Impact of CR before and after allogeneic and autologous transplantation in multiple myeloma: results from the EBMT NMAM2000 prospective trial.

Previous studies have shown that obtaining complete hematologic remission (CR) in multiple myeloma is an important predictor of PFS and OS. This applies both to autologous and allogeneic transplantation. However, the importance of CR obtained before vs after second transplant or following allogeneic vs autologous transplantation is not clear. We investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional prospective study comparing tandem autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to autologous transplantation-single or double (auto/auto). Allocation to treatment was performed according to availability of a matched sibling donor. Cox regression and multi-state models were applied. The long-term probability of survival in CR was superior in auto/RICallo, both comparing groups according to treatment allocated at start (28.8 vs 11.4% at 60 months, P=0.0004) and according to actual administration of second transplant (25.6 vs 9.6% at 60 months, P=0.008). CR achieved before the second transplant was predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047) irrespective of the type of second transplant. CR achieved after auto/RICallo was more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81, P=0.390), indicating a better durability of CR obtained after an allotransplant procedure.

The Finnish evidence-based guideline for open-angle glaucoma.

In most patients, chronic open-angle glaucoma is a slowly progressive disease. Eyes with very high intraocular pressure (IOP > 30 mmHg) represent an exception to this and should be treated and followed extremely intensively. As lowering IOP is, so far, the only means of treating glaucoma, the majority of research reports deal with the IOP-lowering effect of the treatment. The primary goal of treatment, however, is to prevent glaucomatous damage to the structures and function of the eye. The effectiveness of treatment is monitored with optic disc and retinal nerve fibre layer imaging and with visual field examinations. If the glaucomatous changes are progressing, more effective treatment should be given. In the course of follow-up, it should be noted that the changes in the optic nerve structure and function appear and progress at different time-points with delays of up to several years. The assessment of abnormalities is dependent on the examination method and requires a great deal of experience on the part of the examiner. The important risk factors in glaucoma are elevated IOP (even if IOP is within normal range in half of patients ), age, positive family history, exfoliation, race and myopia.

Efficacy of cumulative doses of salbutamol administered via Turbuhaler or Diskhaler in patients with reversible airway obstruction.

The study aimed to estimate the relative dose potency of salbutamol inhaled via Turbuhaler and Diskhaler. The 24 adult patients participating had chronic reversible airway obstruction. The study was of a double-blind, double-dummy, crossover, randomized design. Five doses of salbutamol Turbuhaler, 50, 50, 100, 200, and 400 microg, were given on one study day at intervals of 30 min. On another study day, five doses of salbutamol Diskhaler, 200, 200, 400, 800, and 1600 microg, were given with the same interval. The treatment days were separated by a washout period of at least 24 h. The inhalation technique was standardized and supervised. Efficacy variables were recorded before and after each study dose. The primary efficacy variable was forced expiratory volume in 1 s (FEV1). When parallel and linear cumulative dose-response curves were statistically compared on a logarithmic scale, the dose potency of salbutamol Turbuhaler vs salbutamol Diskhaler was 1.99 (95% confidence interval 1.52-2.54). This study indicates that only half the dose of salbutamol is required via Turbuhaler as via Diskhaler for the same bronchodilating effect.

Safety and efficacy of a high cumulative dose of salbutamol inhaled via Turbuhaler or via a pressurized metered-dose inhaler in patients with asthma.

