Biomedical subjects

S Pedersen

Publications and source records attributed to S Pedersen.

At least 145 records · Page 8Linked to original sources

PubMed1993

Assignment of an autosomal sex reversal locus (SRA1) and campomelic dysplasia (CMPD1) to 17q24.3-q25.1.

We have mapped the autosomal sex reversal locus, SRA1, associated with campomelic dysplasia (CMPD1) to 17q24.3-q25.1 by three independent apparently balanced de novo reciprocal translocations. Chromosome painting indicates that the translocated segment of 17q involves about 15% of chromosome 17 in all three translocations, corresponding to a breakpoint at the interphase between 17q24-q25. All three 17q breakpoints were localized distal to the growth hormone locus (GH), and proximal to thymidine kinase (TK1). Due to the distal location of the breakpoints, previously mentioned candidate genes, HOX2 and COL1A1, can be excluded as being involved in CMPD1/SRA1. The mouse mutant tail-short (Ts) which maps to the homologous syntenic region on mouse chromosome 11, displays some of the features of CMPD1.

Abnormalities, Multiple↗

PubMed1993

The influence of orally deposited budesonide on the systemic availability of budesonide after inhalation from a Turbuhaler.

1. The aim of this pharmacokinetic study was to evaluate to what extent oropharyngeal deposition of drug contributes to the systemic availability of budesonide inhaled from a dry powder inhaler (Turbuhaler). 2. The design was a randomized cross-over study in eight children aged 7-13 years. The plasma concentrations of the two epimers of budesonide (22R and 22S) after inhalation of 1 mg budesonide from a Turbuhaler were compared with the plasma concentrations obtained when the absorption of the drug deposited in the oropharynx was blocked by drinking and rinsing the mouth with charcoal before and after the inhalation. 3. The plasma concentrations of budesonide were significantly reduced by the charcoal treatment (P < 0.01) and the area under the time vs plasma concentration curve 0-4 h was significantly reduced from 9.5 to 8.0 mmol l-1 h for 22S (P < 0.01) and from 7.6 to 5.7 mmol l-1 h for 22R (P < 0.01). 4. The plasma concentrations and the AUCs after both Turbuhaler administrations were markedly higher than those obtained in earlier studies using other inhalers suggesting a higher intrapulmonary deposition of drug after Turbuhaler treatment. 5. It is concluded that oropharyngeal deposition of drug accounts for about 20% of the total systemic availability of budesonide inhaled from Turbuhaler. Thus, the main contribution to the system comes from budesonide absorbed in the airways.

Administration, Inhalation↗

PubMed1993

Ring chromosome 20 with loss of telomeric sequences detected by multicolour PRINS.

A ring chromosome 20 in a male infant with epileptic seizures, mental and somatic growth retardation, and behavioural disturbances is described. Conventional cytogenetics revealed the karyotype to be 46,XY,r(20)(pter-->qter) and no signs of mosaicism were found. Fluorescence in situ hybridisation using the clone p20Z1 identified the ring to be derived from chromosome 20. By counting 111 metaphases, only 7% were found to be missing the ring. The absence of telomeric sequences in the ring chromosome was demonstrated by multicolour PRINS: a three-step PRimed IN Situ labelling technique, using unlabelled primers. A terminal deletion of both arms thus seems to be the cause of the ring formation in the proband. Bivariate flow-analysis of chromosomes verified a deletion of the ring chromosome. The clinical and cytogenetic findings are compared with previous cases. A specific ring 20 syndrome seems justified.

Abnormalities, Multiple↗

PubMed1993

Application of molecular and cytogenetic techniques to the detection of a de novo unbalanced t(11q;21q) in a patient previously diagnosed as having monosomy 21.

The occurrence of complete autosomal monosomy in man is extremely rare and generally considered to be incompatible with life. Since the introduction of banding techniques in human cytogenetics, several cases of presumptive monosomy for chromosome 21 have nevertheless been reported. However, it has been suggested that most, if not all, of these cases may represent unbalanced translocations or other structural aberrations resulting in only partial monosomy 21. Here we described a patient in whom full monosomy 21 was initially diagnosed by routine karyotyping. Re-examination with a combination of high resolution banding technique, chromosome painting and DNA polymorphism analysis demonstrated the presence of an unbalanced translocation between the long arms of chromosome 11 and 21, respectively. Consequently, the case was re-classified as a partial monosomy for the proximal long arm of chromosome 21.

