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Biomedical subjects

A Forster

Publications and source records attributed to A Forster.

At least 37 records · Page 2Linked to original sources
PubMed1994

The influence of environmental and genetic factors on CYP2D6, CYP1A2 and UDP-glucuronosyltransferases in man using sparteine, caffeine, and paracetamol as probes.

The impact of gender, use of oral contraceptive steroids (OCS), coffee consumption and of smoking on the metabolism of sparteine, caffeine, and paracetamol was studied in 194 randomly selected subjects (98 male and 95 female). Thirty-eight of the male volunteers were cigarette smokers, 40 of the female subjects were smokers and/or users of OCS. The metabolic ratio of sparteine oxidation (MRs) showed a trimodal distribution. 7.7% of the subjects had a MRs > 20 and thus were poor metabolizers (PMs). Within the extensive metabolizer (EM) subjects, a distinct subgroup accounting for 11% was observed with 20 > MRs > 1.2. Six of the 15 phenotypical PMs were heterozygous EMs by genotyping. This indicates the existence of one or several CYP2D6 mutations which cannot be identified by the currently employed genotyping methods. In each subgroup, i.e. smokers/OCS and non-smokers/non-OCS, the cumulative frequency distribution of the heterozygous (wt/B) phenotype caused a shift to higher MRs compared with the wild-type homozygotes (wt/wt). Thus, for the in vivo activity of CYP2D6, genetic determinants prevail over environmental factors. Smoking, use of oral contraceptive steroids, caffeine consumption, or gender had no influence on sparteine metabolism. The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed. Glucuronidation capacity was clearly affected by gender, OCS use and smoking. It was higher in male than in female subjects. Male smokers had the highest, and female non-smokers/non-OCS users the lowest metabolic ratio. CYP1A2 activity, as determined by a caffeine metabolic ratio ((AFMU + 1X + 1U)/1, 7U), was multimodally distributed and was clearly increased in smokers. It was significantly correlated to paracetamol glucoronidation in male heavy smokers (r=0.85), suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes, including UGTI.6.

Acetaminophen↗
PubMed1994

Influence of duration of lateral decubitus on the spread of hyperbaric tetracaine during spinal anesthesia: a prospective time-response study.

Searching for a differential spinal block between dependent and nondependent sides, we evaluated a prospective randomized time-response study of the influence of the duration of lateral decubitus on the spread of hyperbaric local anesthetic solution during spinal anesthesia in 60 patients undergoing lower limb surgery. In a lateral position with the operated side dependent, all patients received 12 mg of lyophilized tetracaine with 0.2 mg epinephrine in 2.5 mL 10% dextrose and were randomized into four groups according to the duration of lateral decubitus after spinal injection: Group 0, patients immediately turned supine after spinal injection; Group 6, 6 min in lateral decubitus then supine; Group 12, 12 min in lateral decubitus then supine; Group 18, 18 min in lateral decubitus then supine. There was no difference in maximum sensory level between both sides in the same group nor between the four groups. In all four groups a comparable number of patients had a Grade 4 motor block on the dependent as well as on the nondependent side. A positive correlation found between duration of lateral decubitus and duration of sensory block on the dependent side suggested a preferential spread of hyperbaric local anesthetics. This differential spread was confirmed by the positive correlation between the duration of lateral decubitus and the difference in duration between dependent and nondependent sides of both sensory and motor blocks. However, because of the minimal differences between groups, we believe there is no reason to routinely maintain patients in the lateral position after performing spinal anesthesia.

Adult↗
PubMed1993

Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation.

The MLL gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). We report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22 t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH2 terminus of MLL, lacking the zinc-finger region, and that translocations occur in early hematopoietic cells, before commitment to distinct lineages.

Acute Disease↗
PubMed1993

Paracetamol glucuronidation by recombinant rat and human phenol UDP-glucuronosyltransferases.

Stably expressed human and rat phenol UDP-glucuronosyltransferases (UGTs) of the UGT1 complex (HlugP1, HlugP4 and 3-methylcholanthrene-inducible rat UGT1A1, the latter considered to be an orthologous enzyme to HlugP1) have been used to investigate the role of UGTs in paracetamol glucuronidation. Kinetic analysis of recombinant UGTs was compared to that of total UGT activities in liver microsomes. Paracetamol was found to be an overlapping substrate of several UGTs. It shows higher affinity for HlugP1 and rat UGT1A1 (apparent Km values of 2 and 3 mM, respectively) than for HlugP4 (Km = 50 mM) and other UGTs present in liver microsomes (Km values of > 12 mM). Glucuronidation of paracetamol with HlugP1 contrasts with that of 6-hydroxychrysene and of 4-methylumbelliferone, which are conjugated with higher affinity by HlugP4 than by HlugP1. Due to the wide tissue distribution of rat UGT1A1, paracetamol glucuronidation was also investigated in extrahepatic rat and human tissues. Paracetamol UGT activity was present and inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat kidney, lung and spleen. It was also detected in human kidney. A selective cDNA probe for exon 1 of HlugP1 cross-reacted with mRNA from both human liver and kidney. The results demonstrate that paracetamol is conjugated by HlugP1 and its rat orthologue UGT1A1 with higher affinity than by HlugP4 and other UGTs.

