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Six cases of chronic granulomatous disese (CGD), three of which correspond to the X-linked genetic form and the three other to the autosomic recessive type are reported. The fact of half of the patients being females is relevant as only 24 are cited by Klebanoff and Clark in their revision in 1978. X-linked CGD: The three patients, two of them brothers, presented their first manifestations in the first year of life; in one of the BCG given at one week of life resulted in adenitis of protracted course with calcificaton. The clinical course has been very severe in two of them. At the present time the patients are 15, 11 and 9 years old. Functional studies have shown very low values in NBT tests, O2 consumption, iodination and bactericidal activity in all three. Intermediate values in the mothers and normal values in the fathers were found. Autosomal CGD: Of our three patients, two were sisters. The first manifestations appeared during the first thrimester of life. The eldest had hepatic and pulmonary granulomata at three years old. At five years, she presented an intestinal obstruction syndrome with gastric antral, duodenal and ileal stenosis caused by intramural granulomata and inflammation; she died of pneumonia shortly after. Her sister had dermatitis, hepatic abscess, pneumonia, adenitis and osteomyuelitis of the ribs; she died at six years old after a bronchopneumonia. Last patient had a sister who died at two years old affected probably gy CGD. At present our patient is 17 months old and so far had recurrent otitis, adenitis, a pneumonia and, recently, hepatic granulomata have been found. Fonctional studies in the two sisters showed similar alterations as those of the three boys. In this patient an alteration of chemotaxis of cellular origen was found as well.

The pathophysiology of posttraumatic pulmonary failure is today reasonably well known. Interaction of altered granulocytes with the pulmonary parenchyma in the form of an inflammatory reaction plays an important role. Gas exchange failure can be a major problem in these patients and influence the prognosis. No effective preventive treatment is known at present except for rapid and appropriate surgical management together with an adequate fluid resuscitation. In addition, the risk of infection and sepsis must be reduced as far as possible and dysfunction of other organ systems prevented if the prognosis is to be improved. Administration of anti-inflammatory agents and corticosteroids has been shown to be without beneficial effect and dangerous in this situation. Intubation and ventilatory assistance should be used depending on respiratory status and pulmonary gas exchange, although potentially lifethreatening side effects of this treatment must be considered. Continuous specific monitoring of respiratory function must be started in the patient after multiple trauma to follow the course of pulmonary dysfunction and adapt therapy.

Chronic granulomatous disease is a usually X-linked disorder of granulocyte bacterial killing. At least 8 variants can be distinguished biochemically. Two male patients aged 20 and 24 years with a relatively benign clinical course are presented. A partial defect of the membrane-bound cytochrome b-245 with a residual bactericidal capacity was detected in both. Due to continuous antibacterial prophylaxis (trimethoprim/sulfamethoxazol) and treatment of infections with intracellularly accumulating agents (e.g. rifampicin, fosfomycin, clindamycin), even patients with complete defects of bacterial killing can reach adulthood today. Physicians and surgeons should be aware of this disorder, which is no longer a "fatal granulomatous disease of childhood".

In paroxysmal nocturnal hemoglobinuria (PNH), infection, both viral and bacterial, disproportionate to the mild neutropenia seen in many such patients is responsible for significant morbidity. We report impaired granulocyte chemotaxis efficiency which may contribute to the problems induced by bacterial infections. PNH (but not normal) granulocytes, after exposure to very small concentrations of activated serum complement components, migrate poorly, as documented by their inhibited chemotaxis toward bacterial products or activated complement components in Boyden chambers. The granulocytes remain intact, excluding trypan blue, phagocytosing, and killing bacteria, despite this activated complement exposure. It is also suggested that this chemotactic defect may involve only a clone of cells, analogous to the clonal lysis of PNH erythrocytes; those few granulocytes capable of migration after exposure to activated complement contain normal quantities of leukocyte alkaline phosphatase (LAP), in contrast to the LAP deficiency of the overall PNH granulocyte population. Since bacterial infection may initiate or potentiate hemolysis, one of the major symptoms of the disease, these results could explain much of the morbidity of PNH.