Chromosome Banding↗

PubMed1993

Identification of a supernumerary der(18) chromosome by a rational strategy for the cytogenetic typing of small marker chromosomes with chromosome-specific DNA probes.

A case of a supernumerary der(18) marker chromosome is presented. The chromosomal origin of the marker chromosome was not evident by traditional chromosome analysis, but was determined by PRimed IN Situ labelling (PRINS) with chromosome specific centromere probes as primers for chain elongation in situ. For this purpose a strategy was developed which, in a few simple reactions, makes it possible unequivocally to determine the origin of any small marker chromosome. The approach does not require any hints about the origin of the chromosome prior to the analysis, since the chromosomal origin of the marker is established through PRINS reactions with pooled and single chromosome-specific centromere probes. Identification, mosaic screening and structural analysis require a total of 8-9 such reactions and may, due to the extreme speed of the PRINS reaction, be obtained within a single working day.

Chromosome Aberrations↗

PubMed1993

Nasal powder administration of budesonide for seasonal rhinitis in children and adolescents.

The effect of intranasal budesonide delivered from a new dry powder inhaler (Rhinocort Turbuhaler) was evaluated in a randomized, double blind, group parallel study of 83 children aged 4-16 years with seasonal allergic rhinitis. The doses 100 and 200 micrograms taken once daily in each nostril were compared with placebo. A one week run-in period was followed by a 4 weeks treatment period. Diary recordings of nasal symptoms, p.r.n. use of terfenadine tablets were made at home and rhinoscopy performed at hospital before and at the end of each treatment period. Total or substantial control of symptoms was achieved in 41% of the children in the 400 micrograms group (p < 0.05 compared with placebo), in 33% in the 200 micrograms group (p = 0.07 compared with placebo) and in 14% in the placebo group. The 400 micrograms but not the 200 micrograms group was statistically significantly better than placebo for most of the clinical effect parameters studied. The treatment was well tolerated and a battery of laboratory tests including cortisol excretion in the urine was not influenced by the various treatments. These results indicate that 400 micrograms budesonide given once daily from a Rhinocort Turbuhaler is clinically effective and safe in children with rhinitis. Further studies are needed to evaluate if this inhaler is preferable to other inhalers currently used for the treatment of rhinitis.

Administration, Inhalation↗

PubMed1993

Short-term growth in children with allergic rhinitis treated with oral antihistamine, depot and intranasal glucocorticosteroids.

Short-term growth was studied during the grass pollen season with weekly knemometry in 44 schoolchildren with allergic rhinitis. The design was a randomized, parallel group study. After a four-weeks run-in period, the children were allocated to six weeks' treatment with either a single im injection of methylprednisolone acetate 60 mg at the beginning of the period, intranasal budesonide 200 micrograms bid (aerosol spray) or terfenadine tablets 60 mg daily. Treatment with methylprednisolone acetate was open, whereas treatment with budesonide and terfenadine was double-blinded. Twelve children in the methylprednisolone acetate group, 11 in the budesonide group and 12 in the terfenadine group completed the study. Compared with the run-in period, treatment with methylprednisolone acetate and budesonide (run-in growth velocities 0.46 and 0.59 mm/week, respectively) was associated with a reduction in mean lower leg growth velocity of 0.28 and 0.54 mm/week (p < 0.01, t = 3.3, 95% confidence interval 0.09-0.47 mm/week; and p < 0.001, t = 6.1, 95% confidence interval 0.34-0.72 mm/week, respectively). Terfenadine (run-in and treatment mean growth velocity 0.35 and 0.51 mm/week) did not influence lower leg growth significantly. Short-term lower leg growth is suppressed in children with allergic rhinitis treated with intranasal and depot steroids in the doses investigated. No conclusions can be drawn with respect to long-term statural growth.

Administration, Intranasal↗

PubMed1993

Treatment of croup with nebulised steroid (budesonide): a double blind, placebo controlled study.

