flush shoots; for adults on mature leaves; and for adults captured on yellow sticky card traps. Because infestations of immature D. citri develop strictly on young flush, the abundance of flush was assessed weekly. Overall means of 26.5, 16.8, and 0.27 eggs, nymphs, and adults per flush shoot, respectively, were observed in the young grapefruit trees. In the grove of mature orange trees, overall means of 16.0, 12.7, and 0.31 eggs, nymphs, and adults per flush shoot were observed, respectively. Flush abundance was an inconsistent indicator of the mean density of D. citri per flush shoot. Mean density per shoot by itself was an inconsistent indicator of overall population levels of D. citri at each study site because few shoots were sometimes present when mean densities per shoot were high. May, June, and July were periods of time when immature D. citri were consistently present and most abundant at each study site, but the study indicated large infestations could occur at any time of the year depending on environmental factors and flush availability. Yellow sticky traps were effective for both male and female D. citri and useful for gauging adult population trends.

Using Monte Carlo techniques, I calculate the effects of internally generated noise on information transfer through the passage of action potential spikes along unmyelinated axons in a simple nervous system. I take the Hodgkin–Huxley (HH) description of Na and K channels in squid giant axons as the basis of the calculations and find that most signal transmission noise is generated by fluctuations in the channel open and closed populations. To bring the model closer to conventional descriptions in terms of thermal noise energy, kT , and to determine gating currents, I express the HH equations in the form of simple relations from statistical mechanics where the states are separated by a Gibbs energy that is modified by the action of the transmembrane potential on dipole moments held by the domains. Using the HH equations, I find that the output response (in the probability of action potential spikes) from small input potential pulses across the cell membrane is increased by added noise but falls off when the input noise becomes large, as in stochastic resonance models. That output noise response is sharply reduced by a small increase in the membrane polarization potential or a moderate increase in the channel densities. Because any reduction of noise incurs metabolic and developmental costs to an animal, the natural noise level is probably optimal and any increase in noise is likely to be harmful. Although these results are specific to signal transmission in unmyelinated axons, I suggest that the conclusions are likely to be general.

Using biophysical criteria, I show that continuous radiofrequency (RF) and microwave radiation with intensity less than 10 mW/cm(2) are unlikely to affect physiology significantly through athermal mechanisms. Biological systems are fundamentally noisy on the molecular scale as a consequence of thermal agitation and are noisy macroscopically as a consequence of physiological functions and animal behavior. If electromagnetic fields are to significantly affect physiology, their direct physical effect must be greater than that from the ubiquitous endogenous noise. Using that criterion, I show that none of a set of interactions of weak fields, which I argue is nearly complete on dimensional grounds, can affect biology on the molecular scale. Moreover, I conclude that such weak fields are quite unlikely to generate significant effects in their interactions with larger biological elements such as cells. In the course of that analysis, I examine important special examples of electromagnetic interactions: "direct" interactions where biology is modified simply by the motion of charged elements generated by the electric field; resonance interactions; the effects of electrostrictive forces and induced dipole moments; and modifications of radical pair recombination probabilities. In each case, I show that it is unlikely that low intensity fields can generate significant physiological consequences.

Many biological systems can be expected to exhibit resonance behavior involving the mechanical vibration of system elements. The natural frequencies of such resonances will, generally, be in the microwave frequency range. Some of these systems will be coupled to the electromagnetic field by the charge distributions they carry, thus admitting the possibility that microwave exposures may generate physiological effects in man and other species. However, such microwave excitable resonances are expected to be strongly damped by interaction with their aqueous biological environment. Although those dissipation mechanisms have been studied, the limitations on energy transfers that follow from the limited coupling of these resonances to the electromagnetic field have not generally been considered. We show that this coupling must generally be very small and thus the absorbed energy is so strongly limited that such resonances cannot affect biology significantly even if the systems are much less strongly damped than expected from basic dissipation models.

Many biological processes are affected by electromagnetic fields. Hence incremental internal fields generated by external magnetic fields can be expected to affect that biology. With some exceptions, most of the present interest in the effects of exogenous static and low-frequency magnetic fields centres on three intensity regions. (1) There are concerns that 50-60 Hz power distribution fields as small as 0.2 µT, may affect the health of populations. (2) ac fields that are larger than 1 mT (and usually smaller than 100 mT) with frequencies of a few kHz or less may have therapeutic value with respect to the healing of bone fractures and soft-tissue injuries. (3) The very large slowly varying fields of the order of 2 T used in magnetic resonance imaging might affect the physiology of the patients. Magnetic fields interact with biological systems through forces on the electrical currents associated with physiological functions and through the torques exerted on the magnetic moments of biologically important molecules and the electrons that play a role in the binding of geminate radicals. The torques that the Earth's magnetic field applies to the ferrimagnetic domains of biologically formed magnetite affects the biology of species in several different phyla and may have consequences in humans. Low-frequency magnetic fields also induce electric fields through the Faraday effect that may have biological consequences. For either the direct magnetic fields or the magnetically induced electric fields to affect the biology of living systems, the interactions with such systems must generally be larger then the interactions with endogenous physiological and thermal noise. This constraint seems to exclude the possibility that the environmental fields less than 1 µT from the electric power distribution system affect health and places important constraints on the minimal fields that can be expected to have therapeutic value.

