Male quality, signal reliability and female choice: assessing the expectations of inter-sexual selection.

Numerous models have attempted to explain the evolution of extravagant male ornaments found in many species. Inter-sexual indicator models postulate that male ornaments evolved as signals of quality, and that females use these signals to select the highest quality males. These models involve three traits--male quality, male signals and female preferences--and have specific expectations about the relative strengths of the phenotypic relationships between these traits. Using data from anuran species, we assessed the relative strengths of the phenotypic relationships using meta-analysis. The relative strengths of these phenotypic correlations were as expected by indicator models, providing support for indicator models of inter-sexual selection. We also found much variation in our data, suggesting that additional, untested factors may mediate inter-sexual interactions in this taxon, such as differences in the importance of quality signalling between species. These factors require investigation, in order to improve our understanding of inter-sexual selection.

A static magnetic field modulates severity of audiogenic seizures and anticonvulsant effects of phenytoin in DBA/2 mice.

RATIONALE: In a search for potential supplements or alternatives to the pharmacological treatment of epilepsy, we examined the effects of static magnetic fields on audiogenic seizures of DBA/2 mice. METHODS: Two strains of DBA/2 mice were subjected to auditory stimulation that resulted sequentially in wild running, loss of righting, clonus, tonic hindlimb extension, and death in 80-95% of animals in different experiments. The incidence of seizure stages in groups of animals pretreated with a static magnetic field, phenytoin (PHT) or both was compared to the incidence in sham-exposed control mice. RESULTS: Depending on magnetic flux density and duration of exposure to the field, seizure severity decreased significantly, but not completely, in both strains. However, incidence of five seizure stages was reduced in one strain, with about half of the mice seizure free. Two seizure stages (tonic hindlimb extension and death) were reduced significantly in the other. Magnetic field pretreatment potentiated the effect of PHT. Clonic seizures refractory to PHT or magnetic field pretreatment in DBA/2J mice responded to pretreatment with a combination of PHT and the magnetic field. CONCLUSIONS: A static magnetic field had some anticonvulsant effects when employed alone. More robust effects were seen in combination with PHT. Further testing of magnetic fields for anticonvulsant effects and elucidation of mechanisms of action seem to be warranted.

Two configurations of static magnetic fields for treating rheumatoid arthritis of the knee: a double-blind clinical trial.

OBJECTIVE: To assess the efficacy of a nonpharmacologic, noninvasive static magnetic device as adjunctive therapy for knee pain in patients with rheumatoid arthritis (RA). DESIGN: Randomized, double-blind, controlled, multisite clinical trial. SETTING: An American and a Japanese academic medical center as well as 4 community rheumatology and orthopedics practices. PATIENTS: Cohort of 64 patients over age 18 years with rheumatoid arthritis and persistent knee pain, rated greater than 40/100mm, despite appropriate use of medications. INTERVENTION: Four blinded MagnaBloc (with 4 steep field gradients) or control devices (with 1 steep field gradient) were taped to a knee of each subject for 1 week. MAIN OUTCOME MEASURES: The American College of Rheumatology recommended core set of disease activity measures for RA clinical trials and subjects' assessment of treatment outcome. RESULTS: Subjects randomly assigned to the MagnaBloc (n = 38) and control treatment groups (n = 26) reported baseline pain levels of 63/100mm and 61/100mm, respectively. A greater reduction in reported pain in the MagnaBloc group was sustained through the 1-week follow-up (40.4% vs 25.9%) and corroborated by twice daily pain diary results (p < .0001 for each vs baseline). However, comparison between the 2 groups demonstrated a statistically insignificant difference (p < .23). Subjects in the MagnaBloc group reported an average decrease in their global assessment of disease activity of 33% over 1 week, as compared with a 2% decline in the control group (p < .01). After 1 week, 68% of the MagnaBloc treatment group reported feeling better or much better, compared with 27% of the control group, and 29% and 65%, respectively, reported feeling the same as before treatment (p < .01). CONCLUSIONS: Both devices demonstrated statistically significant pain reduction in comparison to baseline, with concordance across multiple indices. However, a significant difference was not observed between the 2 treatment groups (p < .23). In future studies, the MagnaBloc treatment should be compared with a nonmagnetic placebo treatment to characterize further its therapeutic potential for treating RA. This study did elucidate methods for conducting clinical trials with magnetic devices.

