Effect of transferrin concentration on bacterial growth in human ascitic fluid from cirrhotic and neoplastic patients

Abstract. Cirrhotic patients with ascites have an unusually high frequency of development of spontaneous bacterial peritonitis. Iron availability is a key factor in bacterial growth and the ability of the host to limit it is associated with resistance to infection. The present study was undertaken to evaluate the influence of iron and transferrin on bacterial growth in ascitic fluid from 25 biopsy-proven cirrhotic and nine neoplastic carcinomatous patients. No significant differences were found when comparing total ascitic fluid iron between the two groups but ascitic fluid transferrin concentration was significantly lower in cirrhotic (29.26 mg dl^-1 SD 29.58) than neoplastic (96.57 mg dl^-1 SD 76.01) patients. Moreover, a significant negative correlation was found between bacterial growth and transferrin concentration in ascitic fluid (P = 0.039). When the iron concentration in ascitic fluid was experimentally elevated (50 μg dl^-1 or 150 μg dl^-1) we observed a progressive increase in bacterial growth. If transferrin concentration is simultaneously elevated (250 mg dl^-1) this increase does not occur. These findings indicate that the transferrin level is an important factor in the regulation of bacterial growth in ascitic fluid and that the low concentration found in cirrhotic patients could facilitate spontaneous bacterial peritonitis.     

The relationship of serum total sialic acid with serum acute phase proteins and lipoprotein (a) in patients with severe hypertriglyceridaemia

Abstract. Total serum sialic acid (TSA), recently shown to be a cardiovascular risk factor, was measured in 15 patients with severe hypertriglyceridaemia (fasting triglyceride > 2·3 mmol l^-1) and 15 age and sex matched normal control subjects.
To test the hypothesis that serum TSA is related in some way to serum acute phase proteins we also measured five acute phase proteins, namely alpha-1-antichymotrypsin (ACT), alpha-1-acid-glycoprotein (AGP), alpha-2-macroglobulin (AMG), C-reactive protein (CRP) and haptoglobin (HAP) in both groups.
Of note was the significantly elevated serum TSA in the severely hypertriglyceridaemic group as compared to normal subjects. Serum TSA being 71·9 ± 11·7 mg dl^-1 and 59·6 ± 10·2 mg dl^-1 respectively ( P < 0·01 Mann-Whitney test).
Serum CRP was significantly elevated in the type IV patients as compared to controls (6·4 ± 4·5 mg l^-1 vs. 3·3 ± 1·9 mg l^-1 P <0·05 Mann Whitney test) as was serum AMG (2·1 ± 0·89 g l^-1 vs. 1·5 ± 0·53 g l^-1 P < 0·05 Mann Whitney test).
There was no correlation between serum TSA and lipoprotein (a) in either the normal or severely hypertriglyceridaemic subjects. We suggest that serum TSA could in part be related to hypertriglyceridaemia and serum acute phase proteins but that its property as a cardiovascular risk factor is not related to serum lipoprotein (a) concentrations.     

Kinetics of circulating hyaluronan in humans

Abstract The elimination of intravenously injected hyaluronan (HA) from the blood was investigated in 12 healthy volunteers. Three consecutive 30 min infusions of HA were given, separated by 90 min washout periods. Blood samples were taken before, during and after each infusion and the plasma HA concentration was determined. The deposition of HA was modelled according to a Michaelis–Menten kinetic model which included natural synthesis of HA. K_m and V_max was estimated to 0·34 ± 0·13 μgml^-1 and 3·48 ± 0·97/μmin^-1kg^-1 b.w., respectively. The endogenous input was calculated to be 24 ± 11 μg min^-1 and was found to correlate to the age of the subjects ( P < 0·05). As the baseline HA concentration was 0·031 ± 0·21 μg ml^-1, the rate of elimination was linear in the normal concentration range. The calculated V_d was about 75% higher than a weight-estimated plasma volume. The total amount of HA excreted by the kidneys during the study period was 394 ± 77 μg, which corresponded to approximately 1·7% of the total input of HA into the circulation during the experiment.     