Warmth and cold sensations are known to derive from separate warm and cold cutaneous thermoreceptors in the form of differentiated afferent nerves. The firing rate of warm-sensing nerves increases as the temperature increases; the firing rate of cold-sensing nerves increases if the temperature is reduced. I postulate that the primary sensitivity of the warm sensors derives from voltage-gated Ca 2+ membrane channels configured such that an increase in temperature opens channels and increases the ion influx while a reduction in temperature increases the ion influx through voltage-gated Na + channels in the cold sensory nerve ends. In either case, the initial cation influx causes a small cellular depolarization that further opens Ca 2+ channels, admitting more cations in a positive feedback process that leads to the depolarization of the membrane, thus initiating an action potential pulse. Monte Carlo calculations based on a well defined model of such processes, which include effects of noise, demonstrate quantitative agreement of the model with an extensive body of data.

We can expect that biological responses to very weak ELF electromagnetic fields will be masked by thermal noise. However, the spin of electrons bound to biologically important molecules is not strongly coupled to the thermal bath, and the effects of the precession of those spins by external magnetic fields is not bounded by thermal noise. Hence, the known role of spin orientation in the recombination of radical pairs (RP) may constitute a mechanism for the biological effects of very weak fields. That recombination will generally take place only if the valence electrons in the two radicals are in a singlet state and the effect of the magnetic field is manifest through differential spin precessions that affect the occupation of that state. Because the spin relaxation times are of the order of microseconds, any effects must be largely independent of frequency up to values of a few megahertz. Using exact calculations on an appropriately general model system, we show that one can expect small, but significant, modifications of the recombination rate by a 50 microT field only under a narrow range of circumstances: the cage time during which the two elements are together must be exceptionally long--of the order of 50 ns or longer; the hyperfine field of either radical must not be so great as to generate a precession period greater than the cage containment time; and the characteristic recombination time of the radical pair in the singlet state must be about equal to the containment time. Thus, even under such singularly favorable conditions, fields as small as 5 microT (50 milligauss) cannot change the recombination rate by as much as 1%. Hence, we conclude that environmental magnetic fields much weaker than the earth's field cannot be expected to affect biology significantly by modifying radical pair recombination probabilities.

Understanding exposure thresholds for the response of biological systems to extremely low frequency (ELF) electric and magnetic fields is a fundamental problem of long-standing interest. We consider a two-state model for voltage-gated channels in the membrane of an isolated elongated cell (Lcell = 1 mm; rcell = 25 micron) and use a previously described process of ionic and molecular flux rectification to set lower bounds for a threshold exposure. A key assumption is that it is the ability of weak physical fields to alter biochemistry that is limiting, not the ability of a small number of molecules to alter biological systems. Moreover, molecular shot noise, not thermal voltage noise, is the basis of threshold estimates. Models with and without stochastic resonance are used, with a long exposure time, texp = 10(4) s. We also determined the dependence of the threshold on the basal transport rate. By considering both spherical and elongated cells, we find that the lowest bound for the threshold is Emin approximately 9 x 10(-3) V m-1 (9 x 10(-5) V cm-1). Using a conservative value for the loop radius rloop = 0.3 m for induced current, the corresponding lower bound in the human body for a magnetic field exposure is Bmin approximately 6 x 10(-4) T (6 G). Unless large, organized, and electrically amplifying multicellular systems such as the ampullae of Lorenzini of elasmobranch fish are involved, these results strongly suggest that the biophysical mechanism of voltage-gated macromolecules in the membranes of cells can be ruled out as a basis of possible effects of weak ELF electric and magnetic fields in humans.

