Outcome measures for chronic rhinosinusitis with nasal polyps.

BACKGROUND: With the recent proliferation of novel therapeutics for chronic rhinosinusitis with nasal polyps (CRSwNP), there is an immediate need for comprehensive means to assess CRSwNP disease status as well as to determine treatment efficacy. Outcome measures exist in different forms. Patient-reported outcome measures (PROMs) allow patients to provide direct input about their condition that is not possible to obtain in any other way. Common constructs that are measured using PROMs include quality of life or the burden of disease manifestations (e.g., symptom severity). Outcomes may also include the results of objective diagnostic testing/measurement of clinical signs or measured using psychophysical tests. Biomarkers represent an emerging class of outcome measures for CRSwNP and are chosen to directly reflect the active pathophysiologic processes of CRSwNP in the peripheral blood, sinus/polyp tissues, and sinonasal mucus. METHODS: Narrative review of the literature, identifying and describing outcome measures that may be used in the evaluation of CRSwNP and for assessment of treatment responses. RESULTS: In this review, we identify many different outcome measures for CRSwNP that fall under the categories of PROM, objective test, psychophysical test or biomarker. We describe the history of each - including seminal studies - and demonstrate the formal validation, psychometric performance, and limitations of each. CONCLUSIONS: PROMs, objective tests, psychophysical tests and biomarkers represent different classes of outcome measures that are complementary means of assessing CRSwNP disease status and treatment efficacy. The choice or interpretation of a CRSwNP outcome measure should be undertaken with full knowledge of its formal validation, psychometric performance, and limitations.

Features of inhalant allergy on nasal endoscopy: a systematic review and meta-analysis.

BACKGROUND: Nasal endoscopy is increasingly accessible to ENT surgeons. The characteristics of the allergic upper airway are not well recognised. METHODOLOGY: MEDLINE (1946-2021), EMBASE (1974-2021), and the Cochrane Library were searched on 16th November 2021 to identify articles that reported endoscopic findings of patients with documented allergy who had undergone nasal endoscopy. The review followed the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy. Meta-analysis was performed by pooling sensitivities and specificities using the hierarchical summary receiver operating characteristics model. RESULTS: A total of 4108 articles were identified, of which 15 manuscripts met the inclusion criteria. The included studies involved 4660 patients who had undergone nasal endoscopy. Middle turbinate (diffuse/polypoid) oedema (sensitivity 58.0%, specificity 84.5%), watery secretions (sensitivity 65.7%, specificity 76.5%), inferior turbinate hypertrophy (sensitivity 86.2%, specificity 32.2%), and unspecified turbinate hypertrophy (sensitivity 82.0%, specificity 42.9%) were identified as the features with the highest predictive value of inhalant allergy. CONCLUSIONS: Diffuse or polypoid oedema of the middle turbinate or watery secretions seen on nasal endoscopy can be a useful adjunct in the identification and diagnosis of inhalant allergy. These clinical features should be part of the diagnostic workup for patients that includes a clinical history and surrogate markers of allergic sensitisation from the skin and serum.

Phosphaturic Mesenchymal Tumors in the Head and Neck Demonstrate a Broad Clinical and Morphologic Spectrum.

Phosphaturic mesenchymal tumour (PMT) is a rare tumour that occurs in bone or soft tissue and is associated with production of fibroblast growth factor 23 (FGF23) leading to tumor-induced osteomalacia. We report three cases of PMT involving the head and neck that highlight the broad spectrum of clinical and histologic features of PMT. One of these lesions from the hard palate demonstrated an admixture of epithelial and mesenchymal elements, a feature that can pose a diagnostic challenge. The diagnostic utility of immunohistochemistry including FGF23, somatostatin receptor 2A, SATB2, ERG and CD56 is discussed. The biochemical pathway in the development of PMT associated tumor induced osteomalacia and its role in investigations and management of PMT is also described.

Hunger in humans induced by 2-deoxy-D-glucose: glucoprivic control of taste preference and food intake.

