Oral magnesium supplementation in insulin-requiring Type 2 diabetic patients.

Oral magnesium (Mg) supplementation can improve insulin sensitivity and secretion in patients with Type 2 diabetes mellitus (DM). We studied the effect of Mg supplementation on glycaemic control, blood pressure, and plasma lipids in insulin-requiring patients with Type 2 DM. Fifty moderately controlled patients were randomized to 15 mmol Mg or placebo daily for 3 months. Plasma Mg, glucose, HbA1c, lipids, erythrocyte Mg, Mg and glucose concentrations in 24-h urine, and systolic and diastolic pressure were measured before and after 3 months treatment. Plasma Mg concentration was higher after supplementation than after placebo (0.82 +/- 0.07 vs 0.78 +/- 0.08 mmol l(-1), p < 0.05), as was Mg excretion (5.5 +/- 1.9 vs 3.7 +/- 1.4 mmol 24 h(-1), p = 0.004) but erythrocyte Mg concentrations were similar. No significant differences were found in glycaemic control (glucose: 10.7 +/- 3.8 vs 11.6 +/- 6.2 mmol l(-1), p = 0.8; HbA1c: 8.9 +/- 1.6 vs 9.1 +/- 1.2%, p = 0.8), lipids or blood pressure. On-treatment analysis (34 patients: 18 on Mg, 16 on placebo) yielded similar results. An increase in plasma Mg concentration irrespective of medication was associated with a tendency to a decrease in diastolic pressure (increased plasma Mg vs no increase: -4.0 +/- 10.1 vs +2.5 +/- 12.0 mmHg, p = 0.059). Three months' oral Mg supplementation of insulin-requiring patients with Type 2 DM increased plasma Mg concentration and urinary Mg excretion but had no effect on glycaemic control or plasma lipid concentrations.

Iron absorption in erythropoietin-treated haemodialysis patients: effects of iron availability, inflammation and aluminium.

BACKGROUND: The response to recombinant human erythropoietin (rHuEpo) is determined primarily by the availability of iron. In contrast to i.v., iron, oral iron supplementation is often insufficient for an optimal response. METHOD: We studied iron absorption and the effects of iron status, aluminium status and inflammation in 19 chronic haemodialysis patients on maintenance rHuEpo therapy. Iron mucosal uptake after 24 h, iron retention after 2 weeks and mucosal transfer of iron were determined with a whole-body counter using an oral dose 59Fe. Iron absorption was measured once without, and once after the ingestion of 2 g aluminium hydroxide. RESULTS: On the basis of transferrin saturation, two groups of dialysis patients were distinguished: a group with a functional iron deficiency (n = 9), and an iron-replete group (n = 10). In the iron-deficient dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 49.9% +/- 29.4, 0.73 +/- 0.29, and 41.6% +/- 32.2, being significantly lower than in a non-uraemic iron deficient population (P < 0.01, P < 0.05, P < 0.01 respectively). In the iron-replete dialysis patients group, mucosal uptake, mucosal transfer, and iron retention were 20.0 +/- 12.3, 0.59 +/- 0.18, and 11.1 +/- 6.7, mucosal uptake and iron retention being lower than in a normal iron-replete population (P < 0.0005 and P < 0.003 respectively). Dialysis patients with high C-reactive protein (CRP) values showed lower iron absorption. Iron absorption data correlated significantly with transferrin saturation and CRP in the iron-deficient group, and with serum ferritin in the iron-replete group. Iron absorption decreased after an aluminium hydroxide challenge in the iron-deficient patients to the lower levels of the iron-replete subjects. Body aluminium stores, estimated by the desferrioxamine test, did not correlate with parameters of iron absorption. CONCLUSION: The absorption of iron in dialysis patients is decreased in haemodialysis patients, which may, at least in part, be due to inflammation. Aluminium ingestion further reduces absorption in functional iron-deficient patients.

Insect-sting challenge in 324 subjects with a previous anaphylactic reaction: current criteria for insect-venom hypersensitivity do not predict the occurrence and the severity of anaphylaxis.

