Search

This work investigated whether multiple freshwater populations of three-spined stickleback Gasterosteus aculeatus in different freshwater catchments in the Jutland Peninsula, Denmark, derived from the same marine populations show repeated adaptive responses. A total of 327 G. aculeatus collected at 13 sampling locations were screened for genetic variation using a combination of 70 genes putatively under selection and 26 neutral genes along with a marker linked to the ectodysplasin gene (eda), which is strongly correlated with plate armour morphs in the species. A highly significant genetic differentiation was found that was higher among different freshwater samples than between marine-freshwater samples. Tests for selection between marine and freshwater populations showed a very low degree of parallelism and no single nucleotide polymorphism was detected as outlier in all freshwater-marine pairwise comparisons, including the eda. This suggests that G. aculeatus is not necessarily the prime example of parallel local adaptation suggested in much of the literature and that important exceptions exist (i.e. the Jutland Peninsula). While marine populations in the results described here showed a high phenotype-genotype correlation at eda, a low association was found for most of the freshwater populations. The most extreme case was found in the freshwater Lake Hald where all low-plated phenotypes were either homozygotes for the allele supposed to be associated with completely plated morphs or heterozygotes, but none were homozygotes for the putative low-plated allele. Re-examination of data from seven G. aculeatus studies agrees in showing a high but partial association between phenotype-genotype at eda in G. aculeatus freshwater populations and that mismatches occur everywhere in the European regions studied (higher in some areas, i.e. Denmark). This is independent of the eda marker used.

Summary Objectives: As technology continues to evolve and rise in various industries, such as healthcare, science, education, and gaming, a sophisticated concept known as Big Data is surfacing. The concept of analytics aims to understand data. We set out to portray and discuss perspectives of the evolving use of Big Data in science and healthcare and, to examine some of the opportunities and challenges. Methods: A literature review was conducted to highlight the implications associated with the use of Big Data in scientific research and healthcare innovations, both on a large and small scale. Results: Scientists and health-care providers may learn from one another when it comes to understanding the value of Big Data and analytics. Small data, derived by patients and consumers, also requires analytics to become actionable. Connectivism provides a framework for the use of Big Data and analytics in the areas of science and healthcare. This theory assists individuals to recognize and synthesize how human connections are driving the increase in data. Despite the volume and velocity of Big Data, it is truly about technology connecting humans and assisting them to construct knowledge in new ways. Concluding Thoughts: The concept of Big Data and associated analytics are to be taken seriously when approaching the use of vast volumes of both structured and unstructured data in science and health-care. Future exploration of issues surrounding data privacy, confidentiality, and education are needed. A greater focus on data from social media, the quantified self-movement, and the application of analytics to “small data” would also be useful.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p < 0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

Thirty-two series of treatment with cephalothin and gentamicin for 5-10 days have been administered to 26 patients. An increase in serum creatinine occurred in 6 series. Important factors for the renal damage were elevated pretreatment serum creatinine, elevated serum gentamicin and probably a high serum cephalothin. In 2 patients the nephrotoxicity was fully reversible; the others died before a dicisive improvement in renal function could be expected. In 11 out of 28 treatment series there was a transient drop in serum potassium. Since the combination of cephalothin and gentamicin as the primary treatment of life-threatening infection has often proved effective, and since short-lasting treatment seems to entail only a minute risk of nephrotoxicity in patients with normal pretreatment serum creatinine, we still prefer this treatment in such cases.