The aim of this prospective, randomised, double blind study was to evaluate whether nebulised local steroid treatment is effective in the treatment of croup. Thirty six infants and children (0.4-4.9 years of age) admitted to hospital with moderate to severe croup were allocated to receive either 2 mg nebulised budesonide (20 children) or saline (16 children). Disease severity was assessed by a clinical total croup score based on stridor, cough, retractions, dyspnoea, and cyanosis. In addition the overall clinical impression was evaluated (0-100). Two hours after treatment there was a significant improvement in the total croup score in the group treated with budesonide (8 to 4.5), but not in the group treated with saline (8 to 8). Furthermore, the overall clinical impression assessment score decreased significantly (50 to 25) in the group treated with budesonide, whereas it remained constant in the placebo group (60 to 62). The total croup score and overall clinical severity were significantly better in the group treated with budesonide than in the placebo group. No side effects were observed. The results indicate that nebulised budesonide can be used as a safe and effective alternative treatment in children and infants with moderate to severe croup.

Bronchodilator Agents↗

PubMed1993

Treatment of severe steroid dependent preschool asthma with nebulised budesonide suspension.

The steroid sparing effect of nebulised budesonide suspension was assessed in a double blind placebo controlled parallel group study of 36 preschool children with severe asthma who were dependent on treatment with oral steroids. Nebulised budesonide suspension significantly reduced the requirement for treatment with oral steroids, and produced a marked improvement in overall health as scored on a visual analogue scale during the clinic visits. This study shows a significant step forward in the prophylactic treatment of asthma in children under the age of 3 years, in whom the efficacy of many other nebulised treatments has been questioned.

Asthma↗

PubMed1993

Short-term growth during treatment with inhaled fluticasone propionate and beclomethasone dipropionate.

Short-term lower leg growth was investigated with twice weekly knemometry measurements in 19 schoolchildren with mild asthma during treatment with daily doses of 200 micrograms fluticasone propionate, 400 micrograms, and 800 micrograms beclomethasone dipropionate from a dry powder inhaler. The design was a randomised, double blind, crossover trial. After a run in period of four days (period 1) the children were allocated to a sequence of active treatments in periods 2, 4, and 6. In periods 3 and 5 (wash out) placebo was given. All periods except the run in were two weeks long. The mean lower leg growth velocities during the wash out periods were 0.61 and 0.80 mm/week. Mean growth velocities during treatment with fluticasone propionate and low and high doses of beclomethasone dipropionate were 0.34, 0.09, and 0.06 mm/week respectively. Compared with fluticasone propionate, treatment with beclomethasone dipropionate 400 and 800 micrograms/day was associated with a statistically significant reduction in growth velocity.

Administration, Inhalation↗

PubMed1993

Importance of the inhalation device on the effect of budesonide.

Two hundred and forty one children with chronic perennial asthma, who had been treated with budesonide via a metered dose inhaler with a spacer device (Nebuhaler), had their normal dose of budesonide reduced by 50% to determine if they had been overtreated. Within three weeks, asthma control deteriorated in 126 patients to such an extent that budesonide had to be increased to the normal dose. After stabilising their asthma, these children were enrolled in a randomised, double blind, double dummy, parallel study, performed to compare the effect of budesonide via Nebuhaler with that of half the dose of budesonide via Turbuhaler. The study started with a two week run-in during which patients were treated with their normal dose of budesonide via Nebuhaler. After run-in, 64 children were randomised to treatment with their normal budesonide treatment and the remaining 62 children to treatment with half their normal dose via Turbuhaler for nine weeks. Throughout the study, patients recorded asthma symptoms, peak flow measurements, and beta 2 agonist use in a diary. Pulmonary function tests, exercise tests, and 24 hour urine sample collections were performed at hospital visits during run-in and the study period. Apart from beta 2 agonist use, which was significantly lower for patients on Turbuhaler treatment than on Nebuhaler treatment, there were no differences between the groups in any of the parameters studied during run-in or during the study period. Furthermore, there was no trend of deterioration in asthma control when the dose of budesonide was reduced by 50% when Turbuhaler was the inhalation device. It is concluded that budesonide via Turbuhaler is more effective than via Nebuhaler in the treatment of asthma. Based on this finding, attempts should be made to reduce the dose of budesonide when patients are switched from Nebuhaler to Turbuhaler treatment.

Administration, Inhalation↗

PubMed1993

Sex dependent transmission of Beckwith-Wiedemann syndrome associated with a reciprocal translocation t(9;11)(p11.2;p15.5).

