A deadly capillary leak attack. Clarkson's disease: a narrative review.

A previously 42-year-old healthy man was brought in by an ambulance to the emergency department with symptoms of a distributive shock. He experienced a rapid decline in his clinical state that evolved into a cardiac arrest. Despite all the performed measures and a prolonged resuscitation, the patient died a few hours later without an initial clear diagnosis. Lab results showed an extremely high haemoconcentration leading to further investigations which suggested the possibility of Clarkson's disease, although septic shock as an alternative diagnosis could not be excluded. Nevertheless, because of its presentation, especially emergency and intensive care physicians should be aware of the existence of this condition in the event of an unexplained refractory distributive shock in combination with haemoconcentration and hypoalbuminemia given its possible fatal outcome.

Subset characterization of myeloid-derived suppressor cells arising during induction of BM chimerism in mice.

To date, myeloid-derived suppressor cells (MDSC) have been best studied in cancer, where they represent an escape mechanism for immune surveillance. MDSC are now also gaining interest in the context of transplantation. Suppressive CD11b(+) myeloid progenitor cells have been reported to expand endogenously during BM chimerism induction in mice; in particular, in irradiated MHC-matched BM chimeras and in parent-in-F1 BM chimeras. Myeloid cell expansion coincided with a time frame where donor lymphocyte infusion (DLI) therapy-mediated GVL effects without GVHD. Hypothesizing that regulatory myeloid cells may have a role in regulating post-transplant T-cell alloreactivity, we performed a detailed phenotypic and functional characterization of these cells in the parent-in-F1 C57BL/6 → [C57BL/6xDBA2] model. We found that transiently expanding CD11b(+) myeloid progenitor cells comprise the two phenotypically and functionally distinct mononuclear and polymorphonuclear MDSC subsets that were recently described in tumor-bearing mice. Both MDSC subsets suppressed in vitro and in vivo alloreactive T-cell proliferation. Also, both the subsets mediated enhanced in vitro suppression when harvested from chimeras, given a prior in vivo challenge with non-tolerant donor T cells, indicating that allo-activated T cells can activate MDSC in vivo. This study provides the basis to investigate the-potentially beneficial-role of expanding MDSC in influencing the risk of GVHD during chimerism induction.

Subclinical GvHD in non-irradiated F1 hybrids: severe lymphoid-tissue GvHD causing prolonged immune dysfunction.

GvHD is an important complication of allogeneic hematopoietic SCT. Parent-in-F1 models are frequently used to study GvHD immunobiology; the characteristics of parent-in-F1 GvHD vary between strain combinations and induction protocols. Here, we observed that a high-dose challenge of non-irradiated B6DBA2F1 and B6SJLF1 recipients with C57BL/6 splenocytes left the majority of recipients clinically healthy, while inducing progressive high-grade donor T-cell chimerism. We investigated this previously undescribed pattern of parent-in-F1 T-cell alloreactivity and studied the effect of serial parental splenocyte infusions on epithelial and lymphohematopoietic tissues. The majority of recipients of 4 weekly splenocyte infusions showed long-term survival with gradual establishment of high-grade donor chimerism and without any signs of epithelial-tissue GvHD. A minority of recipients showed BM failure type of GvHD and, respectively, graft rejection. Moreover, long-term F1 chimeras showed protracted pancytopenia, and in peripheral lymphoid tissues severe lymphopenia and near-complete eradication of APCs and dysfunction in antigen-presenting capacity in remaining APC. Hematopoiesis and lymphoid tissue composition recovered only after multilineage donor chimerism had established. In conclusion, we report on a novel type of parent-in-F1 hybrid GvHD, where a cumulative high dose of C57BL/6 parental splenocytes in non-irradiated F1 mice induces subclinical but severe hematolymphoid-tissue GvHD, causing prolonged immuno-incompetence.

Allogeneic bone marrow transplantation and donor lymphocyte infusion in a mouse model of irradiation-induced myelodysplastic/myeloproliferation syndrome (MD/MPS): evidence for a graft-versus-MD/MPS effect.