An open, crossover and randomized study was carried out to compare the safety and efficacy of salbutamol inhaled using the dry-powder inhaler Turbuhaler, and using a pressurized metered-dose inhaler (pMDI). Twelve patients with moderate to severe asthma, aged 47-68 years, were included in the study. On two separate days, patients received a total dose of 1600 micrograms of salbutamol administered in a cumulative dose fashion: 100, 100, 200, 400 and 800 micrograms at 3-min intervals. Salbutamol inhaled via Turbuhaler caused a larger decrease in serum potassium concentration than did salbutamol inhaled via pMDI. The estimated relative dose potency of the hypokalaemic effect of salbutamol Turbuhaler vs salbutamol pMDI was 2.0 with a 95% confidence interval of 1.3-3.6. Turbuhaler caused a small (but statistically significantly greater than with pMDI) increase in heart rate, QTc interval and tremor. Blood pressure was unaffected by the treatments. No adverse events of clinical relevance were reported. The estimated relative dose potency of the bronchodilating effect (FEV1) of salbutamol Turbuhaler vs salbutamol pMDI was 3.0 with a 95% confidence interval of 1.8-5.8. In conclusion, salbutamol inhaled via Turbuhaler was more potent and seemed to have a better therapeutic ratio than salbutamol inhaled via pMDI. Both treatments were equally well tolerated.

Albuterol via Turbuhaler versus albuterol via pressurized metered-dose inhaler in asthma.

BACKGROUND: Inhaled albuterol is most commonly self-administered by patients using a pressurized metered-dose inhaler (pMDI) but patients often have difficulty using the device. Dry powder devices such as the multi-dose, inspiratory flow driven inhaler (Turbuhaler) are often better handled by patients. OBJECTIVE: We sought to compare the efficacy and tolerability of 100 micrograms of albuterol delivered by a multi-dose, inspiratory flow driven inhaler (Turbuhaler) to a standard dose (200 micrograms) delivered by a pMDI (Ventolin) in chronic reversible obstructive airways disease. METHOD: In 6 centers, we studied 37 adults [19 men and 18 women, mean age 39 +/- 12 years; mean baseline forced expiratory volume in one second (FEV1) 72 +/- 13% (% predicted)] with stable but symptomatic reversible obstructive airways disease as demonstrated by 15% or greater increase in FEV1 following two puffs (200 micrograms) albuterol by pMDI. The crossover design comprised a 1-week run-in and two 2-week treatment periods separated by a 1-week washout. At the start and end of each treatment period, FEV1 was measured at the clinic. Patients self-administered albuterol 100 micrograms (2 x 50 micrograms) via Turbuhaler or 200 micrograms (2 x 100 micrograms) via pMDI in a double-blind fashion four times daily. Morning and evening peak expiratory flow (PEF) was noted daily. All non-study bronchodilators were withheld while open-label albuterol pMDI was offered for rescue. RESULTS: Of the 37 patients, 30 used inhaled steroids in constant doses throughout the study, one used inhaled cromoglycate and six used no anti-inflammatory therapy. There was no difference between treatment periods in morning PEF, diurnal fluctuation in PEF, increase in PEF following study drug, baseline FEV1 and FEV1 increase following study drug. Although there was no difference in symptom scores between treatments, the use of rescue beta 2-agonist was slightly but significantly higher during the Turbuhaler treatment period (1.34 versus 1.08 inhalations/ day, P = .04). Compliance with study drug was slightly but significantly lower during the Turbuhaler treatment period (87 versus 95%) such that the total number of beta 2-agonist puffs inhaled (scheduled plus rescue) was similar between treatments. With regard to adverse events, both treatments were well tolerated. CONCLUSIONS: These results suggest that the efficacy and tolerability of albuterol 100 micrograms qid inhaled via Turbuhaler is similar to albuterol 200 micrograms qid, inhaled via pMDI in stable reversible obstructive airways disease.

Differences in bronchodilating potency of salbutamol in Turbuhaler as compared with a pressurized metered-dose inhaler formulation in patients with reversible airway obstruction.

