The effects of administrations of HCI, NH4CI and NH4HCO3 on the excretion of urea and ammonium in man

In man, HCl acidosis reduces blood and urinary urea with a concomitant rise in ammonium (NH4+) excretion. Significantly less urea is excreted following NH4Cl administration than following equimolar ingestion of NH4 HCO3. The results of these alterations in nitrogen excretion are interpreted in terms of bicarbonate utilization and production.     

Basophil Histamine Release and Leukotriene (LTB4 - LTC4) Production in Cluster Headache

Histamine release and leukotrienes (LTB4 and LTC4) production from circulating basophil have been studied in 13 patients with episodic cluster headache (CH) during the remission phase of symptoms, and in 9 normal subjects. Cell suspensions of basophils were stimulated with scalar dilutions of anti-IgE, f-met-peptide and Ca2+ ionophore A23187. Histamine was measured by an automated fluorimetric method; LTB4 and LTC4 with RIA in individual cases, and with Reverse-Phase HPLC in the two pools obtained from the supernatants of CH patients and controls. Mean values of histamine release in patients with CH were significantly lower when compared to those obtained in control subjects after stimulation with anti-IgE at the three dilutions used. LTC4 mean levels measured in CH patients were significantly lower than those of supernatants from controls after stimulation with 0.05 gamma/ml of A23187. A reduction of LTC4 and LTB4 levels in CH patients was also observed in R-P HPLC, which showed different elution patterns in the two groups. The histamine release in individual cases was related to leukotriene production: LTC4 levels were significantly (p less than .05) higher in "high histamine releasers" than in "low histamine releasers". Our results indicate that CH patients have complex abnormalities of histamine release and of leukotriene production during the painless phase of the disease.     

Erythrocyte Na+-H+ exchanger and Na+-Li+ countertransport activity in primary aldosteronism

Abstract. Several authors have described increased Na-H exchanger activity in essential hypertension but no data are available in secondary forms of hypertension such as primary aldosteronism. We measured Na-H exchanger kinetics together with Na-Li countertransport V _max in the erythrocytes of eight patients with primary aldosteronism and in 15 normotensive control subjects. Plasma aldosterone, plasma renin and plasma potassium were also evaluated. Na-H exchanger V _max appear to be increased in patients with primary aldosteronism and Hill's n , an index of co-operativity amongst intracellular proton binding sites, was significantly lower in patients than in controls. No statistically significant differences were found between affinity for intracellular protons (K50%) and for Na-Li countertransport V _max between the two groups studied. We were unable to find any correlations between Na-H exchanger V _max and Na-Li countertransport V _max in the two groups considered as a whole. From the present data Na-H exchanger overactivity would not appear to be a specific feature of essential hypertension but seems to be characteristic in patients with primary aldosteronism.     

Comparative Absorption of Ferri-Haemoglobin-59Fe/Ferro-Haemoglobin-59Fe and 59Fe3+/59Fe2+ in Humans with Normal and Depleted Iron Stores*

Abstract. The intestinal ⁵⁹Fe absorption from ferri- and ferro-haemogIobin-⁵⁹Fe and ⁵⁹Fe³⁺ and ⁵⁹Fe⁺ was calculated from whole body-⁵⁹Fe-retention measurements in subjects with normal and depleted iron stores. A ferri-haemoglobin-⁵⁹Fe/ferro-haemoglobin-⁵⁹Fe absorption ratio of 1.03 ±0.11 was observed for the absorption of ferri-haemoglobin-⁵⁹Fe (8.6± 0.77%) and ferro-haemogIobin-⁵⁹Fe (8.7±0.94%) in persons with normal iron stores. Depletion of iron stores caused a slight but significant higher rise of ferri-haemoglobin-⁵⁹Fe absorption (22 ± 1.7%) than the increase of ferro-haemoglobin-⁵⁹Fe absorption (18 ±0.9%) so that the absorption ratio was 1.24±0.073.—This remarkable iron valence independence of haemoglobin iron absorption is in considerable contrast to the well-established valence dependence of inorganic iron absorption which favours ferrous iron absorption especially with rising iron doses. The ⁵⁹Fe³⁺/⁵⁹Fe²⁺ absorption ratio for a diagnostic 0.56 mg Fe dose increased from 0.43 in subjects with normal iron stores to 0.74 in persons with depleted iron stores, whereas this absorption ratio was augmented only from 0.21 to 0.28 for the therapeutic 50 mg Fe-dose.—The different influence of iron valence on iron absorption from inorganic and haemoglobin iron supports other evidence for the existence of two separate mechanisms for ferrous iron and haem iron absorption in humans.     

