Granulocyte function in chronic granulocytic leukemia. II. Bactericidal capacity, phagocytic rate, oxygen consumption, and granule protein composition in isolated granulocytes.

The initial rate of phagocytosis, oxygen consumption rate during phagocytosis, bactericidal capacity against Escherichia coli, and the granule protein composition of isolated mature-appearing granulocytes were studied in 23 patients with chronic granulocytic leukemia (CGL) with the simultaneous use of normal controls. The initial rate of phagocytosis was decreased (p less than 0.05) in the CGL patient group, as were oxygen consumption rate (p less than 0.001) and bactericidal capacity (p less than 0.001). Kinetic analysis of the ingestion rate showed CGL granulocytes to have the same capacity to bind the particles as normal granulocytes. Both specific and primary granule protein deficiencies were shown for CGL granulocytes, and these deficiencies were more pronounced at or near blast cell transformation. Analysis of all different granulocyte function parameters showed an inverse correlation to white blood cell counts (p less than 0.01) and to the percentage of immature granulocytes in peripheral blood (p less than 0.001). The leukocytosis doubling time was progressively shortened during the chronic course of the disease. A correlation was found between granulocyte function parameters and leukocytosis doubling time (p less than 0.001), indicating that granulocyte function was progressively deteriorating during chronic phase CGL, and may be an expression of increasing disturbance of the differentiation process.     

Cocaine use in Europe - a multi-centre study. Methodology and prevalence estimates

An increase in the use of cocaine and crack in several parts of Europe has raised the question whether this trend is similar to that of the USA in the 1980s. However, research in the field of cocaine use in Europe has been only sporadic. Therefore, a European multi-centre and multi-modal project was designed to study specific aspects of cocaine and crack use in Europe, in order to develop guidelines for public health strategies. Data on prevalence rates were analysed for the general population and for specific subgroups. Despite large differences between countries in the prevalence of cocaine use in the general population, most countries show an increase in the last few years. The highest rate with a lifetime prevalence of 5.2% was found for the United Kingdom, although with a plateau effect around the year 2000. With regard to specific subgroups, three groups seem to show a higher prevalence than the general population: (1) youth, especially in the party scene; (2) socially marginalized groups, such as homeless and prostitutes or those found in open drug scenes; (3) opiate-dependent patients in maintenance treatment who additionally use cocaine. Specific strategies need to be developed to address problematic cocaine use in these subgroups.     

alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.     

Estrogen-progestogen therapy for low bone mineral density in primary biliary cirrhosis

Abstract: Aims/Background: Patients with primary biliary cirrhosis (PBC) often have osteoporosis of the high-turnover type, suggesting that estrogen could have a beneficial effect. However, the cholestatic potential of estrogen could imply a risk of increased cholestasis in a disease characterized by cholestasis. The aim of the present study was to test whether hormone replacement therapy (HRT) could be used to increase bone mineral density (BMD) in PBC patients with osteoporosis, without causing deterioration of the liver function. Methods: Nine female PBC patients with osteoporosis and one with osteopenia were offered HRT for two years. The change in BMD was compared to the change in ten age-matched female PBC patients who had less severe or no osteopenia and who did not receive HRT. Liver function tests were checked at six-month intervals. Results: HRT patients showed a statistically significant increase in lumbar spine BMD and total body BMD whereas control patients showed a significant decrease in lumbar and total body BMD. In contrast to the controls, HRT patients also showed a decrease in truncal fat (–3.8%). Neither of the groups showed any statistically significant changes in the liver function tests. Conclusions: HRT is safe and effective in female PBC patients with osteoporosis.     