A prospective, randomized trial comparing treatment of 61 febrile episodes with cefotaxime (CTX) versus a combination of ampicillin, methicillin, and netilmicin (AMN) was carried out in 58 patients with leukaemia or malignant lymphoma, of whom 28 had a granulocyte count of less than or equal to 500 X 10(6)/l. The overall response frequency was 63% for CTX against 49% for the AMN combination, the latter figure being lower than generally reported in the literature. The difference was not statistically significant. In 21 episodes pathogens were isolated, 16 of them from the blood. All isolated bacteria but one, a strain of Bacteroides fragilis, were fully sensitive to at least one of the three antibiotics in the combination, and all but one, a strain of Listeria monocytogenes, were fully sensitive to CTX. These results indicate that CTX seems to be a promising alternative as monotherapy for empiric treatment of febrile episodes in patients with haematologic malignancies. Further investigations will, however, be required before completely rational choices between mono and combination therapy of febrile episodes in immunosuppressed patients can be made.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has previously been shown in HD, and furthermore dopamine is thought to be implicated in cognition, behavioral and motor disturbances. A substantiated inverse correlation between motor onset and the elongated CAG repeat in the HTT has been established. This relation does not account for the full variability of the motor onset, and efforts have been put into finding genetic modifiers of motor onset, however, mostly with unsuccessful outcome. In this study, we took an alternative approach focusing on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms in a well-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance in HD, and point toward more personalized treatment modalities of HD in the future.

Summary Aims To evaluate the long-term effectiveness of Humalog® insulin in lowering post meal glucose excursions. Methods Twenty young subjects with Type 1 diabetes mellitus (DM) who had received insulin-lispro (Humalog®) for a least 1 year (mean ± SD 1.8 ± 1.6 years) were studied on two occasions, 3–14 days apart. They consumed a similar breakfast consisting of 450–600 kCal having fasted overnight. The same amount of human soluble Humulin® Regular or Humalog® insulin was given 10 min before the meal in a randomized, double-blind fashion. Results Postprandial glucose excursions at 30, 60, and 120 min were significantly lower (P

Of 560 consecutive, newly diagnosed untreated patients with B CLL submitted for chromosome study, G-banded karyotypes could be obtained in 480 cases (86%). Of these, 345 (72%) had normal karyotypes and 135 (28%) had clonal chromosome abnormalities: trisomy 12 (+12) was found in 40 cases, 20 as +12 alone (+12 single ), 20 as +12 with additional abnormalities (+12 complex ). Other frequent findings included abnormalities of 14q, chromosome 17, 13q and 6q. The immunophenotype was typical for CLL in 358 patients (CD5 + , Slg weak , mainly FMC7 − ) and atypical for CLL in 122 patients (25%) (CD5 − , or Slg strong or FMC7 + ). Chromosome abnormalities were found significantly more often in patients with atypical (48%) than in patients with typical CLL phenotype (22%) ( P complex , 14q +, del6q, and abnormalities of chromosome 17 were significantly more frequent in patients with atypical CLL phenotype, whereas +12 single was found equally often in patients with typical and atypical CLL phenotype. The cytomorphology of most of the +12 patients was that of classical CLL irrespective of phenotype. In univariate survival analysis the following cytogenetic findings were significantly correlated to a poor prognosis: chromosome 17 abnormalities, 14q +, an abnormal karyotype, +12 complex , more than one cytogenetic event, and the relative number of abnormal mitoses. In multivariate survival analysis chromosome 17 abnormalities were the only cytogenetic findings with independent prognostic value irrespective of immunophenotype. We conclude that in patients with typical CLL immunopenotype, chromosome abnormalities are somewhat less frequent at the time of diagnosis than hitherto believed. +12 single is compatible with classical CLL, and has no prognostic influence whereas chromosome 17 abnormalities signify a poor prognosis. In patients with an atypical CLL immunophenotype, chromosome abnormalities including +12 complex , 14q +, del 6q and chromosome 17 are found in about 50% of the patients, and in particular chromosome 17 abnormalities suggest a poor prognosis.