Acetaminophen↗
PubMed1993

The cysteine-rich LIM domains inhibit DNA binding by the associated homeodomain in Isl-1.

Recently, a new class of homeobox genes has been identified, called LIM-homeobox genes. These genes encode proteins which have two tandemly repeated cysteine motifs, referred to as LIM domains, in addition to a homeodomain. In addition, proteins with only LIM domains have been described but the function of the LIM domain is unknown. We have analysed the function of LIM domains using Isl-1 as a representative LIM-homeodomain protein. Employing protein prepared in bacterial cells, we show that the presence of the LIM domain in Isl-1 inhibits binding of the homeodomain to its DNA target. This in vitro inhibition can be released either by denaturation/renaturation of the protein or by truncation of the LIM domains. A similar inhibition is observed in vivo using reporter constructs. In addition we show that LIM domains in a chimeric protein can inhibit binding of the Ubx homeodomain to its target. The ability of LIM domains to inhibit DNA binding by the homeodomain provides a possible basis for negative regulation of LIM-homeodomain proteins in vivo.

Base Sequence↗
PubMed1993

Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma.

The search for tumour-specific markers is one of the chief goals in cancer biology. We show that the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma can be a fusion of the CHOP dominant negative transcription factor gene with a novel gene, FUS, which can result in fusion of the FUS glycine-rich protein with the whole CHOP coding region. The data support the concept that protein fusion may commonly occur in solid tumours resulting in tumour-specific markers of potential clinical importance. The data also indicate the importance of transcription disruption in the pathogenesis of solid tumours.

Amino Acid Sequence↗
PubMed1993

Comparison of 5 mg tetracaine diluted in 1 ml, 2 ml and 4 ml of 10% glucose for spinal anesthesia.

The influence of variations in the volume of injectate when maintaining an identical dose of a hyperbaric local anesthetic has not previously been investigated when performing spinal anesthesia. This study compares spinal anesthesia of 5 mg of lyophilized tetracaine diluted in 1 ml, 2 ml or 4 ml of 10% glucose in 45 elderly patients undergoing elective hip surgery. While supine and horizontal, each patient received double-blind one of the three solutions through a catheter inserted 4 cm into the intrathecal space at the L2-L3 or L3-L4 interspace. No difference in the anesthetic effects was found between the three groups. The median value of the maximal sensory level was T6 (range T3-L2), T4 (range T3-T9) and T5 (range T3-T11) in the 1-ml, 2-ml, and 4-ml groups, respectively. The number of patients with a motor blockade of grade 2 or 3 was 12/15, 14/15 and 13/15, and the time from the initial dose to the need for the first top-up dose (mean +/- s.d.) was 88 +/- 35 min, 75 +/- 15 min and 68 +/- 15 min for the 1-ml, 2-ml and 4-ml groups, respectively. Hemodynamic changes were also comparable between the three groups. The authors conclude that in elderly patients, undergoing spinal anesthesia while supine and horizontal, variations in volume from 1 to 4 ml do not influence the characteristics of hyperbaric spinal anesthesia while injecting an identical dose of local anesthetic.

Aged↗
PubMed1993

Continuous spinal anesthesia: where do spinal catheters go?