The role of graft-versus-malignancy reactivity in the effects of allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion (DLI) for myelodysplastic syndromes is as yet not well established. Clinical data are limited and animal models are scarce. Here, we report on the effects of allogeneic bone marrow transplantation (alloBMT) and DLI in a novel model of irradiation-induced murine myelodysplastic/myeloproliferation syndrome (MD/MPS). Total body irradiation with 8.5 Gy in SJL/J mice gave rise to a lethal wasting syndrome in 60% of mice, characterized by 1 degrees normocellular bone marrow with dysplastic features in erythroid, myeloid and megakaryocytic cell lineages, 2 degrees lymphosplenomegaly with spleens harboring a prominent extramedullary hematopoiesis with erythroid, myeloid and megakaryocytic lineages exhibiting dysplastic features, and foci of dysplastic hematomyelopoiesis in the liver, 3 degrees peripheral thrombocytopenia and 4 degrees evidence of disseminated infection or leukemic transformation in selected animals. This clinicopathological picture was consistent with a murine form of MD/MPS. Syngeneic or allogeneic (BALB/c) T cell-depleted BMT could not prevent the occurrence of lethal MD/MPS. In contrast, DLI at weeks 2-4 after BMT led to restoration of the dysbalanced hematomyelopoiesis. However, severe DLI-induced acute graft-versus-host disease occurred, precluding a survival advantage. We present evidence of the existence of a post-alloBMT DLI-induced graft-versus-MD/MPS effect in murine irradiation-induced MD/MPS.

Pharmacokinetics and pharmacological properties of two galenical preparations of glibenclamide, HB419 and HB420, in non insulin-dependent (type 2) diabetes.

The pharmacokinetics and pharmacological properties of a new micronized preparation of glibenclamide (HB420, 3.5 mg/tablet) were compared to those of the classical formulation (HB419, 5 mg/tablet) in non insulin-dependent diabetics. In a double-blind cross-over randomized acute study, blood glucose, plasma insulin, C-peptide and glibenclamide levels were determined in 10 patients after a standardized breakfast taken 15 min following the ingestion of 1.1 +/- 0.2 tablets of HB419 or HB420. Plasma glibenclamide levels rose faster, the peak value was higher (637 +/- 154 versus 411 +/- 76 nmol/l, p less than 0.05) and the area under the curve from 0 to 240 min was 35% greater (p less than 0.05) on HB420 than on HB419. Nevertheless, the post-breakfast hormonal and metabolic changes were similar with both preparations. In a single-blind cross-over chronic study, 12 patients were treated during 3 successive 6 to 8-week periods--HB419, HB420, HB419--with glibenclamide at a dose of 1.8 +/- 0.3 tablets/day. While fasting blood glucose concentrations remained unchanged throughout the study, postprandial levels decreased from 10.9 +/- 0.8 mmol/l during the HB419 pre-period to 9.2 +/- 0.6 mmol/l during HB420 (p less than 0.02) and rose again up to 10.4 +/- 0.8 mmol/l during the last HB419 period (p less than 0.05). Similarly HbA1c decreased slightly from 7.4 +/- 0.3 to 7.2 +/- 0.4% (NS) and increased again up to 7.8 +/- 0.4% (p less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulsatile hyperglucagonemia fails to increase hepatic glucose production in normal man.