Epidemiological, microbiological and clinical characteristics of 14 episodes of Xanthomonas maltophilia bacteremia in 12 seriously immunocompromised hematological patients, admitted to Rigshospitalet in Copenhagen over the 3-year period 1989-91, were evaluated. The results were compared with a randomly selected control group of 25 patients with Escherichia coli bacteremia. Hospital acquired bacteremia was more common among the patients with X. maltophilia bacteremia (p < 0.01). Treatment with broad-spectrum antibiotics before the bacteremic episode was markedly more common among the patients with X. maltophilia bacteremia (p < 0.001). The presence of a central venous catheter and previous treatment with corticosteroids were more frequent in patients with X. maltophilia bacteremia (p < 0.05). The X. maltophilia blood culture isolates were generally resistant to aminoglycosides and most beta-lactams. The mortality rates related to bacteremia caused by X. maltophilia and E. coli were 14% and 20%, respectively.

Since 2001, the Danish healthcare system has been characterized by a focus on the reduction of waiting lists. By introducing activity-based funding of the regions and hospitals, there has been an increase in activity, a reasonably positive development in productivity, a high degree of patient and citizen satisfaction, and a successful reduction of waiting lists. One of the reasons for this success is that it was possible to use Casemix-based economic incentives actively.

A study of 17 patients with autoimmune axonal or demyelinating peripheral neuropathy in combination with M-component is described. The M-component was associated with MGUS (monoclonal gammopathy of undetermined significance) in 12 patients, CLL in one patient, Waldenström's disease in one patient, and myeloma in three patients. Immunohistological examination with direct and indirect fluorescence showed binding of antibodies to nerve structures of the same class and light chain as seen in the M-component. In five cases of IgM M-component, the demyelinating neuropathy was caused by binding of the IgM M-protein and complement C3b to myelin-associated glycoproteins (MAG). In 12 cases with axonal neuropathy, binding of IgG to the connective tissue of the peri- and endoneurium was found in 50% of cases, IgM in five cases, and IgD in one case. None of the patients had central nervous system (CNS) symptoms. The clinical and therapeutic difficulties are discussed; only two patients with an acute course responded to immunosuppression. A marked co-expression of other autoimmune phenomena is interpreted in the light of cross-reactions between the autoantibody and similar tissue autoantigens.

Aims To determine if one method of short-acting insulin bolus administration is superior to other methods in managing a meal high in carbohydrates, calories and fat. Methods Nine subjects receiving continuous subcutaneous insulin infusion using insulin lispro (Humalog®) agreed to consume the same meal high in carbohydrates, calories and fat on four occasions 1 week apart. They received the same dose of bolus insulin on each of the four occasions randomly assigned and beginning 10 min prior to the meal as either a single bolus, two separate boluses of one-half the same total dose (the second after 90 min), the entire bolus given as a square-wave (over 2 h) or a dual-wave (70% as a bolus and 30% as a square-wave over 2 h). Blood glucose levels were measured at –60 and –30 min and at zero time, and then every half-hour for 6 h using the Hemacue® in the out-patient clinic. Results Changes in blood glucose values from fasting were the lowest after 90 and 120 min (P

Most of the world's cod (Gadus morhua) fisheries are now tightly regulated or closed altogether. Being able to link individual fish to their population of origin would assist enormously in policing regulations and in identifying poachers. Here we show that microsatellite genetic markers can be used to assign individual cod from three different populations in the northeastern Atlantic Ocean to their population of origin.

To evaluate the long-term effectiveness of Humalog insulin in lowering post meal glucose excursions.Twenty young subjects with Type 1 diabetes mellitus (DM) who had received insulin-lispro (Humalog) for a least 1 year (mean +/- SD 1.8+/-1.6 years) were studied on two occasions, 3-14 days apart. They consumed a similar breakfast consisting of 450-600 kCal having fasted overnight. The same amount of human soluble Humulin Regular or Humalog insulin was given 10 min before the meal in a randomized, double-blind fashion.Postprandial glucose excursions at 30, 60, and 120 min were significantly lower (P0.001, ANCOVA) when subjects received Humalog as compared to human soluble insulin. Serum-free insulin levels were significantly higher (P0.001, ANOVA) at 30 and 60 min when subjects received Humalog as compared with human soluble insulin. Humalog antibody levels after up to 5.4 years of receiving Humalog insulin were not elevated beyond the values at 1 year.We conclude that Humalog insulin is effective in lowering postprandial glucose excursions even after up to 5.4 years of treatment.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of granulocytes in peripheral blood and myeloid cells in the bone marrow were studied in seven patients with chronic lymphocytic leukemia (CLL). The neutrophil count in the peripheral blood rose by a median of 193% (range 142-980%), p = 0.02, and the increase persisted for more than 2 weeks after discontinuation of the treatment. The percentage of myeloid cells in bone marrow increased by 166% (range--57-1800%). In neutropenic CLL patients with recurrent infections GM-CSF treatment may constitute a new treatment modality.

