Margaret A. Kenny

Circadian temperature and cortisol rhythms during a constant routine are phase-delayed in hypersomnic winter depression

Circadian temperature, cortisol, and thyroid-stimulating hormone (TSH) rhythms during a constant routine were assessed in 6 female controls and 6 female patients with hypersomnic winter depression (seasonal affective disorder, SAD) before and after morning bright light treatment. After sleep was standardized for 6 days, the subjects were sleep-deprived and at bed rest for 27 hours while rectal temperature, cortisol, and TSH levels were assessed. The minimum of the fitted rectal temperature rhythm was phase-delayed in the SAD group compared to the controls 5:42 AM vs. 3:16 AM (p < .005); with bright light treatment, the minimum advanced from 5:42 AM to 3:36 AM (p = .06). The minimum of the cortisol rhythm was phase-delayed in the SAD group compared to the control group, 12:11 AM vs. 10:03 PM (P < .05); with bright light treatment, the minimum advanced from 12:11 AM to 10:38 PM (P = .06) [corrected]. The acrophase of the TSH rhythm was not significantly phase-delayed in SAD subjects compared to control, though the trend appeared to be toward a phase-delay (p = .07). After bright light therapy, the TSH acrophase was not significantly different in the SAD subjects; the trend was a phase-advance (p = .09). Overall, the data suggest that circadian rhythms are phase-delayed relative to sleep in SAD patients and that morning bright light phase-advances those rhythms.

Treatment of feline leukemia and reversal of FeLV by ex vivo removal of IgG: A preliminary report

Cats that were spontaneously infected with feline leukemia virus (FeLV) were treated with a combination of low‐dose irradiation and extracorporeal immunosorption using formalin and heat‐fixed S. aureus as a non‐specific immunosorbent to remove plasma IgG and immune complexes. The treatment resulted in reduction of circulating lymphoblasts within two weeks and clinical improvement of three of the five animals. A reversal of the FeLV status is reported in five of five cats. Two of the five cats remain FeLV negative and completely tumor free seven and eight months post‐therapy at the time of writing (July 1979). A third cat returned to an FeLV positive state but remained tumor free for 24 weeks. Another cat responded to the therapy by reduction of lymphoblasts and became FeLV negative but died of a hemorrhage during an immunosorption. The last cats status was FeLV positive, then FeLV negative, and finally FeLV positive again. He died 20 weeks after initiation of therapy. During the treatment there was a weight gain in the three cats responding by tumor regression. The results are discussed in terms of a removal of some type of immunoinhibiting factors such as antigen‐antibody complexes or suppressor molecules.

Simultaneous Self-Referencing Analyte Determination in Complex Sample Solutions Using Microfabricated Flow Structures (T-Sensors™)

In microfluidic channels, fluids with viscosities similar to or higher than water and flowing at low velocities show laminar behavior. This allows the movement of different layers of fluid and particles next to each other in a channel without mixing other than by diffusion. A sample solution (e.g., whole blood), and a receptor solution (e. g., an indicator solution), and a reference solution (a known analyte standard) are introduced in a common channel (T-Sensor™), and flow next to each other until they exit the structure. Smaller particles such as ions or small proteins diffuse rapidly across the fluid boundaries, whereas larger molecules diffuse more slowly. Large particles (e. g., blood cells) show no significant diffusion within the time the two flow streams are in contact. Two interface zones are formed between the fluid layers. The ratio of a property (e. g., fluorescence intensity) of the two interface zones is a function of the concentration of the analyte, and is largely free of cross-sensitivities to other sample components and instrument parameters. This device allows, for example, one-time or continuous monitoring of the concentration of analytes in microliters of whole blood without the use of membranes or prior removal of blood cells.