Intracellular glucopenia induced by 2-deoxy-D-glucose (2DG) administration in man produces increased hunger ratings and magnitude estimates of pleasantness for sucrose solutions. Augmented food intake substantiates these changes in affective behavior and relieves experimentally induced hunger. Intracellular glucopenia activates counterregulatory mechanisms to raise plasma glucose concentrations. Inducing hunger experimentally with 2DG provides a useful method for studying appetitive behavior in humans. The neurohumoral control of pituitary hormone release and other hypothalamic functions may be examined after 2DG infusion.

Genetic engineering of livestock.

Genetic engineering of livestock is expected to have a major effect on the agricultural industry. However, accurate assessment of the consequences of transgene expression is impossible without multigenerational studies. A systematic study of the beneficial and adverse consequences of long-term elevations in the plasma levels of bovine growth hormone (bGH) was conducted on two lines of transgenic pigs. Two successive generations of pigs expressing the bGH gene showed significant improvements in both daily weight gain and feed efficiency and exhibited changes in carcass composition that included a marked reduction in subcutaneous fat. However, long-term elevation of bGH was generally detrimental to health: the pigs had a high incidence of gastric ulcers, arthritis, cardiomegaly, dermatitis, and renal disease. The ability to produce pigs exhibiting only the beneficial, growth-promoting effects of growth hormone by a transgenic approach may require better control of transgene expression, a different genetic background, or a modified husbandry regimen.

Stimulation of thermogenesis by carbohydrate overfeeding. Evidence against sympathetic nervous system mediation.

Daily carbohydrate intake of seven men with normal weight was limited to 220-265 g/d for 6 d and then increased to 620-770 g/d for 20 d, while intake of protein, fat, and sodium remained constant. Carbohydrate overfeeding increased body weight by 4.8%, basal oxygen consumption (VO2) by 7.4%, BMR by 11.5%, and serum triiodothyronine levels by 32%. Overfeeding did not affect the thermic effect of a standard meal. Intravenous propranolol reduced the thermic effect of a meal by 22% during the base-line feeding period, and by 13% during carbohydrate overfeeding, but did not affect preprandial VO2. Overfeeding attenuated the rise in plasma glucose and FFA levels induced by infusion of norepinephrine, but had no effect on the increase in VO2 induced by norepinephrine. Overfeeding did not alter 24-h urinary excretion of vanillylmandelic acid, supine plasma catecholamine levels (pre- and postprandial), blood pressure, or plasma renin activity, but increased peak standing plasma norepinephrine levels by 45% and resting pulse rate by 9%. Even though short-term carbohydrate overfeeding may produce modest stimulation of sympathetic nervous system activity in man, the increase in thermogenesis induced by such overfeeding is neither suppressed by beta adrenergic blockade nor accompanied by an increased sensitivity to the thermogenic effects of norepinephrine. These data do not support an important role for the sympathetic nervous system in mediating the thermogenic response to carbohydrate overfeeding.

Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans.

Because intravenous infusion of beta-hydroxybutyrate (beta-OHB) has been reported to decrease urinary nitrogen excretion, we investigated in vivo metabolism of leucine, an essential amino acid, using L-[1-13C]leucine as a tracer during beta-OHB infusion. Leucine flux during beta-OHB infusion did not differ from leucine flux during normal saline infusion in nine normal subjects, whereas leucine oxidation decreased 18-41% (mean = 30%) from 18.1 +/- 1.1 mumol.kg-1.h-1 (P less than 0.01), and incorporation of leucine into skeletal muscle protein increased 5-17% (mean = 10%) from 0.048 + 0.003%/h (P less than 0.02). Since blood pH during beta-OHB infusion was higher than the pH during saline infusion, we performed separate experiments to study the effect of increased blood pH on leucine kinetics by infusing sodium bicarbonate intravenously. Blood pH during sodium bicarbonate infusion was similar to that observed during the beta-OHB infusion, but bicarbonate infusion had no effect on leucine flux or leucine oxidation. We conclude that beta-OHB decreases leucine oxidation and promotes protein synthesis in human beings.

Neural control of counter-regulatory events during glucopenia in man.

