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Effect of inflammatory cytokines and plasma metabolome on OSA: a bidirectional two- sample Mendelian randomization study and mediation analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a common sleep disorder. Inflammatory factors and plasma metabolites are important in assessing its progression. However, the causal relationship between them and OSA remains unclear, hampering early clinical diagnosis and treatment decisions. METHODS: We conducted a large-scale study using data from the FinnGen database, with 43,901 cases and 366,484 controls for our discovery MR analysis. We employed 91 plasma proteins from 11 cohorts (totaling 14,824 participants of European descent) as instrumental variables (IVs). Additionally, we conducted a GWAS involving 13,818 cases and 463,035 controls to replicate the MR analysis. We primarily used the IVW method, supplemented by MR Egger, weighted median, simple mode, and weighted mode methods. Meta-analysis was used to synthesize MR findings, followed by tests for heterogeneity, pleiotropy, and sensitivity analysis (LOO). Reverse MR analysis was also performed to explore causal relationships. RESULTS: The meta-analysis showed a correlation between elevated Eotaxin levels and an increased risk of OSA (OR=1.050, 95% CI: 1.008-1.096; p < 0.05). Furthermore, we found that the increased risk of OSA could be attributed to reduced levels of X-11849 and X-24978 (decreases of 7.1% and 8.4%, respectively). Sensitivity analysis results supported the reliability of these findings. CONCLUSIONS: In this study, we uncovered a novel biomarker and identified two previously unknown metabolites strongly linked to OSA. These findings underscore the potential significance of inflammatory factors and metabolites in the genetic underpinnings of OSA development and prognosis.

Female

Gut Microbiota, Lipidome, and Metabolites Mediate Immune Dysregulation in Diabetic Microvascular Disease: A Two-sample Mendelian Randomization and Mediation Analysis.

INTRODUCTION: Diabetic microvascular disease (DMiVD) involves dysregulated immune cell function, but the precise pathogenic mechanisms remain unclear. MATERIALS AND METHODS: We conducted a two-sample Mendelian randomization (MR) study using comprehensive GWAS and FinnGen summary statistics, encompassing 731 immune cell phenotypes, 473 gut microbial taxa, 91 inflammatory proteins, 179 lipid types, 1,400 plasma metabolites, 20 micronutrients, and DMiVD cases. The analysis aimed to evaluate causal associations between these variables and DMiVD. We further explored potential mediating roles of gut microbiota, plasma lipidome, and metabolites using mediation analysis, with multiple sensitivity tests confirming the robustness of our findings. RESULTS: We identified 20 immune cell phenotypes, 33 gut microbial taxa, 31 lipid types, and 83 plasma metabolites with significant causal associations with DMiVD. Mediation analysis revealed that the risk effect of CD3+ resting Tregs on diabetic nephropathy was partly mediated by phosphatidylcholine (16:0_18:2) (10.7%). Additionally, the protective effect of CX3CR1 on monocytes against DMiVD was partly mediated by Unclassified Bacilli A (35%), Species CAG-177 sp003538135 (22.6%), and triacylglycerol (52:6) (25.5%). DISCUSSION: These findings advance understanding of DMiVD pathogenesis, highlighting that modulation of key metabolic pathways and immune regulatory nodes may represent promising therapeutic strategies. Further experimental studies are needed to validate these potential causal relationships. CONCLUSION: Using causal inference approaches, this study identifies immune cell-mediated mechanisms underlying DMiVD, involving gut microbiota, plasma lipids, and metabolites. The results suggest potential intervention targets for mechanistic studies and therapeutic development.

Mendelian Randomization Analysis

Pharmacokinetics of papaverine hydrochloride and the biopharmaceutics of its oral dosage forms.

