Modelling Tumor Treating Fields for the treatment of lung-based tumors.

Tumor Treating Fields (TTFields), low-intensity electric fields in the frequency range of 100-500 kHz, exhibit antimitotic activity in cancer cells. TTFields were approved by the U. S. Food and Drug Administration for the treatment of recurrent glioblastoma in 2011. Preclinical evidence and pilot studies suggest that TTFields could be effective for treating certain types of lung cancer, and that treatment efficacy depends on the electric field intensity. To optimize TTFields delivery to the lungs, it is important to understand how TTFields distribute within the chest. Here we present simulations showing how TTFields are distributed in the thorax and torso, and demonstrate how the electric field distribution within the body can be controlled by personalizing the layout of the arrays used to deliver the field.

Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study.

Sleep deprivation is extremely common in the intensive care unit (ICU), and this lack of sleep is associated with low melatonin secretion. The objective of the current study was to explore the effect of exogenous melatonin administration on sleep quality in patients hospitalized in the pulmonary intensive care unit (ICU). We performed a double-blind, placebo-controlled study in the pulmonary ICU of a tertiary care hospital. Eight adult patients hospitalized in the pulmonary ICU with respiratory failure caused by exacerbation of chronic obstructive pulmonary disease (COPD) or with pneumonia were studied. Patients received either 3 mg of controlled-release melatonin or a placebo at 22:00, and sleep quality was evaluated by wrist actigraphy. Treatment with controlled-release melatonin dramatically improved both the duration and quality of sleep in this group of patients. Our results suggest that melatonin administration to patients in intensive care units may be indicated as a treatment for sleep induction and resynchronization of the "biologic clock." This treatment may also help in the prevention of the "ICU syndrome" and accelerate the healing process.

Patients in the intensive care unit suffer from severe lack of sleep associated with loss of normal melatonin secretion pattern.

BACKGROUND: Patients hospitalized in the intensive care unit (ICU) tend to become agitated and confused, and many even develop temporary psychoses (the ICU syndrome). We wondered whether the regulation of sleep and the secretion of melatonin is abnormal in ICU patients. Therefore, we studied the association of sleep-wake pattern in patients hospitalized in the ICU, their melatonin secretion rates, and profile compared with a control group of patients in general medical wards. METHODS: Sleep was assessed by actigraphy. Urine was collected every 3 hours for 24 hours. Melatonin secretion was assessed by measuring the melatonin metabolite 6-sulphatoxymelatonin by enzyme-linked immunosorbent assay. RESULTS: Actigraphy suggested that the ICU patients lacked normal sleep behavior for the entire study period, except for occasional short naps. Compared with controls, the nocturnal peak of melatonin secretion was absent, except in two patients in the nonventilated group, and showed a flat curve. CONCLUSIONS: Our results suggest that lack of sleep is indeed a severe problem in ICU patients and is accompanied by impairment of normal melatonin secretion. The possibility that melatonin administration may prove useful in improving sleep patterns in ICU patients deserves further study.

Digoxinlike immunoreactive factor isolated from human pleural fluid is structurally similar to digoxin.

To further define the chemical structure of human endogenous digoxinlike immunoreactive factors (DLIF) we used human pleural effusions as a source of the substance. Digoxinlike immunoreactive factor activity was detected by radioimmunoassay in the pleural fluid of each of four patients; average concentration was 0.35 ng/mL. The chemical profile of DLIF was determined by initial extraction and concentration of DLIF by ion exchange chromatography followed by reverse phase-high-pressure liquid chromatography (RP-HPLC) separation and purification. Using high-pressure liquid chromatography cochromatography of DLIF, together with several radioactively marked glycosides, we observed a single peak of DLIF activity that was chromatographically identical to digoxin. The present study further supports the recent finding that DLIF is related structurally to the cardiac glycosides, and for the first time it has been proven that DLIF is present in pleural fluids.