Two studies are presented, with the aim of establishing the dose potency ratio for salbutamol given via Turbuhaler and via a pressurized metered-dose inhaler (pMDI). Both studies were of a double-blind, randomized design. Outpatients with mild-to-moderate chronic reversible airway obstruction were given single doses of salbutamol administered via Turbuhaler and via pMDI. Efficacy and safety variables were measured before and during 6 h after each dose. The first study was a four-way crossover study including 12 patients. The salbutamol doses given were: 50, 100 and 2x100 microg via Turbuhaler and 2x100 microg via pMDI (Ventolin). The study showed that 2x100 microg of salbutamol inhaled via Turbuhaler is more potent than 2x100 microg salbutamol inhaled via a pMDI, and that 100 microg salbutamol via Turbuhaler is at least as potent as 2x100 microg salbutamol inhaled via a pMDI. The second study including 50 patients was a placebo-controlled five-way crossover, study. Two doses of salbutamol via Turbuhaler, 50 and 2x100 microg, and via pMDI, 100 and 2x200 microg, were given. There was a dose-dependent response in forced expiratory volume in one second (FEV1) for both inhalers. Adjusted for differences in baseline FEV1 values, the estimated relative dose potency for Turbuhaler versus pMDI was 1.98:1 (95% confidence interval 12-3.2). These studies showed that the same bronchodilating effect can be achieved when half the dose of salbutamol given via a conventional pressurized metered-dose inhaler is given via Turbuhaler.

Differential expression of mRNAs for neuropeptide Y-related peptides in rat nervous tissues: possible evolutionary conservation.

Neuropeptide Y (NPY) is the only member of its peptide family that has been isolated from the mammalian CNS. We have recently found that two different NPY-related molecules are present in the CNS of a cyclostome, the river lamprey (Lampetra fluviatilis) (Söderberg et al., 1991). Here we show that this is also true for the rat CNS, by demonstrating expression of peptide YY (PYY) mRNA in brainstem neurons distinct from those neurons that express NPY mRNA. Dissimilar oligonucleotide DNA probes complementary to 3' untranslated regions of the rat PYY, NPY, and pancreatic polypeptide (PP) mRNA were used in in situ hybridization experiments on sections of rat brain and spinal cord, visceral organs, and peripheral nerve ganglia. The PYY probe hybridized with two populations of neurons in the brainstem: one dispersed along the midline in the rostral medulla and another in the lateral caudal medulla (A1 region). No additional labeling was detected in the remainder of the neuraxis. In the periphery, PYY hybridization was seen only in endocrine cells of the colon, and not in sympathetic ganglia or the adrenal gland, suggesting that previous observations of PYY immunoreactivity in these latter structures were due to antibody cross-reactivity with NPY. The NPY probe did not hybridize with cells on the midline region that contains PYY neurons, but it did label large numbers of neurons throughout the neuraxis. No expression of PP mRNA was detected in the CNS. Northern blot analysis failed to detect PYY mRNA in the CNS, further supporting the observation that PYY is only expressed by a discrete collection of CNS neurons. The anatomy of PYY- and NPY-expressing cells in the CNS and gut shows a striking similarity between rat and lamprey (Brodin et al., 1989), vertebrates that diverged evolutionarily about 450 million years ago, suggesting that both peptide systems have been conserved throughout vertebrate evolution.

Sensitive mRNA detection using unfixed tissue: combined radioactive and non-radioactive in situ hybridization histochemistry.

In the present study some experimental parameters for in situ hybridization histochemistry (ISHH) have been analysed using 35S-labelled and alkaline phosphatase-conjugated probes, in order to develop a reproducible double-labelling procedure. We have compared the total exclusion of tissue fixation with tissue sections fixed by immersion in formalin. In addition, the effect of dithiothreitol was assessed both when combining radiolabelled and non-radioactive probes on a single tissue section and when the probes were used separately. Hybridization of unfixed tissue resulted in stronger specific labelling and lower background both for radiolabelled and alkaline phosphatase-conjugated probes. No loss in tissue preservation was seen at the light microscopic level after hybridization of unfixed tissue. High concentrations (200 mM) of dithiothreitol strongly suppressed background when using 35S-labelled probes, whereas in the non-radioactive procedure, alkaline phosphatase labelling could only be achieved with very low dithiothreitol concentrations (less than 1 mM). This incompatibility led to a protocol using unfixed tissue sections and a sequential hybridization procedure, with the radiolabelled probe and high concentrations of dithiothreitol in the first step and the alkaline phosphatase-conjugated probe without dithiothreitol in the second step.