Treatment with antibodies in patients with lymphoproliferative diseases was, until recently, limited to phase I studies due to limited response or subsequent development of anti-globulin response. The introduction of the hybridoma technique during the 1970s facilitated large scale production of antibodies, including the development of the Campath rat-antibodies. The epitope was launched against CD52, a glycoprotein present in large amounts on the surface of lymphocytes, and the primary use was in-vitro depletion of bone marrow from allogeneic bone marrow transplantation donors. The development of the human Campath-1H antibody was successful in 1988, leading to minimized anti-globulin response when used in vivo, and large multi-center studies were initiated. In this study we present an overview of the preclinical and clinical experiences with Campath-1H, including data from patients treated with the antibody in our clinic.

Subcutaneous lesions were seen in three of 13 neutropenia patients who had Stenotrophomonas (Xanthomonas) maltophilia bacteraemia. The characteristic clinical presentation resembled leukaemic infiltrates, and were different from deep ulcers or subcutaneous nodules caused by Pseudomonas aeruginosa. The three patients had acute leukaemia and were treated with intensive combination chemotherapy. All had previously been treated with broad-spectrum antibiotics, and each patient recovered after proper combination antibiotic treatment given according to sensitivity testing.

Ten patients with newly diagnosed B-chronic lymphocytic leukaemia were treated with cladribin orally for five days every four weeks with a median of four series. This is the first reported clinical study where a purine analogue is administered orally. The tumour reducing effect was fast. Eight out of 10 patients responded with a partial or clinical complete remission. Two of these were in molecular biological complete remission. With an observation time of 22 months we have seen no serious side effects so far. A randomized study (including a long term follow up) between chlorambucil, fludarabin and cladribin is needed to clarify the future role of cladribin in B-CLL treatment.

In a multicentre study of 635 consecutive newly diagnosed patients with B-CLL, the histological bone marrow (BM) specimens were reviewed independently by each of 3 pathologists and found evaluable for BM infiltration pattern in 575 patients, 404 of whom had a CD5+, mainly FMC7-, faint surface-membrane immunoglobulin (SIg) fluorescence-intensity ppenotype. In these 404 patients the following BM infiltration patterns were found: mixed nodular-interstitial (30%), moderate interstitial (44%), heavy interstitial (20%) and diffuse packed (6%). In univariate survival analysis, significant differences were found according to BM pattern (p0.05), the presence of nodules being a favorable prognostic sign. In multivariate survival analysis in a model including age, clinical stage, BM pattern, BM lymphocytosis, WBC and sex, only age and stage but not BM pattern or BM lymphocytosis had independent prognostic significance. In stage A, progression-free survival was significantly longer in patients with nodular than in patients with non-nodular bone-marrow pattern. The overall survival of these patients, however, did not differ, possibly owing to the prompt and prolonged treatment given to most patients at the time of progression to stage B or C. We conclude that in CD5+, SIg(faint), mainly FMC7-B-CLL, bone-marrow histology may predict unstable disease in early clinical stage but is not important for treatment decisions, when these are based on clinical stage.