Fluorescence and absorbance analyte sensing in whole blood and plasma based on diffusion separation in silicon-microfabricated flow structures

Based on the recently introduced T-Sensor method, we demonstrate the fluorescence-determination of various analytes directly in whole blood and in serum. The method relies on microfluidic flow in silicon structures, diffusion-based separation, and analyte determination using fluorescent and absorption indicator dyes. Due to extremely small inertial forces in such structures, practically all flow in microstructures is laminar. This allows the movement of different layers of fluid and particles next to each other in a channel without mixing other than by diffusion. A sample solution (e.g., blood), and a receptor solution containing the indicator dye are introduced in a common channel, and flow laminarly next to each other until they exit the structure. Small ions such as H+, and Na+ diffuse rapidly across the channel, whereas larger molecules diffuse more slowly. Larger particles such as blood cells and polymer beads show no significant diffusion within the time the two flow streams are in contact. The fluorescence emission of indicator dyes is a function of the concentration of the analyte molecules and the dye concentration in the interaction zone between the two streams. This device allows continuous monitoring of the concentration of analytes in whole blood without the use of membranes or prior removal of blood cells. This principle is illustrated by the determination of human albumin, total calcium, and pH in whole blood and serum.

Thyroid function and lipids in patients with chronic renal disease treated by hemodialysis: With comments on the “free thyroxine index”

Abstract It is known that hypertriglyceridemia and abnormal thyroid function tests are common in patients with chronic renal disease treated by hemodialysis, but a possible association between these abnormalities has not been investigated. We measured serum thyroid hormone and lipid levels in one hundred patients receiving chronic hemodialysis. There were ten patients with elevations in serum thyrotropin (TSH). In the remaining patients with normal TSH, those receiving no drugs known to affect thyroid function had low mean values for thyroxine (T 4 ) and triiodothyronine (T 3 ), while the mean T 3 resin uptake (fraction of T 3 bound to resin, T 3 U) was normal, resulting in low mean values for free T 4 index (FT 4 I = T 4 × T 3 U) and free T 3 index (FT 3 I = T 3 × T 3 U). The depression in T 3 was greater than the depression in T 4 , so that T 3 T 4 ratios were also low. Androgen-treated male patients had the lowest T 3 and T 4 levels; their T 3 Us were high, presumably reflecting androgen-induced depression of T 4 -binding globulin, but their mean FT 4 I and FT 3 I were still lower than those of the other patients. Evidence is presented that the conventional T 3 U underestimates the proportion of free hormone when binding protein levels are low, and that a “new T 3 U,” the ratio of resin-bound T 3 to serum protein-bound T 3 , more accurately reflects the proportion of free hormone. Computing a “new FT 4 I,” as new T 3 U × T 4 , yielded values in the androgen-treated group similar to those of the other patients. Patients receiving propranolol had lower T 3 T 4 ratios than the other patients, presumably due to propranolols inhibitory effect on peripheral conversion of T 4 to T 3 . No relationship was found between indexes of thyroid function and lipid levels. Subjects with high TSH levels had levels of triglyceride and cholesterol similar to the remaining patients. Among those with normal TSH levels, low levels of T 3 or T 4 did not correlate with abnormal lipid levels. It is concluded that thyroid hormone abnormalities do not explain the hypertriglyceridemia of patients on chronic hemodialysis. The frequency of low T 4 and T 3 values in such patients, in the absence of clinical evidence of hypothyroidism and, in most instances, in the absence of TSH hypersecretion, remains unexplained.