The elasmobranchs-sharks, rays, and skates-can detect very weak electric fields in their aqueous environment through a complex sensory system, the ampullae of Lorenzini. The ampullae are conducting tubes that connect the surface of the animal to its interior. In the presence of an electric field, the potential of the surface of the animal will differ from that of the interior and that potential is applied across the apical membrane of the special sensory cells that line the ampullae. The firing rate of the afferent neurons that transmit signals from the ampullae has been shown to vary with that potential. We show that those firing rates can be described quantitatively in terms of synchronous firing of the sensory cells that feed the neurons. We demonstrate that such synchronism follows naturally from a hypothetical weak cell-to-cell interaction that results in a self-organization of the sensory cells. Moreover, the pulse rates of those cells-and the neurons that service the cells-can be expected to vary with the imposed electric fields in accord with measured values through actions of voltage gated transmembrane proteins in the apical sector of the cell membranes that admit Ca(++) ions. We also present a more conjectural model of signal processing at the neuron level that could exploit small differences in firing rates of nerve fibers servicing different ampullae to send an unambiguous signal to the central nervous system of the animal. (c) 1998 American Institute of Physics.

We show, in elementary terms, using for the most part only elementary mathematics, the physical bases for the ion parametric resonance model so as to clarify the assumptions and consequences of the model. The analysis shows why, contrary to earlier conclusions, no combination of weak DC and AC magnetic fields can modify the transition rate to the ground state of excited ions. Although reinterpretations of the biological consequences of the motion of the excited ions circumvent that particular objection to the model, those changes introduce other difficulties. Also, other objections to the mechanism still stand; hence the model cannot account for any purported biological effects of weak extremely low frequency magnetic fields. Bioelectromagnetics 19:181–191, 1998. © 1998 Wiley-Liss, Inc.

I show that the interaction of weak DC and ELF magnetic fields with contained ions cannot generate significant biological effects through changing the character of the ion orbits.

A simple, paradigmatic, model is used to illustrate some general properties of effects subsumed under the label "stochastic resonance." In particular, analyses of the transparent model show that 1) a small amount of noise added to a much larger signal can greatly increase the response to the signal, but 2) a weak signal added to much larger noise will not generate a substantial added response. The conclusions drawn from the model illustrate the general result that stochastic resonance effects do not provide an avenue for signals that are much smaller than noise to affect biology. A further analysis demonstrates the effects of small signals in the shifting of biologically important chemical equilibria under conditions where stochastic resonance effects are significant.

Oscillating electric fields can be rectified by proteins in cell membranes to give rise to a dc transport of a substance across the membrane or a net conversion of a substrate to a product. This provides a basis for signal averaging and may be important for understanding the effects of weak extremely low frequency (ELF) electric fields on cellular systems. We consider the limits imposed by thermal and "excess" biological noise on the magnitude and exposure duration of such electric field-induced membrane activity. Under certain circumstances, the excess noise leads to an increase in the signal-to-noise ratio in a manner similar to processes labeled "stochastic resonance." Numerical results indicate that it is difficult to reconcile biological effects with low field strengths.

Edward Nichols and Ernest Merritt began the physical review at Cornell University in 1893. Any new journal incurs a financial risk; Cornell assumed that risk.

The effects of 60 Hz magnetic fields of 5 [mu]T (50 mG) or less on biological structures holding magnetite (Fe[sub 3]0[sub 4]) are shown to be much smaller than that from thermal agitation; hence such interactions cannot be expected to be biologically significant. Various species have been shown to manufacture magnetite, which is used in some cases in conjunction with the earth's magnetic field to determine direction ([Frankel, 1986; Kirschvink and Kobayashi-Kirschvink, 1991].) This magnetite is usually found in sets of single domain grains, about 500[angstrom] in diameter, where all grains are magnetized in the same direction. Typically, such grains are enclosed by a membrane and are called magnetosomes. Hence, the possibility that weak ELF magnetic fields may cause biological effects in humans by the interaction of the field with magnetosomes must be considered.

Results of a search for the decay mode {ital K}{sub {ital L}}{sup 0}{r arrow}{gamma}{gamma}{ital ee} ({ital K}{sub {ital L}}{sup 0}{r arrow}{gamma}{ital ee} with a hard internal bremsstrahlung) are reported. The measured branching ratio is (6.6{plus minus}3.2){times}10{sup {minus}7}, in agreement with the QED prediction of 5.8{times}10{sup {minus}7}. The infrared cutoff for both branching ratios is the requirement that both photons have an energy of at least 5 MeV in the center of mass.

Results are presented of a recent search by AGS Experiment 845 for the CP violating decay K 0 L → π 0 e + e − . The 90% C.L. limit B ( K 0 L → π 0 e + e − ) −9 was obtained. The background to the π 0 e + e − search, K 0 L → e + e − γ with an internal bremsstrahlung is discussed.

