Deficits in elevating membrane potential of rat fibrosarcoma cells after cell contact.

Most cancer cells are known to have lower resting cellular potentials than do their normal counterparts. This study investigates how these potentials establish themselves during growth and cellular contact in tissue culture. Normal quail embryonic fibroblasts and quail fibrosarcoma (QT-35) and normal rat kidney cells and rat fibrosarcoma (from rat fibroblasts chemically transformed by nitroquinoline oxide) were recorded intracellularly using high-impedance micropipets. In high-density high-contact cultures, both quail and rat cancer cells had lower potentials than did normal cells (-20.7 compared to -40.1 mV for quail and -30.7 compared to -61.9 mV for rat). In low-density mitotically synchronous cultures, the rat cells were recorded every 4 hr for 96 hr. Starting at a low density, normal cell membrane potential is maintained at a low level through subsequent cell divisions. Without any additional change in cell density, the potential suddenly elevates to a high level. The membrane potential of cancer cells is by contrast unrelated either to cell density or to time. Cancer cells maintained an intermediate potential from low to very high densities and never elevated their potential to high values. The failure of cancer cells to reach high potentials may be linked to their uncontrolled cell division.

Relationship between cell membrane potential and natural killer cell cytolysis in human hepatocellular carcinoma cells.

One of the body's natural defense mechanisms against tumor cells is lysis of the invading cell by cytotoxic T-cells and natural killer (NK) cells. Five human hepatocellular carcinoma cell lines were found to have different sensitivities to killing by peripheral blood monocytes in a 51Cr release assay. This killing was demonstrated to be due to NK cell lysis. Electrical recording measurements of the membrane potentials of these five cell lines showed different values for each line, all below values reported for normal hepatocytes. Correlation between mean cell membrane potential, and sensitivity to NK lysis, revealed an inverse relationship. In this study we demonstrate that the lower the mean membrane potential of a human hepatocellular carcinoma cell line, the more sensitive it is to NK cell cytolysis. Cell surface positive potential did not correlate with NK cytolysis and only a weak correlation was found between cell membrane negative potential and cell surface positive potential between cell lines.

Seventh nerve spasm: effect of modification of cholinergic balance.

The seventh cranial nerve spasms of the face and the eyelids, including essential blepharospasm, are usually intractable and sometimes disabling. Deanol acetamidobenzoate was compared with the anticholinergic orphenadrine for relief of these spasms. Deanol cured two of 16 (12%) subjects and improved a third. Orphenadrine was much more effective, improving the conditions of 16 of 26 (62%) subjects between 57% and 100%. A crossover double-blind experiment showed high significance over a placebo.

Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions.

Based on several convergent lines of investigation, we make two hypotheses which are sufficient to explain many phenomena of growth regulation in both normal and cancer cells. 1. The first hypothesis is that there is a boundary or threshold of resting cell membrane potential that separates normal resting cells from normal proliferating cells and cancer cells. The basis for this in existing literature values of membrane potentials in resting and proliferating cells is established. A discussion of how these differences in potential can be explained focuses on changes in sodium permeability and internal sodium concentration. Of many sodium transfer mechanisms, the sodium channel is emphasized and how increased intracellular transfer may stimulate DNA synthesis. The effects of changing cell junctions, in particular gap junctions, on membrane potentials is also discussed, as well as the indications of altered junctions in tumor cells. The linking factor of the effects of growth factors on both cell junctions and sodium permeability leads to the second hypothesis. 2. Since growth initiation and inhibition involve sodium channels and gap junctions, several phenomena can be explained by postulating that they are one and the same entity. The basis for this hypothesis in existing descriptions of functional and structural similarities is outlined. The possible interchange of these elements in the cell cycle lead to several corollaries consequent to the conservation of their total number. The formation of gap junctions would consume sodium channels, decrease sodium permeability and stop DNA synthesis. Conversely, growth factors may competitively bind to channel-connexon elements, cleave gap junctions, liberate sodium channels to increase sodium permeability, and trigger DNA synthesis. Alterations in the structure of gap junction-channel elements in tumor cells would be sufficient to explain some carcinogenesis.

Calcium ion and the membrane potential of tumor cells.

Calcium ion affects ion permeability and membrane potential among many other aspects of cell function. Initial effects of increasing extracellular calcium upon membrane potential were studied in a quail fibrosarcoma (QT35) where calcium had a dose dependent effect, and normal quail fibroblasts, where there was little effect. Comparisons were then made in six different human hepatocellular carcinomas (Tong, HepG2, Hep3B, PLC/PRF/5, Mahlavu, and HA22T) in response to smaller changes in concentration. There were insignificant changes in membrane potential in two cell lines and significant elevations in four. Cytolysis by natural killer cells also declined in rough proportion to the increase in membrane potential. The less differentiated hepatocellular carcinoma cells have both higher baseline membrane potentials and a greater potential increase to increased calcium. By contrast, more highly differentiated tumor cells had paradoxically smaller membrane potentials and along with normal cells had small potential responses to calcium increases.

Noradrenergic cerebral stimulation of sensorineural impaired subjects: yohimbine effects on speech intelligibility and the auditory brain response.

Norepinephrine has been shown to improve signal-to-noise ratios of sensory systems, including that of the auditory system. Yohimbine has been observed to cause a selective increase of cerebral norepinephrine. It was administered in one dose to sensorineurally impaired subjects with the object of improving their speech hearing in noise. Speech intelligibility was measured by the adaptive procedure. Mild, significant improvement was noted in one of the hearing components, "attenuation," and an adverse effect was shown on "distortion," owing to noise. Auditory brainstem response was improved significantly. The objective of temporarily improving intelligibility in noise was not attained.

Food sensitivity in attention deficit disorder with hyperactivity (ADD/HA): a procedure for differential diagnosis.

A diagnostic procedure developed for adults and children which includes a week-long fast nutritionally supported with a chemically defined diet was applied to a pilot group of children having ADD/HA syndrome. A probable etiology of food hypersensitivity was shown for a majority of the panel with several standard subjective tests. Three neurological tests, one of which was of the corpus callosum, were evaluated as objective measurements of ADD/HA. Management procedures are not discussed. A follow-up at one year showed substantial continuing control for many of the subjects. It is suggested that this type of general diagnostic procedure be employed to indicate for treatment those having food sensitivity as the primary etiology.

Migraine: a diagnostic test for etiology of food sensitivity by a nutritionally supported fast and confirmed by long-term report.

A diagnostic procedure during a nutritionally supported fast week followed by conventional food sensitivity management achieved major improvement for 80% of a migraine panel. This procedure gave a reliable (0.8 correlation coefficient) prognosis on the substantial value of this approach for selection of the treatment of migraine. The study gave two lines of evidence which indicate that migraine has an etiology of food sensitivity.