Use of recombinant human erythropoietin in combination with parenteral iron in the treatment of postpartum anaemia

The authors compared the effect of recombinant human erythropoietin (rhEPO) in combination with iron with that of iron therapy only in the treatment of postpartum anaemia. Ninety patients (30 patients/group) received either rhEPO (300 U kg⁻¹, i.v. or s.c., once) and iron (parenteral and oral), or iron therapy only. Erythropoiesis was assessed by haemoglobin and haematocrit increase, absolute reticulocyte counting and reticulocyte flow cytometry. Ferrokinetics was assessed by serum ferritin, transferrin and transferrin saturation measurements. There was no difference before therapy for baseline haematological values or iron status. Patients with endogenous EPO levels below 145 mU mL⁻¹ had a significant benefit from intravenous rhEPO administration with highest haematocrit and haemoglobin levels 4 and 14 days after therapy. rhEPO-treated groups showed a higher absolute reticulocyte count 1 and 4 days after therapy and an elevated percentage of high fluorescent reticulocytes (HFRs). Parenteral iron therapy caused a significant increase of ferritin and transferrin saturation, while transferrin concentration decreased. Ferritin and transferrin levels were lowest after i.v. administration of rhEPO, 1 and 4 days after therapy. C-reactive protein concentration was highest in patients who underwent caesarean section until the end of the observation period. A single dose of rhEPO in combination with iron was more effective in treating postpartum anaemia than iron therapy only, in patients who had low EPO levels despite peripartal blood loss. Postpartum low endogenous EPO levels might be a consequence of inhibiting inflammatory cytokines that are released after spontaneous or operative deliveries.     

A study of factors governing fluid filtration in the diabetic foot

Abstract. The effect of lowering the foot on the factors governing fluid filtration in the foot were studied in 12 male insulin-dependent diabetic subjects and 10 controls. Toe skin blood flow, measured by laser Doppler flowmetry, was significantly higher during dependency in the diabetic group. In the control subjects, the colloid osmotic pressure of venous blood sampled from the foot rose to 47·7 mmHg (range 45·1–53·8) after 50 min of foot dependency. In the diabetic group, colloid osmotic pressure failed to rise to the same extent (median 36·7 mmHg; range 28·6–43·0; P < 0·001). Capillary pressure, measured directly by the Landis microinjection technique, was significantly higher in the diabetic group (85·3±1·7 ( n = 6) vs. 92·2±4·6 cm H₂O ( n = 6); P < 0·007), as was foot swelling rate determined by mercury strain gauge plethysmography (0·069±0·022 vs. 0·099±0·025 ml min^-1 100ml^-1; P < 0·02). These results suggest an impairment of the oedema-preventing mechanisms in diabetic subjects which may contribute to the risks of ulceration in the diabetic foot.     

Identification of defective binding of low density lipoprotein by the U937 proliferation assay in German patients with familial defective apolipoprotein B-100

Abstract. Familial defective apolipoprotein B-100 (FDB) is a dominantly inherited disorder characterized by decreased binding of low density lipoprotein (LDL) to the LDL receptor due to a substitution of glutamine for arginine in residue 3500 of apolipoprotein B-100. We present the results of the U937 cell proliferation assay for the detection of familial defective apo B100 in 13 German FDB patients. Due to a defect in the pathway of cholesterol synthesis the human myelomonocytic tumour cell line U937 lacks the ability to synthesize cholesterol which makes proliferation of these cells dependent on the presence of exogenous LDL-cholesterol. U937 cells were incubated with LDL from 13 FDB-patients, 10 healthy normocholesterolaemic individuals (NC) and 26 patients with familial hypercholesterolaemia due to a defective LDL-receptor (FH). At LDL-cholesterol concentrations below 1 μg ml^-1 no proliferation occurred. In the presence of LDL from FDB patients at concentrations between 2·5 μg ml^-1 and 15·0 μg ml^-1, the proliferation was significantly reduced compared to LDL from FH-patients and normocholesterolaemic controls. At 5 μg ml^-1 the reduction was 31–80% regardless of age, sex, apo E genotype, Lp (a)- and lipid levels. At concentrations above 25·0 μg ml^-1 no further differences were observed. The present results indicate that the U937 proliferation assay is a reliable test for the detection of defective LDL-binding due to the 3500 mutation in FDB patients. It may be useful for the detection of defective binding of LDL due to other mutations in the apo B-100 gene.     

The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide (GIP) in man

Abstract. The pharmacokinetics of porcine glucose-dependent insulinotropic polypeptide were investigated in six healthy volunteers. At the maximum infusion dose (0·5 pmol kg^-1 min^-1) a plateau concentration of 115 ± 5·0 pmol/l plasma was obtained. On discontinuation of the infusion, the half-time of disappearance was calculated to be 20·3 ± 1·2 min. The metabolic clearance rate was 2·6 ± 0·1 ml kg^-1 min^-1 and the apparent space of distribution was 75·8 ± 5·7 ml kg^-1. Blood glucose, pancreatic and gastrointestinal hormones remained at basal concentrations throughout. No side effects were noted by any of the subjects studied.     