Static magnetic field therapy for pain in the abdomen and genitals.

Two adolescents with debilitating, medication-resistant, chronic pain of the low back and abdomen with intermittent pain of the genitalia were diagnosed with intervertebral disk disease at spinal cord levels that correlated with their signs. Both patients had undergone multiple evaluations by physicians of different specialties and both underwent appendectomy without relief of their pain. The history of the onset of pain was important in determining the affected levels. The pain of both individuals was mimicked and localized by percussion of the vertebral spines at the level of disk protrusion. This maneuver and careful review of the history were important in making the correct diagnosis in each case. In both patients, treatment with novel magnetic devices provided rapid relief that was sustained for more than 2 years. These cases highlight the need for careful evaluation and correct diagnosis of abdominal and genital pain in young patients to avoid costly and unnecessary medical intervention and the stigma of painful debility.

Efficacy of gabapentin as adjunctive therapy in a large, multicenter study. The Steps Study Group.

The objective of this study was to determine the efficacy of gabapentin as adjunctive therapy in doses required to achieve the most effective seizure control. There were 2016 patients with partial seizures requiring adjunctive therapy who received gabapentin at doses up to 3600 mg/day in this open-label, multicenter, 16-week study. Of the 1055 patients evaluable for efficacy, 573 received gabapentin < or =1800 mg/day and 482 received > 1800 mg/day as the highest dose received. For the overall efficacy evaluable population, the percentage of patients achieving at least a 50% reduction in seizure frequency was 76.0%; 46.4% of the patients were seizure free. Patients whose highest gabapentin dose did not require > 1800 mg/day had, at baseline, fewer seizures and were receiving fewer concomitant antiepileptic drugs (AEDs) at baseline than those patients requiring > 1800 mg/day. This suggests that patients requiring higher doses of gabapentin were more refractory to drug treatment at the start of the study. Gabapentin was well tolerated at all doses in this study. The results of the study demonstrate that gabapentin is effective as adjunctive therapy in patients with partial seizures whose seizures are inadequately controlled by traditional AEDs.

Effects of topiramate on sodium-dependent action-potential firing by mouse spinal cord neurons in cell culture.

PURPOSE: The effects of topiramate (TPM) on sodium-dependent action potentials were studied by using cultured mouse spinal cord neurons. METHODS: The ability of TPM to limit (block) depolarization-induced spontaneous repetitive firing (SRF) was determined and compared with corresponding effects of phenytoin (PHT) and lamotrigine (LTG) in cultured mouse spinal neurons. RESULTS: Topiramate at concentrations of > or =3 microM caused a voltage-sensitive and time-dependent limitation of SRF that was associated with a decrease in the velocity of the upstroke of the action potential. At high concentrations (30-600 microM), TPM rapidly blocked SRF in about one third of the neurons tested and did not affect SRF in about one third. In some neurons, TPM caused an intermittent limitation (sputtering) of SRF (approximately 30% of the neurons) or blocked SRF only after a delay of several seconds (approximately 10%). This complex pattern of effects is distinctly different from that of PHT and LTG, in which the effect was always a rapid limitation or complete blockade of SRF. Another difference between TPM and the other anticonvulsants (AEDs) is that the effects of TPM were more dependent on the length of time the neurons were exposed to the compound and the intensity or duration of neuronal activity. CONCLUSIONS: The results of this study do not support the concept that Na+ channel blockade is the primary mechanism responsible for the anticonvulsant activity of TPM.

Gabapentin in the management of convulsive disorders.

Gabapentin, in clinical use since 1993, is indicated as an adjunctive antiepileptic drug (AED) for treatment of complex partial seizures, with or without secondary generalization, in patients over 12 years of age. Although several cellular actions have been described in the literature, the molecular mechanism(s) of action responsible for the anticonvulsant effect of gabapentin has not been conclusively determined. It is likely that gabapentin has multiple concentration-dependent actions that combine in a unique manner to produce antiepileptic efficacy. The pharmacokinetic properties of this water-soluble, amino-acid AED are generally favorable. Absorption appears to be dependent on transport by the L-system amino acid transporter. Elimination of unmetabolized drug occurs by the renal route. Although its therapeutic range is not well characterized, gabapentin has a broad therapeutic index. This implies that a wide range of doses can be used, based on individual patient needs, without significant limitation due to dose-dependent side effects. Gabapentin has few drug-drug interactions, none of which is clinically limiting. Several studies have demonstrated the long-term efficacy of gabapentin with no systematic evidence of tachyphylaxis. In addition, there is increasing evidence to support the use of gabapentin as monotherapy. Gabapentin is safe and is generally well tolerated. To date, nearly 3 million patients have been treated in studies and in open use without causal relationship to a specific life-threatening organ toxicity. Seizure control superior to that observed in well-controlled trials has been reported at higher doses used in clinical practice and in studies. Therefore, gabapentin dosing must be optimized on an individual basis to achieve an adequate trial of the drug and obtain the best seizure control.