The pharmacokinetics of completely metabolized papaverine hydrochloride were characterized by a linear sum of three exponentials on intravenous administration with respective 1.5, 19 and 107 min apparent half lives. There was a time-dependent partition from plasma water into red blood cells with an apparent half life of 1.5--3 min. The partition coefficient normally ranged between 8 and 15 at therapeutic levels but approached unity at high plasma concentrations to indicate a saturable partition. Apparent compartmental volumes of distribution referenced to total concentrations in the plasma were 4.3--4.8, 11--13 and 20--25 liters. Protein binding was 91--95%. The hepatic clearance of blood was 960 ml/min, corresponding to a hepatic efficiency of 69%, and indicated that the clearance of protein-bound drug was consistent with the observed first pass metabolism of 70% for oral solutions. No dose dependency was observed on intravenous administration or on oral administration of solutions and tablets. Tablets with release lag times of 10--15 min showed relative bioavailabilities of 52%. Two different lots of sustained release capsules showed 68 and 89% relative bioavailabilities. Release lag times among capsules ranged between 0 and 170 min. Loo-Riegelman calculations and analog computer fittings were consistent with a half life of absorption from oral solutions of 19 min and zero order release rates from tablets and sustained release capsules. Chronic studies of tablets q.i.d. and capsules b.i.d. confirmed lack of accumulation. An appropriately designed 300 mg sustained release capsule, b.i.d., for an arbitrary plasma level of 0.200 microgram/ml should have one tenth the release rate of the studied capsules.

Administration, Oral

Pharmacokinetics and metabolite-pattern of 8-methoxypsoralen in man following oral administration as compared to the pharmacokinetics in rat and dog.

Following oral administration of 14C labelled 8-methoxypsoralen (8-MOP) in man the plasma level course, the metabolite-patterns and the elimination of the parent compound and its metabolites have been investigated. Additionally the results discovered have been compared with the data of pharmacokinetics on dog and rat. In man and rat the plasma protein binding of 8-MOP has been determined. Maximal levels of the total radioactivity in the plasma were achieved 2 h after dosing. At this time 8-MOP represents 50% of the radioactivity in the plasma. The plasma protein binding in vitro of 14C 8-MOP valued from 88% to 91% in man, and between 75% and 83% in the rat. Urinary elimination of the total radioactivity as a measure of the extent of absorption varies greatly and depends on the therapeutic formulation being employed. Following the administration of the solution 74% is recovered within 48 h. Faecal elimination of the total radioactivity reached 14% within 3 days. The metabolite-pattern does not show the unchanged 14C 8-MOP. Several polar metabolites occur in the urine among which biochemical conjugates have been recognized. Only polar metabolites are observable in the faeces from which the radioactivity is incompletely extractable. From a comparison of the metabolite profiles, the rat as well as the dog seem to be a useful animal species for experimental investigations with 8-MOP.

Administration, Oral

Transport of steroid hormones through the rat blood-brain barrier. Primary role of albumin-bound hormone.

These studies were undertaken to investigate (a) the permeability properties of the blood-brain barrier (BBB) to the major gonadal and adrenal steroid hormones, and (b) the role of the binding proteins of plasma (albumin and specific globulins) in the regulation of BBB steroid hormone transport. The permeability of the BBB to [(3)H]-labeled progesterone, testosterone, estradiol, corticosterone, aldosterone, and cortisol, was measured relative to [(14)C]butanol, a freely diffusable reference, in the barbiturate anesthetized rat using a tissue sampling-single injection technique. The isotopes were rapidly injected in a 200-mul bolus of Ringer's solution (0.1 g/dl albumin) via the common carotid artery and the percent extraction of unidirectional influx of hormone was determined after a single pass through brain: progesterone, 83+/-4%; testosterone, 85+/-1%; estradiol, 83+/-3%; corticosterone, 39+/-2%; aldosterone, 3.5+/-0.8%; and cortisol, 1.4+/-0.3%. The selective permeability of the BBB was inversely related to the number of hydrogen bonds each steroid formed in aqueous solution and directly related to the respective 1-octanol/Ringer's partition coefficient. When the bolus injection was 67% human serum, >95% of the labeled steroid was bound as determined by equilibrium dialysis. However, the influx of the steroids through the BBB was inhibited by human serum to a much less extent than would be expected if only the free (dialyzable) hormone was transported; progesterone, estradiol, testosterone, and corticosterone transport was inhibited 18, 47, 70, and 85% respectively, or in proportion to the steroid binding to plasma globulins. Rat serum (67%) only inhibited the transport of these four hormones, 0, 13, 12, and 69%, respectively, reflecting the absence of a sex hormone-binding globulin in rat plasma. However, neonatal rat serum (67%) inhibited progesterone, testosterone, and estradiol transport 0, 0, and 91%, respectively, consistent with the presence of an estradiol-binding protein in neonatal rat serum. The binding of steroid hormone to bovine albumin in vitro (as determined by equilibrium dialysis) was compared to albumin binding in vivo (as determined by the single injection technique). The ratio of apparent dissociation constant in vivo, K(D)(app), to the in vitro K(D) was: >>200 for progesterone, >200 for testosterone, 120 for estradiol, and 7.7 for corticosterone. Assuming the steady-state condition, the K(D)(app)/K(D) was found to be proportional to the BBB permeability for each steroid. These data demonstrate (a) the selective permeability properties of the BBB to the major steroid hormones is proportional to the tendency of the steroid to partition in a polar lipid phase and is inversely related to the number of hydrogen bond-forming functional groups on the steroid nucleus; (b) the presence of albumin in serum may bind considerable quantities of steroid hormone, but exerts little inhibitory effects on the transport of steroids into brain, whereas globulin-bound hormone does not appear to be transported into brain to a significant extent. Therefore, the hormone fraction in plasma that is available for transport into brain is not restricted to the free (dialyzable) fraction, but includes the larger albumin-bound moiety.