Erythrocyte uroporphyrinogen-I-synthase activity in β-thalassaemic patients

Abstract. The haem pathway enzyme uroporphyrino-gen-I-synthase (UPGS) was assayed in erythrocyte samples from twenty normal, twenty β-thalassaemia heterozygotic and twenty jS-thalassaemia homozygotic subjects, after partial separation of the erythrocytes according to their age. UPGS erythrocyte enzyme concentration activity was significantly higher in the young than in the old erythrocytes of normal (66·5 ± 11·8 v. 45 ± 9·5 nmol h^-1 I^-1, mean ± SD, P < 0·001) and β-thalassaemia heterozygotic subjects (70·1 ± 18·7 v. 49·8 ± 14·5 nmol h^-1 I^-1, P lt; 0·001), but not in patients with homozygous β-thalassaemia (46·0 ± 12·8 v. 44·1 ± 12·5 nmol h^-1 I^-1, P = 0·65). Furthermore, UPGS enzyme concentration of both young and old erythrocytes of homozygous β-thalassaemia was significantly lower than that of the young ( P < 0·001) but similar to that of the old ( P > 0·2) erythrocytes of either normal or β-thalassaemia heterozygotic subjects. Since severe chronic haemolysis due to haemoglobinopathies is associated with increased UPGS enzyme concentration, these results suggest that UPGS activity may be suppressed in homozygous β-thalassaemia.     

Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria

Abstract. Two enzymes of the haem biosynthetic pathway were investigated in patients with variegate porphyria. Protoporphyrinogen oxidase in cultures of Epstein-Barr virus transformed lymphoblasts from twenty-seven patients showed a mean maximal velocity ( V _max) of 0·39 ± 0·08⁺ nmol of protoporphyrin mg protein^-1 h^-1, a 52% reduction ( P < 0·001) from a non-porphyric control group (0·82 ± 0·10). K _m values (1·00 ± 0·27 μ M) did not differ significantly ( P > 0·05) from control values in any of the patients. The mean V _max of porphobilinogen deaminase in the cultures was 1·50 ± 0·18 nmol of uroporphyrin mg protein^-1 min^-1, a 24% reduction ( P < 0·001) from controls (1·94 ± 0·14). Mean porphobilinogen deaminase activity in the erythrocytes of twenty-one patients with variegate porphyria was 8·37 ± 1·99 nmol of uroporphyrin 1 erythrocytes^-1 s^-1, a 28% reduction ( P < 0·001) from normal (11·98 ± 2·11). The reduced activities of these two enzymes comply with the expression of variegate porphyria during its quiescent and acute phases.     

Time course of haemodynamic changes after maximal exercise

Abstract. The haemodynamic changes during 4 h following maximal upright bicycle exercise were evaluated in six normals in a randomized controlled crossover design. Total peripheral resistance was reduced to 2 h (-6·7 mmHgmin l^-1, P < 0·05); exercising and non-exercising vascular beds were vasodilated for 2h (-24·1 and -23·8 mmHg min ml^-1 100ml^-1 tissue, respectively, P < 0·05), associated with reductions in systolic (-5·8 mmHg, P < 0·05) and diastolic pressure (-8·3mmHg, P < 0·05). Rise in cardiac index for 1 h (+0·51min^-1 m^-2, P < 0·05) was accounted for by an elevated heart rate (+14·4 beats min^-1, P < 0·01) as stroke volume was unchanged. Body temperature was elevated until 40min (+0·20°C, P < 0·05). The return of all haemodynamic variables to control by 3h suggests a 3 h limit for a hypotensive effect of exercise. Rise in body temperature is not the only factor responsible for the hypotension.     

