The digoxin-amiodarone interaction

Summary To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4–8 months.Mean (±SD) peak plasma digoxin concentration rose from 1.55±0.6 g/l prior to amiodarone therapy to 2.85±1.3 g/l after 1 week of combined therapy (p<0.01). Mean AUC also rose from 7.2±2.1 g/l.h to 12.1±6.4 g/l.h (p<0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4–8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses.This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.     

Effects of ischemia, preconditioning, and adenosine deaminase inhibition on interstitial adenosine levels and infarct size

In order to examine the relationship between local adenosine concentrations before, during, and after ischemia and the extent of ischemic myocardial damage, measurements of interstitial fluid (ISF) nucleosides were made using microdialysis probes implanted in the ischemic region of isoflurane anesthetized Micropigs undergoing 60 coronary artery occlusion (CAO) and 3h of reperfusion (REP). Nucleoside concentrations in the dialysate collected from the microdialysis probes were used as an index of ISF levels. Dialysate nucleoside concentrations (ADO, inosine and hypoxanthine), myocardial infarct size, and myocardial blood flow (MBF) were determined in control animals (n=6), animals preconditioned with a single 10 cycle of CAO and REP (PC, n=6), and those treated with the adenosine deaminase inhibitor pentostatin (n=6, 0.2 mg/Kg IV 30 prior to CAO). The brief PC occlusion resulted in a transient but significant increase in dialysate ADO (6.7±1.8 M vs. 0.67±0.1 M at baseline). Pentostatin administration had no significant effect on either dialysate nucleosides or MBF at baseline. During the 60 CAO, dialystate ADO increased in control animals. In PC animals, however, dialysate ADO during CAO was lower than control. Pretreatment with pentostatin resulted in a six-fold augmentation in dialysate ADO during the 60 min CAO when compared to the control values (110.62±30.2 M vs. 16.31±2.1 M at 60 min of ischemia). Pentostatin also resulted in a significant reduction in the accumulation of inosine and hypoxanthine, indicating inhibition of adenosine deaminase activity. There were no significant differences in MBF between groups at any time point. Following 3 h REP, infarct size was 35.4±5.5%, 8.1±1.5% and 8.3±1.8% of the region at control, PC, and pentostatin groups, respectively. These data suggest that marked increase in ISF ADO during CAO, may be as effective in reducing INF as a modest increase in ISF ADO prior to prolonged CAO.Supported in part by NIH grant R01 HL32043     

A Three-dimensional Analysis of Blood Vessels in Bronchioloalveolar Carcinoma

The three-dimensional architecture of blood vessels within lung adenocarcinomas has not been well studied. In 19 cases with bronchioloalveolar carcinoma with central fibrosis, we three-dimensionally examined blood vessel architecture in 150 m thick sections stained with elastin staining and anti-CD34 antibody. We examined four regions: normal alveoli and three regions within the tumor including an area adjacent to the normal alveoli (external area), an area in which tumor cells were replacing epithelial cells (replacement area), and a central fibrotic area (fibrotic area). Elastin staining showed that elastic fibers formed the framework of the alveoli, and the alveolar structure shrank more strongly to the center of the tumor due to folding of alveolar walls invaded by adenocarcinoma cells. We also measured three vessel parameters in these four regions. The vessel diameters were 4.08±1.10 m, 3.95±1.02 m, 5.04±1.56 m, and 6.11±2.23 m, the circumferences of those vessels seen as complete circles were 43.11±12.78 m, 43.71±12.87 m, 95.21±39.32 m, and 126.77±54.65 m; the lengths between vessel bifurcations were 13.28±3.08 m, 13.47±4.58 m, 24.91±9.66 m, and 41.82±28.08 m in the normal alveoli, and the external, replacement, and fibrotic areas, respectively. Blood vessel architecture changed such that the vessels became larger and coarser towards the center of the tumor. Our three-dimensional analysis suggests continuous remodeling of alveolar capillaries rather than angiogenesis within bronchioloalveolar carcinoma.     

