Vasoactive substances in early dumping syndrome: effects of dumping provocation with and without octreotide

In patients after gastric surgery, early dumping symptoms can be provoked by oral glucose challenge. Octreotide effectively prevents the occurrence of dumping symptoms. We have studied plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP) concentrations in nine patients with early dumping, 10 surgical control subjects and nine healthy control subjects after an oral glucose challenge preceded by either placebo or 25 μg of octreotide subcutaneously (s.c.). In the dumping group, basal PRA was signifi-cantly ( P  < 0.01) higher (3.9 ± 0.6 μg L⁻¹ h⁻¹) than in either surgical or healthy control subjects (1.1 ± 0.3 μg L⁻¹ h⁻¹ and 1.1 ± 0.2 μg L⁻¹ h⁻¹ respectively) and showed a significant rise after glucose ingestion to 5.4 ± 0.9 μg L⁻¹ h⁻¹ that did not occur in control subjects. Aldosterone concentration showed a concomitant rise. In dumping patients, plasma ANP decreased after glucose ingestion from 31 ± 6 ng L⁻¹ to 21 ± 5 ng L⁻¹ ( P  < 0.05). This decrease did not occur in control subjects. Early dumping is associated with an activation of the renin–aldosterone axis and a decrease in plasma ANP, reflecting a hypovolaemic state. Octreotide prevents the occurrence of these changes.     

Inhibition of paracrine angiotensin-converting enzyme in vivo: effects on interstitial glucose and lactate concentrations in human skeletal muscle

Microdialysis was used to selectively assess the effect of the paracrine renin–angiotensin system (RAS) on interstitial glucose and lactate concentration profiles in skeletal muscle of healthy volunteers ( n  = 8) during basal and insulin-stimulated conditions. Paracrine RAS was selectively inhibited by local retrodialysis with enalaprilate. Under basal conditions, local administration of enalaprilate (2 μg mL⁻¹) increased interstitial dialysate glucose concentration from 0.71 ± 0.14 mmol L⁻¹ to 0.84 ± 0.14 mmol L⁻¹ and decreased the serum interstitial gradient (SIG_glu) compared with baseline ( P  < 0.02). Under clamp conditions, enalaprilate, even at the lowest concentration (0.02 μg mL⁻¹), increased interstitial dialysate glucose concentration from 0.77 ± 0.11 mmol L⁻¹ to 1.02 ± 0.09 mmol L⁻¹ and decreased SIG_glu compared with baseline ( P  < 0.01). Interstitial lactate concentrations slightly increased during basal as well as during clamp conditions ( P  < 0.05 vs. baseline). Selective inhibition of paracrine muscle angiotensin-converting enzyme (ACE) increases interstitial glucose and lactate concentrations and decreases SIG_glu in muscle by facilitating transcapillary glucose transport. This effect is more pronounced during hyperinsulinaemia and may be of clinical relevance in diabetic patients treated with therapeutic doses of enalapril.     

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.     

The association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences

Summary.  Low birth weight is associated with an increased risk of atherothrombosis, which may be related in part to the association between low birth weight and high plasma fibrinogen. The association between birth weight and fibrinogen may be explained by intrauterine, socio-economic or genetic factors. We examined birth weight and fibrinogen in 52 dizygotic and 56 adolescent monozygotic (genetically identical) twin pairs. The dizygotic but not the monozygotic twins with the lowest birth weight from each pair had a fibrinogen level that was higher compared with their co-twins with the highest birth weight [dizygotic twins: 2.62 ± 0.46 g L⁻¹ vs. 2.50 ± 0.41 g L⁻¹ ( P  = 0.04); monozygotic twins: 2.42 ± 0.45 g L⁻¹ vs. 2.49 ± 0.39 g L⁻¹ ( P  = 0.2)]. These findings suggest that the association between birth weight and plasma fibrinogen is abolished after the elimination of genetic influences and therefore that this association has genetic causes. Improvement of intrauterine nutrition may not lower fibrinogen levels in later life.     