Three hundred twenty-four patients with a history of yellow jacket- (n = 272) or honeybee- (n = 52) sting anaphylaxis were prospectively subjected to an in-hospital sting challenge. Plasma levels of specific IgE and IgG4, skin venom tests, severity of previous reaction, sex, age, atopic constitution, histamine skin test results, location and number of previous stings, time interval between previous anaphylactic reaction and sting challenge, and time interval between sting challenge and onset of anaphylaxis were studied in relation to the clinical severity of a reaction after sting challenge. A recurrent anaphylactic reaction after sting challenge was observed in 25% of yellow jacket- and in 52% of honeybee-sensitive persons. The severity of this reaction correlated significantly with age and the time interval between sting challenge and onset of anaphylaxis only: older persons with faster reactions had more severe symptoms after sting challenge. None of the current criteria for insect-sting hypersensitivity (IgE, IgG4, skin test) significantly related on an individual basis or in combinations to the reaction after sting challenge. We conclude that the current criteria to assess insect-venom hypersensitivity do not relate to the occurrence and severity of anaphylactic symptoms after an insect-sting challenge.

Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin.

Treatment of the anaemia of renal disease with recombinant human erythropoietin results in an improvement of haemostasis and an increased risk of thrombovascular accidents. In this prospective, placebo-controlled, double-blind, and cross-over study, the effects of low-dose acetylsalicylic acid (30 mg daily) on thrombotic and bleeding events during the initial period of treatment with erythropoietin in anaemic haemodialysis patients without previous thrombovascular accidents or known increased risk for thrombosis were investigated. During correction of the haematocrit and the first 3 months thereafter, group A (n = 68) received placebo and group B (n = 69) 30 mg acetylsalicylic acid daily. Cross-over took place after the 3rd month of a stable haematocrit. The study ended 3 months later. Target haematocrit (30-35%) was reached in 12.4 +/- 8 weeks (M +/- SD). In group A the bleeding time was 382 +/- 285 s, decreasing to 282 +/- 208 before cross-over (P < 0.01), and increasing to 395 +/- 271 (P < 0.05) thereafter. In group B the bleeding time was 390 +/- 381 s, 406 +/- 267 (NS), and 285 +/- 238 (P < 0.05) respectively. Twenty-two thrombovascular accidents were seen (16%, 13 during acetylsalicylic acid and 9 during placebo, NS), including 17 fistula thromboses. The incidence of bleeding events was not significantly different between regimens. In conclusion, erythropoietin treatment resulted in a reduction of the bleeding time. When 30 mg acetylsalicylic acid was taken during the treatment, the bleeding time did not decrease.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cefepime in patients with the sepsis syndrome.

We investigated the pharmacokinetics of cefepime after administration of multiple doses to seven patients with the sepsis syndrome. Patients ranged in age from 66 to 78 years (mean +/- S.D.: 74 +/- 5 years); all fulfilled the criteria of the sepsis syndrome and had APACHE-II scores between 14 and 21 (mean +/- S.D.: 17 +/- 2). Serial blood and urine samples were collected after a minimum of 3 days (steady state) of treatment with cefepime 2.0 g bd i.v. Cefepime was assayed by HPLC. Data were analysed using non-compartmental methods. The mean +/- S.D. creatinine clearance (Clcr) was 55 +/- 8 mL/min. Mean +/- S.D. values for selected pharmacokinetic parameters on day 5 were Cmax (94.2 +/- 23.9 mg/L), T1/2 (3.4 +/- 1.1 h), Vdss (32.6 +/- 17.5 L), and the total clearance Cl(total) (125 +/- 51 mL/min). Time to peak plasma concentration (Tmax) and area under curve (AUC) averaged 0.7 +/- 0.2 h and 305 +/- 115 mg.h/L, respectively. Cefepime plasma concentrations were above the MIC90 for Pseudomonas aeruginosa (7 mg/L) for approximately 80% of the time and in the case of Enterobacteriaceae (0.5 mg/L) for 100% of the time. The more prolonged T1/2 in comparison with young healthy volunteers (T1/2 = 2.1 h) is consistent with the changes in renal function associated with increased age, and is comparable to data obtained in healthy elderly subjects (T1/2 = 3.7 h). Cmax, AUC and Cl(tot) were more variable than those observed in previous studies and are probably a reflection of the clinical conditions under which dosing and sampling occurred.

The sepsis syndrome in a Dutch university hospital. Clinical observations.