To study the metabolic effects of pulsatile glucagon administration, six male volunteers were submitted to a 260-min glucose-controlled glucose intravenous infusion using the Biostator. The endogenous secretion of the pancreatic hormones was inhibited by somatostatin (100 micrograms X h-1), basal insulin secretion was replaced by a continuous insulin infusion (0.2 mU X kg-1 X min-1), and glucagon was infused intravenously in two conditions at random: either continuously (125 ng X min-1) or intermittently (812.5 ng X min-1, with a switching on/off length of 2/11 min). Blood glucose levels and glucose infusion rate were monitored continuously by the Biostator, and classical methodology using a D-[3-3H]glucose infusion allowed us to study glucose turnover. While basal plasma glucagon levels were similar in both conditions (122 +/- 31 vs. 115 +/- 18 pg X ml-1), they plateaued at 189 +/- 38 pg X ml-1 during continuous infusion and varied between 95 and 501 pg X ml-1 during pulsatile infusion. When compared with continuous administration, pulsatile glucagon infusion initially induced a similar increase in endogenous (hepatic) glucose production and blood glucose, did not prevent the so-called "evanescent" effect of glucagon on blood glucose, and after 3 h tended to reduce rather than increase hepatic glucose production. In conclusion, in vivo pulsatile hyperglucagonemia in normal man fails to increase hepatic glucose production.

Utilization of oral sucrose load during exercise in humans. Effect of the alpha-glucosidase inhibitor acarbose.

We investigated the hormonal and metabolic response to a 100-g sucrose load given 15 min after adaptation to moderate-intensity (50% VmaxO2) long-duration (4-h) exercise in healthy volunteers. The effect of a 100-mg dose of the alpha-glucosidase inhibitor Acarbose ingested with the sucrose load was also investigated. "Naturally labeled [13C] sucrose" was used to follow the conversion to expired-air CO2 of the sugar ingested by isotope-ratio mass spectrometry. Circulating hormone and metabolite data were obtained in nine subjects, and indirect calorimetry and stable isotope methodology were applied to six of them. Under placebo, 93 +/- 4 g sucrose were entirely oxidized during the 4 h of exercise, total carbohydrate utilization was 235 +/- 14 g, endogenous carbohydrate utilization was 142 +/- 13 g, and total lipid oxidation was 121 +/- 7 g. A single oral dose of 100 mg Acarbose ingested with the sucrose load did not significantly modify total carbohydrate (239 +/- 2 g/4 h) or lipid (122 +/- 6 g/4 h) oxidation. In contrast, sucrose oxidation was reduced to 53 +/- 6 g/4 h and endogenous carbohydrate utilization increased to 186 +/- 7 g/4 h. Reduction of the rises in blood glucose and fructose and of the increases in plasma insulin and C peptide under Acarbose confirmed these effects, whereas lower circulating levels of alanine suggested a higher rate of gluconeogenesis. These data show that a 100-g glucose load ingested soon after initiation of exercise is a perfect available metabolic substrate.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin oscillations per se do not affect glucose turnover parameters in normal man.

To compare the metabolic effects of pulsatile vs. continuous iv insulin infusion, normal men had two glucose-controlled iv glucose infusions using the Biostator for 260 min, during which endogenous pancreatic hormone secretion was inhibited by a somatostatin infusion and glucagon was replaced by continuous glucagon infusion. The two tests were performed at 1-week intervals, during which human insulin was infused either continuously at a constant rate of 0.2 mU kg-1 min-1 or in a pulsatile manner at a rate of 1.3 mU kg-1 min-1 with a switching on/off length of 2/11 min. Blood glucose levels and glucose infusion rates (GIR) were continuously monitored, and glucose turnover was estimated using a [3H]glucose infusion. In both tests, plasma C-peptide dropped markedly, whereas plasma glucagon levels were about twice basal values. Plasma insulin averaged 7 mU liter-1 during continuous infusion and oscillated between 1.5 and 35 mU liter-1 during pulsatile delivery. During the first 30-60 min of both tests, the glucose appearance rate and endogenous glucose production (EGP) increased, resulting in moderate hyperglycemia, which completely suppressed GIR. During the last 65 min, EGP declined, while the glucose disappearance rate and the glucose MCR increased, so that GIR increased progressively to maintain the blood glucose clamped at about 5 mmol liter-1. During this period, no significant differences were found between the two modes of insulin administration for any of the parameters studied. Thus, continuous and pulsatile insulin iv infusion, resulting in physiological peripheral plasma insulin levels, altered the glucose turnover parameters equally, in particular inhibiting EGP, which was stimulated by glucagon during the first part of the study, and stimulating peripheral glucose uptake at the end of the study period.