Effects of high-altitude chronic hypoxia on platelet α2-receptors in man

During chronic high-altitude (HA) exposure, basal and exercise-induced noradrenaline (NA) increases do not parallel blood pressure (BP) changes observed; unlike β-adrenergic receptors, to our knowledge no data are available on α-receptors. We studied platelet α₂- and leucocyte β-receptors and basal catecholamine levels in 11 trained climbers before and after they had spent a 15-day period at a height of over 4400 m. In six of the climbers we also evaluated catecholamines after maximal bicycle ergometer exercise. After chronic high-altitude exposure, a significant decrease was found in platelet α₂-receptor density and affinity [ B _max from 92.6 ± 6.7 to 54.6 ± 4.2 fmol mg⁻¹ protein ( P  < 0.001) and K _D from 1.271 ± 0.034 to 1.724 ± 0.077 nmol L⁻¹ ( P  < 0.05)], although no changes to β-receptors were observed. No changes were found in basal pre- and post-expedition NA and adrenaline (A), and there was only a slight decrease in post-expedition NA after maximal exercise. Our results suggest that prolonged exposure to hypoxia induces a down-regulation of α₂-receptors, which may be a contributory factor in the regulation of the physiological vascular response to acclimatization.     

Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus

Oxidative damage by free radicals has been implicated in the pathogenesis of vascular disease in diabetes. We compared the radical-scavenging antioxidant activity of serum from 28 patients with insulin-dependent diabetes mellitus and 24 patients with non-insulin-dependent diabetes mellitus uncomplicated by vascular disease with age-matched non-diabetic control subjects. Patients with insulin-dependent diabetes had significantly reduced total antioxidant activity (320.2 ± 11.3 vs. 427.5 ± 19.2 μmol L⁻¹; P  < 0.001). This was attributable to lower urate (209.4 ± 10.4 vs. 297.1 ± 16.7 μmol L⁻¹; P  < 0.001) and vitamin C levels (63.6 ± 6.0 vs. 87.5 ± 4.9 μmol L⁻¹; P  < 0.01). Patients with non-insulin-dependent diabetes had lower total antioxidant activity than age-matched control subjects (433.8 ± 25.4 vs. 473.9 ± 30.2 μmol L⁻¹; NS), reflecting lower urate (299.5 ± 19.4 vs. 324.8 ± 21.4 μmol L⁻¹; NS) and vitamin C levels (38.6 ± 5.7 vs. 58.5 ± 5.3 μmol L⁻¹; P  < 0.05). Multiple regression analysis showed that urate, vitamin C and vitamin E were the major contributors to serum total antioxidant activity. These results show that diabetic patients have significant defects of antioxidant protection, which may increase vulnerability to oxidative damage and the development of diabetic complications.     

Insulin inhibits tissue factor expression in monocytes

Summary.  Objectives:  Platelets from healthy subjects are inhibited by insulin but type 2 diabetes mellitus (T2DM) platelets have become insulin-resistant, which might explain their hyperactivity. In the present study we investigated whether monocytes are responsive to insulin. Methods and results:  LPS-induced tissue factor (TF) upregulation was measured in human monocytes and monocytic THP-1 cells in a factor Xa generation assay. Insulin (0.1–100 nmol L⁻¹) induced a dose-dependent inhibition in both cell types and in monocytes 100 nmol L⁻¹ insulin inhibited cytosolic, membrane-bound and microparticle TF by 32 ± 2, 27 ± 3 and 52 ± 4% ( n  = 3). Insulin induced Tyr phosphorylation of the insulin receptor (INS-R) and formation of an INS-R – G_iα₂ complex, suggesting interference with LPS-induced cAMP control. Indeed, insulin interfered with LPS-induced cAMP decrease and TF upregulation in a manner similar to an inhibitor of G_i (pertussis toxin) and agents that raise cAMP (iloprost, forskolin, IBMX) reduced TF upregulation. Although LPS failed to raise cytosolic Ca²⁺, quenching of Ca²⁺ increases (BAPTA-AM) reduced and induction of Ca²⁺ entry (ionophore, P2X7 activation) enhanced upregulation of TF mRNA and procoagulant activity. Insulin interfered with MCP-1-induced Ca²⁺ mobilization but not with ATP-induced Ca²⁺ rises. Conclusions:  Insulin inhibits TF expression in monocytes and monocyte-derived microparticles through interference with G_iα₂-mediated cAMP suppression, which attenuates Ca²⁺-mediated TF synthesis.     