Met5-enkephalin-Arg6-Phe7 (MEAP): A Cardioprotective Hormonal Opioid

Background: Acute myocardial ischemia is an important cause of morbidity and mortality worldwide. The heart and other organs can be rendered more resistant to the deleterious effects of ischemia through a variety of preconditioning strategies, including treadmill exercise and brief ischemia of skeletal muscle. Some of the beneficial effects of these preconditioning strategies appear to be mediated by as‐of‐yet unidentified hormonal opioids. Objectives: To test the hypothesis that endogenous opioids of the enkephalin class are capable of improving ischemic tolerance and acting in a hormonal manner. Methods: In phase one of the investigation, the authors assessed the cardioprotective potential of all four known enkephalins. This was achieved by subjecting isolated buffer‐perfused rabbit hearts to a 25‐minute period of test ischemia and two hours of reperfusion (protocol 1) after receiving treatment with either saline vehicle (controls) or increasing concentrations of purified enkephalins. On the basis of results from these initial studies, the authors performed additional experiments (protocol 2) to determine whether Met⁵‐enkephalin‐Arg⁶‐Phe⁷ (MEAP) could be absorbed from skeletal muscle and exert a cardioprotective effect. Specifically, MEAP or vehicle (controls) was given intramuscularly 24 hours before the hearts were harvested. A similar assessment of ischemic tolerance as described in protocol 1 was then performed. Postischemic myocardial viability (infarct size) was assessed in all cases by triphenyltetrazolium chloride (TTC) staining. Hemodynamic parameters and infarct sizes for concentration‐dependence studies were compared by two‐way analysis of variance, and infarct sizes from protocol 2 studies were compared by using Student's t‐test (significance set at p ≤ 0.05). Results: Mean infarct size in control hearts (± SEM) was 33% (± 4%) and 36% (± 6%) for protocol 1 and 2, respectively. Of the four enkephalins tested in protocol 1, only MEAP treatment showed a tendency toward cardioprotection. Interestingly, an alternative enkephalin, methionine⁵‐enkephalin‐Arg⁶‐Gly⁷‐Leu⁸, tended to exert an injurious effect. In protocol 2, MEAP treatment 24 hours before ischemia significantly reduced infarct size (14%± 4%) compared with controls, suggesting that it can be released from muscle and exert a distant cardioprotective effect. Conclusions: When given either directly to the heart or absorbed from a distant tissue, MEAP induces cardioprotection, supporting the hypothesis that it can act as a hormonal modulator of ischemic tolerance.     

PREVENTION OF CCL4-INDUCED LIVER CIRRHOSIS BY SILYMARIN

The efficacy of silymarin treatment in preventing biochemical and histological alterations in CCL4-induced liver cirrhosis in rats was studied. Four groups of rats were treated with: (1) CCL4; (2) mineral oil; (3) CCL4 + silymarin; and (4) silymarin. All animals were sacrificed 72 h after the end of treatments. The activities of alkaline phosphatase (alk. phosp.), gamma-glutamyl transpeptidase (GGTP), glutamic pyruvic transaminase (GPT) and glucose-6-phosphatase (G6Pase), and bilirubin content were determined in serum. Na+, K+-ATPase and Ca++-ATPase activities were measured in isolated plasma membranes. Lipoperoxidation, triglycerides (TG), and glycogen contents were also measured in liver homogenates. Liver cirrhosis was evidenced by significant increases in liver collagen, lipoperoxidation, serum activities of alk. phosp., GGTP, GPT, G6Pase, bilirubin content, and liver TG. Activities of ATPases determined in plasma membranes were significantly reduced, as was liver glycogen content. Silymarin cotreatment (50 mg/kg b.wt) completely prevented all the changes observed in CCL4-cirrhotic rats, except for liver collagen content which was reduced only 30% as compared to CCL4-cirrhotic rats. Silymarin protection can be attributed to the agent's antioxidant and membrane-stabilizing actions.     