[Amelioration of glucose tolerance and correction of reactive hypoglycemias induced by intravenous calcium infusion cannot be explained by modifications in blood glucagon levels]. / L'amélioration de la tolérance au glucose et la correction des hypoglycémies réactionnelles induites par la perfusion intraveineuse de calcium ne peuvent s'expliquer par des modifications de la glucagonémie.

Glucagon is not involved in intravenous calcium-induced improvement in glucose tolerance nor in correction of reactive hypoglycemia. Recent investigations have shown that intravenous (IV) calcium infusion improved blood glucose values in patients with moderately impaired glucose tolerance, and suppressed hypoglycemia in patients with isolated reactive hypoglycemia. The aim of this study was to investigate the possibility that these changes were secondary to calcium induced alterations in glucagon (IRG) secretion. Four groups of subjects were studied: group 1: normal controls (n = 7); group 2: patients with isolated hypoglycemia (n = 9); group 3: patients with impaired glucose tolerance without reactive hypoglycemia (n = 9) and group 4: patients with impaired glucose tolerance and reactive hypoglycemia (n = 10). All patients were submitted in randomized order to two 5 hour oral glucose tolerance tests (OGTT, 75 g glucose), during a simultaneous infusion, either of saline or of calcium (calcium gluconate 36.3 mEq/5 h.), starting 30 minutes before the OGTT. In none of the groups did calcium infusion influence basal plasma IRG. In group 1 and 3, oral glucose significantly suppressed IRG, and during IV calcium infusion this suppression disappeared. In group 2, glucose ingestion resulted in a paradoxical increase in IRG both during saline and during calcium infusion. In group 4, oral glucose induced a significant drop in plasma IRG and a rebound rise during hypoglycemia, results which were unaffected by IV calcium infusion. These data suggest that glucagon is not involved in the alterations of blood glucose profiles during OGTT observed during intravenous calcium infusion.

Carbohydrate metabolism in women who used oral contraceptives containing levonorgestrel or desogestrel: a 6-month prospective study.

Blood glucose and pyruvate, plasma insulin, and glucagon levels as well as erythrocyte insulin receptors were measured during an oral glucose tolerance test in 38 normal women before and after 6 months' use of one of three new oral contraceptives containing low doses of 19 nortestosterone-derived progestogens, levonorgestrel, and desogestrel. A slight deterioration of glucose tolerance was observed, with the area under the glucose curve increasing by only 7%, 9%, and 12% after Ovidol (Aaciphar SA, Brussels, Belgium), Marvelon (Organon, SA, Brussels, Belgium), and Trigynon (Schering SA, Brussels, Belgium) administration, respectively. We did not find any argument in favor of the development of a state of insulin resistance in women using these compounds, because erythrocyte receptor binding was not modified and plasma insulin responses to glucose were decreased. The glucose-induced suppression of plasma glucagon levels seemed less effective for treatment with the desogestrel-containing preparations than with the levonorgestrel-containing oral contraceptives.

Immunogenicity of semisynthetic human insulin in man. Long-term comparison with porcine monocomponent insulin.

The levels of circulating IgG-insulin antibodies were determined in two groups of diabetic patients before and at 3-month intervals after starting insulin treatment either with monocomponent porcine insulin (n = 17) or with human semisynthetic insulin (SH) (n = 16). Patients were followed during 15.1 +/- 1.0 and 19.9 +/- 1.1 months, respectively (m +/- SEM). In addition, the quality of metabolic control and residual B-cell function were evaluated in the group under treatment with SHI. The percentage of patients who remained antibody-free after 12-21 months of treatment was 67.75% in the human insulin-treated group and only 25-43% in the one receiving porcine insulin (p less than 0.01). Moreover, insulin antibody titers, when present, were usually lower in subjects treated with human insulin. In SHI-treated patients: metabolic control was excellent during the first months of treatment as evidenced by values of mean daily blood glucose (7.3 +/- 0.6 mmol/l), M-index according to Schlichtkrull (7.4 +/- 2.4) and Hb1c (6.8 +/- 0.6%); residual B-cell function, evaluated at 3-month intervals by a circadian profile of plasma C-peptide did not decrease throughout the study; and a significant deterioration of blood glucose control occurred after 18 months of treatment, which might have been due to a less intensive supervision of the patients by the physicians and/or less careful attention by the patients themselves. This observation confirms the need for a continuous education of the patients regardless of the type of insulin used.