One hundred consecutive autologous stem cell transplants are reported: Non-Hodgkin's lymphoma 51 cases, Hodgkin's disease 27 cases, acute leukaemia 14 cases, multiple myeloma seven cases and chronic myeloid leukaemia one case. Most patients were in their second or later remission. The overall three-year survival for all patients was 60% and the three-year disease-free survival was 50% for lymphoma patients and 30% for acute leukaemia patients. The dominant source of stem cells was bone marrow during 1993, but from 1994 it has been peripheral blood, now totalling 33 cases. There were 12 toxic deaths, all among patients who were heavily treated before bone marrow harvest and transplantation. The patients transplanted with blood stem cells had significantly shorter duration of pancytopenia, and hospital stay, but their disease-free survival was not longer than that of a comparable group of bone marrow transplanted patients. Six patients were transplanted with purified CD34+ cells (selected by avidity column (Ceprate (R)), and had duration of thrombocytopenia and hospital stay similar to the patients transplanted with unmanipulated blood stem cells, but slightly longer duration of neutropenia. We conclude that high-dose therapy with autologous stem cell transplantation in not too heavily pretreated patients is a safe procedure irrespective of the source of stem cells.

Thirty patients with B-chronic lymphocytic leukemia, aged 45-82 years, were treated with fludarabine. CLL was diagnosed 8-120 months earlier. The patients had been exposed to a median of 3 different regimens before treatment with fludarabine, and all had progressive disease when they entered the study. Among the 30 patients, 1 had a metastatic carcinoma and 7 patients with WHO performance status 3 died before the second cycle of fludarabine treatment could be given. The remaining 22 patients were considered eligible for response evaluation. The response rate was 32% with 1 complete response and 6 partial responses. However, seven patients achieved stable disease and 8 progressed. The median survival for responders was 24 months and for non-responders 9 months. Response to treatment was correlated with low tumor burden and performance status. In a total of 94 treatment courses, 17 febrile episodes were registered in 10 patients. We conclude that treatment with fludarabine can be useful in patients with progressive and refractory disease.

In 18 cases of monoclonal gammopathy of undetermined significance, MGUS (monoclonal gammopathy of undetermined significance), admitted for diagnosed or suspected peripheral neuropathy, 11 patients showed other co-existing autoimmune manifestations. Two had POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component, and skin symptoms), the others mainly endocrinopathy and polyclonal pseudolymphoma. There were 13 cases of sensorimotor neuropathy, two cases of neuritis, while neuropathy could not be confirmed in three cases. Compared with a retrospective review of autoimmunity in a randomly selected CLL (chronic lymphocytic leukemia) cohort of 115 patients, 13 out of 42 patients with clinical and/or laboratory features of autoimmunity showed co-expression of autoimmune signs, the dominating traits being Coombs positive AIHA (auto-immune hemolytic anemia), platelet autoantibodies, endocrinopathy mainly associated with the thyroid gland, serological and/or rheumatological symptoms, but only one case of sensorimotor neuropathy. Viewed from a current model of acquired autoimmunity it is perhaps not surprising that such autoimmunity is seen predominantly in patients with monoclonal gammopathy. Thus, a high concentration of cross-reacting polyreactive autoantibodies related to the M-component might be present in these patients. Furthermore, quantitative defects of the immunoglobulins including the hypogammaglobulinemia associated with M-components can presumably give rise to a defect of the anti-idiotypic network's regulation of natural autoantibodies and autoimmune manifestations in vivo. Such autoimmune manifestations, which are easily overlooked in CLL may call for additional treatment with immunosuppression and/or intravenous, polyclonal IgG.