Aldosterone

An analysis of the protein, glycoprotein and monosaccharide composition of Dictyostelium discoideum plasma membranes during development.

Qualitative and quantitative changes in the protein and glycoprotein components of the plasma membrane of the cellular slime mould Dictyostelium discoideum have been detected by analysis of sodium dodecyl sulphate-polyacrylamide gel electrophoretic patterns. The amounts of proteins of subunit molecular weight 220 000, 91 000, 63 000, 59 000, 56 000 increased during the acquisition of aggregation competence, while proteins of subunit molecular weight 82 000 and 22 000 decreased. The amounts of glycoproteins with apparent subunit molecular weights 285 000, 150 000, 137 000, 100 000, 53 000, 50 500 and 30 500 increased during differentiation while a 125 000 dalton component decreased dramatically in amount. The neutral and amino sugar composition of the plasma membrane was also analyzed and found to remain essentially unchanged during the first 12 h of differentiation. The major sugars were mannose, fucose, and glucosamine; galactose and galactosamine were also present, but in lower amounts.

Carbohydrates

Cardiac edema in dogs: distribution of renal blood flow and glomerular filtrate.

The injection of Freund's adjuvant into the pericardial sac of 29 dogs resulted in chronic pericardial tamponade with persistent sodium retention. Micropuncture, clearance, and radioactive microsphere experiments were initiated 6--13 days after pericardial injection and 60 min after pericardiocentesis. Pericardiocentesis increased sodium excretion (from 12.2 to 41.3 microequiv./min) and mean arterial pressure (+ 20 mmHg (1 mmHg = 133.322 Pa)). Central venous pressure decreased 6.5 mmHg, as did hematocrit (from 45.7 to 39.8%) and plasma protein concentration (from 5.88 to 5.15 g%). Pericardiocentesis had no significant effect on renal blood flow (RBF), nor plasma flow. Redistribution of glomerular filtrate was suggested by the observation that superficial nephron glomerular filtration rate increased (from 91 to 108 nL/min) while glomerular filtration rate remained unaltered. Determination of intrarenal distribution of RBF revealed that cortical blood flow also distributed superficially. A significant increase in the fraction of RBF perfusing zone 1 (outer cortex) and a decrease in fractional perfusion of zones 2, 3 and 4 (juxtamedullary cortex) were observed in each experiment following pericardiocentesis. RBF distribution examined in a series of six animals prior to and during the development of pericardial tamponade showed the opposite effect. These results indicate that pericardiocentesis causes redistribution of both glomerular filtrate and RBF to superficial nephrons. The development of pericardial tamponade was associated with increased fractional juxtamedullary blood flow. These changes may have been the result of altered blood pressure, hematocrit, plasma protein concentration, or altered renal resistance.

Animals

Plasma amino acids as predictors of the severity and outcome of sepsis.