Records of the mean annual global surface temperatures from 1850 to 1970 show annual temperatures that are correlated with temperatures of the previous years as a one-dimensional random walk with a limiting feedback. This description accounts for the variation in those temperatures observed until the present by assuming that the base temperature is proportional to the increase in carbon dioxide concentration over the level in 1890. Climate models that better fit the observed variations are shown to be statistically improbable and thus likely to be artifacts.

Sam Goudsmit implemented his vision of converting the Letters section of Physical Review into a distinct journal fifty years ago. Physical Review Letters was designed to publish "only papers that really deserve rapid communication." The new journal became so successful with physicists throughout the world that Physical Review Letters now publishes 3500 Letters per year.

We report on measurements of the {ital K}{sub {ital L}} Dalitz decay {ital K}{sub {ital L}}{r arrow}{ital e}{sup +}{ital e}{sup {minus}}{gamma}. The results are based on a sample of 919 events. Through an evaluation of the form factor, we have established evidence for a nonvanishing contribution due to the {ital KK}{sup *}{gamma} coupling. We have determined the branching ratio to be {ital B}({ital K}{sub {ital L}}{r arrow}{ital e}{sup +}{ital e}{sup {minus}}{gamma})=(9.1{plus minus}0.4{sub {minus}0.5}{sup +0.6}){times}10{sup {minus}6}.

We report on results of a dedicated search for the {ital CP}-violating decay {ital K}{sub {ital L}}{r arrow}{pi}{sup 0}{ital e+}{ital e{minus}}. We have found no evidence for this decay mode and obtain a 90%-confidence upper limit of 5.5{times}10{sup {minus}9} for its branching ratio.

Evolutionary pressures are presumed to act so as to maximize the efficiency of biological systems. However, the utility of that premise is marred by the difficulties in defining and evaluating both the efficiency of systems and the character of the available variation space. Following Hodgkin and Adrian, we examine the character of voltage gated ion channels in the nonmyelinated giant axons of the squid and find that both the channel densities and channel transition rates have values that nearly optimize signal sensitivity as well as signal velocity.

Adair, R. K. Environmental Objections to the PAVE PAWS Radar System: A Scientific Review. Radiat. Res. 159, 128–134 (2003). As part of our continental defense system, the United States Air Force has operated a radar system, known generally by the label PAVE PAWS, off of Cape Cod, MA since 1978. Some populated areas in the vicinity of the system are subject to a low level of background radiofrequency radiation from the system, and local citizens' groups have expressed concern that this radiofrequency radiation may affect their health. These concerns have been fueled by presentations and letters by Dr. R. A. Albanese, an applied mathematician at the Air Force Research Laboratory, who has proposed standards by which that PAVE PAWS radiofrequency radiation which is incident on populations should be judged. I discuss those standards that are sufficiently well defined to be subject to analysis and show that they are not based on sound quantitative reasoning.

We report on a measurement of the branching ratio for the [ital K][sub [ital L]] double Dalitz decay [ital K][sub [ital L]][r arrow][ital e][sup +][ital e[minus]][ital e+][ital e[minus]]. The result, based on the observation of six events, is [ital B]([ital K][sub [ital L]][r arrow][ital e][sup +][ital e[minus]][ital e+][ital e[minus]]) =(3.07[plus minus]1.25[plus minus]0.26)[times]10[sup [minus]8].

Kirschvink [preceding Comment, Phys. Rev. A 46, 2178 (1992)] objects to my conclusions [Phys. Rev. A 43, 1039 (1991)] that weak extremely-low-frequency (ELF) electromagnetic fields cannot affect biology on the cell level. He argues that I did not properly consider the interaction of such fields with magnetite (${\mathrm{Fe}}_{3}$${\mathrm{O}}_{4}$) grains in cells and that such interactions can induce biological effects. However, his model, designed as a proof of principle that the interaction of weak 60-Hz ELF fields with magnetite domains in a cell can affect cell biology, requires, by his account, a magnetic field of 0.14 mT (1400 mG) to operate, while my paper purported to demonstrate only that fields smaller than 0.05 mT (500 mG) must be ineffective. I then discuss ELF interactions with magnetite generally and show that the failure of Kirschvink's model to respond to weak fields must be general and that no plausible interaction with biological magnetite of 60-Hz magnetic fields with a strength less than 0.05 mT can affect biology on the cell level.

Very large amplitude pulsed fields are important in many technical applications. Accordingly, the biological effects of such fields is of considerable practical interest. Even as many parameters are required to describe such pulsed fields, the set of such fields that are different in important ways is large and it is impractical to examine the biological effects of the whole set experimentally. Hence, we examine a representive set of such pulses in some detail with the view that the analyses of these pulses will provide a useful overview to the consideration of most specific pulses.