Erythrocyte Li+/Na+ and Na+/H+ exchange, cardiac anatomy and function in insulin-dependent diabetics

It has been proposed that an increased activity of cell membrane Na+/H+ exchange, mirrored by increased erythrocyte Li+/Na+ exchange, may facilitate cell hypertrophy and hyperplasia. Patients with insulin-dependent diabetes mellitus may develop a specific cardiomyopathy with systolic and diastolic abnormalities and increased thickness of the left ventricle. Therefore, we have investigated the relationships between erythrocyte Li+/Na+ and Na+/H+ exchange and echocardiographic parameters in 31 male insulin-dependent diabetics (aged 17-68), in good metabolic control. Three had untreated mild hypertension. In all patients the urinary albumin excretion rate was less than 200 micrograms min-1. Ten patients had a Li+/Na+ countertransport higher than 0.37 mmol l-1 cell h-1, the upper normal limit for our laboratory (0.49 +/- 0.10, mean +/- SD). In comparison with the patients with normal countertransport, they had increased interventricular septum thickness and relative wall thickness (h/r). End diastolic volume and cardiac index were reduced while blood pressure and urinary albumin excretion rate were similar. In the whole study group, interventricular septum thickness was significantly correlated to Li+/Na+ exchange (r = 0.61, P less than 0.001) and Na+/H+ exchange (r = 0.35, P less than 0.05), independently of the effect of age and blood pressure. Posterior wall thickness was correlated to Li+/Na+ exchange (r = 0.38, P less than 0.05) and h/r to Li+/Na+ exchange (r = 0.41, P less than 0.05) and to Na+/H+ exchange (r = 0.44, P less than 0.05). Li+/Na+ exchange was negatively correlated to cardiac index (r = -0.37, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The Expected "Bombay" Groups OhA1 and OhA2

An American family of English extraction is reported in which two Oh ("Bombay") members have transmitted A ₂ genes to their children thus demonstrating that the expression of the gene A ₂, like that of the gene B , can be suppressed in this phenotype. Another American family, of French extraction, shows with a high degree of probability that the expression of the gene A ₁ can be similarly suppressed.     

Compared effects of ruthenium red and cis [Ru(NH3)4Cl2]Cl on the isolated ischaemic-reperfused rat heart

Summary— The sequence ischaemia-reperfusion is characterized by reperfusion damage. The calcium overload occurring at the beginning of reperfusion is one of the main mechanisms responsible for reperfusion damage. Ruthenium red, a blocker of the mitochondrial calcium uniport system, could prevent this damage by preserving the ATP synthesis in the mitochondria. We tested ruthenium red and another ruthenium compound, cis-tetrammine dichlororuthenium (III) chloride in our experimental model of ischaemic-reperfused rat hearts. After a 15 minute-stabilization period, the hearts were submitted to a 30 minute global ischaemia period and then reperfused for 45 minutes with the standard perfusion solution or with ruthenium red or cis-tetrammine dichlororuthenium (III) chloride at 1, 3 or 9 μM. Ruthenium red at 3 μM exerted a protective effect in our experimental conditions by showing a significant improvement of the contractility recovery at the end of reperfusion and a significant decrease of the malondialdehyde production, which reflects free radical production. The cis-tetrammine dichlororuthenium (III) chloride (containing 1 Ru ion per molecule) at 9 μM was slighty less efficient than ruthenium red at 3 μM (containing 3 Ru ions per molecule). The heart ruthenium binding was better for the ruthenium red than for the cis-tetrammine dichlororuthenium (III) chloride, suggesting a role of the ruthenium ion complexation in the crossing of the membrane, whereas the cardiac effect seemed to be linked to the ruthenium ion heart concentration, which was similar for the ruthenium red at 3 μM and for the cis-tetrammine dichlororuthenium (III) chloride at 9 μM. One can hope that ruthenium compounds would limit reperfusion damage and infarct size after ischaemia in in vivo models.     