Muscle-nerve involvement in autosomal dominant progressive external ophthalmoplegia with hypogonadism

Sixteen members of a family with a history of autosomal dominant progressive external ophthalmoplegia (adPEO) with hypogonadism were examined. The muscular involvement commenced cranially and descended in relation to increasing disease duration. The neuromuscular signs were PEO, dysarthria, dysphonia, limb muscle weakness with wasting, absence of Achilles tendon reflexes, and distal vibration sensory loss. The electromyogram (EMG) was myopathic in facial and proximal limb muscles. Neurogenic involvement was suspected in a few tibial anterior muscles. Neurography showed signs of axonal neuropathy correlated to clinical signs. F-responses were reduced in number or absent in peroneal nerves, and did not correlate to clinical signs or disease duration. Muscle biopsies in advanced cases had structural abnormalities of mitochondria, ragged-red fibers, and focal cytochrome c oxidase deficiency. A combination of muscle-nerve involvement with PEO, Achilles tendon areflexia, distal vibration sensory impairment, myopathic EMG, and abnormally low sural nerve responses seems to be typical of this type of mitochondrial disorder. © 1996 John Wiley & Sons, Inc.     

Proliferative activity and number of clonal chromosome aberrations in non-Hodgkin's lymphomas

Thymidine labelling indices (LI) and the number of clonal chromosome aberrations were assessed in fine-needle aspirates from enlarged lymph nodes in 22 patients with non-Hodgkin's lymphoma (NHL). 11 patients had LI greater than 3.0 (median 8.4) and 11 others had LI less than 3.0 (median 1.0). Three categories of chromosome aberration were recorded: normal karyotype, 1-5 aberrations, and greater than or equal to 6 aberrations or multiple complex changes. The distribution of these categories was different among the patients with LI greater than 3.0 compared to those with LI less than 3.0 (p = 0.02). 8 of 11 patients with LI greater than 3.0 had greater than or equal to 6 or complex changes. The corresponding figures for patients with LI less than 3.0 were 2 out of 11. When 16 previously untreated patients were analysed separately, the median number of clonal aberrations was 6.5 in 8 patients with LI greater than 3.0 and 2.5 in 8 others with LI less than 3.0 (p = 0.025). The results suggest that early and spontaneous changes in the genetic material are common in lymphomas with a high proliferative activity. According to previous studies, therapeutic results are especially poor in NHL with high LI. It is proposed that a high proliferative activity of lymphoma cells facilitates an early development of several new mutants and that some of these may be resistant to chemotherapeutic agents.     

Evaluation of specific IgE to the recombinant group 2 mite allergens Lep d 2 and Tyr p 2 in the Pharmacia CAP system.

BACKGROUND: Several recombinant allergens have been shown to be potentially useful for diagnosis of IgE-mediated allergy, but only a few recombinant allergens are at present commercially available in serological assays for detection of specific IgE. The aim of this study was to evaluate the IgE binding to the recombinant major dust mite allergens rLep d 2 and rTyr p 2 and compare it with the IgE binding to the commercial mite extracts Lepidoglyphus destructor and Tyrophagus putrescentiae in the Pharmacia RAST CAP System. METHODS: The recombinant allergens rLep d 2 and rTyr p 2 were immobilised on ImmunoCAPs, and sera from 461 Swedish farmers who are frequently exposed to mites were analysed for specific IgE antibodies. Immunoblotting was performed to evaluate discrepancies between the results obtained with the recombinant and the commercial CAP assays. RESULTS: The IgE values of each recombinant assay significantly correlated with the IgE values of the corresponding commercial CAP assay. The sensitivity of the rLep d 2 assay was 73.3% and that of the rTyr p 2 assay, 60.5% of that provided by the commercial L. destructor and T. putrescentiae assays. Two subjects out of 416, who tested negative in the commercial L. destructor assay, were positive to rLep d 2. The corresponding figures for rTyr p 2 and the T. putrescentiae extract were 5/418. The possibility that these subjects were sensitised to L. destructor and T. putrescentiae could not be excluded. CONCLUSIONS: The data suggest that it may be possible to use rLep d 2 and rTyr p 2 on ImmunoCAPs to detect and quantify IgE antibodies to these, the major allergens of L. destructor and T. putrescentiae. It appears likely that the addition of just a few more recombinant L. destructor and T. putrescentiae allergens in the CAP assay will be sufficient for in vitro diagnosis of IgE mediated allergy to L. destructor and T. putrescentiae.