Low tissue factor pathway inhibitor (TFPI) together with low antithrombin allows sufficient thrombin generation in neonates

Summary.  Neonates have an excellent hemostasis despite, in comparison to adults, markedly decreased and delayed ability to generate thrombin. Only 30–50% of peak adult thrombin activity can be produced in neonatal plasma by means of conventional in vitro assays. We show that in contrast to conventional activation, activation with small amounts of lipidated tissue factor (<10 pmol L⁻¹) results in shorter clotting times and faster activated factor X- and thrombin generation in neonates compared with adults due to the concomitant action of low tissue factor pathway inhibitor and antithrombin. The concentrations of both inhibitors in cord plasma are approximately 50% of the respective adult values. After addition of 2.5 pmol L⁻¹ lipidated tissue factor, cord plasma clotted ∼90 s earlier than adult plasma and the amount of free thrombin generated was ∼90% of adult value (291 ± 14 vs. 329 ± 16 nmol L⁻¹ min⁻¹, P  < 0.01). Our results might help to explain the clinically observed excellent hemostasis of neonates despite low levels of procoagulant factors.     

The effect of folic acid on the homocysteine metabolism in human umbilical vein endothelial cells (HUVECs)

Mild hyperhomocysteinaemia is associated with increased risk for vascular disease. We studied homocysteine export from human umbilical vein endothelial cells (HUVECs) by measuring total homocysteine (tHcy) concentrations in the culture medium. Under standard culture conditions tHcy concentrations in the HUVEC culture medium increased by constant amounts after 24, 48 and 72 h [mean = 2.5 (SD ± 0.7) μmol L⁻¹ homocysteine every 24 h]. As the cells are the only source of homocysteine increase in the culture medium, we designate this as homocysteine export from HUVEC. Folic acid supplementation to the culture medium lowered the homocysteine export in a dose-dependent manner. Methyl-tetrahydrofolate (MeTHF) and folinic acid (a stable precursor of MeTHF) were in this respect about 10 times more effective than folic acid. A 50% reduction in the homocysteine export was seen with 10–30 nmol L⁻¹ MeTHF supplementation; reduction to almost zero was seen with 100–300 nmol L⁻¹ MeTHF. Additions to the culture medium of the other vitamins involved in the homocysteine metabolism, such as vitamin B₁₂, vitamin B₆ and flavin adenine dinucleotide, did not show any effect on homocysteine export. Because homocysteine export reflects an imbalance in the homocysteine metabolism, our observations showed a susceptible dependency of this metabolism on folic acid in endothelial cells.     

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.     

The promoting effect of epinephrine on lipopolysaccharide-induced interleukin-8 production in whole blood may be mediated by thromboxane A2

Summary.  Epinephrine is known to enhance lipopolysaccharide (LPS)-induced interleukin (IL)-8 secretion in a platelet dependent manner. To determine whether thromboxane A₂ (TxA₂; a product from activated platelets) is involved in this process, blood samples drawn either before or 2 h after oral administration of 440 mg acetylsalicylic acid (ASA) were stimulated with LPS (5 ng mL⁻¹) and different concentrations of epinephrine were added (0.1–100.0 µmol L⁻¹). ASA ingestion significantly (global P  < 0.05) reduced the enhancing effect of epinephrine on LPS-induced IL-8 release by 15–28%. To further explore whether TxA₂ may be involved in this process, a TxA₂ agonist (U46619) was added to whole blood together with LPS instead of epinephrine. U46619 mimicked the epinephrine effect: 20 ng mL⁻¹ U46619 enhanced LPS-induced IL-8 release by 39% ( P  < 0.05). Furthermore, preincubation of whole blood with 75 µmol L⁻¹ or 150 µmol L⁻¹ SQ29548, a TxA₂ receptor antagonist, completely blocked epinephrine's promoting effect on LPS-induced IL-8 release. Since thrombin-activated platelets have been reported to be important in the production of IL-8 in monocytes through the activation of monocytes by exposed RANTES in a P-selectin-dependent reaction, we suggest that the epinephrine effect is mediated by enhanced TxA₂ production and subsequent rise in the exposure of RANTES and P-selectin on the platelets of whole blood.     

Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine

We hypothesized that intravenous infusion of the parasympathetic transmitter, vasoactive intestinal peptide (VIP), might induce migraine attacks in migraineurs. Twelve patients with migraine without aura were allocated to receive 8 pmol kg⁻¹ min⁻¹ VIP or placebo in a randomized, double-blind crossover study. Headache was scored on a verbal rating scale (VRS), mean blood flow velocity in the middle cerebral artery ( V _{mean MCA}) was measured by transcranial Doppler ultrasonography, and diameter of the superficial temporal artery (STA) by high-frequency ultrasound. None of the subjects reported a migraine attack after VIP infusion. VIP induced a mild immediate headache (maximum 2 on VRS) compared with placebo ( P  = 0.005). Three patients reported delayed headache (3–11 h after infusion) after VIP and two after placebo ( P  = 0.89). V _{mean MCA} decreased (16.3 ± 5.9%) and diameter of STA increased significantly after VIP (45.9 ± 13.9%). VIP mediates a marked dilation of cranial arteries, but does not trigger migraine attacks in migraineurs. These data provide further evidence against a purely vascular origin of migraine.     

Homocysteine levels are associated with the severity of peripheral arterial disease in Type 2 diabetic patients

Summary.  Background : Homocysteine levels are positively associated with the risk of cardiovascular disease. They might be determined by both MTHFR677C→T polymorphisms and folate or B-vitamin status. Objectives : To investigate the possible association between plasma homocysteine levels and its genetic or environmental determinants and either the presence or the severity of peripheral arterial disease (PAD), in Type 2 diabetic patients. Methods : From a cohort of 944 patients with Type 2 diabetes, 135 patients with PAD were selected, and frequency-matched for age and sex with 219 Type 2 diabetic control patients without macrovascular complications. According to the increasing severity of the disease, patients were divided into PAD₁ (only diffuse calcifications of the arteries without any stenosis or occlusion), PAD₂ (one or two stenosis or occlusions) and PAD₃ (three or more). Results : Homocysteine levels were similar in control and case patients (10.3 µmol L⁻¹ vs. 10.7 µmol L⁻¹, P  = 0.53); however, a significant increase was found in PAD₃ patients: odds ratio = 2.77 (95% confidence interval 1.14, 6.72) for patients with homocysteine levels above the median vs. those under the median in multivariate analysis. Although all significantly associated with homocysteine levels, neither MTHFR genotype nor folic acid or vitamin B₁₂ levels were associated with severity of PAD. A significant interaction ( P  < 0.05) was found between folic acid and MTHFR polymorphism in determining the levels of homocysteine. Conclusions : In Type 2 diabetes, homocysteine was associated with the angiographic severity of PAD, but neither the genotypes nor vitamin levels contributed to this association.     

Kinetics of absorption and elimination of ofloxacin in humans after oral and rectal administrations

Ofloxacin pharmacokinetics have been studied in four healthy subjects after a single oral or rectal dose, each of 200 mg. For the oral dose t _max was about 2 h, C _max 1·96±0·56 μ g/ml and AUC _1–15 15·22  μ g/ml.h. Two‐phase elimination pharmacol kinetics were observed for the oral dose, t_1/2 for the rapid elimination phase was 3·3 h and for the slow phase 10 h. With the rectal dose t _max was 6 h, C _max 0·71±0·44 μ g/ml and AUC _0–15 7·58  μ g/ml.h. The relative rectal bioavailability ( AUC rectal/ AUC oral) was 49·8%.%Elimination rate of the rectal dose was generally slow ( t_1/2=9 h), an observation attributable to the sustained‐release effect of the rectal suppository base, PEG 6000. The indication is that the rectal formulation cannot be substituted totally for the oral without first increasing the rectal dose; the 200 mg suppository can however be employed as a follow‐up therapy to the oral dose in certain situations.     