MCL1 and MCL6 Compared to V1 and V6 in Distinguishing Aberrant Supraventricular from Ventricular Ectopic Beats

Use of V1 and V6 has been suggested for distinguishing aberrant supraventricular from ventricular ectopy. For two decades, "modified" leads MCL1 and MCL6 have been widely used as V1 and V6 substitutes for bedside monitoring, but their use has never been validated. To determine the value of MCL1 and MCL6, 81 morphologically distinct wide QRS ectopic beats were recorded from 46 patients during cardiac electrophysiological study. As determined by the His-bundle electrogram, 31 of the ectopics were aberrant supraventricular, 50 were ventricular. A new criterion, measurement of QRS onset to the predominant peak or nadir of the complex, was valuable in diagnosing wide complexes in MCL6 and V6. An interval of 50 msec or less predicted aberrant supraventricular ectopy; an interval of 70 msec or more predicted ventricular ectopy. There was agreement between the modified and conventional precordial leads regarding which QRS patterns were useful in distinguishing aberrant supraventricular from ventricular ectopy. A greater proportion of wide complexes in MCL1 and V1 exhibited patterns useful in making the diagnosis compared to MCL6 and V6. Using well-established criteria, the proportion of correct diagnoses that was made from individual leads was: MCL1 = 86%, V1 = 85%, MCL6 = 72%, V6 = 67%. The bedside leads (MCL1 and MCL6) were not statistically different in diagnostic accuracy from their conventional lead counterparts (V1 and V6); however, MCL1 and V1 were superior to MCL6 and V6. When the new criterion was added to make the diagnosis from MCL6 and V6, no difference in diagnostic accuracy was present between the four leads.     

Erythrocyte Na+–H+ exchanger kinetics and Na+–Li+ countertransport activity in essential hypertensive patients

The authors measured Na⁺–H⁺ exchanger kinetics together with Na⁺–Li⁺ countertransport V _max in the erythrocytes of 21 subjects with essential hypertension and 16 normotensive control subjects. Na⁺–H⁺ exchanger V _max appeared to be increased in patients with essential hypertension, while the Na⁺–H⁺ exchanger affinity for intracellular proton sites ( K _50%) proved to be unchanged and the index of cooperativity among intracellular proton binding sites as measured by Hill's coefficient (Hill's n ) decreased as compared with normotensive control subjects. Na⁺–Li⁺ countertransport V _max appeared to be higher in patients with essential hypertension than in control subjects. The authors were unable to find any correlations between Na⁺–H⁺ exchanger kinetic parameters and metabolic variables such as parameters of insulin resistance and plasma lipids. On the basis of the data obtained, erythrocyte Na⁺–H⁺ exchanger activity was found to be abnormal in two kinetic variables in essential hypertensive patients and showed no simple linear correlations with the main variables of glucose metabolism, plasma lipids, renin or aldosterone.     