Secretory component and lactoferrin in pure pancreatic juice in chronic pancreatitis

To evaluate pathophysiological roles of proteins in pancreatic secretion, immunoreactive lactoferrin (LF) and secretory component (SC) were measured in the first fraction of the pure pancreatic juice obtained endoscopically from 17 control, 21 suspected (SCP), 14 noncalcified (NCP), and 14 calcified chronic pancreatitis (CCP) subjects. The protein and amylase tended to decrease both in concentration and output from control to CCP. LF concentration was elevated in CCP (18.0±4.9/ml) when compared with controls (2.3±0.2g/ml), and LF output in NCP (12.3±3.8 g/min) was increased from controls (3.8±0.6 g/min). The combination of high LF concentration with low protein output was observed in 10/14 in CCP but 0/14 in NCP and can be a biochemical discriminator of CCP from NCP. SC concentrations were also elevated in NCP (8.5±2.0 g/ml) and CCP (5.6±1.6 g/ml) from controls (1.2±0.2 g/ml). SC outputs in SCP (9.8±3.1 g/min) and NCP (21.1±4.8 g/min) were increased from controls (1.7±0.3 g/min), but there was no further increase in CCP. Hypersecretion of LF and SC in chronic pancreatitis is different, especially in CCP, although the mechanisms for hypersecretion are unknown.This study was supported in part by a research grant for intractable pancreatic disease from the Ministry of Health and Welfare, Japan.     

Granulocyte Elastase in Cirrhotic Patients with Spontaneous Bacterial Peritonitis

Granulocyte elastase (GE) is a powerfulproteolytic enzyme that is released by PMNs whendegranulated in infectious processes. The aim of thisstudy was to measure GE in ascites and plasma ofcirrhotic patients with spontaneous bacterial peritonitis(SBP). We studied 29 cirrhotic patients, 17 of themhaving SBP (group A). Twelve patients with noninfectedascites formed the control group (group B). At the time of diagnosis of SBP, GE levels inascites (183.17 ± 86.11 g/liter) and plasma(114.6 ± 35.99 g/liter) were higher in groupA than in group B (27.41 ± 11.54 g/liter, P< 0.00001 and 82.54 ± 20.52 g/liter, P = 0.01,respectively). Levels of GE in ascites had a high valuefor discriminating between patients with and withoutSBP. In the patients who responded to the initialantibiotic treatment, these values significantly decreasedin ascites (67.69 ± 54.22 g/liter, P = 0.003)and plasma (67 ± 22.39 g/liter, P = 0.01) 48hr after therapy was started, in parallel with thedecrease of PMN in ascites. In patients who did notrespond, the production of GE remained elevated.Patients who developed renal insufficiency following SBPhad more marked elevation of GE in plasma (144.8± 33.43 g/liter) than those with normal renalfunction (99.5 ± 27.53 g/liter, P = 0.02).These results suggest that the measurement of GE may behelpful for the diagnosis of SBP in patients withcirrhosis and for assessing the efficacy of therapy. Inaddition, the release of GE into plasma may contributeto the impairment of renal function that follows SBP insome patients.     

Developmental changes in the fatty (fafa) rat: Evidence for defective thermogenesis preceding the hyperlipogenesis and hyperinsulinaemia

Summary Preobese fatty rats have been identified by their lower rectal temperature. Of 51 pups born from matings of heterozygote (Fafa) parents, 16 had low rectal temperatures from day 16 onward (34.6±0.2° C v 35.4±0.3° C) and all subsequently became obese. No animal with the higher normal rectal temperature developed obesity. Hepatic fatty acid synthesis (preobese 0.6±0.1; lean 0.6±0.1 mol/ g/h), hepatic glucose-6-phosphate dehydrogenase activity (G6PDH) (preobese 0.68±0.07; lean 0.71 ±0.03 mol/g/min) and serum insulin (preobese 64 ±2; lean 58±4 U/ml) were unchanged in 18 day preobese, suckling fafa rats. 3 days after weaning hepatic lipogenesis (preobese 25.3±2.0; lean 5.4±0.7 mol/g/h) and G6PDH activity (preobese 4.5±0.5; lean 0.90±0.05 mol/g/min) had increased in both lean and preobese rats although the values attained in preobese rats were significantly greater than in lean rats. When weaning was delayed there was no enhancement in lipogenesis, G6PDH or serum insulin in the preobese rat. The results suggest that the primary genetic defect in fatty rats is not related to the increase in lipogenesis or serum insulin but may reflect a defective thermogenic process.     