Increased serum concentrations of the carboxy-terminal cross-linked telopeptide of collagen type I in patients with Gram-negative septicaemia

The authors determined serum levels of the carboxy-terminal cross-linked telopeptide and the carboxy-terminal propeptide of type 1 collagen (ICTP and PICP) in 18 patients with Gramnegative septicaemia before (day 0) and 28 days after therapy and in 18 age- and sex-matched controls by radioimmunoassay. Elevated levels of ICTP were observed in septicaemic patients [median (range): 15 (7–49) μg L⁻¹ before therapy and 14 (6–45) μg L⁻¹ 28 days after therapy vs. 2.1 (1.4–4.3) μg L⁻¹ in normal subjects; P  < 0.01 for both], whereas PICP levels were not different between patients and controls [median (range): 119 (52–275) μg L⁻¹ (day 0) and 133 (79–288) μg L⁻¹ (day 28) vs. 91 (54–213) μg L⁻¹ in normal subjects, P  > 0.05 for all]. The findings suggest an increased production or release of ICTP in Gram-negative septicaemia, presumably owing to an alteration of extracellular matrix during septicaemia-related vascular inflammation.     

Post-prandial metabolism of triglyceride-rich lipoproteins in non-insulin-dependent diabetic patients before and after bezafibrate treatment

Retarded post-prandial (pp) lipid clearance is potentially a major component of the increased cardiovascular risk incurred by hypertriglyceridaemic non-insulin-dependent diabetic mellitus (NIDDM) patients. The effect of bezafibrate (Bz, 400 mg per day for 5 weeks on chylomicron (CM) and remnant clearance after loads of 100 g of fat and vitamin A was therefore explored in 10 male patients (glycaemia 11.9 ±3.3 TG 4.5 ±2.4 mmol L^–1). In all subjects CM-TG and retinyl palmitate (RP) were reduced by 50%, but 8-h non-CM (remnant) RP decreased only in initially mildly hypertriglyceridaemic subjects (−35%, P  <0.05), while in three patients with very elevated initialTG (ε3/3, ε_3/2 and ε_2/2 genotypes) 8-h remnant RP increased by 100%. The decrease in pp CM-TG correlated with that of fasting Sf 20–400 ( r  = 0.686, P  = 0.026), suggesting that improved lipolysis was a major determinant of hypolipidaemic effect. Apo CIII synthesis is known to be depressed by Bz: concentrations were lower under Bz ( P  <0.05). A positive correlation ( r  =0.880, P  <0.001) with fasting TG before treatment and its disappearance after treatment suggested an involvement of high concentrations with hypertriglyceridaemia. Post-prandial non-esterified fatty acids were decreased by 35 in correlation with a significant (−19%, P  <0.05) improvement in fasting glycaemia ( r  =-.801, P  <0.005). These results suggest that Bz acts both on lipolysis and on removal of CM remnants, but that removal can become saturated when lipolysis is massively improved.     

Immunosuppressive effects of endotoxins and bile acids in vivo in the rat

Cell-mediated immunity is impaired during cholestasis. The aim of this study was to evaluate in vivo the effects on this immune defect of high serum levels of endotoxin and bile acids. Heterotopic cardiac allotransplantations were performed in the DA/Lewis rat combination. Cholestasis, induced by ligation/section of the common bile duct, was responsible for a significant delay in the rejection time (16 ± 0.5 vs. 7.1 ± 0.4 days in controls, P <0.01). Elimination of Gram-negative intestinal bacteria from cholestatic rats by a vancocin/colimycin/tobramycin (VCT) mixture induced a significant reduction in endotoxin levels and a reduction in rejection times (9.5 ± 1.0 days, P <0.01) that remained, however, significantly longer than those of controls ( P <0.05). Oral administration of chenodeoxycholic acid in non-cholestatic rats significantly enhanced the serum concentration of total bile acids (60.6 ± 15.3 μmol L⁻¹ vs. 17.4 ± 1.9 μmol L⁻¹ in controls, P <0.01) and postponed allograft rejection (10.7 ± 0.6 days, P <0.01 vs. controls). These data suggest that increased endotoxin level and serum bile acid concentration may play a role in the immunosuppressive effect of cholestasis.     