The effect of autonomic denervation on the metabolic and hormonal responses during intracellular glucopenia in man was investigated. 2-Deoxy-d-glucose (2 DG), a competitive inhibitor of glucose metabolism, was administered intravenously to nine normal volunteers and to five patients, three with complete cervical cord transection (C-6) and two with idiopathic orthostatic hypotension. Before, during, and after a 20 min infusion of 2 DG (50 mg/kg) plasma concentrations of glucose, lactate, FFA, total catecholamines, immunoreactive insulin (IRI), human growth hormone (HGH), and cortisol were determined for periods up to 150 min. In control subjects, the initial elevation of FFA, glucose. HGH, and cortisol corresponded with the rise in total catecholamines, with maximal levels attained at 60 min, lactate rose at a slower rate, reaching peak levels at 150 min: although no change in IRI was noted. In contrast, 2 DG-induced glucopenic stress in the autonomic denervated subjects was characterized by no detectable catecholamine release or significant rise in glucose, FFA, lactate, or IRI. However, HGH and cortisol responses in four of the five patients were of a similar or greater magnitude than controls.These studies demonstrate that the integrity of the sympathoadrenomedullary axis is essential for the counter-regulatory response to intracellular glucopenia in man. Cortisol and HGH have no apparent role in these events.

Increased thirst and plasma arginine vasopressin levels during 2-deoxy-D-glucose-induced glucoprivation in humans.

Insulin-induced hypoglycemia by unknown mechanism(s) increases plasma arginine vasopressin (AVP) levels in humans. Mechanisms for increased AVP levels during central nervous system glucoprivation were investigated by administering 20-min i.v. infusions of 2-deoxy-d-glucose (50 mg/kg), a competitive inhibitor of glucose utilization, or normal saline (sham), to 24 normal volunteers. Some of the infusions were administered in combination with neuropharmacological blocking agents (placebo). The behavioral, physiological, metabolic, and hormonal correlates of 2-deoxy-d-glucose (2DG)-induced gluco-privation and AVP secretion were studied in a group (n = 5) pretreated for 1 wk with either mazindol (1 mg per os three times per day), a potent norepinephrine and dopamine-reuptake blocker, or placebo. A second group (n = 5) received either propranolol (3 mg/3 min followed by 80 mug/min) or normal saline infusion before and during 2DG administration. With 2DG alone, plasma AVP levels increased from 1.3+/-0.3 pg/ml at base line to a peak of 4.5+/-1.4 pg/ml at 60 min and remained elevated for 150 min. From 30 to 180 min after 2DG administration, the 2DG-infused volunteers increased their water intake in comparison with sham-infused volunteers. Marked increases in epinephrine and slight increases in norepinephrine were associated with increases in plasma glucose and renin activity and decreases in plasma potassium. Plasma sodium and osmolality increased transiently and mean arterial pressure (MAP) fell. These changes, however, were small and inconstant and could not account for the observed increases in thirst and AVP levels. Pretreatment with mazindol prevented the decrease in MAP and the increase in plasma renin activity (PRA) following 2DG infusions without modifying increased thirst, water intake, or AVP responses to glucoprivation. Pretreatment with propranolol effectively blocked beta-adrenoreceptors as evidenced by increased MAP and plasma epinephrine, and abolition of the RPA increases during 2DG-induced glycoprivation, but did not suppress AVP and thirst responses. A cervical cord-sectioned patient lacking descending sympathetic out-flow had a potentiated thirst response to 2DG-induced glucoprivation in the absence of increases in sodium, catecholamines, and PRA. Thus 2DG administration activates mechanisms for increased thirst and AVP which are unrelated to changes in peripheral catecholamines, MAP, PRA, and osmolality.

Counterregulatory hormonal responses to rapid glucose lowering in diabetic man.