Islet B-cell dysfunction and the time course of recovery following chronic overinsulinisation of normal rats

Summary Appropriate insulin therapy may preserve or improve islet B-cell function whereas the effects of overinsulinisation are unclear. Pancreatic islet B-cell function was therefore studied after overinsulinisation of normal rats for 4 weeks (fed blood glucose 2.2–4.5 mmol/l, controls 4.1–7.0 mmol/l). Insulin secretion was assessed by a 3-h hyperglycaemic clamp (10.0 mmol/l) performed 1, 48, and 120 h after insulin withdrawal (n=6 in each group). When the clamp was performed 1 h after insulin withdrawal, clamp insulin concentration was 1.6±0.1 g/l, compared to 9.3±1.0 g/l in control rats. The integrated area under the plasma insulin concentration curve was also significantly decreased (4.8±0.4 vs 20.3±2.2 g·l^–1·h^–1, p<0.001), but recovered to 9.4±1.0 g·l^–1·h^–1 after 48 h, and to 17.5±1.4 g·l^–1·h^–1 after 120 h. Pancreatic insulin contents were decreased at 1 h (6±1 g/g wet wt) and 48 h (54±12 g/g wet wt) but not at 120 h (221±30 g/g wet wt) after withdrawal (controls, 303±29 /g wet wt) and there was a strong relationship with pancreatic preproinsulin mRNA and the clamp insulin response. Thus, overinsulinisation with prolonged periods of low blood glucose concentrations impairs islet B-cell function, but is reversible over 5 days.     

Serumeisen-Normalwerte und statistische Verteilung der Einzelwerte bei Mann und Frau

Zusammenfassung Die Bestimmung der Normalwerte des Serumeisen bei 608 Erwachsenen und die Untersuchung des Verteilungstyps der Einzelwerte zeigt folgende Ergebnisse: Bei 503 Männern beträgt der Mittelwert (als arithmetisches Mittel) 109 g Fe/100 ml ±25 und der Normalbereich (als ±2 SD-Bereich) 59 bis 158 g Fe/100 ml, bei 105 Frauen 91 g Fe/100 ml±27 als Mittelwert und 37 bis 145 g Fe/100 ml als Normalbereich. Die Untersuchung der Verteilung mittelsFisher- undKolmogoroff-Test führte zur Annahme, einer näherungsweisen Normalverteilung.

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Summary The determination of normal values of serum iron in 608 adults and the examination of the frequency distribution gives the following results: the arithmetic mean in 503 male persons is 109±25 g Fe/100 ml and the normal range (2-SD-range) 59 to 158 g Fe/100 ml; in 105 female persons 91±27 g Fe/100 ml mean and 37 to 145 g Fe/100 ml normal range. The assumption of approximate normal distribution are controlled by theFisher- andKolmogoroff-test.

     

Tannin inhibition of protein kinase C in airway epithelium

Tannin, a polydisperse polyphenol extracted from cotton bracts (CBE), has been implicated in the pathogenesis of byssinosis, a lung disease of mill workers. CBE tannin inhibits chloride secretion in airway epithelial cells by means of an unknown mechanism(s). Activation of protein kinase C (PKC) by PMA (phorbol 12-myristate 13-acetate) in airway cells increases chloride secretion. The effect of tannin on this PKC pathway was examined, using canine tracheal epithelium mounted in Ussing chambers. PMA addition (10 nM) to the mucosal bath resulted in a 0.36 ± 0.07 Eq/cm² · h (mean ± SEM, n = 20) increase in short-circuit current (I_sc) and a 0.38 ± 0.17 Eq/cm² · h increase in net chloride secretion (J_net). The inactive 4-phorbol had no effect. Tannin addition to the mucosal bath produced a dose-dependent decrease in I_sc and J_net. In tissues pretreated with 2–50 g/ml tannin, and subsequently stimulated with PMA, tannin inhibited PMA stimulation of chloride secretion beginning at a tannin concentration of 10 g/ml (0.09 ± 0.05 Eq/cm² · h [n = 10] increase in I_sc and 0.08 ± 0.03 Eq/cm² · h increase in J_net with PMA after tannin pretreatment). At 50 g/ml tannin, the stimulatory effect of PMA was completely abolished. The known PKC inhibitor, H-7 (20 M), inhibited PMA stimulation, while chelerythrine (2 M) had not effect on PMA-stimulated I_sc and J_net, and calphostin C was toxic to the airway epithelium. In membrane fragments, 2.5 g/ml tannin inhibited the rate of histone III phosphorylation by PMA from 32.1 ± 4.4 nmol/mg protein per min to 20.1 ± 2.7 nmol/mg protein per min (n = 7). In bovine airway cells, tannin pretreatment (2.5 g/ml) decreased the cytosolic activity of PKC but had no effect on PKC translocation to the membrane. We conclude that tannin inhibits chloride secretion in airway epithelial cells in part by inhibiting PKC.Offprint requests to: Michelle M. Cloutier     