Identification and preliminary characterization of two human digitalis-like substances that are structurally related to digoxin and ouabain.

In order to characterize the structure of endogenous digitalis-like immunoreactive factor (DLIF), we utilized peritoneal dialysis fluid from patients with chronic renal failure as a source of endogenous digitalis-like immunoreactive factor (DLIF), and subjected it to one-step ion exchange chromatography, followed by one step reverse HPLC. Crude dialysis fluid contained 0.09 ng/ml of DLIF, and using Amberlite XAD-2 chromatography we extracted 110 ng of DLIF from 800 ml of dialysis fluid. By applying this partially purified DLIF to our HPLC system, we discerned three peaks of DLIF activity, with retention times of 34, 58 and 63 minutes. The first peak overlapped the elution profile of ouabain, and the third peak co-eluted precisely with digoxin. The second DLIF peak was not in proximity to any of the digitalis-like markers employed. Thus, our results indicate that DLIF isolated from peritoneal dialysis fluid exists in three distinct forms, one of which resembles ouabain, and one which is identical to digoxin.

Simultaneous study of 24-hour patterns of melatonin and cortisol secretion in depressed patients.

The temporal organization of melatonin and cortisol secretion were studied in depressed patients in order to investigate a possible relationship between the secretory patterns of the two hormones. Women who suffered from a primary affective disorder were studied twice as inpatients, the first time during the depressive episode and the second time after amitriptyline treatment and clinical recovery. During both 24-hour studies blood was collected at 1-hour intervals during the day and at 30-min intervals at night. A dissociation of melatonin and cortisol secretory patterns was observed in the 3 patients in whom the two hormones were determined simultaneously. 2 patients exhibited alterations in the circadian rhythm of both hormones during illness. After recovery, however, the melatonin rhythm remained altered but the cortisol rhythm was normalized. Another patient showed a nocturnal melatonin rise and day-night melatonin differences closer to those seen in normal subjects, but she had altered cortisol secretory patterns during depression which normalized after recovery. These results suggest that the melatonin and cortisol rhythms are controlled by different mechanisms.

Evidence that melatonin retention by the neonatal rat is greatly increased as compared to the adult: a novel biochemical mechanism.

Melatonin, an anti-gonadotropic pineal hormone, is known to have a very short half-life in the adult animal. The objective of the present study was to determine whether the fate of melatonin in the neonate is different from that of the adult rat. Groups of 5-day-old rats were injected intraperitoneally with [3H]melatonin. The animals were killed at 10, 60 and 90 min intervals following the injections and the livers and brains immediately removed and homogenized. A high pressure liquid chromatographic analysis of the liver and brain extracts revealed that in sharp contrast to the rapid disappearance of melatonin in the adult, melatonin disappearance in the neonate is greatly decreased.

The developmental pattern of in vitro rat liver melatonin degrading activity.

The developmental pattern of the in vitro rat liver melatonin degrading activity was studied. Livers from rats 3, 12, 16, 21, 30 and 90 days old were incubated with [3H] melatonin. A high pressure liquid chromatography (HPLC) technique was used to determine the appearance of melatonin metabolic product--6-hydroxymelatonin--in the liver extract. Catabolic activity belong very low at age 3 days, increased rapidly with age and reached maximum activity between the ages 21 to 30 days.

An inverse correlation between serum levels of desmethylimipramine and melatonin-like immunoreactivity in DMI-responsive depressives.

The relationship between plasma levels of the tricyclic antidepressant desmethylimipramine (DMI) and plasma levels of melatonin-like immunoreactivity was studied in 32 endogenously depressed patients. An inverse correlation between plasma levels of DMI and plasma levels of melatonin-like immunoreactivity was found in the group of clinical responders to the chronic administration of the drug. The nonresponders had higher levels of melatonin-like immunoreactivity at comparable levels of DMI. This finding is consistent with the hypothesis that chronic high plasma levels of DMI may down-regulate the beta-adrenergic receptors in man. However, some other homeostatic mechanisms may be involved in the clinical response.

