Richard T. Jackson

Quantitative Assessment of Pharyngeal Bolus Driving Forces

This study analyzes the differences between wet and dry swallows; a manofluorogram is used to determine forces that affect pharyngeal bolus flow. By defining bolus pressures, many of the limitations of pharyngeal manometry are surmounted. This makes manometry a more useful clinical tool. The study results indicate that only a small portion of pharyngeal-generated pressure is directly applied to the bolus. The manofluorogram demonstrates that bolus transit relies on the synergistic action of two pumps—the oropharyngeal propulsion pump and the hypopharyngeal suction pump. A technique is illustrated for quantifying the forces that affect bolus flow. Quantification of force can differentiate abnormal forces responsible for lingual, pharyngeal, and hypopharyngeal pathology in dysphagic patients. The degrees of impairment can be measured.

Expression of a high-affinity serotonin transporter in human lymphocytes

This study was undertaken to assess the capability of lymphocytes to actively transport serotonin (5-HT). The data we obtained showed that lymphocytes isolated from the blood of normal human subjects contained a high-affinity uptake system for [3H]5-HT. Kinetic analysis of the uptake data as computed by regression analysis from Lineweaver--Burk plots, yielded a Km of 180 +/- 20 nM and Vmax of 94 +/- pmole/10(7) cells. The uptake of [3H]5-HT was temperature, sodium and chloride dependent and was potently inhibited by the antidepressants clomipramine, imipramine, fluoxetine and fluvoxamine, which are specific for the 5-HT transporter. Compounds that are more selective for norepinephrine and dopamine transporters such as mazindol, desipramine, and GBR 19209 had a lower inhibitory effect on the uptake of [3H]5-HT in human lymphocytes. The expression of a 5-HT transporter in human lymphocytes that resembles 5-HT uptake by platelets and brain synaptosomes may provide insights into the potential role of 5-HT in immune function and its relationship to the neurobiology of affective and addictive disorders.

Effect of Head Extension on Equilibrium in Normal Subjects

A dynamic posturography system was used to test the effect of 55° head extension on postural sway in 20 normal subjects. There was a highly significant increase in sway with head extension under two conditions; in both, the support surface moves proportionally to body sway angle (sway-referenced feedback). The largest increase in sway occurred when the eyes were closed and the support surface was sway-referenced. This latter condition removes vision, reduces the effectiveness of ankle proprioception, and forces the subject to depend mostly on vestibular information for equilibrium. We suggest that head extension increases sway because the utricular otoliths are put into a disadvantageous position. This may be another example of the role of utricular input in the control of balance.

Active [3H]-Dopamine Uptake by Human Lymphocytes: Correlates with Serotonin Transporter Activity

The main objective of the present investigation was to determine whether the uptake of [3H]-dopamine in human lymphocytes is mediated through a serotonin transporter. This was examined by studying the effects of various monoamine uptake inhibitors on the uptake of [3H]-dopamine in human lymphocytes. Among the compounds tested, indatraline, imipramine and fluoxetine, selective inhibitors of neuronal serotonin transporter, were the most potent inhibitors of [3H]-dopamine uptake in lymphocytes. The 50% inhibiting concentration (IC50) for these inhibitors was in the range of 3.5-17 nmol/l. Bupropion, GBR 12909, nomifensine and xylamine, selective inhibitors of dopamine and norepinephrine transporters, had low affinity for the dopamine uptake system in human lymphocytes with IC50 values ranging between 1,000 and 40,000 nmol/l. These findings provide supportive evidence for the participation of a serotonin transporter in the uptake of [3H]-dopamine in human lymphocytes. The existence of a high affinity transport system for dopamine and serotonin in human lymphocytes may serve as a readily accessible model to detect changes in the neuronal uptake of dopamine and serotonin in addictive and psychiatric disorders.

A new in vitro method of drug assay of nasal blood vessels

ZusammenfassungEntfernt man die Nasenschleimhaut des Hundes vom Septum und bringt sie in ein Muskelbad, so kontrahiert sich die Schleimhaut nach Zufügen von Nasentropfen. Von der Natur des Gewebes und von der Natur der pharmakologischen Antwort aus gesehen, scheint die glatte Muskulatur der Schleimhautgefäße die Kontraktion zu bewirken.Behandelt man die Nasenschleimhaut mit gefäßerweiternden Medikamenten wie Histamin, so beobachtet man keinen Relaxationseffekt, es sei denn, die Schleimhaut wurde mit gefäßverengenden Pharmaka wie etwa Epinephrin vorbehandelt. Gefäßverengende und gefäßerweiternde Pharmaka rufen eine dosisabhängige Antwort hervor.Es scheint, daß dieses neue Modell zur Überprüfung der Wirksamkeit von Präparaten bei gleichzeitiger Ausschaltung nervöser oder humoraler Einflüsse brauchbar ist.SummaryIf nasal mucosa is removed from the dogs septum, mounted in a muscle bath and treated with a small dose of a nasal decongestant, the mucosa contracts. It appears, from the nature of the tissue and the nature of the drug responses, that nasal vascular smooth muscle is the contracting element.If the nasal mucosa is treated with a vasodilating agent, such as histamine, there is no relaxation response unless the mucosa is first pretreated with a vasoconstricting agent such as epinephrine. Both vasoconstricting and vasodilating drugs induce dose-related responses.It appears that this new preparation may be useful to assay drug effects in the absence of nervous and humoral control.

Binding of [3H]-dopamine to human lymphocytes: possible relationship to neurotransmitter uptake sites.