Renal proteinases and kidney hypertrophy in experimental diabetes

Summary IDDM is associated with an increase in kidney size, which is due to cellular hypertrophy and progressive matrix accumulation within the glomerulus and throughout the tubulointerstitium. The present study addressed the potential role of cysteine and metalloproteinases in renal hypertrophy of short-term diabetes. Three weeks after induction of streptozotocin diabetes in rats, intraglomerular gelatinase activity (streptozotocin: 23±4 vs control: 44±3 mU/g DNA) and cathepsin L + B activity (streptozotocin: 6.7±0.8 vs control: 9.3±0.7 U/g DNA) were significantly decreased. Insulin treatment completely prevented the decline in glomerular proteinase activity (gelatinase: 37±6 mU/g DNA; cathepsin L + B: 9.6±0.9 U/g DNA). In isolated proximal tubules a similar pattern of enzyme activity could be observed. Three weeks of diabetes caused a significant decline in cathepsin L + B activity (streptozotocin: 28±2 vs control: 37±3 U/g DNA). Insulin treatment again prevented the decline in these tubular proteinase activities. In parallel, kidney weight increased by 22% and glomerular protein/DNA ratio rose by 17% in untreated diabetic rats. Diabetic rats receiving insulin displayed a normal glomerular protein/DNA ratio and the kidney weight was increased by only 5%. These results show that renal hypertrophy of early diabetes is closely associated with a decline in both glomerular and tubular proteinase activity. Adequate insulin substitution prevented renal hypertrophy and the reduction in proteinase activity.Abbreviations AMC 7-Amino-4-methyl coumarin - EDTA ethylene diamine tetra-acetic acid - PMSF phenylmethylsulfonyl fluoride - TGF- transforming growth factor- - TIMP tissue inhibitor of metalloproteinases - GFR glomerular filtration rate - IDDM insulin-dependent diabetes mellitus     

Phosphodiesterase inhibitors cause relaxation of the internal anal sphincter in vitro

PURPOSE: Pharmacologic treatments are gaining widespread acceptance as first-line therapy for anal fissure. However, existing treatments have limited clinical usefulness because of side effects and incomplete healing rates. METHODS: Fresh human surgical resection specimens containing internal anal sphincter and rectal circular muscle were collected. Strips of smooth muscle were cut from each muscle group and mounted in a superfusion organ bath. The effects of increasing concentrations of phosphodiesterase inhibitors were evaluated. RESULTS: All phosphodiesterase inhibitors tested caused a dose-dependent reduction in the tone of the internal anal sphincter, with potencies as follows: vinpocentine (phosphodiesterase-1 inhibitor; 50 percent maximum inhibition concentration = 0.87 ± 0.10 M), erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (phosphodiesterase-2 inhibitor; 32 ± 4.8 M), trequinsin (phosphodiesterase-3 inhibitor; 0.28 ± 0.041 M), rolipram (phosphodiesterase-4 inhibitor; 63 ± 9 M), zaprinast (phosphodiesterase-1,5,6,9,11 inhibitor; 3 ± 0.69 M), and dipyridamole (phosphodiesterase-5,6,8,10,11 inhibitor; 5.5 ± 2 M). Although all inhibitors were also effective on rectal circular muscle strips, erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride, trequinsin, and rolipram were at least an order of magnitude more potent in this tissue than in the internal anal sphincter. CONCLUSIONS: There are several functionally important phosphodiesterases in the internal anal sphincter and rectal circular muscle. Both adenosine 3, 5-cyclic monophosphate and guanosine 3,5-cyclic monophosphate appear to be important in the myogenic tone of the internal anal sphincter, and this study provides further evidence of the sphincteric specialization of this tissue. Phosphodiesterase inhibitors might represent a new therapy for the treatment of anal fissure.     