Atrial Natriuretic Factor May Mediate the Renal Effects of PEEP Ventilation

hiechnnical ventilation with PEEP decreases urine output and urinary sodium excretion. Observed changes in cardiac output, renal blood flow, renin release, and antidiuretic hormone (ADH) secretion do not adequately explain the renal effects of PEEP. Altered release of atrial natriuretic factor (ANF), which is natriuretic and diuretic, may complete this explanation. The following hypothesis was tested: a PEEP-induced decrease in transmural right atrial pressure decreases ANF release, and this mechanism mediates subsequent alterations in renal function. Seven female mongrel dogs were anesthetized with halothane and their lungs ventilated mechanically for three consecutive 40 min periods of 0 PEEP, 10 cmH2O PEEP, and 0 PEEP. Addition of 10 cmH2O PEEP during mechanical ventilation decreased right atrial dimension and transmural right atrial pressure while intracavitary right atrial pressure was increased. Urine output was significantly decreased during PEEP, as were absolute and fractional excretion of sodium and osmolnr clearance. PEEP ventilation resulted in a consistent and significant decline in plasma ANF concentration (82 ± 11 to 62 ± 11 pg/ml, P < 0.05). Hemodynamic parameters, renal function, and ANF concentration returned to control values after cessation of PEEP. A second series of experiments in five dogs demonstrated a close temporal relationship between changes in atrial dimension or atrial transmural pressure, plasma ANF concentration, and urine output or sodium excretion. The results of this study demonstrate that PEEP-induced decreases in atrial distension resulted in decreased ANF release, which may mediate, in part, the antinatriuretic and antidiuretic effects of PEEP.

Influence of hypothermic cardiopulmonary bypass on atrial natriuretic factor levels

Atrial natriuretic factor (ANF) is a peptide released from the heart in response to atrial distension. This peptide causes diuresis, vasodilatation, decreased blood pressure, and antagonizes the renin-aldosterone and antidiuretic hormone neuraxes. The influence of cardiopulmonary bypass and cardiac surgery on the circulation and release of ANF is unknown. Plasma ANF concentrations were therefore determined in patients undergoing coronary artery revascularization (CABG) and mitral valve replacement (MVR). Peptide levels were unchanged following anaesthetic induction. Plasma ANF concentrations decreased significantly during hypothermic (≤ 28° C) cardiopulmonary bypass in both patient groups. After 60 minutes of cardiac bypass, ANF declined from (mean ± SEM)512 ± 132 to 20± 6 pg · ml− (P < 0.05) during MVR, and from 178 ± 41 to 110 ± 48 pg·ml− during CABG (P < 0.05). Rewarming during bypass was associated with an increase in ANF concentration in both groups. Heparin anticoagulation and protamine reversal had no effect on immunoreactive ANF levels. In patients undergoing CABG, there was a linear relationship between plasma ANF concentration (pg · ml−1) and right atrial pressure (mmHg) prior to cardiopulmonary bypass (r = 0.86, P < 0.005). However, one and three hours after cardiopulmonary bypass there was no significant relationship between right atrial pressure and ANF plasma levels. These results suggest that reduction in plasma ANF concentration occurs during hypothermic cardiopulmonary bypass. Furthermore, the proportional relationship between atrial distension and circulating ANF concentration was altered following cardiac surgery.RésuméEn réponse à la distension de l’oreillette, le cœur libére un peptide, le facteur natriurétique de l’ oreillette (ANF), qui induit diurse et vasodilatation, diminue la tension artérielle et inhibe la libération de la rénine, de l’aldostésterone et de l’hormone anti-diurétique. Pour évaluer l’impact de la circulation extra-corporelle (CEC) et de la chirurgie cardiaque sur la sécrétion d’ANF, nous en avons mesuré la concentration plasmatique ([ANF]) lors de revascularisations coronariennes (pontage) et de remplacements de la valve mitrale (valvuloplastie). Dans les deux types d’interventions, les niveaux d’ANF, inchangés aprés l’induction anesthésique, diminuèrent significativement avec la CEC (temp. 28° C). Après 60 minutes sous CEC, la[ANF] était passé de 512 ± 132 à 20 ± 6 pg·ml−1 (P ≤ 0.05) dans le groupe « valvuloplastie » et de 178 ± 41 à 110 ± 48 pg·ml−1 (P≤ 0.05) dans le groupe « pontage ». La [ANF] augmentait pendant le richauffement sous CEC mais était indifférente à l’ anticoagulation par heparine et à son antagoniste, la protamine. Dans le groupe «pontage», nous avons observi une relation lineaire entre [ANF] et la pression de l’oreillette droite avant CEC (r = 0.86, P ≤ 0.05) mais, cette relation ne tenait plus, une heure et trois heures post-CEC. Il semble done qu’il y ait diminution de la concentration plasmatique d’ANF pendant la CEC hypothermique et qu’en plus il y ait perturbation du couple ANF-pression de l’oreillette apris la chirurgie cardiaque.