The purpose of this study was to investigate the incidence of technical problems encountered when performing continuous spinal anesthesia and the influence of catheter tip position on block height following injection of a hypobaric spinal anesthetic. Twenty-nine elderly patients undergoing hip surgery were studied. Lumbar puncture was performed with an 18-gauge Tuohy needle at the L3-4 (or L2-3) interspace. Threading was defined as easy if a 20-gauge catheter was inserted on the first try, 3-4 cm cephalad. Threading was considered difficult if cephalad insertion of the catheter was impossible on the first try; the Tuohy needle was then rotated with its bevel facing caudally, the catheter inserted for 1-2 mm, and the needle turned back cephalad together with the catheter partially threaded, for further cephalad insertion up to 4 cm. All patients received 7.5 mg of hypobaric bupivacaine or tetracaine in the lateral decubitus position and sensory levels were determined by pinprick. After surgery all catheters were injected with radiographic dye and examined by radiograph for verification of position. The determination of the level of lumbar puncture was falsely judged in 59% of cases, the puncture being performed 1 or 2 spaces higher than assumed. Although threading difficulties were encountered in 4/28 cases, there was a 100% success rate in catheter insertion. One catheter displacement into the epidural space was noted. Twenty of twenty-eight catheters took a cephalad direction, 6 remained coiled in a horizontal position, and 2 took a caudal direction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Influence of injection speed on the subarachnoid distribution of isobaric bupivacaine 0.5%.

The purpose of this study was to compare the anesthetic characteristics after two radically different speeds of intrathecal injection of isobaric 0.5% bupivacaine during continuous spinal anesthesia. Forty consenting patients, undergoing hip surgery using continuous spinal anesthesia, were allocated randomly to two groups of 20 each according to the rate of injection of 2 mL (10 mg) of isobaric 0.5% bupivacaine: FI (fast injection = 2 mL during 2 to 3 s or approximately 0.75 mL/s) or SI (slow injection = 1 mL/min). No difference was observed between the two groups in terms of sensory and motor block or hemodynamic changes. However, the onset time to maximal sensory level was significantly shorter in the SI group (16 +/- 9 min vs. 24 +/- 6 min; P < 0.05). Those patients requiring reinjection entered the second part of the study (n = 23; 15 in the FI group and 8 in the SI group). Each of these remaining patients was used as his or her own proper control. Those in the FI group received a slow reinjection and those in the SI group received a fast reinjection which consisted in all cases of 10 mg (2 mL) of isobaric 0.5% bupivacaine. When looking at the anesthetic characteristics after reinjection, maximal sensory levels, as well as onset times, were very similar in both groups. At all times, the maximal sensory level obtained after reinjection was two dermatomes higher than after the initial injection. Duration of sensory block, which was calculated only in these 23 patients, was also comparable (126 +/- 44 min for FI and slow reinjection group vs 146 +/- 25 min for SI and fast reinjection group). In conclusion, regardless of the speed of injection, there are no differences in anesthetic characteristics of spinal anesthesia using isobaric 0.5% bupivacaine.

Aged↗
PubMed1993

Absence of agonist effects of high-dose flumazenil on ventilation and psychometric performance in human volunteers.

Flumazenil, a specific benzodiazepine antagonist, reverses sedative and respiratory depressant effects of benzodiazepines. We determined whether a large dose of flumazenil, injected alone, induces respiratory depression or alteration of psychomotor performance. After informed consent, eight healthy volunteers participated at three different sessions: 1) flumazenil (0.1 mg/kg) (a dose 7-15 times the clinically recommended dose) injected intravenously over a 5-min period, followed by placebo (NaCl 0.9%); 2) flumazenil at the same dose and injection rate as in Session 1, followed by midazolam (0.1 mg/kg) injected over 5 min; and 3) placebo followed by midazolam at the same dose as above and administered over 5 min. All drug combinations were administered in a randomized and double-blind manner. Tidal volume, respiratory frequency, minute ventilation, and mean inspiratory flow were continuously measured from 15 min before until 120 min after drug injection by noninvasive on-line data acquisition methods. Psychometric performance was evaluated 15 min before the first drug and 15 min after administration of the second drug. During the placebo-midazolam session, tidal volume (-40%), minute ventilation (-25%), and inspiratory flow (-25%) were significantly (P < 0.01) decreased compared both with baseline and with the other two sessions, and psychometric performance was significantly (P < 0.01) altered; in contrast, there was no significant change in any of the measured respiratory or psychometric variables during the flumazenil-placebo or flumazenil-midazolam sessions. We conclude that flumazenil, administered at about 10 times the clinically recommended dose, has no agonist effects on resting ventilation or psychomotor performance in normal subjects.

Adult↗
PubMed1993

The chromosomal translocation t(X;14)(q28;q11) in T-cell pro-lymphocytic leukaemia breaks within one gene and activates another.