Experimental streptozotocin-induced diabetes and intestinal glucose metabolism in the rat,in vivo and in vitro

The intestine has a high glycolytic activity, but its metabolic role could be altered in diabetes mellitus. The aim of the present work was to investigate in vivo the glucose retained and the lactate produced by the intestine of normal and diabetic rats and in vitro the effect of different arterial glucose concentrations on glucose utilization and lactate, alanine, and pyruvate production in normal and diabetic rats when the glucose is supplied to the intestine exclusively via the vascular route. In vivo, the normal and diabetic rats retained similar percentages of the arterially supplied glucose (14.7±3.2 and 12.6±2.4, respectively). In vitro, when the preparations were perfused under hyperglycemic conditions, the glucose consumed, as a fraction of the quantity infused, was significantly lower (P<0.05) in the diabetic (247.0±22.8 mol/mmol infused glucose) than in normal (315.0±16.3 mol/mmol infused glucose) rats. The lactate produced was significantly higher in diabetic than in normal rats whether the preparations were perfused under isoglycemic (P<0.01; 1916.4±124.0 vs 1284±67.7 mol/mmol consumed glucose) or hyperglycemic (P<0.05; 1356.4±199.7 vs 898.0±87.3 mol/mmol consumed glucose) conditions. There was significantly (P<0.05) greater alanine release from the diabetic (123.7±21.8 mol/mmol consumed glucose) than from the normal (40.7±10.3 mol/mmol consumed glucose) rat preparations perfused under isoglycemic conditions.     

Gastric diversion or pylorus ligation for gastric mucosal integrity and acid secretion studies in the rat?

The advantages of gastric diversion over pylorus ligation in rat gastric mucosal integrity and acid secretion studies over 6 hr were investigated. Mucosal injury developed in 80% of pylorus-ligation controls. Atropine (5 mg/kg) or cimetidine (40 mg/kg) had no effect on this injury (2.9 mm²±0.9 and 2.8 mm²±0.7, respectively, vs 3.1 mm²±1, mean±sem, N=10; however vagotomy increased it (13.7 mm²±Pylorus-ligation H⁺ output was higher than that of gastric diversion (390.5 mol±54.8 vs 61 mol±2.5, mean±sem, N=10, P<0.001). Cimetidine (40 mg/kg) depressed H⁺ output of gastric diversion (21.3 mol±1.2 vs 61 mol±2.5, mean±sem, N=10, P<0.001), but not of pylorus ligation (424 mol±74.2 vs 390.5 mol±54.8, mean±sem, N=10). Vagotomy or atropine depressed pylorus-ligation H⁺ output (P<0.001), but each allowed an output (36.6 mol±5.5 and 120 mol±29, respectively, mean±sem, N=10) significantly (P<0.001) higher than that associated with it in gastric diversion (16 mol±1.4 and 17.1 mol±1.6, respectively, mean±sem, N=10). This study demonstrates that in the rat pylorus ligation, in contrast to gastric diversion, injures the gastric mucosa, stimulates H⁺ secretion, and overshadows the efficacy of antisecretory agents.     

Efficacy and Tolerability of the Long-Acting Somatostatin Analog Lanreotide in Acromegaly. A 12-Month Multicenter Study of 58 Acromegalic Patients

Objective: To determine the effects of the new somatostatin analogue, lanreotide, in its prolonged released form (PR), in patients with acromegaly.Design: Prospective open multicenter non comparative study.Setting: Thirty-three university-affiliated medical centers.Patients: One hundred sixteen acromegalic patients with active disease, of whom 58 patients complied with the protocol and completed the 12-month period treatment.Intervention: Lanreotide PR treatment was started at a dose of 30 mg intramuscularly every 14 days. If integrated mean plasma GH levels were not below 5 g/L and/or IGF-I levels were not normalized after one month of treatment, injections were given every 10 days. The duration of the study was 12 months.Results: After one month of treatment mean plasma GH and IGF-I levels had fallen from 10.7 ± 11.1 g/L (mean ± SD; range, 2.6 – 74.8 g/L; median, 7 g/L) and 718 ± 270 g/L (range 338 – 1440 g/L; median, 645 g/L), respectively, to 7.8 ± 10.1 g/L and 575 ± 252 g/L, respectively. Thirty patients (22%) had plasma GH levels below 2.5 g/L, and 8 patients (16%) had age-adjusted normal plasma IGF-I levels. At the sixth month of treatment mean plasma GH levels of 2.5 g/L or less, and normal plasma IGF-I levels were observed in 33%, and 33% of patients, respectively. At the twelvth month of treatment, these percentages were 41%, and 41%, respectively. The interval between two injections was shortened (one injection every 10 days) in 8 of the 58 patients (13%) at the second month of treatment, and at the end of the study, 70% of patients required 3 injections per month. The most frequent adverse event elicited by enquiry was transient diarrhea (76% of patients), followed by abdominal pain (62%) and pain at the injection site (59%). Based on the analysis of a subgroup of 46 patients who had at least a measurement of fecal fat content after day 0 of the study, a non significant increase (from 4.2 ± 3.4 to 5.1 ± 4.3 g/24h, p = 0.3) in mean steatorrhea was observed during treatment. Before treatment, steatorrhea was present in 9 (19%) patients. During the study, 15 additional patients (32%) developed persistent steatorrhea, and there was a transient increase in fecal fat content above 6 g/24 h in another 11 patients. After exclusion of the 7 patients (12%) with gallstones at enrolment, new gallstones were diagnosed in 6 out of 50 patients (12%) during the study.Conclusion: Two or three monthly injections of lanreotide PR decreased GH concentration to less than 2.5 g/L and normalized IGF-I levels in 41% of patients treated during 12 months. The good tolerability of this treatment, and the reduction in the frequency of injections, plus the sustained drug serum concentrations, confirm the usefulness of this new somatostatin analog formulation.     