Freshly isolated human lymphocytes from 11 healthy subjects had specific binding sites for dopamine which were dependent on time, temperature and sodium, and appeared to follow Michaelis-Menten kinetics. The apparent affinity constant (KD) of human lymphocytes for dopamine and the maximal number of binding sites (Bmax) were 109 +/- 21 nM and 2.66 +/- 1.75 pmol/10(7) cells, respectively. Dopamine binding was markedly affected by cocaine (IC50 = 150 nM) and other inhibitors of biogenic amine uptake. The relatively high potency of cocaine in competing for dopamine binding suggested that human lymphocytes may serve as a readily accessible model to detect changes in the neuronal uptake of dopamine and perhaps other monoamine neurotransmitters.

Effects of some steroids on aqueous humor dynamics

We have performed tonographic and histological studies in rabbits, using several locally applied steroid preparations, with a view to analyzing the progression of an ocular hypertensive state. Two of the preparations tested (6α-methylprednisolone 21-acetate and dexamethasone 21-phosphate) induced a dual intraocular pressure response. The third preparation, aldosterone, induced a sustained hypotension. When dexamethasone 21-phosphate was applied topically, a quick drop in pressure, accompanied by an increase in outflow, was observed. This was followed by a small, but significant, rise in intraocular pressure after 2 weeks. Aldosterone was applied subconjunctivally and topically to separate groups of rabbits daily for 14 days. Sustained decreases in intraocular pressure occurred. The administration of 6α-methylprednisolone 21-acetate twice weekly for 2 weeks caused a prolonged hypotensive effect. Single doses of the same drug produced a lowering of the intraocular pressure 3 hr after administration, reaching a maximum effect in 2–4 days. This drop in intraocular pressure was accompanied by a large increase in facility of outflow. Almost identical ocular responses, with no signs of toxicity, were evoked with lower doses of 6α-methylprednisolone 21-acetate. Again, the initial hypotensive response was followed by a hypertensive phase. The response to this steroid was the same on eight occasions in five separate groups of animals. It occurred in old, middle-aged and young animals, it was not invoked by the vehicle or by any premedication used, and it was not produced by changes in ocular rigidity. Tonography suggested that the drop in intraocular pressure was caused by some structural change in the filtration angle. Attempts were made to evaluate these structural changes on the basis of histological findings.

The Effect of Carbon Dioxide Inhalation on Cerebral Blood Flow: A Two-Hour Duration Study in Dogs With Microspheres

Dogs breathed one of four gas mixtures (5% CO2-95% O2, 5% CO2-95% air, 10% CO2-90% O2, and 10% CO2-90% air) for as long as two hours. Regional cerebral blood flow as well as flow in nasal, otic, pituitary and skin tissue were measured by means of 15 ± 5 μ radioactively labeled microspheres. The normal values for cerebral blood flow and arterial blood gases were very similar to those of other investigators. Inhalation of CO2 induced an increase in cerebral blood flow that was significantly higher than is usually reported. Increases varied from 100% (with 5% CO2-95% air) to 250% (with 10% CO2-90% O2). Blood flow in the temporal bone behaved much like that of brain in response to CO2. In most instances, the pituitary gland blood flow did not increase with inhalation of CO2.

Prevalence of high serotonin uptake in lymphocytes of abstinent alcoholics.

An impairment in serotonergic neurotransmission may be associated with alcoholism. We recently identified a high-affinity serotonin transporter (5-HTT) in human peripheral blood lymphocytes (PBLs). Moreover, molecular analysis of RNA samples of human lymphocytes using reverse transcription, coupled with polymerase chain reaction, enabled us to confirm the expression of a 5-HTT identical to the one reported in neuronal tissues, as evidenced by hybridization and sequence analysis. In this investigation, we measured the serotonin (5-HT) uptake in PBLs of recovering alcoholics (N = 10) with long-term abstinence (2-10 years) and non-alcoholic controls (N = 10). 5-HT uptake was measured by incubating 1 x 10(7) cells of PBLs with [3H]5-HT (3-1000 nM; sp. act. 23 Ci/mmol) for 10 min at 37 degrees. The results of this preliminary study revealed that abstinent alcoholics had significantly (P < 0.01) increased uptake of 5-HT (43.6 +/- 5.70 pmol/10(7) cells) as compared with controls (23.33 +/- 2.50 pmol/10(7) cells). An enhanced uptake of 5-HT in PBLs of abstinent alcoholics agrees with previously reported observations of increased 5-HT uptake in brain and platelets of former alcoholics and their descendants. This suggested that a serotonergic mechanism may be linked to the heredity of alcoholism.

Blood Flow in Otorhinologic Tissue after Histamine and Papaverine

A method has evolved that allows one to quantitatively measure nutritional blood flow in the labyrinth. Several otic symptoms (e.g., sudden hearing loss) are thought to be due to decreased labyrinthine blood flow. Our aim was to test two common vasodilators, histamine and papaverine, to determine if they were effective in increasing blood flow to otic tissue. The method employs the intracardiac injection of radioactive microspheres (15 μ in diameter). These spheres become embolized in the microcirculation and provide a measure of blood flow in ml/gm/min. Histamine or papaverine were infused intravenously for five min at several doses. Blood flow was measured before and after infusion. Both drugs cause a significant increase in blood flow to temporal bone tissue if used in the appropriate dose range, i.e., about 1 ug/kg/min for histamine and 0.5 mg/kg/min for papaverine. If the dose of either drug is increased to the point that causes a drop of more than 15 mm Hg in systemic blood pressure, there is either no increase or a drop in otic blood flow. This reversal of the drug response is felt to be due to autoregulatory mechanisms in intracranial blood vessels.