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The capability of empirical models of the earth's thermosphere must continually be updated if they are to keep pace with their many applications in the aerospace industry. This paper briefly summarizes the progress of several such efforts in support of the Space Station Program. The efforts consists of the development of data bases, analytical studies of the data, and evaluation and intercomparison of thermosphere models. A geomagnetic storm model of Slowey does not compare as well to the MSIS-86 model as does the Marshall Engineering Thermosphere (MET). LDEF orbit decay data is used to evaluate the performance of the MET and MSIS-86 during a period of high solar activity; equal to or exceeding the highest levels that existed during the time of the original data sets upon which these models are based.

The minimum, mean, and maximum exospheric temperature on the globe were calculated for every three hour period from 1947 through 1989 using the algorithms in the Marshall Engineering Thermosphere (MET) model and the appropriate solar activity input parameters. Cumulative percent frequency (CPF) distributions were then calculated for each of these temperatures at five levels of solar activity as defined by the 13-month smoothed values of the 10.7-cm solar radio noise flux. Next, the 50, 95, 97.7, and 100 percentile temperature values in each of these five levels of solar activity were curve fit as a function of the 13-month smoothed 10.7-cm flux. The resulting algorithms are used to compute the exospheric temperature in the MET model instead of the technique developed by Jacchia in his 1970 model. These temperatures are then used to enter tables to determine the total mass density and/or the atomic oxygen number density for application to engineering problems. Users can specify the risk level they are willing to accept in the results of analyses that require neutral atmosphere parameters inputs. The model eliminates the guess work in how to combine the solar activity input parameters to insure that the results provide answers at the proper risk levels.

A dentifrice closure (16) on a dentifrice tube (10) can emit a signal upon the opening of the closure (16) to dispense some of the dentifrice. The closure (16) is comprised of a base portion (18) to attach the closure to the dentifrice tube (10) and a lid portion (20) that closes the dispensing opening of the dentifrice tube (10) and which contains switch timer (28) and signal generator. The signal generator can be a light, but preferably is a sound generator, and most preferably a music generator. Upon the lid (20) being opened, a switch (28) activates the timer which in turn activates the signal generator. Regardless of the position of the switch (28) after a lid (20) opening (the lid can be quickly closed) the signal will be emitted for a set period of time.

A popular current theory proposes that the timing of puberty is related to attainment of a critical level of body weight or body fatness. These critical body weight and critical body fat theories have been studied almost exclusively in females. To explore these theories in males, we tested a corollary of these hypotheses: are male rats of the same weight all at the same level of sexual maturation irrespective of prior growth rate? Male rats growing in body weight at five different rates due to various degrees of underfeeding (beginning at weaning) were sacrificed at body weight milestones of 123 and 279 grams. At the first weight milestone, significant (P < 0.01) inverse correlations were observed among these weight-matched rats between the preceding rate of body weight growth and prostate weight, seminal vesicle weight, testis weight, serum testosterone, and daily sperm production rate, indicating that the underfed animals were more sexually mature. Testis histology also showed that spermatogenic development increased progressively as the prior rate of body weight growth was reduced. These parameters of sexual maturation tended to correlate inversely with body fatness (i.e., leaner animals were more sexually mature) and directly with body length (i.e., longer animals were more sexually mature). By the second body weight milestone, however, the degree of prior underfeeding exerted little effect on those indices of sexual development. We conclude that the degree of sexual maturation in weight-matched animals with varying previous patterns of body weight growth correlates inversely with body fatness and the rate of body weight growth but correlates directly with body length. These findings would not support either the critical body weight or critical body fatness theories of pubertal timing in underfed male rats and suggest that body length or chronologic age may be related more closely to sexual development than either body weight or fatness.