Short Procedure of GHRH Plus Arginine Test in Clinical Practice

Either in children or in adults, arginine (ARG) alone and combined with GHRH (GHRH + ARG) are reliable tests for the diagnosis of GH deficiency. The procedures of these tests generally include GH measurement every 15 min from baseline up to 90–120 min. Aim of our study was to verify if the procedure of these tests could be usefully shortened in clinical practice. To this goal we have studied 173 normally growing children and adolescents (C, 117 M and 56 F, age: 11.3 ± 0.4 yr.) and 125 young and middle aged normal adults (A, 68 M and 57 F, age: 30.0 ± 0.6 yr.). ARG alone test was performed by 81 C and 33 A (0.5 g/kg arginine, iv, from 0 to +30 min, up to a maximum of 30 g) while GHRH (1 g/kg iv bolus at 0 min) + ARG test was performed by 92 C and 92 A. After ARG alone, taking into account data from +15 to +105 min, GH values above the 3rd centile limit of arbitrary cut-off (7 or 10 g/1 in C and 5 g/1 in A) occurred in 85% or 64% and 94% subjects, respectively. After GHRH + ARG test, taking into account only data at +30, +45, +60 min GH values above the 3rd centile limit (20 g/1 in C and 16.5 g/1 in A) occurred in 99% of subjects in both groups. Taking into account only these 3 timing points, the percentage of GH peak above the third centile limits after ARG alone was never higher than 60% in C and 85% in A. In conclusion, this study shows that single GHRH + arginine test can be reliably performed in a shortened procedure which makes easier the clinical practice and further reduces costs.     

Granulocyte elastase in assessment of severity of acute pancreatitis

Complexes of granulocyte elastase and ₁-antitrypsin are markers for granulocyte activation. In 75 patients with acute pancreatitis these complexes were immunologically determined daily in plasma during the first week of hospitalization. Patients were classified into three groups: mild pancreatitis (I, 1 complication, N=34), severe pancreatitis (II, 2 complications, N= 29), lethal outcome (III, N=12). Initially, granulocyte elastase (mean±sem) was lower in group I (348±39 g/liter) as compared to groups II (897±183 g/l) and III (799±244 g/liter), P<0.001 for I vs II + III. Initial elastase concentrations >400 g/liter were consistent with a severe or fatal course of the disease but did not distinguish between severe and lethal pancreatitis. In patients with mild or severe disease, mean elastase concentrations decreased continuously during the following days (197±15 g/liter in mild cases, 325±30 g/liter in severe cases at day 7). In patients with lethal disease, however, mean elastase concentrations even increased at day 2 and remained higher than 700 g/liter during the observation period. At days 1 and 2 the predictive value for severe or lethal disease of raised (>400 g/liter) elastase concentrations [positive predictive value (PPV) 82%, negative predictive value (NPV) 81%] was better than that of elevated (>100 mg/liter) C-reactive protein (PPV 73%, NPV 73%), elevated (>4.0 g/liter) ₁-antitrypsin (PPV 59%, NPV 50%), or decreased (<1.5 g/liter) ₂-macroglobulin (PPV 82%, NPV 67%). When the time course of the concentrations of the acute-phase proteins was studied, it was found that rises of granulocyte elastase were followed by elevated C-reactive protein levels after one day, by elevated ₁-antitrypsin levels after two days and by decreased ₂-macroglobulin levels after three to four days. We conclude that granulocyte elastase is a good early marker for the severity of acute pancreatitis. Compared with elevated levels of C-reactive protein and ₁-antitrypsin release of granulocyte elastase reflects an event that precedes acute-phase protein induction.     