BACKGROUND: Most studies of the cause of sepsis syndrome focus on patients hospitalized in intensive care units. In this study, we analyzed the incidence, cause, and outcome of the sepsis syndrome in all hospitalized patients. METHODS: Clinical and microbiologic data were obtained for 382 patients (5.6% of all patients admitted) from whom blood was drawn for culture. RESULTS: The incidence of the sepsis syndrome was 13.6 per 1000 patients admitted (1.06 per 1000 hospital days), while the incidence of septic shock was 4.6 per 1000. The respiratory tract was the predominant infection site. Of all patients with sepsis syndrome, 38% (n = 35) had positive blood cultures. More than half of these cultures (13 [57%]) were caused by gram-positive microorganisms (excluding patients receiving selective decontamination of the digestive tract and those with intravascular device-related bacteremias). The mortality for patients with sepsis syndrome without shock was 28% (17/61), while for patients with septic shock, it was 55% (17/31). Patients with cardiovascular diseases had a significantly (P < .005) greater risk of dying during a sepsis syndrome episode than patients with other predisposing factors. Multivariate analysis of factors influencing outcome identified the development of shock and an immunocompromised state as being significantly associated with outcome in patients with sepsis syndrome. CONCLUSIONS: Patients fulfilling the criteria for the sepsis syndrome are at great risk of developing septic shock or multiple-organ failure and subsequently dying. In our hospital, the majority of bacteremic episodes were associated with gram-positive microorganisms.

Controlled insect-sting challenge in 55 patients: correlation between activation of plasminogen and the development of anaphylactic shock.

The pathogenesis of anaphylactic shock is not completely understood. Mast cell degranulation products may stimulate endothelial cells, leading to activation of fibrinolytic and coagulation systems. We investigated the activation of these systems in insect-sting anaphylaxis. Fifty-five patients with a previous insect-sting anaphylactic reaction and 8 volunteers were challenged with an in-hospital sting. Plasma levels of von Willebrand factor (vWF), coagulation, and fibrinolytic parameters were assessed. After the sting challenge, 20 patients developed anaphylactic symptoms, 7 of whom developed hypotension. In only these 7 patients, but not in the volunteers or in the other patients with no or mild anaphylactic symptoms, vWF levels increased from 107% +/- 33% (mean +/- SD) before, to 235% +/- 134% 60 minutes after the onset of clinical symptoms. This increase of vWF was accompanied by an increase of circulating tissue-type plasminogen-activator (tPA) levels from 5 +/- 3 micrograms/L to 50 +/- 59 micrograms/L and of plasminogen-alpha 2-antiplasmin complex (PAP-c) levels from 6 +/- 3 nmol/L to 297 +/- 225 nmol/L. Both tPA and PAP-c levels peaked 5 minutes after the onset of clinical symptoms. Such increases of tPA and PAP-c were not observed in the volunteers or in the patients who did not develop shock. The increase of tPA and PAP-c levels in the hypotensive patients correlated positively with the degree of mast cell degranulation and inversely with the mean arterial pressure. We conclude that activation of plasminogen may be involved in the pathogenesis of anaphylactic shock induced by insect venom.

Extracellular and intracellular magnesium concentrations in asthmatic patients.

Magnesium deficiency is associated with increased contractility of smooth muscle cells. Since contractility of bronchial smooth muscle is important in patients with asthma, magnesium deficiency could negatively influence the clinical condition. We wanted to assess whether magnesium deficiency exists in patients with asthma. Extracellular (plasma) and intracellular (erythrocytes and mononuclear leucocytes) concentrations of magnesium were determined in 20 mildly symptomatic patients with asthma and compared to 20 healthy controls. In asthmatic patients, the mean +/- SD magnesium level in plasma was 0.81 +/- 0.05 mmol.l-1, in erythrocytes 0.20 +/- 0.02 fmol.cell-1, and in mononuclear leucocytes 5.10 +/- 2.55 fmol.cell-1; these values did not differ significantly from those of the healthy controls: 0.79 +/- 0.06 mmol.l-1, 0.19 +/- 0.02 fmol.cell-1, and 4.61 +/- 1.75 fmol.cell-1, respectively. No evidence for the existence of a magnesium deficit needing chronic magnesium supplementation was, thus, found in these patients.

Activation of the contact system in insect-sting anaphylaxis: association with the development of angioedema and shock.