A single issue program in an isolated area: mammography screening in Darwin, NT.

OBJECTIVE: A process evaluation of the Northern Territory (NT) mammography program, NT Breast Screen (NTBS), during its initial 18 months of operation. METHODS: The study was undertaken in Darwin, NT, from December 1994 to May 1996. Clinical outcomes were obtained by reviewing computerised and manual program records to determine waiting times for results, recall rates and cancer detection rates. Client satisfaction was assessed by a questionnaire sent to all women with normal results over a 12-week period. General practitioner satisfaction was assessed by a questionnaire sent to all general practitioners in the region who had one or more clients who had attended the service. RESULTS: During this time, 2,882 screening mammograms were performed; 98 women were recalled for assessment (3.4%). Breast cancer was detected in 10 women (3.5 per 1000 women screened). The program was well accepted by clients and general practitioners. Performance criteria were not met for waiting times for results. CONCLUSIONS: NTBS faced challenges because of its small and dispersed population, a lack of local radiologists with mammographic experience and the conflict with other pressing health issues, particularly in Aboriginal health. Despite these challenges, the program functioned effectively during its initial 18 months. IMPLICATIONS: Mammography screening programs in isolated areas can function effectively. The constraints encountered by NTBS are likely to apply to similar programs. Issues identified requiring further research are the psychological consequences of long waiting times for results, and the prioritisation of mammography for Aboriginal women.

Safety and tolerability of gabapentin as adjunctive therapy in a large, multicenter study.

PURPOSE: To evaluate the tolerability and safety of gabapentin (GBP) as add-on therapy for seizure control. METHODS: Conducted in an outpatient setting and reflecting usual practice, this study compared tolerability of GBP dosages < or = 1,800 versus >1,800 mg/day, when these doses were required to achieve the most effective seizure control. Two analyses of adverse events are presented: tolerability and safety. In the tolerability analysis, each patient served as his or her own control to compare the occurrence of adverse events at GBP < or =1,800 versus >1,800 mg/day. The safety analysis required patients to receive at least one dose of GBP and have a follow-up contact. RESULTS: A total of 2,216 patients enrolled in this open-label, 16-week study and were evaluable for safety. Of these, 74.0% completed the 16-week study, and 281 met the tolerability criteria. Within these 281 patients, two mutually exclusive groups were compared (a) those reporting adverse events at only < or =1,800 mg/day (low dose); and (b) those reporting adverse events at only >1,800 mg/day (high dose). Three adverse events (asthenia, headache, and dizziness) were observed in a statistically significantly larger number of patients at only the low dose than in the group reporting these same adverse events at only the high dose, suggesting that patients who tolerated GBP at < or = 1,800 mg/day did not experience a significant increase in adverse events with dosages >1,800 mg/day. Overall, 10.6% of the 2,216 patients in the safety population prematurely withdrew because of adverse events, and 3.5% discontinued because of lack of efficacy. Safety and tolerability of GBP was rated as excellent or good for 78.5% of all patients. CONCLUSIONS: Gabapentin doses >1,800 mg/day were as well tolerated as doses < or =1,800 mg/day and were not associated with more adverse events.

Proteome composition and codon usage in spirochaetes: species-specific and DNA strand-specific mutational biases.