Both starvation and feeding of a low protein diet have dramatic effects on serum thyroid hormone concentrations and on the serum binding proteins for thyroid hormones in rats. We examined whether similar changes might be seen in another model of undernutrition, namely underfeeding without alteration of dietary composition, and in particular whether such changes would disappear after prolonged alteration in diet (adaptation). Male rats aged 21 days were put on five different levels of intake of a diet of normal composition (18% protein, 70% carbohydrate), and animals from each dietary group (n = 8-10) were killed after 30, 60, or 100 days of underfeeding. After 30 or 60 days of underfeeding, significant direct correlations were observed between growth rate (used as an index of the degree of underfeeding) and serum T3 (RIA), percent free T3 (equilibrium dialysis), and serum free T3 (T3 X percent free T3). When underfeeding was prolonged to 100 days, however, there was no correlation between growth rate and percent free T3, while the correlation between growth rate and serum free T3 was weak (r = 0.33). Qualitatively similar changes were seen when animals given five different levels of food intake were killed at three body weight milestones rather than three separate age milestones. Polyacrylamide gel electrophoresis of serum thyroid-binding proteins revealed that the low percent free T3 in underfed rats seen after 60 days of underfeeding was associated with the development of a thyroid-binding globulin not normally found, but this had disappeared by 100 days of underfeeding. We conclude that nutrition-related changes in serum thyroid hormone variables show adaptation over time. Because of changes in serum binding of thyroid hormones caused by undernutrition, total serum thyroid hormone concentrations may not be an accurate reflection of thyroid status in any investigational study in which an experimental treatment leads to decreased food intake.

A direct connection has been proposed between body size and sexual maturation by the critical body weight and critical body fat hypotheses. To test these theories in male rats, we compared the degree of sexual maturation in animals with reduced growth rate due to undernutrition with that in weight-matched but normally fed rats. Underfed rats had significantly larger prostate, seminal vesicle, and testis weights than the weight-matched normally fed controls at the three time points studied: the early pubertal period (approximate time of onset of rising serum testosterone), late pubertal period (approximate time of appearance of mature spermatids), and young adult period. At the first time point, testes of underfed rats, but not those of normally fed, weight-matched controls, showed mature step 19 spermatids, and serum testosterone was significantly higher in the underfed animals. At all time points, serum LH levels were similar in both groups, while serum FSH levels were significantly lower in the underfed rats at all points. The Lee index, an index of fatness, was significantly lower in the underfed rats. The current study indicates that underfed rats are more sexually mature than normally fed controls of the same weight despite having a lower percentage of body fat. These findings do not support the critical body weight or critical body fat hypotheses of puberty in male rats.

Undernutrition has proven to be a useful model for exploring the relationship between growth and pubertal development in female rats, such as the "critical body weight" hypothesis of pubertal timing, but corresponding studies in the male have been hampered by lack of specific discrete markers of puberty similar to vaginal opening or first estrus in females. In the current study, we explored the effect of five different levels of food intake (as low as one-third of normal) beginning at weaning on pubertal development and timing in male rats, using the date of the initial successful conception with normal females as a discrete marker for puberty in males. In underfed males, there was a weak inverse correlation (r = -0.31, p less than 0.05) between the age at puberty and the growth rate, the latter being used as an index of the degree of underfeeding. In contrast, there was a strong direct correlation (r=0.78, p less than 0.001) between body weight at puberty and growth rate. In the most severely underfed groups, the Lee index of body fat remained subnormal before and after puberty. Initial litter size also tended to be reduced when the males were underfed. At age 51 days (prior to puberty), graded underfeeding led to progressive reductions in serum luteinizing hormone and follicle-stimulating hormone levels as well as in parameters of androgen status (serum and testicular testosterone, prostate, and seminal vesicle weights). Testicular size was also reduced, but daily sperm production rate was not greatly affected by underfeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

In previous studies, male rats fed a low-protein diet beginning at weaning were found to have impaired sexual development through age 11 weeks when compared to food-restricted, weight-matched controls fed a diet with normal protein content. To determine whether male rats show long-term adaptation of the reproductive axis to low-protein feeding, we assessed sexual maturation and growth in rats fed a low protein (9%) diet from weaning until sacrifice at various points in time between ages 79 and 185 days. After age 80 days, there was no difference in reproductive organ weights (prostate, seminal vesicles, testis) or serum hormone levels (luteinizing hormone, follicle stimulating hormone, testosterone) between protein-deficient animals and food-restricted weight-matched controls given a normal diet. In addition, there was no difference between protein-deficient animals and controls in indices of linear growth (naso-anal and tail length) or fatness (Lee index). We conclude that both growth and reproductive function of male rats show adaptation to long term feeding of a low-protein diet.