Beckwith-Wiedemann syndrome (BWS), a disorder associated with neonatal hypoglycaemia, increased growth potential, and predisposition to Wilms's tumour (WT) and other malignancies, has been mapped to 11p15. The association with 11p15 duplications of paternal origin, of balanced translocations and inversions with breakpoints within 11p15.4-p15.5 of maternal origin, and the demonstration of uniparental paternal 11p15 isodisomy in some sporadic cases point towards the involvement of genomic imprinting. In agreement with this, we show the paternal origin of a de novo 9;11 translocation in a phenotypically normal mother, whose carrier daughter developed BWS. This supports the fact that BWS associated with balanced chromosome mutations is transmitted in the same sex dependent pattern as non-cytogenetic forms of familial BWS.

Base Sequence↗

PubMed1993

Interstitial hyperthermia of colorectal liver metastases with a US-guided Nd-YAG laser with a diffuser tip: a pilot clinical study.

Ultrasound (US)-guided interstitial hyperthermia performed with the neodymium yttrium aluminum garnet laser with a diffuser tip involves placement of a laser fiber in solid tissue followed by irradiation from within the center of the tumor to be treated. The authors previously described the development of a US-guided technique that permits simultaneous interstitial laser irradiation and temperature measurements, with real-time US monitoring. With the use of a dedicated diffuser tip modification of the bare laser fiber, it has proved possible to produce spherical coagulations with a diameter comparable to that of liver metastases of clinical relevance. This technique was used in 11 patients with 16 colorectal liver metastases, 12 of which were radically ablated. Real-time US and interstitial temperature monitoring during treatment had a positive predictive value of 86% and negative predictive value of 100% in judging the final result. The technique is feasible, effective, and safe, but the effect on patient survival must be tested in future randomized clinical studies.

Adult↗

PubMed1993

Repeated primed in situ labeling: formation and labeling of specific DNA sequences in chromosomes and nuclei.

A new version of our previously published PRINS (PRimed IN Situ labeling) method is presented. It represents a significant improvement in the detection of specific DNA sequences in situ. The idea is to perform the reaction repeatedly, rather than just once. This change of strategy results in a localized accumulation of sequence-specific labeled DNA, resulting in up to a 15-fold amplification of the signal as compared to the standard PRINS method. Interestingly, the retention of the labeled DNA is so good that it stays within the chromosomal band where it is synthesized, provided that the reaction is not performed an excessive number of times. The key trick is the performance of the procedure on small glass slides in PCR tubes, thereby avoiding the use of cover slips. In addition, use of the small glass slides seems to give less variance when the signals are quantified in a fluorescence microscope.

Base Sequence↗

PubMed1993

Efficacy and safety of inhaled corticosteroids in asthma. Report of a workshop held in Eze, France, October 1992.

Inhaled glucocorticosteroids have now become first-line therapy for the treatment of chronic asthma in many countries. They are the most effective asthma therapy currently available, and numerous studies have documented their long-term efficacy in asthma control in adults and in children. Inhaled steroids suppress inflammation in asthmatic airways, although their precise molecular mechanism of action is not yet certain. It is likely that steroids affect the transcription of several steroid-responsive genes, and, of particular importance, they may inhibit cytokine gene transcription and cytokine effects, thereby reducing the chronic inflammation in asthmatic airways. Inhaled steroids are now used at a much earlier stage in asthma therapy, and there is a strong argument for their early introduction in both adults and children to prevent asthma morbidity and mortality and possibly the structural changes resulting from uncontrolled chronic inflammation, which may lead to irreversible airflow obstruction in some patients. Of paramount importance is the question of safety as inhaled steroids are likely to be required for a long time. Local side effects caused by oropharyngeal deposition of the inhaled steroid may be reduced by the use of spacer devices and mouthwashing. Systemic side effects caused by gastrointestinal absorption of the fraction deposited in the oropharynx may also be reduced by these devices. There are differences in the systemic bioavailability of the different inhaled steroids currently in use, and inhaled steroids with the lowest bioavailability should be chosen when high doses of inhaled steroids are required for asthma control. Systemic side effects are usually observed only when daily doses of > 800 micrograms are inhaled, and whether effects on very sensitive biochemical indices are relevant to long-term deleterious effects is not yet certain. There is now overwhelming evidence that the doses of inhaled steroids required to control asthma in the majority of adults and children are safe and without systemic side effects. It is important to control asthma with the minimum dose of inhaled steroids possible, however. In the future it may be possible to develop inhaled steroids with even fewer systemic effects if the fraction absorbed from the respiratory tract can be rapidly metabolized in the bloodstream.