Each year approximately 70 males are diagnosed with Hodgkin's disease (HD) in Denmark. Most of these are less than 50 years of age. Since chemotherapy and radiotherapy may induce infertility in about 80% of patients, it has become routine to offer cryopreservation of semen prior to initiation of treatment. In 41 men aged 17-42 years at diagnosis we evaluated the quality of semen (according to the WHO criteria) prior to cryopreservation and after thawing. The median sperm concentration at the time of diagnosis was 33 x 10(6)/ml (range: 0.3-458 x 10(6)/ml) and positively correlated to age (rs = 0.36 p = 0.02) and to the histopathological classification (highest for patients with nodular sclerosis (p = 0.04) but not to semen volume, stage or presence of B-symptoms. The percentage of motile spermatozoa (range: 0-90%, median value 72%) was correlated to the sperm concentration; but not to any of the other parameters studied. Prior to freezing, 19 of 41 patients had normal semen quality according to the WHO criteria, whereas following thawing this was the case for only 14 semen samples. Ten of 23 patients with nodular sclerosis HD had normal semen quality (according to the WHO criteria) after thawing whereas this was the case for only 2 of 15 patients with mixed cellularity HD (p = 0.05). Cryopreservation of semen may secure the possibility of fathering children for patients with HD following therapy, and is to be recommended.

To ascertain whether the microbiological etiology of bacteremia among patients with hematological malignancies has changed in Denmark, the species distribution of clinically relevant blood culture isolates from the Hematological Department at Rigshospitalet, Copenhagen in 1990 was compared with 2 previous studies (1970-72; 1981-85). In addition, time trends of the etiology of bacteremia among hematological patients in Copenhagen (eastern Denmark) and in Arhus (western Denmark) were compared. In contrast to many other studies, a significant increase in the proportion of Gram-negative aerobes was observed in Copenhagen (from 43% in 1981-85 to 55% in 1990; p0.05), whereas in Arhus the proportion of Gram-positive aerobes increased steadily during the 1980s (from 34% to 51%; p0.05). In Copenhagen, non-hemolytic streptococci and Xanthomonas maltophilia increased significantly and accounted for 10% (p0.01) and 5% (p0.05) respectively, of all isolates in 1990, whereas Staphylococcus aureus during the 2 decades studied decreased from 25% to 8% (p0.001). In both regions, a decrease was observed in the proportion of Pseudomonas aeruginosa which accounted for only about 5% of all isolates in 1990. No changes were observed in the rates of anaerobes and yeasts. Several factors may contribute to the reported differences in the etiology of bacteremia among hematological patients, e.g. criteria used to assign the clinical significance of the isolate, blood culture system used, practice of using indwelling intravenous catheters, different policies with respect to antimicrobial treatment, and the degree of immunosuppression. A local surveillance of blood culture isolates is mandatory if changes in etiology and resistance development are to be detected.

One-hundred-and-fifty-one patients with previously untreated multiple myeloma were allocated to treatment with either NOP regimen (mitoxantrone 16 mg/m2 and vincristine 2 mg day 1 and prednisolone 250 mg day 1-4 and 17-20) or M+P regimen (melphalan 0.25 mg/kg and prednisolone 100-200 mg/day day 1-4). Both regimens were repeated every 4 weeks and were scheduled for 1 year. Seventy-seven patients were treated with NOP and 74 patients with M+P. No major clinical differences were recorded between the groups before treatment. Sixty percent of the patients responded (CR+PR) to NOP versus 64% to M+P (NS). The time to progression was 16 months (95% C.L. 14-51) in the NOP group versus 21 months (95% C.L. 15-27) in the M+P group (NS). The median survival was 14 months (7-21) in the NOP group and 31 months (21-43) in the M+P group (p = 0.02). NOP was significantly more toxic than M+P. Seven patients treated with NOP died due to infection and neutropenia and 1 patient died of cardiac toxicity, in contrast to 1 death due to infection and neutropenia in the M+P group. Gastrointestinal toxicity was acceptable in both groups. In conclusion, NOP was inferior to M+P as primary treatment of multiple myeloma.