Chemotactic Responses of Marine Vibrio sp. Strain S14 (CCUG 15956) to Low-Molecular-Weight Substances under Starvation and Recovery Conditions.

The chemotactic responses by starved cells of marine Vibrio sp. strain S14 differed from those elicited by cells that were not nutrient limited. The rate of chemotaxis at different concentrations of several attractants varied for starved and growing cells. Vibrio sp. strain S14 showed positive chemotaxis to leucine, valine, arginine, and glucose at the onset of energy and nutrient deprivation. A continued, though decreased, positive response was demonstrated fro leucine, arginine, and glucose at 10 h of starvation. Cells starved for 3 h displayed a stronger response to glucose than those starved for shorter or longer times. However, cells starved for 5 and 10 h responded more strongly to a lower concentration of glucose than did cells starved for 0 and 3 h. Starvation for 24 h elicited no measurable chemotaxis to leucine, arginine, or glucose. The motility decreased by over 95% in the cell population after 24 h of starvation, which resulted in a low sensitivity in the chemotaxis assay. A switch in the response to valine was observed by 3 h of starvation. The addition of nutrients of 22-h-starved cells elicited a temporary positive chemotactic response to leucine by 2 and 4 h of nutrient recovery, while cells at 1 and 6 h of recovery showed no response. At 2 h of recovery, the greatest response was recorded to 10 M leucine, whereas at 4 h it was to 10 M leucine. Ten to fifty percent of the 22-h-starved cell population regained their motility after 4 h of nutrient-aided recovery. It is possible that two types of chemosensory systems exist in marine bacteria. Starved and growing cells responded to different concentrations of the attractant, and growing cells displayed a saturated chemotactic system with leucine as the attractant, unlike the response during starvation.

Analysis of expression of cholecystokinin in dopamine cells in the ventral mesencephalon of several species and in humans with schizophrenia.

The ventral mesencephalons of hamster, guinea pig, cat, monkey, and several humans with and without the diagnosis of schizophrenia were analyzed with in situ hybridization and immunohistochemistry. Extensive codistribution of cholecystokinin mRNA and tyrosine hydroxylase [L-tyrosine, tetrahydropteridine: oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] mRNA was observed in cats and monkeys as well as in all five human subjects with the diagnosis of schizophrenia and in two out of five control brains. Double labeling revealed coexistence of the two markers in cat, monkey, and human. No cholecystokinin mRNA or cholecystokinin peptide was detected in the substantia nigra/ventral tegmental area of the hamster or guinea pig, even after acute and chronic neuroleptic treatment.

Theophylline pharmacokinetics in children, comparing sustained release spheres (Theo-Dur sprinkle) with elixir.

A new sustained release theophylline preparation (Theo-Dur Sprinkle, TDS) was given b.i.d. and a theophylline elixir t.i.d. to eight children with bronchial asthma, 4-10 years of age, in an open study with a randomized cross over design. The serum concentration curves of theophylline were compared. The individual theophylline dose was close to 20 mg/kg body weight per day. On day 3 of each regimen, blood samples were taken 11 times over 24 h. There were great differences between morning concentrations of theophylline, with a range from 0.9-10.7 mg/l in children given elixir, while corresponding values for children given TDS were 4.1-19.3 mg/l. Fluctuation during a dosing interval was 276% for elixir but only 54% in the case of TDS. The morning theophylline levels on two consecutive days did not differ significantly when the children were treated with TDS. The bioavailability of theophylline from TDS was 94% (range 54%-121%). Parents preferred TDS in seven of the eight cases. TDS showed satisfactory sustained release properties but the study confirmed the need for individually tailored dosage of theophylline based on monitoring of symptoms and serum concentrations.