Electromagnetic fields interact with matter only through forces generated on charges; indeed, those forces define the fields. Hence, the vector force F on a charge q, is described by the Lorentz force law, $$F = q(E + v + B)$$ (1) where the electric field E, the magnetic field B, the velocity of the charge v, and the charge q, are all expressed in SI units. In less artificial units, υ → υ/c emphasizing that the magnetic field is a relativistic correction to the electric field; in a universe such that c →∞, there would be no magnetic fields. (Parenthetically, we note that B is the fundamental magnetic field quantity while H is a subsidiary quantity such as D.)

In the spirit of the general goal of this conference, I have treated the label of the sector I was asked to consider as a broad license to talk briefly about four quite different experiments, connected by little except that their center was, or is, at Brookhaven National Laboratory. I will describe two basic discoveries of the 1950’s that it seemed others would not cover, and with a bow to the present, I discuss two on-going programs that are, at this time, important only in what they have not discovered; that is in the limits they place on breakdowns of symmetries. Moreover, I played no personal role in either of the important discoveries except inasmuch as the critical experiments were conducted by friends and colleagues of mine at Brookhaven. I did play a minor role in one of the two on-going programs and a more significant part in the other.

I examine the constraints on the biological effects of the interactions of radio-frequency and microwave radiation imposed by thermodynamic noise. An analysis of the interaction of radiation with small biological elements at the cellular level shows that at power densities of 10 mw/cm2 (or 200 V/m), a level characteristic of occupational exposure limits, the interaction of electromagnetic fields with elements holding permanent charges or charge distributions will be masked by thermal noise and, hence, cannot be expected to generate biological effects.

In their Comment on the paper of Balzano [2002] on the detection of nonlinear responses, Marino and Frilot [2003] state that certain possible biological systems with a response described by ‘‘non linear differential equations’’ can respond (chaotically) to an interaction that is ‘‘arbitrarily small, say kT/10.’’ This is correct but does not lead to the conclusion that significant biological effects can be generated by signals that are much smaller than kT. Indeed voltage gated ion channels, the best understood nonlinear biological system, have long been known to respond to such infinitessimal signals [Koch, 1999], but the biological effects of such channels are still severely limited by thermal noise. Though a very small signal impulse can generate a response, overwhelmingly, those responses will also be generated by noise impulses swamping the responses from the directed signal. I present a specific example: from numerical simulations using the Hodgkins and Huxley [1952] equations to describe ion channel dynamics, I find that a transmembrane pulse of þ6.905 mV applied to an area of a squid giant axon populated by ion channels never generates action pulses while a pulse of þ6.906 mV always does. This change of 0.001 mV represents an energy transfer of about 2.4 10 4 kT in each sodium channel and a little less in the potassium channels. However, the generation of an action pulse follows with equal efficiency from noise impulses and exogenous signals and neither voltage gated channel systems nor the hypothetical systems suggested by Marino and Frilot can discriminate between signal and noise impulses. Hence, when I include the thermally dependent noise chatter of channel openings and closings from MNa&300 000 Na channels and MK&36 000 K channels that occupy an axon area of 1000m, the probability of a channel opening from a signal impulse of&6.9 mV is approximately one-half and the opening probability changes gradually from near zero to near one over a signal impulse range of about 1 mV, or about 0.25 kT per channel. Hence, with thermal noise considered, effects of a signal S kT=ð ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi MNaþMK p Þ 0:05 mV (a conservative estimate of the noise for signals coherent over M elements) added to an appropriate bias voltage, will not be distinguishable from noise effects. In Balzano’s reply [Balzano, 2003], he says that the nonlinear effects he would investigate can cause ‘‘biological responses that are not limited by the thermal noise level, kT.’’ That statement can be misread to imply that nonlinear systems in general are especially immune to kT noise limitations and that Balzano’s ingenious experiment will be sensitive to all such systems. This is not the case. When voltage gated ion channels are exposed to 900 MHz radiation, those systems will not reradiate 1800 MHz photons at a level detectable by the procedure outlined by Balzano. The voltage sensitive elements of the systems (probably an alpha helix element in the S4 sectors of each of the four domains that largely make up the channel protein), which are accelerated by the 900 MHz incident fields, have masses in excess of 1000 Da. Thus the accelerations of the charged elements are small, they radiate very little, and Balzano’s proposed experiment would not detect that nonlinearity. However, any nonlinearity that led to the reports of rectification of RF radiation that Balzano cited would presumably involve electron currents involving very