Involvement of the β3 E749ATSTFTN756 region in stabilizing integrin αIIbβ3-ligand interaction

Summary. Platelet integrin α_IIbβ₃ must be activated via intracellular mechanisms before it binds soluble ligands, and it is thought to be activated at its extracellular site by surface‐bound ligands. Integrin activation is associated with rearrangement of the cytoskeleton and phosphorylation of proteins that become localized in focal contacts. In these processes, the cytoplasmic tail of the β‐subunit plays a central role. We introduced peptides homologous to the E⁷⁴⁹ATSTFTN⁷⁵⁶ domain (E–N peptide) and the T⁷⁵⁵NITYRGT⁷⁶² domain (T–T peptide) of β₃ in streptolysin O‐permeabilized platelets and analyzed the initial interaction with soluble fibronectin, fibrinogen and PAC‐1 after stimulation with thrombin. E–N peptide left the initial binding of fibronectin intact but interfered with stable receptor occupancy. E–N peptide also inhibited fibrinogen binding, thereby reducing the formation of large aggregates. Strikingly, E–N peptide did not disturb the binding of PAC‐1, which is known to reflect activation of the integrin. E–N peptide also inhibited tyrosine phosphorylation of focal adhesion kinase, a response known to be dependent on α_IIbβ₃. T–T peptide did not affect these processes. In a model for outside‐in integrin activation, E–N peptide disrupted the binding of CHO cells expressing α_IIbβ₃ to surface‐bound ligand. Again, T–T peptide had no effect. We conclude that the E⁷⁴⁹ATSTFTN⁷⁵⁶ region of the β₃‐tail stabilizes the binding of soluble and surface‐bound ligand to integrin α_IIbβ₃ via a mechanism that involves the phosphorylation of FAK.     

Radioimmunoassay of Prostaglandins Fα, E1 and E2 in Human Plasma

Abstract. Antibodies against prostaglandins (PG)F₂α, E₁ and E₂ were obtained in rabbits immunized with respectively PG F₂α, PG E₁ and PG E₂ conjugated to bovine serum albumin by carbodiimide. A radioimmunoassay capable of measuring 7 pg of PG Fα, 2 pg of PG E₂ and 14 pg of PG Ej in human peripheral plasma is described. Plasma samples (pH 3, citric acid) are extracted with cyclohexane: ethyl acetate, 1:1 and then chromatographed on silicic acid columns to separate the prostaglandins into three fractions: fraction I, PG A, PG B and some unknown immunoraactive compounds; fraction II, PG E and fraction III PG Fα. The recovery is 80 %± 6. 2. Mean plasma levels iu adults of PG Fa and PG E, expressed in pg/ml: -PG Fα 12 ± 2. 8 (n = 25 men), 8 ± 2. 3 (n = 18 women, follicular phase), 7 ± 1. 4 (n = 18 women, luteal phase). -PG E₁ 40. 5 + 7. 6 (n = 13 men), 38 + 17. 1 (n = 10 women). -PG E₂ 4. 5 ± 1 (n = 12 adult subjects).
The major characteristics of the method described herein are the following: - a large volume of plasma has to be processed (10 ml or more for PG Fa and PG E₁, 5 ml or more for PG E₂). - a chromatographic step is necessary to separate the different prostaglandins which makes it possible to circumvent problems of immunological cross reactivity and interference with unknown immunoreactive compounds. - great care has been taken in collection of blood samples, especially to insure complete removal of blood cells namely platelets.     

The 13C-mixed triglyceride breath test in healthy adults: determinants of the 13CO2 response