Lack of an effect of melatonin on the basal and L-dopa stimulated growth hormone secretion in men.

The oral administration of melatonin to men has been reported to cause a rapid and significant elevation of serum GH, and to inhibit GH release after stimulation by L-Dopa. We studied the effect of melatonin i.v. on the basal and L-Dopa stimulated GH secretion in four young men. Each subject's control response to L-Dopa was first studied by an oral administration to 500 mg of L-Dopa under a placebo infusion and was followed 2 weeks later by a similar study under melatonin infusion, 2.1 mg/min (total dose of 500 mg). The infusion of melatonin was given for a 4-hour period, 2 hours before and 2 hours after the L-Dopa stimulation. Blood samples for GH were obtained at 30-min intervals. Basal values of serum GH did not rise under the melatonin infusion and peak GH values following L-Dopa stimulation during the control infusion and the melatonin infusion also did not differ (2 +/- 0.5 to 22 +/- 6 and 2 +/- 0.8 to 25 +/- 4 ng/ml respectively). Our data suggest that under an acute constant infusion melatonin does not stimulate GH secretion, nor does it interfere with the L-Dopa stimulated GH response in men.

Melatonin does not suppress the pituitary luteinizing hormone response to luteinizing hormone-releasing hormone in men.

The effect of an iv melatonin infusion on the pituitary LH response to LHRH was studied in five young men. Melatonin (30 micrograms/min; total dose, 7.2 mg) was infused for a 4-h period, 2 h before and 2 h after a LRH stimulation (single iv 150-microgram dose). Each subject's control response to LRH was obtained previously. During the melatonin infusion, supraphysiological concentrations of melatonin (20 times) were documented using a specific RIA. All five subjects had a LH rise after LRH stimulation, and this response was not affected by the melatonin infusion. These results indicate that an acute constant infusion of a pharmacological amount of melatonin does not suppress LRH-induced LH release from the pituitary in men. In addition, no change in sleepiness and behavior was found.

Circulating melatonin in man: episodic secretion throughout the light-dark cycle.

A sensitive and specific RIA for melatonin has been validated for human plasma. Five young adult men had plasma samples obtained every 20 min during two 24-h periods. One was a normal active period and the other a basal period with complete bed rest. Melatonin was found to be secreted episodically throughout the 24 h in each condition, with secretory episodes clearly present during the waking day in the presence of bright light.

Studies of the 24 hour rhythm of melatonin in man.

In a series of four separate studies of the 24-hour pattern of melatonin secretory function in man, the following results were obtained. Sequential measurement of the concentration of melatonin in plasma and urine demonstrated a 24-hour rhythm in which more melatonin is secreted during the sleep-lights off as compared to the waking-lights on period. However, during "free-running" and after an acute phase shift of the sleep-wake cycle, a melatonin rhythm can be dissociated from the sleep-lights out rhythm. A radioimmunoassayable plasma melatonin substance was found in significant amounts throughout the entire 24-hour day using a frequent sampling technique (every 20 min). Melatonin appears to be secreted into the blood in discrete brief episodes superimposed on a maintained "baseline" concentration. The half-life appears to be less than 30 min.

Coexistence of primary endocrine deficiencies: a unique case of male hypergonadism associated with hypoparathyroidism, hypoadrenocorticism, and hypothyroidism.

The unique combination of male hypogonadism with hypoparathyroidism, hypoadrenalism, hypothyroidism, diabetes mellitus, and alopecia totalis has been documented in a male patient who has been followed over the past 28 years. In this patient, first seen at the age of six for hypoparathyroidism alone, repeated clinical and laboratory endocrine evaluation detected the sequential development of the additional endocrine deficiencies. The presence of abnormal serum antibodies is consistent with an atuoimmune pathogenesis of this syndrome.