Sepsis is a major catabolic insult resulting in a peripheral energy deficit which is made up in part by increased breakdown of lean body mass and oxidation of amino acids, principally the branched chain amino acids. The prognosis in any given case of sepsis is difficult to predict, but should theoretically be related to the degree of disturbance in peripheral energy deficit, which may in turn, be related to plasma amino acid pattern. In order to study whether this hypothesis was correct, plasma amino acids and some of their metabolic byproducts, the beta-hydroxyphenylethanolamines, were studied in 25 septic patients, and were used as discriminant variables in a series of computer performed discriminant analyses and multiple regressions. The two functions tested were the degree of metabolic septic encephalopathy as a determinant of the severity of sepsis and the final outcome in the septic patient. Plasma amino acid patterns exhibited elevated levels of the aromatic and sulfur containing amino acids, phenylalanine, tryosine, tryptophan, methionine, cysteine, and taurine, normal concentrations of alanine, and low normal concentrations of the branched chain amino acids, valine, leucine and isoleucine. Arginine levels, as previously noted, were very low. Patients not surviving the septic episode exhibited higher concentrations of aromatic and sulfur containing amino acids, while patients surviving sepsis had higher concentrations of the branched chain amino acids and arginine. When the degree of encephalopathy as a determinant of the severity of sepsis and step wise discriminant analysis with multiple crescent techniques were used, the best discriminant function between patients with and without encephalopathy was found to result from the interaction of cysteine, methionine, phenylalanine, isoleucine, leucine, and valine. These amino acids gave a correct classification in 82% of patients with no encephalopathy, and 80% of patients with septic encephalopathy. When the same amino acids were used for the discriminant analysis for patients dying of sepsis and patients surviving, the best discriminant function was achieved by using plasma concentrations of alanine, cysteine, methionine, isoleucine, arginine, tyrosine and phenylalanine resulting in 91% of the nonsurvivors, and 79% of the survivors correctly classified. The results suggest a close and significant relationship between the deranged energy metabolism and muscle protein breakdown in sepsis, and the outcome. This further suggests a central role for certain amino acids in perhaps predicting the severity of sepsis and its outcome.

2-Hydroxyphenethylamine

Transport ATPases of cardiac sarcolemma in 20,25-diazacholesterol induced myopathy.

20,25-Diazacholesterol, known to induce myotonia in skeletal muscle, also affects cardiac muscle as can be concluded from the development of cardiomegaly. At the same time (Na+, K+) ATPase of cardiac sarcolemmal membranes of the 20,25-diazacholesterol treated rats showed an increased activity as compared with control animals (91 percent and 46 percent stimulation respectively). The Ca++ stimulated ATPase showed the same tendency (96 percent and 64 percent stimulation). In the plasma of the treated rats creatine phosphokinase activity was found to be elevated whereas the amount of protein-bound iodine was decreased, a finding that is common in myotonic dystrophy.

Adenosine Triphosphatases

Progesterone secretion by adrenal glands of hamsters and comparison of ACTH influence in rats and hamsters.

Studies were designed to determine a) if adrenal glands of hamsters secrete progesterone (PROG), b) the effects of adrenocritocotropin (ACTH) administration on adrenocortial function of rats and hamsters under the surgical conditions necessary for collection of adrenal venous blood from the left renal vein, and c) the effects of blood loss during sample collection. PROG was quantitated by the competitive protein-binding method after extraction and separation by sephadex LH-20 column chromatography. The presence of interfering quantities of androstenedione necessitated two column chromatographic steps. Glucocorticoids (11-OHCS) were determined fluorometrically. PROG was detected in adrenal venous plasma of female hamsters. The PROG concentration and secretory rate were 91 +/- 12 ng/ml and 4 +/- 1 ng/min, respectively, while the peripheral plasma level of the same animals was 2 +/- 0.2 ng/ml, indicating that the adrenal glands of female hamsters are capable of secreting PROG. ACTH administration increased PROG secretory rates in both hamsters (3 +/- 1 to 14 +/- 3 ng/min) and rats (62 +/- 9 to 152 +/- 32 ng/min) on estrus, as well as increasing the 11-OHCS secretory rate of hamsters (16 +/- 1 to 33 +/- 4 ng/min), but not of rats. The greater increase in PRCC than in 11-OHCS secretion may be related to excess PROG formation relative to the capacity of the 17alpha- or 21-hydroxylating enzyme systems. The adrenal venous PROG concentration and secretory rate of female hamsters infused with 10% dextran while collecting adrenal venous blood did not differ significantly from those of the non-infused animals, suggesting that this amount of blood loss (1 ml) does not influence PROG secretion.