Liposomal dexamethasone effectiveness in the treatment of hypersensitivity pneumonitis in mice

Abstract. The effects of daily intranasal instillation of liposomal dexamethasone and free dexamethasone phosphate were compared in a murine model of hypersensitivity pneumonitis induced by Saccharopolyspora rectivirgula (formally known as Micropolyspora faeni ). After 3 weeks of antigen and liposome instillations, lung response was evaluated by bronchoalveolar lavage cell counts, lung index and histopathology. Systemic absorption was evaluated by measuring plasma adrenocorticotropic hormone (ACTH) level. Free dexamethasone phosphate induced a dose-dependent response with the maximal effect reached at 1 mgkg^-1. At 0.1 mgkg^-1, liposomal dexamethasone had a greater effect than free dexamethasone phosphate on bronchoalveolar cells ml^-1: 3.01 × 10⁵± 0.35× 10⁵ compared to 4.70×10⁵± 0.34 × 10⁵, and lung index: 1.22 ±0.10 compared to 1.86 ± 0.07. Effect on histopathology was similar. Plasma ACTH levels (pg ml^-1) were: 75.1 ± 14.0 for animals receiving antigen and free dexamethasone phosphate (0.2 mg kg^-1), and 149.7 ± 12.0 for animals receiving antigen and liposomal dexamethasone (0.2 mg kg^-1). In conclusion, liposome-incorporated dexamethasone is efficient in the treatment of experimental hypersensitivity pneumonitis and, contrarily to free dexamethasone phosphate, does not inhibit ACTH secretion.     

Effects of cyclooxygenase inhibitors, prostaglandins F2α and I2, on isolated coeliac and basilar arteries of alloxan-diabetic dogs

Abstract. The effects of prostaglandin synthetase inhibitors PGF_2α and PGI₂ on the tone of isolated basilar and coeliac arteries were studied in healthy and alloxan-diabetic dogs. PGF_2α (1 μmol l^-1) produced a significantly higher tone in diabetic basilar arteries (1·15 ± 0·16 mN) than in normal cerebral vessels (0·7 + 0·10 mN). By contrast, the contractile responses of normal and diabetic coeliac arteries to PGF_2α did not differ. The cyclooxygenase inhibitors indomethacin (3 μmol l^-1) and suprofen (0·58 μmol l^-1) potentiated the PGF_2α-evoked contractions in all of the vessels studied. The percent potentiation was greater (50–60%) in the basilar arteries from alloxan-treated dogs than in normal basilar vessels (22–30%). There was not such a difference between diabetic and normal coeliac arteries. Prostacyclin produced a concentration-related relaxation in the presence of indomethacin or indomethacin + PGF_2α. The relaxant potencies of PGI₂ were similar in the vessels from metabolically healthy and diabetic dogs. The IC₅₀ values for PGI₂ were 11·6 ± 1·3 and 11·8 ± 1·8 nmol l^-1 in normal and diabetic basilar arteries, respectively; they were 25·4 ± 3·2 and 26·2 ± 3·9 nmol l^-1 in control and alloxan-treated coeliac vessels. These results indicate that normal and diabetic vessels may have differential reactivity to cyclooxygenase inhibitors, this difference being dependent on the vascular region.     

Platelet transmembrane signalling responses to collagen in familial hypercholesterolaemia

Abstract Washed platelets from patients with familial hypercholesterolaemia (FH) were found to be more reactive towards collagen than those from control subjects. The dose required to achieve half maximum aggregation was found to be 0·6 ml^-1 for FH patients whilst that for control subjects was 1·25 μg ml^-1. In both types of platelet, intracellular Ca²⁺ levels, as monitored by the Ca²⁺-dependent photoprotein, aequorin, rose on stimulation with collagen and then fell to basal levels, probably due to resequestration by the reticular system. This effect was not due to exhaustion of the supply of aequorin since sustained Ca²⁺ influx induced by the ionophore, A23187, gave a stable signal that did not return to baseline. Similarly, inositol 1,4,5, trisphosphate levels increased in the cytosol after stimulation and then fell to unstimulated values. When stimulated with collagen, platelets from FH patients showed a greater extent of cytoplasmic calcium mobilization ( P < 0·05) when compared to controls, coupled with a greater extent of inositol phospholipid hydrolysis ( P < 0·05). At doses of collagen sufficient to give either 100% or 50% aggregation, platelets from patients or control subjects showed the same amplitude of ATP release at either dose suggesting that the trigger for vesicle release is more sensitive in FH.     