Granulocyte locomotory responses in 5 patients with symptomatic seasonal allergic rhinitis were lower compared with similar responses from 27 normal nonallergic controls. In a subsequent controlled, double-blind crossover study, neither cimetidine (histamine H2-receptor blocker) nor placebo improved these responses. In our in vitro study, histamine did not inhibit granulocyte responses to chemotactic attractant. These results indicate that defective granulocyte response in patients with seasonal allergic rhinitis may be due to factors other than or in addition to histamine.

1. Enzymes that may contribute to liquefaction of the cornea in retinol-deficient animals and in man have been studied using rat cornea. The established technique of culturing tissue fragments and determining the activity of collagenase (EC 3-4-24-3) and other enzymes in the medium after different periods of culture was used. 2. A collagenolytic system was detected in the media from cultures of rat corneas. This system probably consists of at least two enzymes, a collagenase and a neutral proteinase. 3. Both proteolytic and specific collagenolytic activity were greater in media from retinol-deficient rat corneas. The hydroxyproline level increased in parallel with the increase in enzyme activity. 4. In the final stages of retinol deficiency the cornea is invaded by granulocytes and other cells of the blood and we suggest that destruction of cornea collagen may be due largely to the activity of the enzymes from these cells.

The phagocytic and bactericidal activities of neutrophil granulocytes from 5 patients with early acute myelomonocytic or myeloblastic leukaemia and 5 controls have been examined. In each patient the bactericidal activity was lower than in any control and the neutrophil dysfunction was demonstrated before leukaemia could be diagnosed from clinical and haematological findings. During periods of remission, the bactericidal activity was normal. Results of neutrophil granulocyte function studies may be a significant aid in the early diagnosis of acute myelomonocytic and myeloblastic leukaemia.

Prompted by previous reports that in certain patients with aplastic anemia, cell-mediated autoimmune suppression of myeloid stem cell proliferation may be demonstrable in vitro, we studied the effects of bone marrow lymphocytes from 18 patients with myeloid aplasia on the proliferation of committed granulocytic-monocytic progenitor cells (CFU-C). When assayed in soft agar cultures, marrow suspensions from 10 patients with aplastic anemia contained significantly fewer viable CFU-C than similar cell preparations from control subjects. To deplete marrow cell suspensions of lymphocytes, we employed rabbit anti-human thymocyte serum (ATS), which after multiple adsorptions exhibited marked cytotoxicity for human B and T lymphocytes but had negligible effect on normal CFU-C proliferation. Preincubation of marrow samples from 12 patients with ATS and complement resulted in no inhibition or enhancement of CFU-C growth. In further experiments, marrow cells from 8 patients were incubated with marrow from control subjects prior to CFU-C culture. No suppression of donor CFU-C proliferation was observed in any of these studies, and in 4 cocultures, mixture of the 2 marrow suspensions resulted in stimulation of CFU-C growth. Using these assays, we detected no evidence of cell-mediated inhibition of CFU-C proliferation in any of the 18 patients that we evaluated. Our data support the conclusion that in the majority of patients with aplastic anemia, an absolute deficiency of hemopoietic stem cells is present within the marrow that does not appear to be effected or sustained by suppressor lymphocytes. Whether the reduction of viable stem cells is the cause or the consequence of the process that leads to marrow failure remains unknown.

The effects of endotoxin administration on in vitro granulocyte function were studied in normal man. Four healthy volunteers received an intravenous injection of Pseudomonas endotoxin, 0.1 mug/kg. Endotoxemia resulted in transient neutropenia followed by a rebound neutrophilia. The nadir of the granulocyte count occurred at about 1 hr and maximal neutrophilia 2-4 hr after endotoxin administration. Throughout this time period, neutrophil phagocytosis and killing of Candida albicans were normal, as were resting and postphagocytic glucose metabolism and leukocyte random migration. However, postendotoxin neutrophils demonstrated a markedly decreased chemotactic response in Boyden chambers. The defect was maximal 1 hr after endotoxin administration and persisted 3-4 hr. These observations suggest that, in addition to neutropenia, endotoxin can transiently cause a chemotactic defect or select for a population of circulating neutrophils with an impairment of chemotactic activity.