To define whether rapid rate of fall in blood glucose stimulates counterregulatory hormonal responses in diabetic man, blood glucose in eight hyperglycemic diabetic subjects was rapidly lowered by intravenous insulin administration. Despite precipitous declines in blood glucose, plasma epinephrine and growth hormone remained virtually unchanged. In contrast, norepinephrine and cortisol increased significantly (P less than 0.025) in the face of hyperglycemia or euglycemia, while glucagon was suppressed (P less than 0.025). A transient modest fall in mean arterial pressure and a rise in pulse rate were noted. No correlation was observed between glucose disappearance rate or decrement in glucose concentration and the hormonal responses. After sham insulin administration, no change was observed in plasma epinephrine, norepinephrine, and cortisol levels. These findings suggest that rate of fall in blood glucose per se is not a primary signal for counterregulatory hormonal response. Cortisol but not growth hormone release during falling blood glucose in diabetic subjects can occur despite elevated blood glucose levels. The etiology of norepinephrine and cortisol change is unclear.

The influence of sodium restriction on orthostatic sympathetic nervous activity.

To evaluate the influence of low-salt diet on the sympathetic nervous system activity, the adaptation to upright posture in five normal subjects was studied during normal salt and 10mEq sodium and 60-mEq potassium diets. On assuming upright posture, there were similar rises in pulse rate and diastolic blood pressure (BP) but a decline in systolic BP, during both diets. A prompt rise in plasma norepinephrine level during low-sodium diet was greater than during normal diet. Orthostatic response of the plasma epinephrine level was small, although significant, but unaffected by the diets. During normal-sodium diet, plasma renin activity response was delayed, but a prompt and enhanced response was observed during low-sodium diet. These data suggest that sodium deprivation enhances the sympathetic nervous system activity and the orthostatic stimulation of renin release.

The effect of dietary protein intake on glutamine and glutamate nitrogen metabolism in humans.

The response of glutamine and glutamate kinetics were studied in five healthy young adult men on diets containing deficient (0.1), adequate (0.8), or surfeit (2.2 g.kg-1.d-1) amounts of protein. Glutamate, glutamine, and phenylalanine kinetics were measured in the postabsorptive state at the end of each diet period. Urinary urea and ammonia excretion correlated with protein intake (the sum of the two was 2.1 +/- 0.2, 5.7 +/- 0.3, and 11.9 +/- 1.2 g N g.kg-1.d-1 for the respective 0.1, 0.8, and 2.2 g.kg-1.d-1 protein intakes). Glutamate and glutamine concentrations varied inversely with protein intake. Phenylalanine concentrations and phenylalanine flux did not change significantly with the changing protein intake. Both glutamate and glutamine fluxes varied inversely with protein intake (glutamate flux was 177 +/- 15, 120 +/- 10, and 125 +/- 11 mumol.kg-1.h-1 and glutamine flux was 373 +/- 29, 343 +/- 26, and 318 +/- 15 mumol.kg-1.h-1 at the respective 0.1, 0.8, and 2.2 g.kg-1.d-1 protein intakes). These changes in glutamine or glutamate flux in response to alterations in dietary protein intake were attributable to changes in de novo production.

Normal thermic effect of glucose in obese women.

The increase in energy expenditure after intake of 100 g of glucose (thermic effect of glucose), was studied in 11 lean and 13 obese women. Before glucose ingestion, resting metabolic rate, uncorrected for weight or surface area, was 15% higher in the obese subjects than in the lean subjects, but there was no difference between groups in the thermic effect of glucose. The obese subjects were hyperinsulinemic relative to the lean subjects, but the area under their glucose response curves was normal. The increase in norepinephrine levels associated with glucose intake was the same in the obese and lean groups. The magnitude of the thermic effect of glucose was not correlated with the increase in plasma norepinephrine levels, plasma insulin levels, or pulse rate, or with body weight, age or body mass index. Resting metabolic rate did not significantly increase in 10 subjects given a noncaloric control solution. These data show that obese subjects with normal glucose tolerance have a normal thermic response to glucose.

Some metabolic effects of overeating in man.

Metabolic responses to 20 days of overeating were examined in five healthy volunteers. Overfeeding caused a variable increase (1-18%) in basal metabolic rate but no change in metabolic rate during light exercise. Postprandial resting metabolic rate was 8-40% higher (mean 18%) during overeating. The increase in oxygen consumption during a norepinephrine infusion was the same before (20 +/- 2%) and after (17 +/- 3%) overfeeding. Overfeeding elevated basal insulin concentrations in all subjects and increased the insulin response to intravenous glucose in four of five subjects. Overfeeding did not significantly alter mean serum T3 concentrations or erythrocyte 86Rb uptake (an index of Na+,K+-ATPase activity). These data do not confirm reports that overfeeding increases metabolic rate more during exercise than during rest. They also suggest that the increase in resting metabolic rate during overfeeding is not caused by increased responsiveness to norepinephrine or increased serum T3 concentrations.