Defects in lipolysis due to pancreatic insufficiency can be diagnosed by the mixed triglyceride (MTG) ¹³CO₂ breath test. However, the effects of various test conditions on the ¹³CO₂ response have only been partially elucidated. In healthy adults, we performed the ¹³CO₂ mixed triglyceride breath test and we compared (a) the inter- and intra-individual variation in the ¹³CO₂ response; (b) the effect of two different test meals; (c) the effect of an additional meal during the test; and (d) the effect of physical exercise during the test. Upon repeating the test in the same individual (test meal cream), repeatability coefficients were large, with respect to either time to maximum ¹³C excretion rate (3.8 h), maximum ¹³C excretion rate (4.9% ¹³C dose h^?1) or cumulative recovery of ¹³C over the 9-h study period (22.7% ¹³C dose). The cumulative ¹³C expiration over 9 h obtained with the test meal composed of cream was quantitatively similar to that obtained with bread and butter: 42.2 ± 8.4% and 47.7 ± 6.3% respectively. Fasting for 9 h during the test resulted in similar ¹³C expiration rates and cumulative ¹³C expiration (43.4% ± 7.2%) when compared with consumption of an additional meal 3 h after the start of the test (38.3 ± 5.3%). The ¹³CO₂ response increased in five out of seven subjects, but decreased in the other two, when moderate exercise was performed (bicycle ergometer, 50 W for 5 h). We conclude that the repeatability of the MTG test in healthy adults is low. The present results indicate that a solid and a liquid test meal, containing a similar amount of fats, give similar cumulative ¹³CO₂ responses, and that stringent prolonged fasting during the test is unnecessary. Standardization of physical activity seems preferable, since the unequivocal effects of moderate exercise on the ¹³CO₂ response were observed in the individuals studied.     

Leukotriene B4 metabolism in neutrophils of patients with chronic granulomatous disease: phorbol myristate acetate decreases endogenous leukotriene B4via NADPH oxidase-dependent mechanism

We studied the effect of phorbol myristate acetate (PMA) on endogenous leukotriene B4 (LTB4) metabolism of calcium ionophore A23187-stimulated human neutrophils. Preincubation of normal neutrophils with PMA significantly suppressed the recovery of endogenous LTB4 induced by A23187. PMA did not suppress the recovery of LTB4 produced by neutrophils from patients with chronic granulomatous disease (CGD), which is known to be defective in NADPH oxidase activation to produce reactive oxygen species (ROS). PMA inhibited the formation of omega-oxidation products of LTB4, but enhanced arachidonic acid release in normal and CGD neutrophils. Furthermore, 5-lipoxygenase activity of 10,000 x g supernatants from normal neutrophils pretreated with PMA was equivalent to that of the controls. Decrease in LTB4 recovery was not attributed to the suppression of the intracellular Ca2+ increase. Thus, it is suggested that reactive oxygen species (ROS) produced by PMA may directly affect endogenous LTB4 and convert it into metabolite(s) distinct from omega-oxidation products.     

Local and systemic effects of Na+/K+ ATPase inhibition

The positive inotropic and electrophysiological effects of cardiac glycosides on cardiac muscle are mediated through inhibition of Na⁺/K⁺ ATPase by binding to a specific extracytoplasmic site of the a-subunit of this enzyme. The inhibition of Na⁺/K⁺ ATPase affects ionic flux and produces direct local effects on cardiac contractility, electrical excitability and conduction, but also profound systemic effects mainly as a result of haemodynamic changes. These effects are responsible for beneficial therapeutic as well as toxic effects.
Inhibition of Na⁺/K⁺ ATPase results in potentiation of K⁺ loss from cells and Na⁺ entry into cells, so consequently affects action potential generation and propagation. This also underlines the potentiation of certain effects of cardiac glycosides by hypokalemia and hypomagnesaemia, and the effects of changes in calcium homeostasis on the cardiac glycoside pharmacodynamics. Furthermore, inhibition of Na⁺/Ca⁺⁺ exchange enhances Ca⁺⁺ mobilization and promotes contractility. These effects (locally and systemically) differ greatly, depending on the haemodynamic status and myocardial oxygen supply.
Cardiac glycosides have less affinity for Na⁺/K⁺ ATPases at other sites (e.g. skeletal muscle), but some extracardiac effects (vascular effects, effects on colour vision, CNS and autonomic effects, renal effects) may be related to Na⁺/K⁺ ATPase inhibition.     

C5-6 Cervical Dislocation Resulting from Improper Seat Belt Use

Motorists may improperly use the diagonal shoulder belt of newer passive restraint systems by failing to use the lap belt. An unusual case of a patient who did not wear a lap belt and who sustained a cervical C_5–6 distraction injury resulting in quadriplegia is reported. Emergency physicians should be aware of this injury mechanism and should reinforce proper passive restraint use.