The patterns of proliferation of C1498 mouse acute leukemic cells have been studied using the diffusion chamber technique of cell culture. These malignant cells grow to the same maximal cell concentration irrespective of initial cell input. Leukemic cells proliferate equally well with or without the stimulus of prior host irradiation. When cells cultured for several days are diluted to the original input concentration and recultured, they rapidly proliferate back to maximal cell number. All of these findings are in sharp contrast to the behavior of granulocytes from normal mouse marrow grown in the same culture system. Co-culutre of equal numbers of normal marrow cells and leukemic cells results in virtually complete inhibition of normal marrow cells and leukemic cells results in virtually complete inhibition of normal granulocyte growth. These experiments provide a means of studying malignant growth of leukemic cells, as compared to the controlled growth and differentiation of normal granulocytes, and mechanisms by which leukemic cells suppress normal granulocyte development.

Peripheral blood leukocyte counts and plasma hormonal changes in response to acute insulin-induced hypoglycaemia were examined in 16 patients undergoing assessment of pituitary function. Eight subjects had a normal cortisol secretory response (Group 1), and 8 patients had definite hypopituitarism in whom the cortisol responses were deficient or absent (Group 2). An equivalent degree of hypoglycaemia was achieved in both groups. In Group 1a biphasic rise in leukocyte count occurred following hypoglycaemia, with an early rise in lymphocytes at 15 minutes after the acute hypoglycaemic reaction, and a later rise in granulocytes. A similar rise in lymphocytes was observed in Group 2, but the rise in the granulocyte count was attenuated, increasing from a basal value of 3.6 +/- 0.6 x 10(9) cells/L to a peak of 7.4 +/- 1.1 x 10(9) cells/L, compared with a peak of 11.7 +/- 1.2 x 10(9) cells/L in Group 1 (P less than 0.05). The usual increment in plasma cortisol in response to hypoglycaemia occurred in Group 1, but plasma cortisol did not rise in Group 2. A correlation was observed between the magnitude of the granulocyte rise and the increment in plasma cortisol in individual subjects (r = 0.64, P less than 0.02). This suggests that the rise in peripheral granulocytes following insulin-induced hypoglycaemia in man is mediated by cortisol released from the adrenal gland, following activation of the hypothalamic-pituitary-adrenal axis.

It has been suggested, on the basis of impaired granulocyte migration to skin windows, that there is a fundamental granulocyte defect in Crohn's disease. In vitro tests of granulocyte function have, however, failed to confirm this. We have studied granulocyte migration to inflamed bowel in Crohn's disease using a new approach which utilises dynamic gamma camera imaging after injection of 111In labelled autologous granulocytes. In 20 of 22 studies there was rapid migration to diseased bowel, compatible with no migration delay. Only two patients showed delays in migration of 12 and 15 minutes respectively, but neither had any clinical characteristics to distinguish them from the other 20 patients. This study shows that the majority of patients with Crohn's disease in relapse have rapid granulocyte migration to diseased bowel and provides evidence against a significant migration defect in this condition.