Adrenal Glands

[Pharmacokinetic studies on fluoro-alpha-acetyl-digoxin (author's transl)].

Pharmacokinetic studies with a new cardiac glycoside 3H-fluoro-alpha-acetyldigoxin were carried out in humans. The absorption of the drug is 91%. The half-life of tritium label in plasma was 25 h i.v. and 35 h p.o. 73% of the administered radioactivity were excreted after i.v. and 52% after oral administration within 84 h. More than 60% of the radioactivity in the urine could be extracted with chloroform. This fraction corresponded mainly to 3H-fluorodigoxin in the thin-layger chromatogram. Protein binding was 27% using therapeutic concentrations.

Administration, Oral

Hormone-mediated oviductal influence on mouse embryo development.

This study presents evidence that estradiol, mediated through oviduct fluid, may adversely affect the development of early embryos. Two-cell mouse embryos were cultured in Whitten-Biggers medium with or without 0.2 to 20 microgram/ml of estradiol or progesterone or in mouse oviduct fluid from donors treated with estradiol or estradiol and progesterone. Embryos cultured in fluid from estrogen-dominated donors were significantly less able to develop to morula (65%) or blastocyst (14%) than were those cultured in either Whitten-Biggers medium (91% and 41%) or progesterone-dominated fluid (87% and 36%). Transfer of cultured morulae and blastocysts to uteri of pseudopregnant recipients resulted in 2/3, 4/6, and 0/7 recipients' becoming pregnant for control, progesterone-dominated, and estrogen-dominated, respectively. When estradiol or progesterone was added directly to the control medium, no inhibitory effects were observed at levels higher than those found physiologically in plasma. Protein concentration and osmolalities for representative samples of oviduct fluid were 5.2 mg/ml and 329 mOsM for estrogen-dominated fluid and 1.6 mg/ml and 339 mOsM for progesterone-dominated fluid.

Animals

Characteristics of thyroid function in experimental protein malnutrition.

Two experiments were conducted to study the effects of protein malnutrition on thyroid function. Resting oxygen consumption and serum concentrations of triiodothyronine (T3), thyroxine (T4) and thyroid stimulating hormone (TSH) were measured and correlated with thyroid histology, gain in weight, feed efficiency and carcass energy content in male rats fed isoenergetic diets ad libitum containing 22% (control) or 8% (protein malnourished, PM) casein for 28 or 32 days postweaning. A third group was pair-fed to the PM rats with the control diet. In experiment 2 additional groups were pair-fed to the PM rats with 8% casein diets in which the casein was substituted with different mixtures of carbohydrate and fat. Resting oxygen consumption/body weight (0.75) decreased as body weights increased in all groups, but was consistently greatest in PM rats. In PM rats, plasma T3 was 130% of controls after 11 days of the dietary regimen and averaged 215% of controls from days 18 through 32. In experiment 2 both T3 and T4 concentrations were approximately twice controls in all PM groups. TSH concentrations were within the normal range in all groups throughout. Feed efficiency averaged 36 to 40% of controls and mean weight gain was 30 g after 28 days in the PM groups, compared to 114 and 91 g, respectively, in the pair-fed control rats. Carcass energy content of PM rats after 28 days was significantly lower than in control or pair-fed control rats. Thyroid morphology was compatible with increased secretory activity in all the protein-malnourished groups, compared with normal activity in the control and pair-fed control groups. Thermogenesis, as measured by oxygen consumption, was markedly increased in the PM rats compared to controls. These observations are consistent with a diet-induced thermogenesis in the protein-malnourished rats. In contrast to simple under-nutrition where energy expenditure may be conserved by decreases in thyroid function and thermogenesis, increases in thyroid function and thermogenesis in protein malnutrition could provide an energy balancing mechanism whereby unneeded non-protein energy in the diet could be dissipated as heat, and survival enhanced.