Epinephrine produces a prolonged elevation in metabolic rate in humans.

BACKGROUND: Epinephrine increases the metabolic rate and contributes to the hypermetabolic state in severe illness. OBJECTIVE: We sought to determine the effect of prolonged elevation of epinephrine on resting energy expenditure (REE). DESIGN: Thirteen healthy men were placed on a well-defined diet for 5 d. Beginning on the morning of the second diet day, the subjects were infused for 24 h with saline, then for 23 h with epinephrine (0.18 nmol x kg(-1) x min(-1)) to increase plasma epinephrine concentrations into the high physiologic range (4720 +/- 340 pmol/L). REE and the respiratory quotient (RQ) were measured by indirect calorimetry in the postabsorptive state at the same time every morning. RESULTS: Infusion of epinephrine significantly increased heart rate and systolic blood pressure, but the response was transient (values after 23 h of epinephrine infusion were not significantly different from those on the day saline was infused). Infusion of epinephrine significantly increased REE by 12% and increased the RQ. These changes were apparent at the end of the 23-h infusion (REE: 97.5 +/- 2.3 kJ x kg(-1) x d(-1) with saline infusion and 108.9 +/- 2.3 kJ x kg(-1) x d(-1) with epinephrine infusion; RQ: 0.832 +/- 0.012 with saline infusion and 0.879 +/- 0.013 with epinephrine infusion). REE returned to baseline by 24 h after the epinephrine infusion ended, but the postabsorptive RQ remained modestly elevated. Infusion of epinephrine also produced a transient increase in urine flow and in urinary nitrogen excretion. This diuresis was compensated for by a drop in urine volume and nitrogen excretion after the epinephrine infusion was stopped. CONCLUSIONS: Epinephrine produced a prolonged increase in REE in healthy subjects. The fuel for this increase in REE, determined by the RQ, was from increased carbohydrate oxidation, not from that of fat or protein.

Thermic effect of medium-chain and long-chain triglycerides in man.

The thermic effects of 400 kcal meals of medium-chain triglycerides (MCT) and long-chain triglycerides (LCT) were compared in seven healthy men. Metabolic rate was measured before the meals and for 6 h after the meals by indirect calorimetry. Mean postprandial oxygen consumption was 12% higher than basal oxygen consumption after the MCT meal but was only 4% higher than the basal oxygen consumption after the LCT meal. There was a 25-fold increase in plasma beta-hydroxybutyrate concentration and a slight increase in serum insulin concentration after MCT ingestion but not after LCT ingestion. Plasma triglyceride concentrations increased 68% after the LCT meal and did not change after the MCT meal. These data raise the possibility that long-term substitution of MCT for LCT would produce weight loss if energy intake remained constant.

Growth hormone increases insulin-like growth factor-I (IGF-I) and decreases IGF-II in plasma of growing pigs.

Insulin-like growth factor-I (IGF-I) and IGF-II have been measured in plasma obtained from male and female pigs of two strains during daily administration of pituitary-derived porcine GH (pGH; 100 micrograms/kg) from 60 to 90 kg body weight. Each plasma sample was first chromatographed to separate the IGF from binding proteins in order to obtain reliable measurements. IGF-I concentrations showed no differences between strains, but were higher in untreated males (497 +/- 43 (S.E.M.) micrograms/l) than females (299 +/- 15 micrograms/l). GH-treated animals had two-fold higher concentrations of IGF-I. IGF-II concentrations were not significantly different between sexes or strains, but were decreased in pigs treated with pGH (299 +/- 28 micrograms/1) compared with controls (431 +/- 32 micrograms/l). Binding protein concentrations, measured as interference in the IGF-I and IGF-II assays, were not different between sexes or strains, but were increased in pGH-treated animals. Taken together, these results indicate that in addition to the expected increase in IGF-I concentrations, exogenous administration of pGH to pigs leads to an increase in IGF-binding protein and a depression in IGF-II concentrations.