A postulated role of the contact system in anaphylactic reactions to insect stings was investigated. During prospective, in-hospital sting challenge, we collected serial blood samples from five normal volunteers and 16 patients with a history of insect-sting anaphylaxis. Activation of the contact system was assessed by measuring plasma levels of factor XIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes as well as those of cleaved high molecular weight kininogen (HK). In addition, antigenic levels of (pre)kallikrein, factor XII, and HK were measured. No significant changes in contact system parameters were observed in any of the five volunteers or the four patients who did not develop an anaphylactic reaction after sting challenge. In contrast, significant changes in contact system parameters occurred in 7 of the 12 patients with anaphylactic symptoms after challenge. Peak levels of either C1-inhibitor complex were found 5 minutes after the onset of anaphylactic symptoms. The increase in C1-inhibitor was most pronounced in the 4 patients with angioedema, 2 of which also developed shock. However, activation of HK was observed in all four patients with angioedema, the two patients with shock but no angioedema, as well as in 1 of the remaining 6 patients with anaphylactic symptoms other than angioedema or shock. Thus, activation products of the contact system may be involved in the pathogenesis of angioedema and shock in insect-sting anaphylaxis.

The clinical implications of a positive calcitonin test for C-cell hyperplasia in genetically unaffected members of an MEN2A kindred.

C-cell hyperplasia precedes the development of medullary thyroid carcinoma in multiple endocrine neoplasia type 2A (MEN2A). Identification of abnormal calcitonin levels after a provocative stimulus is a technique that has been widely used to diagnose this preneoplastic condition in an early stage during the development of medullary thyroid carcinoma, when total thyroidectomy is likely to be curative. In a MEN2A kindred, we identified seven individuals with abnormal calcitonin test results, whose carrier state was questionable. Five of these people were thyroidectomized, and C-cell hyperplasia was diagnosed. Four of these individuals were the offspring of a mother who is at risk for the development of MEN2A but who has had normal calcitonin test results throughout the years and of a father who is not at risk but who has had abnormal test results over a period of 10 years, without evidence of progressive elevation. None of these people developed other manifestations of MEN2A. DNA analysis using markers linked to the MEN2A gene demonstrated, with > 99% likelihood, that none of the individuals who could be genotyped was a gene carrier. C-cell hyperplasia due to some mechanism other than the presence of the MEN2A gene may also occur in MEN2A kindreds. DNA analysis offers an important additional tool for proper diagnosis in the clinical management of MEN2A families.

Anaphylactic shock after insect-sting challenge in 138 persons with a previous insect-sting reaction.

OBJECTIVE: To study the rate and severity of anaphylactic reaction in relation to plasma levels of cardiovascular mediators in persons with a history of insect-sting anaphylactic shock who were rechallenged with a sting by the same insect. DESIGN: A cohort study with measurements before and after intentional sting challenge. SETTING: Intensive care unit of an 830-bed general hospital, a national center of insect-sting anaphylaxis in The Netherlands. PATIENTS: A total of 138 patients referred after a previous anaphylactic reaction to a Hymenoptera sting; and 8 volunteers. MEASUREMENTS: Signs of anaphylaxis and plasma levels of catecholamines and angiotensins. MAIN RESULTS: Only 39 of 138 (28%) of patients with a previous insect-sting anaphylactic reaction developed anaphylactic symptoms after sting challenge. Values of cardiovascular mediators and mean arterial pressure did not differ after the challenge from initial values in the volunteers or in the patients with a mild or no reaction after challenge. In the 17 patients with anaphylactic shock, mean arterial pressure decreased from 97 +/- 11 (mean +/- SD) to 65 +/- 17 mm Hg (P < 0.001), epinephrine levels rose from a median of 0.3 nmol/L (range, 0.2 to 2.3 nmol/L) to 2.5 nmol/L (0.2 to 35.7 nmol/L; P < 0.05), norepinephrine from 1.5 nmol/L (0.5 to 6.7) to 5.9 nmol/L (1.6 to 30.9 nmol/L; P < 0.01), and angiotensin II from 61 pmol/L (7 to 217 pmol/L) to 105 pmol/L (11 to 286 pmol/L; P < 0.01), all within 5 minutes after the onset of anaphylactic symptoms. The rise of these mediators correlated with the drop in blood pressure (P < 0.001). Dopamine and angiotensin I levels did not change in any participants. CONCLUSIONS: A recurrent insect-sting anaphylactic reaction occurred in only 28% of patients with a previous reaction. During this recurrent reaction, plasma levels of endogenous epinephrine, norepinephrine, and angiotensin II rose in relation to hypotension.

Insect-sting challenge in 138 patients: relation between clinical severity of anaphylaxis and mast cell activation.