Lack of correlation between endotoxaemia and renal hypoperfusion in cirrhotics without overt renal failure

Abstract. Renal involvement in patients with liver cirrhosis is characterized by renal vasoconstriction, the aetiology of which remains obscure. Endotoxaemia, frequently found in patients with liver cirrhosis and renal failure, has been emphasized as a pathogenic factor.
In fifty-seven patients with liver cirrhosis without overt renal failure endotoxin plasma level (Limulus Lysate test), mean renal blood flow (MRBF) (¹³³Xe washout technique), and effective renal plasma flow (ERPF) (p-aminohippurate clearance) were determined.
MRBF was decreased in nineteen out of twenty-seven patients, averaging 1·88 ± 0·51 ml g^-1min^-1 (in fourteen controls 3·17 ± 0·51 ml g^-1ml^-1). ERPF was decreased in seventeen out of thirty patients, averaging 380±164 ml/min (in eighteen controls 624±127 ml/min). Systemic endotoxaemia was found in sixteen out of fifty-seven patients, levels ranging from 0·62 to 200 ng/ml. No significant difference in renal blood flow values was found between patients with and without endotoxaemia (MRBF = 1·78 ± 0·51 and 1·93 ± 0·52 ml g^-1min^-1 respectively; ERPF = 429±119 and 365±175 ml/min respectively). No significant difference in the frequency of endotoxaemia was found between patients with impaired and unimpaired renal blood flow. Moreover no relation was found between endotoxin plasma levels and MRBF and ERPF respectively.
In conclusion in patients with cirrhosis without overt renal failure renal vasoconstriction does not seem to be related to endotoxaemia.     

The in vivo effect of interleukin-1β on urea synthesis is mediated by glucocorticoids in rats

Abstract. Interleukin-1 β has been proposed as one mediator of parts of the catabolic response following surgery. However, it is not known whether such an effect is due to interleukin-1 β itself or the associated changes in glucocorticoids.
The effect of interleukin-1 β on urea synthesis was investigated in rats given a high (10 μg kg^-1) and a low dose (0·1 μg kg^-1) of recombinant interleukin-1 β (NOVO, Denmark) 3 h prior to determination of the rate of urea synthesis in vivo . Urea synthesis increased dose-dependently after the low dose from 4·0±0·3 (control) to 6·3±0·3 ( P <0·01), and after the high dose to 7·7±0·3 μmol (min·100 gBW)^-1 ( P <0·01). The blood concentration of amino acids fell during interleukin-1 β treatment, so the effect on urea synthesis was not due solely to increased proteolysis, but was exerted predominantly in the liver.
Pharmacological glucocorticoid receptor blockade (hormone analogue RU486, Roussel–Uclaf, Paris, France) given 1 h prior to the interleukin treatment, completely abolished the interleukin-1 β induced increases in urea synthesis. The study demonstrates that interleukin-1 β stimulates urea synthesis in vivo , and that the major part of the effect depends on glucocorticoid action.     

Venous compliance and the venodilatory effect of nitroglycerin in insulin-dependent diabetic patients with and without (incipient) nephropathy

Abstract. The venous system plays a pivotal role in volume and blood pressure homeostasis. We tested the hypothesis that the visco-elastic properties of the peripheral venous system are reduced in patients with (incipient) diabetic nephropathy. Twenty-two normotensive patients with long-term insulin-dependent diabetes mellitus (IDDM), 11 without and 11 with (incipient) nephropathy (eight microalbuminuria and three proteinuria, serum creatinine below 100 μmol l^-1), and 14 healthy age/sex matched controls were studied. Forearm venous compliance (VENCOMP) was determined using strain gauge plethysmography and direct intravenous pressure measurements. Furthermore, the venodilatory effect of 0·4 mg sublingual nitroglycerin (NTG) was studied. In comparison with healthy controls, VENCOMP was decreased in patients without and with (incipient) nephropathy, without any differences between the two diabetic groups: 0·059 (0·052–0·066), 0·044 (0·038–0·059) and 0·049 (0·046–0·058) ml 100 ml^-1 mmHg^-1, respectively (medians and interquartile ranges) ( P <0·05). No differences in the increase of forearm volume after NTG were observed: 0·34 (0·11–0·51), 0·37 (0·19–0·50) and 0·39 (0·20–0·55) ml 100 ml^-1, respectively. In conclusion, the visco-elastic properties of the peripheral venous system are reduced in patients with long-term IDDM. This reduction is not related to the presence of nephropathy. No major differences were observed in NTG-induced venodilation between diabetic patients and healthy subjects.     