Cardiac involvement in acute thrombotic thrombocytopenic purpura: association with troponin T and IgG antibodies to ADAMTS 13

Summary.  Introduction: Evidence for cardiac involvement in thrombotic thrombocytopenic purpura (TTP) is uncommonly described. Methodology: We retrospectively reviewed 41 patients assessing troponin T as a marker for cardiac involvement in acute TTP with clinical symptoms, electrocardiograms (ECG) and echocardiograms. A histopathological review of five patients who died of acute TTP was also undertaken. Results: In 54% (22/41) of patients, troponin T was ≥ 0.05μg L⁻¹ (normal range 0–0.01 μg L⁻¹). Half (12/22) had cardiac symptoms and 8/22 with a raised troponin T reported chest pain. ECG changes were present in 62% of patients with a raised troponin T. Median anti-ADAMTS 13 IgG antibody was significantly higher ( P  = 0.018) in patients with troponin T ≥ 0.05 μg L⁻¹ (58.5% (range 17–162%), compared with patients with troponin T < 0.05 μg L⁻¹ (35%, range 9–134%). Patients who died had higher troponin T levels (median 0.305 μg L⁻¹) and raised anti-ADAMTS 13 IgG (median 66.5%). On admission, there were no deaths in those with troponin T ≤ 0.04μg L⁻¹. Histology confirmed widespread myocardial microvascular thrombi. Conclusion: Clinical symptoms, ECG changes and echocardiograms are poor predictors of cardiac disease in acute TTP. Troponin T is specific for cardiac muscle and a sensitive marker of myocardial damage. In TTP patients, raised levels (≥ 0.05 μg L⁻¹) signify myocardial necrosis associated with microvascular thrombi. Mortality and acute morbidity was associated with higher admission troponin T and raised IgG antibody (> 67%) to ADAMTS 13.     

Decreased release of glutathione into the systemic circulation of patients with HIV infection

Low glutathione (GSH) in patients with HIV infection could contribute to their immune deficiency since GSH plays an important role in the function of lymphocytes and sulphydryls decrease the expression of HIV in vitro. In order to gain more insight into the mechanisms responsible for the deranged sulphydryl homeostasis in HIV infection, the release of GSH into the circulation, an estimate of the systemic production of GSH, was determined using a pharmacokinetic approach. The basal plasma concentrations of free GSH (3.3±1.3 vs. 5.3±1.9 μmol L^-1) and cysteine (7.7±2.6 vs. 13.4±4.9 μmol L^-1) were significantly lower in eight HIV-infected patients than in eight controls. Upon infusion of GSH at a constant rate of 1 μmol min^-1 kg^-1, GSH in plasma reached a new plateau. The increment in plasma GSH was significantly larger in the HIV-infected patients than in the controls. The input of GSH into the circulation (12.9±5.7 vs. 30.1±11.7 μmol min^-1 P <0.01) and the clearance of GSH (25±7 vs. 35±7 mL min^-1 kg^-1) were significantly lower in patients with HIV-infection. During infusion of GSH the concentration of cysteine in peripheral blood mononuclear cells of the HIV-infected patients increased significantly. Nevertheless, intracellular GSH did not increase. Thus, the consumption of GSH is not increased in HIV infection. Rather, the present data suggest that GSH in patients with HIV infection is low because of a decreased systemic synthesis of GSH.     

Prostaglandin E2 (PGE2) induces headache in healthy subjects

The role of prostanoids in nociception is well established. The headache-eliciting effects of prostaglandin E₂ (PGE₂) and its possible mechanisms have previously not been systematically studied in man. We hypothesized that infusion of PGE₂ might induce headache and vasodilation of cranial vessels. PGE₂ (0.40 µg kg⁻¹ min⁻¹) or saline was infused for 25 min into 11 healthy subjects in a cross-over, double-blind study. Headache intensity was scored on a verbal rating scale from 0 to 10. In addition, we recorded mean flow in the middle cerebral artery (V_MCA) by transcranial Doppler and diameter of the superficial temporal artery (STA) by high-resolution ultrasonography. All 11 subjects reported headache on the PGE₂ day and no subjects reported headache on the placebo day ( P  = 0.001). During the immediate phase (0–30 min) ( P  = 0.005) and the postinfusion phase (30–90 min) ( P  = 0.005), the area under the curve for headache score was significantly larger on the PGE₂ day compared with the placebo day. PGE₂ caused dilatation of the STA (23.5%; 95% CI 14.0, 37.8) and the MCA (8.3%; 95% CI 4.0, 12.6). We suggest that PGE₂ induces headache by activation and sensitization of cranial perivascular sensory afferents.