Animals

Inflammatory cytokines mediate thoracic aortic aneurysm formation via plasma metabolites: A two-step Mendelian randomization and single cell sequencing-based investigation.

Thoracic aortic aneurysm (TAA) is a life-threatening condition characterized by pathological dilation of the aorta. While inflammatory responses have been implicated in TAA pathogenesis, the causal relationships remain elusive. This study aimed to elucidate potential causal associations between inflammatory cytokines, plasma metabolites, and TAA risk using Mendelian randomization (MR) analysis. We conducted bidirectional two-sample MR analysis utilizing genome-wide association study data from 91 inflammatory cytokines (n&#x2005;=&#x2005;14,824), 1400 plasma metabolites (n&#x2005;=&#x2005;8299), and TAA (n&#x2005;=&#x2005;385,857). The inverse-variance weighted method served as the primary analytical approach, with comprehensive sensitivity analyses performed to assess pleiotropy and heterogeneity. Two-step MR analysis was employed to explore potential mediating roles of plasma metabolites. Single-cell sequencing analysis was utilized to detect cell type enrichment and elucidate cellular functions of identified cytokines. Additionally, we conducted an analysis to identify druggable proteins as potential therapeutic targets for TAA. MR analysis revealed that genetically-determined increases in C-X-C motif chemokine 10 (CXCL10) (odds ratios [OR]&#x2005;=&#x2005;1.149, 95% confidence interval [CI]: 1.009-1.309, P&#x2005;=&#x2005;.037) and fibroblast growth factor 5 (OR&#x2005;=&#x2005;1.101, 95% CI: 1.013-1.196, P&#x2005;=&#x2005;.024) were associated with elevated TAA risk. Conversely, C-C motif chemokine 20 (CCL20) (OR&#x2005;=&#x2005;0.870, 95% CI: 0.759-0.996, P&#x2005;=&#x2005;.043) and CD40L receptor (CD40) (OR&#x2005;=&#x2005;0.906, 95% CI: 0.827-0.992, P&#x2005;=&#x2005;.033) demonstrated inverse associations with TAA risk. Two-step MR analysis identified potential mediating metabolites: the phosphate to linoleoyl-arachidonoyl-glycerol ratio for CXCL10, thyroxine and X-24585 for FGF-5, and the creatine to carnitine ratio for CCL20. Single-cell sequencing analysis revealed enrichment of these cytokines in specific cell types and pathways relevant to TAA pathogenesis. Drug-gene interaction analysis identified CXCL10, CCL20, and CD40 as potential targets for treatment of TAA. This study provides robust genetic evidence supporting causal relationships between specific inflammatory cytokines and TAA risk, with plasma metabolites potentially mediating these effects. CXCL10 and FGF-5 were identified as potential risk factors, while CCL20 and CD40 may confer protective effects. These findings offer novel insights into TAA pathogenesis and suggest potential targets for intervention. Further research is warranted to elucidate the underlying mechanisms and validate these results across diverse populations.

Aortic Aneurysm, Thoracic

Afrikander cattle congenital goiter: characteristics of its morphology and iodoprotein pattern.

The morphology and some properties of the complex iodoprotein pattern of the genetically determined congenital goiter in Afrikander cattle is described. The goiter contained irregularly shaped follicles which were devoid of colloid and the follicular epithelial cells were elongated, measuring about 20 micrometer in length compared to 10 micrometer for normal thyroid cells. The goiter cells contained apical clusters of larger and more numerous lysosomes than normal thyroid cells. Apical vesicles containing electron-dense material which were in contact with the plasma membrane could be seen in most normal thyroid cells, but were extremely scarce in the goiter. In 36 cell profiles studied none was found. The endoplasmic reticulum cisternae of the goiter differed significantly from normal thyroid cells. Fewer ribosomes were seen to be attached to the membranes of goiter cells. Furthermore, unlike normal thyroid cells, many free polysomes were seen in goiter cells. The characteristics of the unusual iodoprotein pattern of the goiter extract, resolved by gel chromatography and sucrose density gradient centrifugation, were qualitatively and quantitatively similar to that described previously (Endocrinology 91, 470, 1972). A relatively small amount of the total soluble protein was iodinated. Of these, only a 12S sedimenting species was precipitated by antithyroglobulin immunoglobulin. When separated on polyacrylamide gels containing sodium dodecyl sulfate and mercaptoethanol, this 12S species was resolved into at least 14 polypeptide components ranging in molecular weights from less than 66,000--330,000. Three of the bands, representing a small percentage of the total protein, seemed to comigrate with the major polypeptides of thyroglobulin and were also precipitated with rabbit antihyroglobulin immunoglobulin. The data indicate that glycosylation of iodoproteins was not affected although 19S thyroglobulin synthesis and subsequent storage were drastically impaired.