Transfusion trigger – how precise are we? Intraoperative blood transfusion practices in a tertiary centre in Nigeria

summary .  To determine how well anaesthetists in Nigeria determine the need for transfusion based solely on physiological variables and estimated blood loss. To determine the incidence of inappropriate blood transfusion. Anaesthetists in our hospital determine when to transfuse patients based solely on clinical acumen. This may result in inappropriate transfusion especially in this subregion where blood donors are scarce and risk of transmission of infection high. All surgical patients requiring blood transfusion were prospectively studied over 3 months. Transfusion was based solely on the discretion of the attending anaesthetist. Haemoglobin (Hb) concentration was measured prior to transfusion and 24 h postoperatively. Appropriate transfusion was defined as blood transfusion at Hb < 8 g dL⁻¹ or 10 g dL⁻¹ in the elderly and those with medical comorbidities. The trigger for transfusion was documented as well as estimated blood loss. Thirty-four patients were studied. The mean pretransfusion Hb was 8·09 ± 2·45 g dL⁻¹ (range 4·6–14·2). Twenty-one patients (61·8%) had appropriate blood transfusion. The commonest transfusion triggers were clinical pallor (82·4%), excessive blood loss (76·4%), delayed capillary refill (55·9%) and severe hypotension (50%). The use of near patient monitoring devices might further improve blood transfusion practice in this setting where donor blood is scarce.     

Gastric acid regulates the release of plasma secretin in man

Abstract. Fasting plasma secretin determined in nine healthy subjects, twelve patients with active duodenal ulcer and four with Zollinger-Ellison syndrome were 3·2±0·4, 5·1±1·2 and 20·3±1·3 pmol/l respectively (mean ±SEM). Cimetidine significantly ( P <0·05) reduced levels in those with duodenal ulcer, as did gastric aspiration in the Zollinger-Ellison group. A significant correlation ( P <0·001) was found between basal acid output and mean fasting plasma secretin. After a solid meal and subsequent liquid soft drink, no sustained mean rise in plasma secretin was observed; changes in secretin appeared to coincide in time with rapid falls in duodenal pH, though little relationship could be established between the absolute level of pH and changes in plasma secretin. The mean peak post-prandial rise in plasma secretin observed after solids was significantly ( P <0·05) greater in duodenal ulcer patients than controls (9·1±1·1 versus 6·7±0·5 pmol/l) as was the mean integrated post-prandial release (1002±110 versus 710±67 pmol min^-1 l^-1). Cimetidine reduced both rises ( P <0·05) and was associated with significantly less duodenal pH readings below 4 ( P <0·001). These results suggest that gastric acid is a major release mechanism for plasma secretin both fasting and after meals but it is likely the acid load rather than absolute pH in the duodenum which determines circulating levels.     

Population pharmacokinetics of amikacin in intensive care unit patients studied by NPEM algorithm

Summary— The population pharmacokinetics of amikacin was studied in 40 intensive care unit patients (212 plasma concentrations) by NPEM algorithm using a one-compartment model. The population was best characterized by the following pharmacokinetic parameters: renal clearance relative to creatinine clearance (C_s = 0.96 ± 0.33), and either the total volume of distribution (V_d = 23.9 ± 7.0 I) or the volume of distribution relative to body weight (V_s = 0.36 ± 0.10 1·kg⁻¹. The volume of distribution was increased with respect to the usual value of 0.25 1·kg⁻¹. The statistical distribution of these pharmacokinetic parameters was approximately gaussian, with no significant correlation between volume of distribution and clearance. The medians and standard deviations of C_s and V_s were used as reference population values to estimate the pharmacokinetics of amikacin in a second group of 29 patients by the bayesian method, with two blood samples per patient. For each patient, the fitted parameters were able to predict the plasma concentrations of amikacin during the next 72 h with no significant bias and good precision (2.9 mg·1⁻¹ for peaks and 0.5 mg·1⁻¹ for troughs). This study confirms the ability of the NPEM algorithm to provide reference population values for use in bayesian monitoring of aminoglycoside therapy.     

The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance

Backround Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene.
Materials and methods The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects.
Results No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30·6 ± 0·9 kg m⁻² (mean ± SD) in subjects with the C/G genotype and 24·8 ± 4·6 in subjects with the C/C genotype, P  = 0·012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70·1 ± 14·7 vs. 56·7 ± 14·2 µmol kg⁻¹ min⁻¹, P  = 0·014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4·51 ± 1·12 vs. 5·17 ± 1·28 mmol L⁻¹, P  = 0·049), but not in women.
Conclusions The HSL gene is not a major gene for FCHL. However, the − 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.