Remarkable metabolic availability of oral glucose during long-duration exercise in humans.

It was reported previously that glucose ingestion prior to or at the beginning of muscular exercise was a readily available metabolic substrate. The aim of this study was to see what percentage of carbohydrate utilization can be covered by glucose ingested regularly during exercise. Male healthy volunteers exercised for 285 min at approximately 45% of their individual maximal O2 uptake on a 10% uphill treadmill. After 15 min adaptation to exercise they received either 200 g (group G 200) or 400 g (group G 400) glucose (0.25 g X ml H2O-1) orally in eight equal doses repeated every 30 min (G 200 = 8 X 25 g, n = 4; G 400 = 8 X 50 g, n = 4). Indirect calorimetry was used to evaluate carbohydrate and lipid oxidation. Naturally labeled [13C]glucose was used to follow the oxidation of the exogenous glucose. Total carbohydrate oxidation was 341 +/- 22 and 332 +/- 32 g, lipid oxidation was 119 +/- 8 and 105 +/- 5 g, and exogenous glucose oxidation was 137 +/- 4 and 227 +/- 13 g (P less than 0.005) in groups G 200 and G 400, respectively. Endogenous glucose oxidation was about half in G 400 of what it was in G 200: 106 +/- 27 vs. 204 +/- 24 g (P less than 0.02). During the last hour of exercise, exogenous oxidation represented 55.3 and 87.5% of total carbohydrate oxidation for groups G 200 and G 400, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Diuretic activity of torasemide and furosemide in chronic heart failure: a comparative double blind cross-over study.

The diuretic effects of torasemide and of furosemide were compared in a double blind cross-over study in 13 patients with stable chronic heart failure. Single doses of 10 mg and 20 mg of torasemide and of 40 mg of furosemide were given orally, in a randomized order on 3 consecutive days. In addition, a placebo was administered on the day preceding the 3 active drug treatment days to obtain control data. Each experimental day was divided into three urine collection periods - 0 to 4 h, 4 to 12 h and 12 to 24 h. Urine output, ion excretion and clearance were measured during each of the 3 periods as well as for the 24-h period. Torasemide 20 mg was distinctly more active in each of the 3 collection periods and in the 24-h period than furosemide 40 mg, whereas no significant difference was found between furosemide 40 mg and torasemide 10 mg for most of the experimental data. From 0 to 4 h, both torasemide and furosemide significantly increased the urinary flow rate and the urinary excretion of sodium, chloride and calcium, while they decreased the urinary osmolality when compared to placebo. All the effects persisted in the 4 to 12 h period after torasemide 20 mg in contrast to furosemide, whose effects were limited to the 0 to 4 h period. In the third period (12-24 h), the urine volume fell below the placebo value after furosemide but not torasemide, and only torasemide 20 mg was followed by a persistent decrease in the urine osmolality.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipsic hypernatremia in a patient with pseudotumor cerebri and the primary empty sella syndrome.

Adipsic hypernatremia, a rare disorder, usually secondary to a hypothalamic lesion, is caused by the combination of partial central diabetes insipidus with hypo- or adipsia. We studied a patient who presented with a global hypothalamic dysfunction including adipsic hypernatremia. An extensive work-up disclosed the presence of pseudotumor cerebri and an empty sella turcica. Although endocrine abnormalities including true diabetes insipidus have been reported in conjunction with pseudotumor cerebri or an empty sella, no patient described presented such a global hypothalamic dysfunction or adipsic hypernatremia. The increased intracranial pressure is postulated to be the responsible mechanism for both the empty sella and the hypothalamic dysfunction.