Acute edematous lung injury is associated with a marked increase in the number of granulocytes in the alveoli and microvasculature of the lung. Phorbol myristate acetate (PMA) causes granulocytes to adhere, aggregate, and release oxygen radicals and granular enzymes. We found that intravenously injected PMA caused a protein-rich edema in lungs of control rabbits but not in granulocytopenic rabbits pretreated with nitrogen mustard. Specifically, control rabbits treated with PMA had higher lung weight to body weight ratios (6.4 +/- 1.0 X 10(-3)) and lung lavage albumin concentrations (190 +/- 44 mg/dl) than granulocytopenic rabbits pretreated with nitrogen mustard and then given PMA (4.74 +/- 0.23 X 10(-3) and 9.9 +/- 3.8 mg/dl, respectively). To further clarify the role of granulocytes in the production of edema, additional experiments were conducted in an isolated perfused rabbit lung. Addition of purified granulocytes and PMA to the balanced salt perfusate caused lung edema, whereas neither granulocytes nor PMA alone caused edema. Specifically, increases in lung weights (42 +/- 9.2 g) and albumin concentrations (1,182 +/- mg/dl) in lung lavages from isolated lungs exposed to granulocytes and PMA were greater than increases in lung weights or albumin concentrations in lung lavages from isolated lungs exposed to granulocytes alone (2.0 +/- 0.4 g and 15 +/- 0.6 mg/dl), or to PMA alone (6.0 +/- 0.6 g and 81 +/- 34 mg/dl). To determine the contribution of oxygen radicals to the pathogenesis of the edema, chronic granulomatous disease granulocytes, which are deficient in oxygen radical production, were added to the isolated lung perfusate. Chronic granulomatous disease granulocytes and PMA did not cause edema in isolated lungs (delta lung weight 1.0 +/- 0.2 g and lavage albumin 12 +/- 5.0 mg/dl) whereas granulocytes from normal human subjects and PMA did (delta lung weight 43 +/- 5.2 g and lavage albumin 1,120 +/- 54 mg/dl). These data suggest that oxygen radicals released from stimulated granulocytes contribute to the pathogenesis of acute edematous lung injury.

We report the case of a 1-year-old girl with the typical symptoms of Shwachman syndrome: neutropenia, insufficiency of the exocrine pancreas, and metaphyseal dysostosis. The clinical course is complicated by recurrent infections caused by the neutropenia and an additional defect of granulocyte function. We demonstrate a severe defect of chemotactic activity as well as a disturbance of the intracellular oxidative metabolism leading to defective killing of Staphylococcus aureus and Candida albicans.

The ingestion, bactericidal activity and metabolism of isolated mature neutrophil leucocytes during phagocytosis was studied in 17 patients with chronic granulocytic leukaemia (CGL) with the simultaneous use of normal controls. Seven patients had received no treatment and the others had been treated previously with Busulphan. The phagocytic indices for killed yeast cells did not differ from those of the controls. A diminished bactericidal activity against E. coli was found in nine CGL cases. The bactericidal capacity closely correlated with the degree of leucocytosis since patients with a WBC count of 90 000/mul or higher with one exception showed decreased bactericidal activities while patients with WBC counts below 90 000/mul with two exceptions showed normal bactericidal activities. The [I-14C]-glucose oxidation during phagocytosis was increased in four patients and decreased in three patients. Some correlation was found between abnormally high or low [I-14C]glucose oxidation and diminished bactericidal activity. The intracellular iodination reaction during phagocytosis was decreased in 10 cases while the extracellular iodination was increased in six cases and decreased in one case. The data for granulocyte iodination did not correlate with WBC count, bactericidal capacity or [I-14C]glucose oxidation. The time course for the bactericidal activity and granulocyte iodination seemed to deviate from the controls indicating a slow initial ingestion and/or degranulation phase. The CGL granulocyte content of myeloperoxidase was normal or increased, the lysozyme content was decreased in half of the cases while the amount of antibacterial cationic proteins was increased, normal or low. The present findings indicate a variety of abnormalities in the mature CGL granulocyte, which are not closely interrelated.

The importance of granulocytes and/or platelets in endotoxin-induced generalized intravascular coagulation was studied as well as thrombocytopenic rabbits. Neutropenia and thrombocytopenia were induced by oral administration of busulphan. Generalized intravascular coagulation, as indicated by renal glomerular microclot formation, was initiated by two intravenous injections of endotoxin. Granulocyte counts before the second injection of endotoxin were most significantly related to activation of intravascular coagulation whereas platelet counts either before the first or second injection of endotoxin were not definitely related to the activation process. Renal glomerular microclots occurred in rabbits after two injections of endotoxin even when the platelet counts were between 500 and 5000/mul. These experiments indicated that granulocytes but not platelets are essential to the activation of endotoxin-induced intravascular coagulation.