Consistency of chromosomal aberrations in chronic B-lymphocytic leukemia. A longitudinal cytogenetic study of 41 patients.

Serial chromosome analyses with a mean of 3.7 samplings during a mean interval of 4.2 years (range, 1.5 to 8.6 years) were performed on B-cell mitogen-activated chronic B-lymphocytic leukemia (CLL) cells from 41 patients. Twenty-four of these patients (59%) had progressive disease. Clonal chromosomal aberrations were found in 28 patients; 12 had an extra chromosome 12. Thirty patients (73%), 17 with and 13 without clonal aberrations, retained their karyotype throughout the study, although six lost minor subclones. In five patients (12%), a clonal aberration was found only once. Six patients (15%) showed changes of the karyotype. One treated patient with multiple aberrations acquired another monosomy. Another patient with multiple aberrations and prolymphocytic transformation gained a marker chromosome. One treated patient with an initially normal karyotype acquired two independent clonal aberrations. Three patients lost one subclone but retained another clone that increased in frequency. In two cases, clonal changes were associated with clinical changes. The chromosomal aberrations are mostly established already at diagnosis and mark the disease of the CLL patient. Cytogenetic analysis at any time is representative and useful in the prognosis prediction.

Chromosomal aberrations in progressive and indolent chronic B-lymphocytic leukaemia. A longitudinal study.

Chromosome analyses of B-cell mitogen-activated cells from 95 patients with chronic B-lymphocytic leukaemia revealed clonal chromosomal aberrations in 50 patients (53%), of which 24 had an extra chromosome 12 with or without other aberrations. Patients with clonal aberrations, especially those with +12, had poorer survival than other patients. Longitudinal studies, with a mean of 3.5 samplings during a median interval of 3.5 years, were performed in 41 patients, of which 24 (59%) had progressive disease. Twenty-nine of the patients in the longitudinal study (71%), 16 with and 13 without clonal aberrations, retained their karyotype unaltered. In 6 patients a clonal aberration was found only once. Six patients showed minor changes of the karyotype. The karyotype seems to be established at diagnosis, and marks the disease of the individual CLL-patient.

Role of chromosomal abnormalities in chronic lymphocytic leukemia.

Chromosomal aberrations occur in both B-CLL and T-CLL. The polyclonal B-cell mitogens, in particular Epstein-Barr virus and lipopolysaccharide from E. coli, have been used successfully to reveal chromosomal abnormalities in 40-60% of patients with B-CLL, while T-cell mitogens have shown chromosomal aberrations in T-CLL. The most common clonal chromosomal aberration in B-CLL is an extra chromosome 12, alone or together with other abnormalities. Other common aberrations are 14q+, structural aberrations on 6, 11, 12 and 13. Proto-oncogenes are frequently located close to breakpoints. The proto-oncogene c-K-ras is located on chromosome 12 and an abnormal transcript has recently been implicated in a subset of B-CLL-patients. An extra chromosome 12 as well as multiple chromosomal abnormalities in B-CLL appear to predict a less favourable prognosis. T-CLL is in most patients characterized by an inv(14), an extra 8q and structural abnormalities in chromosome 7. The genes for the specific T-cell receptor as well as the immunoglobulin heavy chain are located on these chromosomes. Chromosomal aberrations appear to have pathogenetic importance in both B-CLL and T-CLL.

Concentration of angiotensin-converting enzyme in tears of patients with sarcoidosis.

The concentration of angiotensin-converting enzyme (ACE) was studied in 39 patients with sarcoidosis, 6 of whom had active uveitis, 7 patients with non-sarcoid uveitis and 36 healthy controls. ACE concentration in tears was also compared with total protein concentration in tears in order to exclude the effect of varying dilution of tears at sampling. Mean tear ACE concentration and ACE/protein ratio were higher in patients with sarcoidosis than in controls. There were no significant differences in tear ACE concentration or ACE/protein ratio between sarcoidosis patients with uveitis and those with no eye involvement. Tear ACE concentration and ACE/protein ratio did not correlate significantly with serum ACE concentration. It is concluded that the mean concentration of tear ACE and ACE/protein ratio are elevated in sarcoidosis, but that this elevation is independent of any eye involvement.