Leptin expression in offspring is programmed by nutrition in pregnancy.

Birth weight is a determinant of blood leptin concentrations in adults. Since nutrition during pregnancy can affect birth weight, the hypothesis that feed intake during pregnancy alters leptin expression in progeny was examined. Leptin mRNA was measured in subcutaneous adipose tissue and leptin protein was measuredin blood plasma from 59 day old female pigs whose mothers were fed at the same restricted rate except that half were permitted to consume 35% more feed during the second quarter of pregnancy. Leptin mRNA abundance in adipose tissue (P=0.015) and plasma leptin concentration (P=0.01) were higher in progeny from mothers provided with more feed. Body weight at birth was negatively correlated with the abundance of leptin mRNA in subcutaneous fat at 59 days of age (P=0.01). This study shows for the first time that maternal nutrition during pregnancy programs postnatal leptin expression in offspring.

Developmental changes in growth hormone, insulin-like growth factors (IGF-I and IGF-II) and IGF-binding proteins in plasma of young growing pigs.

The relationship between plasma concentrations of normally secreted GH and insulin-like growth factor-I (IGF-I) was investigated in pigs after weaning. Frequent blood sampling for between 12 and 24 h showed that plasma GH was pulsatile in pigs of 10, 20 and 35 kg liveweight. Pulses were brief in duration, low in amplitude and variable in frequency. Basal and average daily plasma concentrations of GH changed significantly with development, increasing by about 50% between 10 and 20 kg liveweight. Concentrations of IGF-I in plasma showed little or no evidence of diurnal periodicity and were not increased by GH pulses. Average daily concentrations of both IGF-I and IGF-II in plasma progressively increased between 10 and 35 kg liveweight, as did the total desaturated IGF-binding protein (IGFBP) activity of plasma. A strong positive correlation was observed between the total concentration of IGFs (IGF-I plus IGF-II) in the circulation and plasma IGFBP activity. The developmental rise in IGFBP activity of plasma was associated with increased labelling with 125I-labelled human IGF-II in ligand blots of binding proteins of apparent molecular masses greater than 200, 50, 43 and 29 kDa. One class of binding proteins of 34.5 kDa decreased with development. This study of young growing pigs shows that normally secreted endogenous GH exerts no significant immediate control over plasma IGF-I concentrations, and that plasma levels of IGF-I and IGF-II increase with maturation in this species.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of underfed pigs with GH throughout the second quarter of pregnancy increases fetal growth.

Circulating growth hormone (GH) concentrations increase in pregnancy and administration of GH during early-mid pregnancy increases fetal growth in well-fed pigs. To determine whether increased maternal GH could promote fetal growth when feed availability is restricted, fifteen cross-bred primiparous sows (gilts) were fed at approximately 30% of ad libitum intake, from mating onwards and were injected daily i.m. with recombinant porcine GH (pGH) at doses of 0, 13.4+/-0.3 and 25.6+/-0.5 microg/kg live weight from day 25 to day 51 of pregnancy (term approximately 115 days). Treatment with pGH increased maternal backfat loss between day 25 and day 51 of pregnancy, and increased maternal plasma IGF-I concentrations measured at day 51 of pregnancy. Fetal body weight, length and skull width at day 51 of pregnancy were increased by maternal treatment with pGH. Fetal plasma glucose concentrations were increased and maternal/fetal plasma glucose concentration gradients were decreased by maternal pGH treatment at 13.4, but not 25.6 microg/kg.day. Fetal plasma concentrations of urea were decreased by both levels of pGH treatment. Overall, fetal weight was negatively correlated with fetal plasma concentrations of urea, positively correlated with maternal plasma alpha-amino nitrogen concentrations and unrelated to glucose concentrations in either maternal or fetal plasma. This suggests that the availability of amino acids, not glucose, limits fetal growth in the first half of pregnancy in underfed gilts, and that maternal GH treatment may improve amino acid delivery to the fetus.