One hundred thirty-eight patients with a previous anaphylactic reaction to a yellow jacket or a honeybee sting, as well as eight volunteers, were subjected to an in-hospital sting challenge. Plasma levels of histamine, tryptase, and prostaglandin D2 (PGD2) during sting challenge were studied in relation to clinical symptoms. Prechallenge levels (mean +/- SD) of histamine, tryptase, and PGD2 were 2 +/- 1 nmol/L, 0.3 +/- 0.3 U/L, and 320 +/- 223 ng/L, respectively. In the volunteers and in none except for one of the nonreacting patients, these levels did not change significantly after challenge. In contrast, mean increases in the group of 18 patients with a mild reaction were significant for histamine and tryptase at one or more time points after the challenge. (Five patients demonstrated no increase in histamine; nine demonstrated no increase in tryptase.) Except for histamine levels in one patient, these increases were considerably more in all 17 patients with a severe reaction, starting from the first anaphylactic symptoms. Fifteen minutes later, peak values were reached of 1275 +/- 2994 nmol of histamine per liter (range, 3 to 12800 nmol/L; median, 11 nmol/L) and 406 +/- 1062 U of tryptase per liter (range, 1.8 to 4400 U/L; median, 17 U/L). This rise in levels inversely correlated with the mean arterial pressure. Plasma levels of PGD2 in severely reacting patients did not differ significantly from those in patients with a mild or no reaction. In conclusion, only 28% of patients with a history of Hymenoptera anaphylaxis developed an anaphylactic reaction after an in-hospital challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term follow-up in four large MEN 2 families in The Netherlands.

Results of follow-up studies in four large multiple endocrine neoplasia type 2A families (total of 95 patients affected) have shown a positive effect on the course of the disease since early screening and intervention were initiated in 1974.

Iron metabolism in patients with the anaemia of end-stage renal disease during treatment with recombinant human erythropoietin.

Iron metabolism was studied in 21 patients with the anaemia of end-stage renal disease during 40 weeks of treatment with recombinant human erythropoietin (rhEPO). Oral iron was prescribed to all patients. Initial serum iron concentrations and transferrin saturation levels were subnormal, decreased during the correction period of treatment, and increased thereafter. In 81% of patients in whom pretreatment transferrin saturation was below 0.25, transferrin saturation decreased below 0.16, despite sufficiently high serum ferritin levels. Serum ferritin concentrations decreased significantly. There was no correlation between serum ferritin levels and serum iron or transferrin saturation. Ferrokinetic studies, performed before and during treatment, showed an increase in plasma iron turnover, in erythron transferrin uptake, and in the flux of iron binding sites through the plasma. The rhEPO dose needed to keep the haematocrit at the target level during the maintenance period of treatment was significantly correlated with transferrin saturation, and iron binding capacity, but not with serum ferritin concentrations. This suggests that the functional availability of iron in plasma, rather than the size of body iron stores, is a major factor in the determination of the response to rhEPO treatment in end-stage renal disease.

Treatment of uremic anemia with recombinant erythropoietin also reduces the defects in platelet adhesion and aggregation caused by uremic plasma.

In the present study, uremic patients on chronic maintenance hemodialysis were treated with recombinant erythropoietin. Before and after 20 weeks of treatment, platelet adhesion and aggregation were studied with perfusions over a sprayed collagen surface and over matrix of cultured endothelial cells with high tissue factor activity. The influence of the erythropoietin induced raise in hematocrit on platelet transport and adhesion was excluded by performing the perfusions at a standard red blood cell concentration. The present study clearly demonstrates that erythropoietin treatment improves platelet adhesion and aggregation in addition to and independent of its effect on the hematocrit. Studies with control platelets resuspended in plasma of untreated patients showed that a uremic plasma factor reduced adhesion and thrombin- and collagen-dependent aggregation. Patient platelets resuspended in control plasma showed no defects. After erythropoietin treatment, the plasma-induced inhibition of adhesion and aggregation had almost completely disappeared from patient plasma. The beneficial effect of the erythropoietin treatment on uremic hemostasis is therefore twofold. The increase of the red blood cell mass improves transport of platelets, and thus adhesion to the vessel wall. The intrinsic defect due to the presence of an inhibitory toxin in uremic plasma is, in large part, corrected. Improved neutralization of uremic toxins by red blood cells or less production of toxins by better oxygenated tissue might play a role in the observed phenomena.