The genomes of the spirochaetes Borrelia burgdorferi and Treponema pallidum show strong strand-specific skews in nucleotide composition, with the leading strand in replication being richer in G and T than the lagging strand in both species. This mutation bias results in codon usage and amino acid composition patterns that are significantly different between genes encoded on the two strands, in both species. There are also substantial differences between the species, with T.pallidum having a much higher G+C content than B. burgdorferi. These changes in amino acid and codon compositions represent neutral sequence change that has been caused by strong strand- and species-specific mutation pressures. Genes that have been relocated between the leading and lagging strands since B. burgdorferi and T.pallidum diverged from a common ancestor now show codon and amino acid compositions typical of their current locations. There is no evidence that translational selection operates on codon usage in highly expressed genes in these species, and the primary influence on codon usage is whether a gene is transcribed in the same direction as replication, or opposite to it. The dnaA gene in both species has codon usage patterns distinctive of a lagging strand gene, indicating that the origin of replication lies downstream of this gene, possibly within dnaN. Our findings strongly suggest that gene-finding algorithms that ignore variability within the genome may be flawed.

Fatal familial insomnia: clinical and pathologic heterogeneity in genetic half brothers.

We describe clinical and pathologic features of a patient with fatal familial insomnia (FFI) whose prion (PrP) genotype is D178N coupled with methionine at codon 129 on his mutant allele and valine at codon 129 on his normal allele. A cousin (genetic half brother) with identical PrP genotypes exhibited strikingly different clinical and pathologic changes. Comparison of these cousins shows the phenotypic heterogeneity of FFI and suggests that the phenotypic expression of D178N is influenced by multiple factors.

Base composition skews, replication orientation, and gene orientation in 12 prokaryote genomes.

Variation in GC content, GC skew and AT skew along genomic regions was examined at third codon positions in completely sequenced prokaryotes. Eight out of nine eubacteria studied show GC and AT skews that change sign at the origin of replication. The leading strand in DNA replication is G-T rich at codon position 3 in six eubacteria, but C-T rich in two Mycoplasma species. In M. genitalium the AT and GC skews are symmetrical around the origin and terminus of replication, whereas its GC content variation has been shown to have a centre of symmetry elsewhere in the genome. Borrelia burgdorferi and Treponema pallidum show extraordinary extents of base composition skew correlated with direction of DNA replication. Base composition skews measured at third codon positions probably reflect mutational biases, whereas those measured over all bases in a sequence (or at codon positions 1 and 2) can be strongly affected by protein considerations due to the tendency in some bacteria for genes to be transcribed in the same direction that they are replicated. Consequently in some species the direction of skew for total genomic DNA is opposite to that for codon position 3.

Trans-2-en-valproic acid limits action potential firing frequency in mouse central neurons in cell culture.

Effects of the trans-isomer of 2-en-valproate (trans-2-en-NaVP; E-delta2-en-valproate or 2-en-valproate), an unsaturated metabolite of valproic acid (VPA), on intracellularly recorded sodium-dependent action potentials of cultured mouse spinal cord and cortical neurons were compared with those of the anticonvulsant sodium valproate (NaVP). The maximal rate of rise of action potentials triggered by trains of 1-msec or 400-msec pulses declined progressively until failure to fire in both cell types during exposure to trans-2-en-NaVP or NaVP was observed. The limitation of firing by both drugs was concentration, voltage, rate and time dependent. The IC50 of trans-2-en-NaVP was 1.2 x 10(-3) at < or =1 hr and 4.8 x 10(-5) M at 24 to 48 hr. Trans-2-en-NaVP did not limit sustained repetitive firing in all cortical neurons. This may reflect slower rates of firing during 400-msec depolarizations in neurons of this type. In paired-pulse experiments, the absolute refractory period was 7 msec in control solution and 15 msec (P < .01 vs. control; n = 9) in solution containing 6 x 10(-4) M trans-2-en-NaVP. Firing was limited in all spinal cord neurons after exposure to 0.5 mM NaVP for 24 to 48 hr; 80% were limited by 1 mM NaVP at < or =1 hr. Coincubation of the spinal cord neurons with trans-2-en-NaVP and NaVP for 24 hr showed no hyperadditive effect of these two drugs in vitro. Limitation of sustained repetitive firing was reversed by hyperpolarization in the continuing presence of either drug and incubation in drug-free medium. Limitation of sodium-dependent action potential firing rates could contribute, at least in part, to the anticonvulsant effect of trans-2-en-NaVP.

Remacemide HCl and its metabolite, FPL 12495AA, limit action potential firing frequency and block NMDA responses of mouse spinal cord neurons in cell culture.