Tricyclic Antidepressant-Specific fab fragments alter the distribution and elimination of desipramine in the rabbit: A Model for overdose treatment

The effects of tricyclic antidepressant (TCA)-specific Fab fragments (Fab) on total and free desipramine (DMI) levels in serum and urine of DMI-treated rabbits were studied to determine the feasibility of using these Fab for antidotal treatment of TCA overdoses in humans. Serial samples of blood and urine were collected from two 3 kg rabbits after arterial injection of 2 mg 3H-DMI and, about 1.5 hr later, after injection of approximately 1 g Fab (prepared from sheep total IgG). Protein-free filtrates of serum and urine samples were obtained by ultrafiltration; concentrations of apparent total and apparent free DMI (apparent DMI, aDMI = DMI + metabolites) were calculated based on the radioactivity in the sample and ultrafiltrate, respectively. Treatment with Fab induced significant changes in the absolute and relative concentrations of free and total aDMI in both serum and urine. Changes in the serum included increases in the total and free aDMI levels. Changes in the urine included the appearances of a protein-bound aDMI fraction and Fab, and an increase in the percent of unmetabolized DMI. These results demonstrate that TCA-specific Fab influence the distribution and elimination of desipramine in DMI-treated rabbits and suggest that further studies on the use of TCA-specific Fab for antidotal treatment of TCA overdose are warranted.

Oral nifedipine for the treatment of patients with severe hypertension

Ten mg of nifedipine was administered to 19 patients with severe hypertension (mean blood pressure 187 +/- 17/122 +/- 12 mm Hg) without intensive care monitoring. Patients were instructed to bite and swallow the contents of the capsule. Blood pressure declined significantly to a mean of 149 +/- 17/92 +/- 10 mm Hg. No adverse side effects or hypotension occurred. Ten patients required an additional dose 30 to 60 minutes after the initial dose. Mean heart rate increased from 79 to 95 beats per minute without symptomatic consequences. Laboratory parameters measured before and after the four-hour study did not change significantly, although peripheral renin activity rose transiently. Urinary sodium excretion increased 43 percent over four hours after therapy in three patients in whom it was measured. Cardiac output, which was measured noninvasively in seven patients, rose nonsignificantly whereas systemic vascular resistance declined from 2,070 dynes/second/cm-5 to 1,271 dynes/second/cm-5 (statistically significant difference) in 20 minutes. These results indicate that oral nifedipine, when bitten and swallowed, effectively lowers blood pressure in patients with severe hypertension without the occurrence of adverse side effects or hypotension. Oral nifedipine may be used safely in an outpatient setting when urgent intervention is required.

Two novel endogenous digoxin-like immunoreactive substances isolated from human plasma ultrafiltrate

Two digoxin-like immunoreactive substances (DLIS 1 and DLIS-2) were isolated from human plasma by ultrafiltration, alkaline solvent extraction, and HPLC. Both inhibit canine Na, K-ATPase and cross-react with anti-digoxin antibodies. Their UV spectra are similar, with absorption peaks at 190 and 220 nm. FAB mass spectral analysis of both compounds yield a single dominant (M+H)+ component at m/z 532 otherwise, the fragmentation patterns are slightly different. The spectral data are consistent with the postulate that these compounds are related. Their identity as the natriuretic hormone is being investigated.