Blood mononuclear cells from 540 newly diagnosed, unselected patients with B-cell chronic lymphocytic leukemia (CLL) were examined by immunofluorescence flow cytometry for a panel of surface membrane markers, including IgM and IgD, the monoclonal antibodies anti-CD3, -5, -20, -21, -22, -FMC7, and, for the final 125 patients, anti-CD23. There were 503 CD5+ and 37 CD5- cases. In the CD5+ cases, the cells typically expressed IgM, IgD, CD20, CD21, CD22, and CD23. In univariate analysis, age, clinical stage, IgM-fluorescence intensity, CD23, and FMC7 had significant prognostic importance, with high IgM-fluorescence intensity, high FMC7, and low CD23 expression being associated with a short survival. There was no significant difference in survival between 351 cases expressing IgMD and 55 cases expressing IgM without IgD, or between kappa and lambda light chain monoclonal cases. CD20, CD21, and CD22 had no prognostic importance. In Cox multiple regression analyses, age, CD23, IgM-fluorescence intensity, and clinical stage (International Workshop System) had independent prognostic importance. Thus, besides clinical variables, CD23 and IgM intensity might be useful prognostic markers in the management of CD5+, B-cell CLL. The survival of CD5- patients was on the borderline of being significantly shorter than that of CD5+ patients. The majority of the CD5- cases were FMC7+, CD23-, had strong IgM fluorescence, and had splenomegaly.

In a phase II study, patients with refractory myelomatosis were treated with a combination chemotherapy (NOP regimen): mitoxantrone (bolus injection of 4 mg/m2 on days 1-4), vincristine (continuous infusion of 0.4 mg/24 h on days 1-4) and prednisone (250 mg/d on days 1-4 and 17-20). The treatment was repeated every 4 weeks. Ninety-two patients were treated after they were found refractory to treatment with melphalan and prednisone (and occasionally vincristine) (n = 50) or more intensive treatment regimens (n = 42) including anthracyclines (n = 18). Response (greater than or equal to 50% reduction of M protein) was obtained in 23 patients and minor response (clinical improvement but less than 50% reduction in M protein) in 22 patients. The median duration of the response was 7.5 months. Equal response rates were observed irrespective of the type of previous treatment. The major toxicity was myelosuppression with severe granulocytopenia and infections. However, the frequency decreased throughout the cycles. The NOP treatment is recommended in refractory myelomatosis, especially in patients refractory to other intensive regimens. Patients in a poor clinical condition or with thrombocytopenia before treatment should have a reduced mitoxantrone dose in the first treatment cycles.

The objective of the study was to determine the direct actions of sodium nitroprusside (SNP) on the pulmonary vasculature actively constricted by hypoxic ventilation in the closed-chest dog. In 21 supine anesthetized (pentobarbital sodium, 25 mg/kg) dogs the left lower lobe was catheterized with a 20 F wedged-flow catheter. With constant flow to this lung lobe, lobar pulmonary artery pressure (PAP), left ventricular end-diastolic pressure (LVEDP), and lobar pulmonary vascular resistance (PVR) were studied during room air and 10% O2 mechanical ventilation. With lobar flow and LVEDP constant, observed changes of lobar PAP and PVR represent direct effects on vascular tone unaffected by passive factors. Ventilation with 10% O2 resulted in a significant increase in lobar PAP [12.2 +/- 1.6 to 17.2 +/- 1.2 (SE) Torr] and PVR [42.2 +/- 13.3 to 61.2 +/- 15.0 (SE) Torr X 1(-1) X min]. Then during continued hypoxia in 12 animals, femoral vein infusion of SNP at doses of 1, 2, and 5 microgram X kg-1 X min-1 resulted in significant decreases in lobar PAP to 14.8 +/- 1.5, 14.8 +/- 1.5, and 13.4 +/- 1.6 Torr, respectively, and in PVR to 56.7 +/- 14.1, 54.0 +/- 13.9, and 47.8 %/- 13.2 Torr X 1(-1) X min, respectively. In six animals the sequence of drug infusion was then reversed with similar results. It is concluded that the actively constricted pulmonary vascular bed is directly dilated by SNP infusion.