The novel anticonvulsant, remacemide HCl [(+/-)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide monohydrochloride; FPL12924AA], and a desglycinated metabolite [(+/-)-1-methyl-1,2-diphenylethylamine monohydrochloride; FPL 12495AA] reversibly limited sustained high-frequency repetitive firing (SRF) of sodium-dependent action potentials by mouse spinal cord neurons in monolayer dissociated cell culture. Limitation occurred with an IC50 of 7.9 X 10(-6) M for remacemide and 1.2 X 10(-6) M for FPL 12495AA (P < 0.05 vs. remacemide). Stereoisomers of the desglycinate limited SRF with IC50 values of 3.3 X 10(-6) M and 3.5 X 10(-6) M for the S(+) and R(-) compounds, respectively. The concentration of racemic desglycinate and of either stereoisomer that produced limitation in all neurons tested was 10(-4) M. Maximal rate of rise (Vmax) of action potentials decreased progressively until firing ceased during 400-ms depolarizing pulses. Efficacy of remacemide, but not of the desglycinate, increased with time (maximum at 16-36 h). The limitation was voltage dependent. In addition, reduction of Vmax and action potential failure occurred during stimulation with 400-ms pulses and trains of brief (1 ms) depolarizations at different frequencies. These findings suggest an effect on voltage-sensitive sodium current that generates the action potential upstroke. Remacemide and the desglycinate also significantly reduced the amplitude of neuronal responses to pressure application of NMDA in use-dependent manner at concentrations equal to the IC50 values for limitation of action potential firing. Resting potential and input resistance were not changed significantly by either drug. Limitation of high-frequency firing of action potentials by both remacemide HCl and FPL 12495AA may contribute to the anticonvulsant efficacy of these compounds at concentrations overlapping the range required to block glutamatergic hyperexcitability.

Characteristics of triplex-directed photoadduct formation by psoralen-linked oligodeoxynucleotides.

A triplex-forming oligopyrimidine has been attached at its 5'-end to a photoreactive psoralen derivative and used to target a sequence which forms part of the coding region of the human aromatase gene. The 20 base pair sequence is not a perfect triplex target since it contains three pyrimidine interruptions within the purine-rich strand. Despite this, we have detected triplex-directed photoadduct formation at pH 7.0 between the psoralen-linked oligonucleotide and a 30mer duplex representing the aromatase target. Photoadduct formation was found to be sensitive to pH, temperature, cation concentration and the base composition of the third strand. By varying the base sequence of the target duplex around the psoralen intercalation site, we have characterised the site and mode of psoralen intercalation. The attached psoralen has been found to intercalate at the triplex-duplex junction with a strong preference for one orientation. We have shown that the psoralen will bind at the junction even when there is a preferred TpA step at an adjacent site. We have also compared the binding affinity and photoreactivity of oligodeoxyribonucleotides linked to two different psoralen derivatives and found differences in the rate of crosslinking and the extent of crosslink formation. Finally, we have examined oligodeoxyribonucleotides which are attached to psoralen by polymethylene linkers of different lengths.

Inhibition of aromatase expression by a psoralen-linked triplex-forming oligonucleotide targeted to a coding sequence.

The cytochrome P450 enzyme aromatase (P450arom) is an important target in breast cancer treatment. We have designed a 20-base pyrimidine oligodeoxynucleotide (ODN) which forms a sequence-specific triple helix (triplex) with a purine-rich tract in the P450arom coding sequence. The psoralen-linked ODN (Pso20T) formed photo-induced cross-linked products with target double-stranded DNA. Cross-linked adducts formed in vitro between ODNs and P450arom expression constructs were used to transfect COS and human MCF-7 breast cancer cells. Levels of aromatase transcripts and enzyme activity were significantly lower in cultures transfected with Pso20T-treated cDNA relative to controls. Pso20T had a lesser inhibitory effect on aromatase expression from a mutant P450arom construct, consistent with predicted effects of the mutations on triplex formation. These results are compatible with triplex-mediated interruption of transcription within intact cells.

Regional distribution of protease-resistant prion protein in fatal familial insomnia.

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 +/- 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 +/- 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration.(ABSTRACT TRUNCATED AT 250 WORDS)

Gabapentin.