Cellular ionic effects of insulin in normal human erythrocytes: a nuclear magnetic resonance study

Summary Elevated erythrocyte cytosolic free calcium, and suppressed free magnesium and pH values are associated with the hyperinsulinaemia and insulin resistance of hypertension, obesity, and Type 2 (non-insulin-dependent) diabetes mellitus. To determine the role of insulin in this process, we utilized ¹⁹F- and ³¹P-nuclear magnetic resonance spectroscopy to study the cellular ionic effects of insulin in vitro on normal human erythrocytes. Insulin elevated cytosolic free calcium levels in a dose- and time-dependent manner. The effect began at 10 U/ml, peaked at 200 U/ml, and continued at both the 500 U/ml and 1000 U/ml doses. At 200 U/ml, free calcium levels rose from 24.6±2.5 nmol/l to a peak value at 120 min of 66.4±11 nmol/l (p<0.05 vs basal), levels remaining elevated throughout the incubation (45.7±5.6 nmol/l at 60 min, and 47.9±9.1 nmol/l at 180 min, p<0.05 vs basal, respectively). Similarly, insulin also increased intracellular free magnesium at all time points (basal: 177± 11 mol/l; 60 min: 209±19 mol/l; 120 min: 206±22 mol/l; and 180 min: 202±12 mol/l; p<0.05 vs basal at all times). No insulin-induced changes in pH were observed. We conclude (i) that insulin in physiological concentrations may participate in regulating divalent cations in the mature human erythrocyte, (ii) that insulin per se cannot account for the previously described cellular ionic lesions of hypertension and diabetes, and (iii) that future clinical studies of cell ion metabolism should be conducted in the fasting state, be controlled for ambient circulating insulin levels, or both.     

Effects of Piclamilast,a Selective Phosphodiesterase-4 Inhibitor,on Oxidative Burst of Sputum Cells From Mild Asthmatics and Stable COPD Patients

Oxidative stress associated with increased presence of neutrophils is an important feature of inflammatory airways diseases like asthma or chronic obstructive pulmonary disease. We studied the in vitro effect of piclamilast (RP73401), a selective phosphodiesterase (PDE)-4 inhibitor, compared to theophylline and prednisolone, on respiratory burst of sputum cells from mild asthmatics and COPD patients. Sputum cells were harvested from mild asthmatics and stable COPD patients and treated with piclamilast, theophylline or prednisolone. Respiratory burst was assessed by luminol-dependent chemoluminescence after stimulation with 10 M n-formyl-met-leu-phe (FMLP). Piclamilast inhibited FMLP-induced respiratory burst of sputum cells in a concentration-dependent manner (asthma: EC₅₀ approximately 100 nM, max. inhibition: 97.5±5% at 100 M; COPD: EC₅₀ approximately 1 M, max. inhibition: 70.6±4.5% at 100 M), whereas maximal inhibition observed with theophylline (asthma: max. inhib. 27±15%; COPD: 6±2%, both p < 0.05 vs. piclamilast) and prednisolone (asthma: 16±6%; COPD: 7.8±6.2%, both p < 0.05 vs. piclamilast) was weaker. Inhibition by piclamilast was largely reversed through pretreatment of cells with the adenylcyclase inhibitor SQ22536. We concluded that piclamilast, a selective PDE-4 inhibitor, attenuates the respiratory burst of sputum cells from mild asthmatics and COPD patients in vitro. These data underline the potential of PDE-4 inhibition as a novel therapeutic approach to inflammatory airway diseases like asthma or COPD.     