Angiotensin-converting enzyme in sarcoid and chalazion granulomas of the conjunctiva.

Angiotensin-converting enzyme (ACE) was studied immunohistochemically in conjunctival biopsies from 6 patients with systemic sarcoidosis, 4 patients with posterior non-sarcoid uveitis and in specimens from 4 patients with chalazion of the eyelid. Specimens with sarcoid granulomas showed intense ACE-positive immunoreactivity in epitheloid cells of the granuloma, whereas chalazion granulomas did not contain ACE-immunoreactivity. There was no difference in staining patterns between specimens without granulomas. Thus immunohistochemical staining for ACE may be of help in differentiating conjunctival granulomatous tissue of a chalazion from sarcoid granuloma.

Prognostic information from cytogenetic analysis in chronic B-lymphocytic leukemia and leukemic immunocytoma.

Fifty-five patients with a clonal expansion of B lymphocytes in the peripheral blood were studied. According to the Kiel classification, 22 patients had chronic lymphocytic leukemia (CLL), 29 had immunocytoma (IC), two had prolymphocytic leukemia, and one had centrocytic lymphoma; one was not subclassified. Cytogenetic studies after B cell mitogen stimulation showed that six patients had an extra chromosome 12 as the sole abnormality. Another ten patients had an extra chromosome 12 together with other abnormalities. One patient had dup(12). Fifteen patients showed clonal aberrations without +12. Eleven patients showed only normal metaphases, and 12 patients were not evaluated cytogenetically. The cytogenetic subgroup pattern did not distinguish between CLL and IC patients. There was no significant difference between the CLL and IC groups as regards clinical findings and prognosis. However, the cytogenetic typing proved to be of prognostic significance. Increasing numbers of chromosomal aberrations within the cell clone were significantly associated with a poorer prognosis, ie, with impairment of survival (P = .04) and therapy-free survival (P less than 10(-4]. Patients with complex karyotypes (at least clonal aberrations) showed the poorest survival (P = .007). Patients with +12 required treatment earlier than patients with a normal karyotype (P = .01) and patients with karyotypic changes other than +12 (P = .006). These latter differences were even more pronounced when only IC patients were considered (P = .005 and P = .002, respectively). A multivariate analysis revealed that +12 was as strong an indicator of poor survival as advanced Rai or Binet stages and a stronger predictor of therapy-demanding disease.

Del(3)(p13) in B-prolymphocytic leukemia--a new nonrandom chromosomal aberration possibly related to the c-ras oncogene.

Cytogenetic analysis was performed on the leukemic cells from two patients with B-prolymphocytic leukemia. Both patients had del(3)(p13) chromosomal abnormality, as well as other clonal aberrations. Del(3p) was previously reported in one case of B-cell prolymphocytic leukemia, and is known to be a specific aberration in small-cell carcinoma of the lung. In B-cell prolymphocytic leukemia, as in other B-lymphocytic leukemias/lymphomas, the karyotype often involves chromosomes #3, #6, #11, and #12. All of these chromosomes are suggested sites for the c-ras oncogene family.

Ph chromosome and B-cell malignancy-associated chromosomal aberrations in non-leukaemic immunoblastic B-cell lymphoma.

A 62-year-old female with a microK phenotypic immunoblastic B-cell lymphoma with bone marrow involvement but without leukaemia is reported. Bone marrow cells, cytogenetically studied at diagnosis, showed a Philadelphia chromosome due to a (9p;22q) translocation, deleted chromosomes 3 and 6, a 14q+ marker, and two extra chromosomes 18. The Ph chromosome is previously only once reported in a well-characterized B-cell lymphoma, whereas the latter aberrations are common findings in B-cell malignancies.