The amino acid antiepileptic drug (AED) gabapentin (GBP) is indicated for adjunctive use in the treatment of partial seizures with or without becoming secondarily generalized in individuals older than 12 years. GBP was about as potent as phenytoin in the maximal electroshock test, but had a different profile of efficacy than standard antiepileptics in a range of animal models. Possible mechanisms of action include biochemical effects enhancing the ratio of gamma-aminobutyric acid (GABA) to glutamate, ion-channel actions (direct or indirect), and/ or enhancement of nonsynaptic GABA release. The anticonvulsant effect appears to depend on concentration of gabapentin in neurons, presumably by the L-system amino acid transporter that has been implicated in absorption from the gut. Data from studies for U.S. Food and Drug Administration (FDA) approval suggested a direct relationship of clinical response to dose and efficacy did not plateau at the doses used. The maximally effective dose, relationship of efficacy to blood level, and maximum tolerable dose are not yet known conclusively. Lack of significant binding to plasma proteins and lack of liver metabolism contribute to the absence of known limiting drug-drug interactions, particularly with other AEDs. Excretion intact in the urine affords dose adjustment on the basis of creatinine clearance. A half-life of approximately 7 h necessitates multiple doses daily for many individuals. The medication is well tolerated, in general. Side effects tend to be mild to moderate in intensity, most frequently affect the central nervous system, and resolve with time in many individuals. GBP has been prescribed for approximately 70,000 individuals worldwide without untoward incidence of severe systemic toxicity to date. Safety data continue to accumulate. GBP has been labeled category C on the basis of effects on rodent fetuses. Experience with use in pregnant women is limited and human teratogenic effects have not been reported. Data from ongoing monotherapy trials will help to clarify the range of clinical utility of gabapentin.

Blockade of sensory neuron action potentials by a static magnetic field in the 10 mT range.

To characterize the inhibitory effect of a static magnetic field, action potentials (AP) were elicited by intracellular application of 1 ms depolarizing current pulses of constant amplitude to the somata of adult mouse dorsal root ganglion neurons in monolayer dissociated cell culture. During the control period, < 5% of stimuli failed to elicit AP. During exposure to an approximately 11 mT static magnetic field at the cell position produced by an array of four permanent center-charged neodymium magnets of alternating polarity (MAG-4A), 66% of stimuli failed to elicit AP. The number of failures was maximal after about 200-250 s in the field and returned gradually to baseline over 400-600 s. A direct or indirect effect on the conformation of AP generating sodium channels could account for these results because 1) failure was preceded often by reduction of maximal rate of rise, an indirect measure of sodium current; 2) recovery was significantly prolonged in more than one-half of neurons that were not stimulated during exposure to the MAG-4A field; and 3) resting membrane potential, input resistance, and chronaxie were unaffected by the field. The effect was diminished or prevented by moving the MAG-4A array along the X or Z axis away from the neuron under study and by increasing the distance between magnets in the XY plane. Reduction of AP firing during exposure to the approximately 0.1 mT field produced by a MAG-4A array of micromagnets was about the same as that produced by a MAG-4A array of the large magnets above. The approximately 28 mT field produced at cell position by two magnets of alternating polarity and the approximately 88 mT field produced by a single magnet had no significant effect on AP firing. These findings suggest that field strength alone cannot account for AP blockade.

Measurement and analysis of static magnetic fields that block action potentials in cultured neurons.

To characterize the properties of static magnetic fields on firing of action potentials (AP) by sensory neurons in cell culture, we developed a mathematical formalism based on the expression for the magnetic field of a single circular current loop. The calculated fields fit closely the field measurements taken with a Hall effect gaussmeter. The biological effect induced by different arrays of permanent magnets depended principally on the spatial variation of the fields, quantified by the value of the gradient of the field magnitude. Magnetic arrays of different sizes (macroarray: four center-charged neodymium magnets of approximately 14 mm diameter; microarray; four micromagnets of the same material but of approximately 0.4 mm diameter) allowed comparison of fields with similar gradients but different intensities at the cell position. These two arrays had a common gradient value of approximately 1 mT/mm and blocked > 70% of AP. Alternatively, cells placed in a field strength of approximately 0.2 mT and a gradient of approximately 0.02 mT/mm produced by the macroarray resulted in no significant reduction of firing; a microarray field of the same strength but with a higher gradient of approximately 1.5 mT/mm caused approximately 80% AP blockade. The experimental threshold gradient and the calculated threshold field intensity for blockade of action potentials by these arrays were estimated to be approximately 0.02 mT/mm and approximately 0.02 mT, respectively, In conclusion, these findings suggest that spatial variation of the magnetic field is the principal cause of AP blockade in dorsal root ganglia in vitro.