Iron stores in 1359, 30- to 60-year-old Danish women: Evaluation by serum ferritin and hemoglobin

Summary Iron status, including serum (S-)ferritin and hemoglobin (Hb), was assessed in a population survey comprising 1359 nonpregnant Danish women in age cohorts of 30, 40, 50, and 60 years. S-ferritin levels were similar in 30- and 40-year-old women; they displayed a significant increase in 50-year-old women and a further significant increase in 60-year-old women. In the 30- and 40-year-old women, median S-ferritin was 38g/l, 5–95 percentile 6–135g/l; 17.2% had values < 15,g/l (i.e., depleted iron stores), 22.7% values from 15 to 30g/l (i.e., small iron stores), and 60.1% values > 30g/l (i.e., replete iron stores). In the 50-year-old women, median S-ferritin was 54g/l, 5–95 percentile 10–164g/l; 10.3% had values < 15g/l, 16.5% values from 15 to 30g/l, and 73.2% values > 30g/l. For the 60-year-old women, median S-ferritin was 84g/l, 5–95 percentile 25–249g/l; 1.6% had values < 15g/l, 8.6% values from 15 to 30g/l, and 89.8% values > 30g/l. Blood donors (n=180) had lower S-ferritin than nondonors in all age-groups (p<0.001). In the entire series, Hb levels were similar in 30- and 40-year-old women, median 137 g/l (8.5 mmol/l), 5–95 percentile 121–152 g/1 (7.5–9.4 mmol/l), and higher in 50- and 60-year-old women, median 140 g/l (8.7 mmol/l), 5–95 percentile 123-158 g/l (7.6–9.8 mmol/l) (p<0.0001). Hb values < 121 g/l (7.5 mmol/l) were observed in 3.8% of the women. Women with S-ferritin < 15 g/l (n=161) had lower Hb, median 134 g/l (8.3 mmol/l), than those with S-ferritin > 15 g/l, median 139 g/l (8.6 mmol/l) (p<0.001). Iron deficiency anemia (S-ferritin < 15 g/l and Hb < 121 g/l) was seen in 2.3% of 30- and 40-year-old women, and in 1.1% of 50- and 60-year-old women.     

Insulin levels in the umbilical vein and in the umbilical artery of newborns of normal and gestational diabetic mothers

Summary Insulin levels (by double antibody radioimmunological assay) were studied in the venous blood of mothers at vaginal delivery and in the umbilical vein and artery of their newborns. — In 14 normal mothers the insulin levels after 10 hours fasting were 18.5±3.6 U/ml (mean±S.E.M.). In their newborns (mean: 3.420 kg, all < 4.000 kg, 38–41 weeks gestation) the insulin levels were low and similar in the umbilical vein (5.6±0.7 U/ml) and in the umbilical artery (6.6±0.7 U/ml). The plasma glucose levels in the mothers were 99.7±3.9 mg/100 ml and in the umbilical vein 77.3±3.7 mg/100 ml and the umbilical artery 65.5±3.2 mg/100 ml. They were significantly different from each other. — Eleven normal mothers receiving a glucose infusion (ca. 15 g/3 hours) during delivery had 42.0±9.9 U/ml insulin in their venous blood. In their newborns with a normal birth-weight (mean: 3.585 kg, all < 4.000 kg) the insulin levels were not increased either in the umbilical vein (7.0±1.0 U/ml) or in the artery (7.9±1.0 U/ml). The plasma glucose levels in the mothers were 128.0±7.7 mg/100 ml, and in the umbilical vein 105.0±7.5 mg/ 100 ml and in the umbilical artery 88.8±8.6 mg/100 ml. The plasma glucose levels were significantly different from each other. — In six infants with large birthweight (> 4.100 kg) born to untreated mothers with gestational diabetes the insulin levels were superior to the values found in normal newborns. In three of these infants, born to mothers who did not receive a glucose infusion, the insulin levels in the umbilical vein were 38, 42 and 13 U/ml, and in the artery they were 17, 34.5 and 18.5 U/ml. The other three mothers received a glucose infusion, their newborns had in the umbilical vein an insulin level of 15.5, 65 and 19 U/ml and in the artery 20, 72.5 and 14 U/ml. — In conclusion, the normal infant at birth has a low insulin level, which is equal in the umbilical vein and artery. In 6 heavy infants born to untreated latent diabetic mothers, the insulin levels were significantly higher than in normals, and the levels in the umbilical vein and the artery were different from one another. This latter data on hyperinsulinism is discussed in relation with hyperplasia of the islets of Langerhans observed in stillborn infants of mothers with insulin-dependant diabetes or gestational diabetes.Aspirant du Fonds National de la Recherche Scientifique