This multicenter, double-blind, randomized, parallel study compared the effectiveness and tolerance of intravenous esmolol with intravenous propranolol in patients with supraventricular tachyarrhythmia (heart rate [HR] greater than 120 beats/min). Efficacy was evaluated in 53 patients receiving esmolol and in 57 patients receiving propranolol. Patients randomized to esmolol received infusions of various doses of esmolol ranging from 50 to 300 micrograms/kg/min (each dose infused for 5 minutes) over a 30-minute titration period with intermittent placebo boluses of propranolol. Those randomized for propranolol received 1 mg/min for the first 3 minutes, and then another 3 mg from minutes 5 to 8 with continuous placebo esmolol infusion during the 30-minute titration period. A therapeutic response, defined by 20% or greater reduction in HR, HR less than 100 beats/min or conversion to normal sinus rhythm, was achieved in 72% of patients on esmolol compared with 69% of patients on propranolol (difference not significant). The therapeutic response was maintained in 67% of patients on esmolol and 58% of patients on propranolol (difference not significant) during a 4-hour maintenance period. Conversion to normal sinus rhythm occurred in 14% of esmolol patients and 16% of propranolol patients during titration and 10% of esmolol and 8% of propranolol patients during maintenance. After discontinuation of study drugs, a more rapid reversal of the reduction in HR was observed in esmolol patients compared with those patients receiving propranolol. Adverse reactions were seen in 29 (45%) patients on esmolol and 11 (18%) patients on propranolol. The principle adverse reaction was hypotension, which was predominantly asymptomatic and found in 23 patients receiving esmolol and 4 receiving propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

LBA101 Background: Overexpression of PD-L1 in HCC has a poor prognosis. Safety and preliminary antitumor efficacy of nivolumab, a fully human IgG4 monoclonal antibody PD-1 inhibitor, was evaluated in a multiple ascending-dose, phase I/II study in patients (pts) with HCC. Methods: Pts with histologically confirmed advanced HCC with Child-Pugh (CP) score ≤ B7 and progressive disease (PD) on, intolerant of, or refusing sorafenib were enrolled. Dose escalation occurred in parallel cohorts based on etiology: no active hepatitis virus infection or virus-infected HCC pts. Pts received nivolumab 0.1 – 10 mg/kg intravenously for up to two years. The primary endpoint was safety. Secondary endpoints included antitumor activity using mRECIST criteria, pharmacokinetics, and immunogenicity. Results: The study has enrolled 41 pts with a CP score of 5 (n = 35) or 6 (n = 6), ECOG score of 0 (n = 26) or 1 (n = 15), 73% with extrahepatic metastasis and/or portal vein invasion, and 77% with prior sorafenib use. Eighteen pts remain on study, and 23 discontinued treatment due to PD (n = 17), complete response (CR; n = 2), drug-related adverse events (AEs; n = 2) and non-drug–related AEs (n = 2). Drug-related AEs of any grade occurred in 29 pts (71%; 17% grade 3/4), with ≥ 10% of pts experiencing aspartate aminotransferase (AST) increase and rash (each 17%), alanine aminotransferase(ALT) and lipase increase (each 15%), and amylase increase (12%). Grade 3 and 4 AEs ≥ 5% were AST increase (12%), ALT increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in an uninfected pt at 10 mg/kg; no maximum tolerated dose was defined in any cohort. Response was evaluable in 39 pts: 2 CR (5%) and 7 partial responses (PR; 18%). Response duration was 14–17+ months for CR, < 1–8+ months for PR, and 1.5–17+ months for stable disease (SD). Overall survival (OS) rate at 6 months is 72%. Conclusions: Nivolumab has a manageable AE profile and produced durable responses across all dose levels and HCC cohorts, with a favorable 6-month OS rate. Updated safety, antitumor activity, and biomarker data will be presented. Clinical trial information: NCT01658878. [Table: see text]