VP-16-213 has been used in 5-day courses together with cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone for treatment of 74 consecutive patients with non-Hodgkin's lymphomas. Ninety-one percent of patients with favourable histology and 69% with unfavorable histology achieved complete or partial remissions (overall response rate of 76%). The frequency of complete remission was disappointingly low (22%), possibly due to reduction of doses of the other myelosuppressive agents in the present combination. Further trials with VP-16-213 in other combination chemotherapy are required.

Prednimustine, a chlorambucil ester of prednisolone, was administered to 16 patients with non-Hodgkin lymphomata (NHL) and 14 patients with chronic lymphocytic leukaemia (CLL), all previously treated with steroids and alkylating agents. Response was obtained in 8 patients with NHL and 11 patients with CLL. Two NHL patients had long-lasting complete remissions. Median duration of response for lymphomata was 12 weeks, for CLL more than 15 weeks. Delayed reversible and rather pronounced myelosuppression was the major side-effect observed in median 6 weeks from the start of Prednimustine with a median duration of 4 weeks.

Seventy-four febrile patients with leukaemia or malignant lymphoma, of whom 42 had severe granulocytopenia, were treated with netilmicin in combination with other antibiotics, usually ampicillin and methicillin. Of 36 patients with proven bacterial infection, 72% responded to treatment with complete resolution or improvement. Moderate and reversible renal affection occurred in 10 patients of whom 8 concomitantly were treated with other potentially nephrotoxic drugs. Five of the 10 patients had unintendedly high valley concentrations of netilmicin. Ototoxicity was not documented. It is concluded that netilmicin is an effective and tolerable aminoglycoside.

8 patients with chronic myeloid leukaemia in the chronic phase who had previously received chemotherapy were given alpha-interferon (Intron A). The Intron A was administered subcutaneously at a dose of 2 x 10(6) I.U./m2 three times a week and this was increased to 4-5 million I.U./m2 daily if no response was obtained after 6-8 months. 1 patient was Philadelphia chromosome-negative and was the only one who showed a major response to treatment. The other 7 patients never achieved haematologic remissions, or even a significant reduction in the immature blood leucocyte count or spleen size.

Five hundred and fifty consecutive patients with newly diagnosed B-CLL have been registered and classified in a Danish multicenter study. The study includes a protocol for primary treatment of patients in stage B or C (at diagnosis or after demonstrated progression), below 76 years of age, and without complicating serious disease. Until now 144 such patients have been randomized to either prednisolone (PRD) plus chlorambucil (CLB) 5 days every 4 weeks or monthly intensive CHOP treatment. Twenty-nine percent of the treated patients achieved CR on PRD + CLB versus 63% on CHOP (p less than 0.005). No response was found in 29% versus 18%, respectively (NS). A significant difference in survival between patients achieving CR, PR and NR was also demonstrated, whereas to date no difference in survival could be demonstrated between the two regimens. The toxicity was limited, and only 2 treatment-related deaths occurred in approximately 700 CHOP treatment series.

Cefotaxime at a dosage of 3 gm intravenously every eight hours was administered to 80 patients with hematological malignancies and suspected septicemia. Blood samples for culturing were taken before and during antibiotic therapy. Nineteen patients had verified bacteremia and ten of them responded completely to cefotaxime. Twelve of the 19 patients had granulocyte counts of less than 0.5 X 10(9)/L. Minimal inhibitory concentrations of cefotaxime, ceftazidime, moxalactam, cefsulodin, cefoxitin, cefuroxime, and cefamandole against the pathogens were measured: cefotaxime was the best cephalosporin against gram-negative isolates and was found acceptable against gram-positive bacteria. In 61 patients no bacteremia could be demonstrated, but specific pathogens were isolated in 11 patients: from the urine in five, from the sputum in five, and from a perianal abscess in one. Complete response was obtained with cefotaxime in seven of these 11 patients. Monotherapy with cefotaxime in septicemic patients with hematological malignancies appears to be a valuable alternative to other antibiotic regimens.