Animals

An evaluation of upper arm measurements used in nutritional assessment.

Triceps skinfold thickness and upper arm circumference (parameters used in assessing protein-calorie malnutrition) were measured on both arms of 91 adult volunteers who fulfilled criteria for absence of disease and conditions affecting nutritional status. For the total study group and subgroups of men only and women only, no significant differences were noted between right and left arm measurements of triceps skinfold thickness, arm circumference, or arm muscle circumference. Median values for significant right-left arm measurement differences were + 1.7 mm for the triceps skinfold thickness of left-handed subjects (P less than 0.05) and + 0.3 cm for the arm circumference of volunteers regularly engaged in predominately right-armed activities (P less than 0.05). Criteria of weight within 15% of "ideal" and nine serum and plasma values within a specified range were fulfilled by 77 subjects, and they comprised the "healthy" subgroup. Left arm median values for healthy men and healthy women differed from a currently accepted standard for each of three anthropometric parameters: triceps skinfold thickness (P less than 0.05), arm circumference (P less than 0.05), and arm muscle circumference (P less than 0.01).

Adult

Beta-endorphin: stimulation of growth hormone release in vivo.

Two micrograms of beta-endorphin (beta-lipotropin61-91) injected intraventricularly in rats that had been treated with antiserum against somatostatin led to a 6- and 10-fold stimulation of the concentration of plasma growth hormone (somatotropin) measured 10 and 20 min after injection of the peptide, whereas 400 mug of methionine-enkephalin led to a 4- to 6-fold increase of levels of plasma growth hormone at 10 min with a rapid return to basal levels at later time intervals. At doses of 5 and 25 mug, beta-endorphin led to a 20- to 30-fold stimulation of levels of plasma growth hormone, the maximal effect being measured between 20 and 30 min after injection. These data suggest the possible role of the endogenous opiate-like peptides in the control of growth hormone secretion.

Animals

[Proteolytic enzymes produced by Aspergillus ochraceus in relation to their plasma coagulating and fibrinolytic activities].

The paper describes some properties of coagulases and fibrinolytic enzymes isolated from a proteolytic complex produced by Aspergillus ochraceus HP-19 during submerged cultivation on a synthetic medium. Proteolytic enzymes with the plasmocoagulating activity hydrolyzed casein at the maximum rate at 45 degrees C and pH 8.0--10.0. The coagulases were stable at pH 5.0--7.0 and were rather resistant to low pH values. The enzymes were entirely inactivated at 55 degrees C within 20--30 min. The activity of the coagulases was inhibited with the ions of Cu, Co, Ag, Pb, Mn, Zn and Hg (1.10(-3) M) by 100, 91, 85, 50, 50, 38 and 25%, respectively. The coagulases were entirely inhibited with EDTA whereas PCMB and PMSF inhibited their activity only to a small extent. The mechanism for blood clotting with the coagulases of Aspergillus ochraceus HP-19 is presumed to consist in the activation of protrombin via its limited specific proteolysis. The fibrinolytic enzymes of Aspergillus ochraceus HP-19 had the optimal pH 8.5 for casein, were stable at pH 6.0, and entirely inactivated at 55 degrees C within 5 min. In contrast to coagulases, they were resistant to the action of heavy metal ions. The enzymes were stabilized by the ions of Ca. The activity of the fibrinolytic enzymes of Aspergillus ochraceus HP-19 was completely inhibited with PMSF. Therefore, they belong to the class of serine proteases.

Aspergillus