Administration, Inhalation↗

PubMed1992

Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children.

The magnitude and duration of protection against exercise-induced asthma (EIA) afforded by salbutamol and the new, long-acting beta 2-agonist, formoterol, were compared in a double-blind, placebo-controlled crossover study. Twelve children with asthma and EIA (greater than 25% fall from baseline at a pretrial exercise test) were studied on 3 different days receiving, in random order, either formoterol, 12 micrograms, salbutamol, 200 micrograms, or placebo by inhalation. The effect on EIA was evaluated by standardized treadmill-exercise tests repeated at the following times after medication: 1/2 hour (test 1), 3 hours (test 2), and, if the trial drug still demonstrated an effect, 5 1/2 hours (test 3) and 8 hours (test 4). The mean (SD) maximum percent fall in FEV1 at the pretrial test was 45% (14%). Placebo treatment had no effect on EIA. The mean (SD) maximum percent fall in FEV1 was 44% (14%) (test 1) and 39% (13%) (test 2) (not significant). Salbutamol offered good protection against EIA after 1/2 hour (percent fall in FEV1, 18% [18%]; p less than 0.02) but was not significantly different from that of placebo after 3 hours, 39% (13%) fall in FEV1. Formoterol blocked EIA in all the children and demonstrated a significant effect in most children for at least 8 hours. The percent fall in FEV1 after the various tests were 8% (16%) (test 1), 10% (9%) (test 2), 18% (15%) (test 3), and 18% (7%) (test 4; N = 9) (all tests, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1992

Decreasing transcription elongation rate in Escherichia coli exposed to amino acid starvation.

The time required for transcription of the lacZ gene in Escherichia coli was determined during exponential growth and under conditions, when the bacterium was exposed to partial isoleucine starvation. To do this, RNA was extracted from the cells at 10 s intervals following induction and quantified by Northern hybridization with probes complementary to either the beginning or the end of the lacZ mRNA. The time lag between inducer addition and the appearance of a hybridization signal at the 'late' probe represents the transit time for RNA polymerase on the lacZ gene, and this parameter and the known length of the transcribed sequence were used to calculate the lacZ mRNA chain growth-rate. The transcription elongation rate was c. 43 nucleotides s-1 during exponential growth and decreased abruptly to c. 20 nucleotides s-1 in a relA+ strain after the onset of isoleucine starvation, when massive concentrations of guanosine tetraphosphate (ppGpp) accumulated in the cells. The starvation condition did not affect initiation of transcription at the lac-promoter, but a substantial fraction of the initiated lacZ mRNA chains was never completed. For the rel+ strain the polarity was moderate, since c. 25% of the initiated lacZ mRNA' chains were continued into full-length mRNAs, but for the relA strain the polarity was so strong that no completed lacZ mRNA could be detected. The protein chain elongation rates decreased from 13 amino acids (aa) s-1 in the unperturbed growth phase to approximately 6 as s-1, when the cells starved for isoleucine. In combination, these results suggest that ppGpp plays a major role in maintaining the coupling between transcription and translation during the downshift by inhibiting mRNA chain elongation. The implications of this result for the control of stable RNA synthesis during the stringent response are discussed.

Amino Acids↗

PubMed1992

A double-blind, placebo-controlled study of the effect of intranasal budesonide in the treatment of children with seasonal rhinitis.

The effectiveness of the intranasal glucocorticosteroid budesonide was investigated in children with grass pollen-induced rhinitis during a pollen season. The trial was of a randomized, double-blind, placebo-controlled, parallel-group design with a one-week run-in period and a three-week treatment period. Twenty-four children received treatment with budesonide 200 micrograms bid and 27 children with placebo, administered by a nasal aerosol. Concomitant terfenadine, as required, was allowed in both groups. Recordings of nasal symptom severity, use of terfenadine and adverse effects were made in diaries. Nasal symptoms were significantly less severe in patients treated with budesonide as compared with placebo-treated patients. An overall assessment of treatment effect made by the children was significantly in favour of budesonide, and the consumption of terfenadine was significantly larger in the placebo than in the budesonide group. These results provide good evidence that intranasal budesonide is effective in seasonal rhinitis in children.

Administration, Intranasal↗