Chromosomal translocation t(X;14)(q28;q11) has been observed in patients with pro-lymphocytic T-cell leukaemia (T-PLL). In two cases of T-PLL, one of which was associated with Ataxia telangiectasia (AT), the chromosomal break occurred in two different introns of a gene c6.1A, located at the Xq28 locus. Fusion transcripts, consisting of 5' sequences of c6.1A and the TCR alpha constant (C) region, were expressed at high levels in the leukaemic cells from both patients, but in only one case did this fusion generate an in-frame c6.1A-C alpha mRNA. However, the breaks within c6.1A seem to affect another gene, c6.1B, which is transcribed from the same CpG rich island as c6.1A but in the opposite transcriptional orientation. The c6.1B gene is not damaged by the translocation but is transcribed in both T-PLL cases. Furthermore, c6.1B may lack protein coding capacity and thus this translocation might result in a novel mechanism in tumorigenesis. In any event, this is the first cloned gene which is implicated in pathogenesis of chronic/pro-lymphocytic leukaemia of the T-cell lineage.

Aged↗
PubMed1993

Day hospital and home physiotherapy for stroke patients: a comparative cost-effectiveness study.

The financial cost of stroke rehabilitation is considerable but few cost-effectiveness studies are available to guide clinical practice. The Bradford community stroke trial was a randomised trial comparing day hospital attendance with home physiotherapy for elderly stroke patients leaving hospital. The outcome measurements used indicated a consistent modest advantage in favour of home physiotherapy. This advantage is now re-examined in conjunction with the quantified costs of the rehabilitation services and community support received by the two patient groups. The results show that the median cost for the day hospital patients over the first eight weeks was 620.00 pounds (interquartile range 555.00-730.00 pounds) and 385.00 pounds for the home physiotherapy group (interquartile range 240.00-510.00 pounds). These costs were significantly different (median difference 265.00 pounds, 95% confidence interval 190.00-340.00 pounds; p < 0.01). There were no significant differences between the two groups for the indirect costs. This cost-effectiveness study supports the clinical trial result that home physiotherapy should be the treatment of choice for stroke aftercare.

Aged↗
PubMed1993

A method for identifying genes within yeast artificial chromosomes: application to isolation of MLL fusion cDNAs from acute leukaemia translocations.

The majority of chromosomal translocations breakpoints are within regions of the genome where few DNA probes are available. The use of yeast artificial chromosomes (YACs) containing long stretches of human DNA allows dispersed DNA markers to be used to identify the position of breakpoints but does not readily allow subcloning of the precise breakpoint within the YAC DNA nor the cDNAs containing the affected genes. We describe a procedure allowing rapid isolation of cDNAs corresponding to genes within a YAC clone. Random cDNA is hybridised to PCR-generated biotinylated fragments of total DNA from a yeast strain harbouring a YAC clone. The hybrids can be recovered to facilitate subsequent cloning of the cDNA molecules. The application of this method to the cloning of cDNA molecules carrying sequences involved in the translocation t(4;11)(q21;q23) is illustrated.

Acute Disease↗
PubMed1992

The rhombotin gene family encode related LIM-domain proteins whose differing expression suggests multiple roles in mouse development.

The rhombotin (RBTN1 or Ttg-1) gene was first identified at a chromosome translocation in a T-cell acute leukaemia and later used to isolate two related genes (RBTN2 or Ttg-2 and RBTN3). Complete characterization of these genes in man and mouse shows that all three encode cysteine-rich proteins with typical LIM domains. RBTN1 and RBTN3-derived proteins have 98% identity in the LIM domains but are located on separate chromosomes in man and in mouse while RBTN1 and RBTN2, both located on human chromosome 11p but are on separate chromosomes in mouse, are only 48% identical in this part of the protein. The exon organization of RBTN1 and RBTN3 genes are similar, both having an intron, absent from the RBTN2 gene, in the LIM2-encoding region. The remarkable similarity between rbtn-1 and rbtn-3 proteins is parallelled in their expression patterns in mouse development, since both genes show high expression in restricted areas of the brain, but little lymphoid expression. rbtn-2 expression, however, is more ubiquitous. This gene shows a low level of thymus expression but high expression in fetal liver, adult spleen and B-cell lines, consistent with a role in B-cell development. These results suggest multiple cellular targets for the action of these proteins during development.

Adult↗
PubMed1992

The Bradford community stroke trial: results at six months.

OBJECTIVE: Comparison of day hospital attendance and home physiotherapy for stroke patients leaving hospital to determine which service produces greater functional and social improvement for the patient, reduces emotional stress for the care giver, and lessens the need for community support. DESIGN: Stratified, randomised trial of stroke patients attending day hospital two days a week or receiving home treatment from a community physiotherapist. The six month assessment results are reported in this paper. SUBJECTS: Patients over 60 years old resident within the Bradford metropolitan district discharged home after a new stroke with residual disability. SETTING: Four day hospitals in two health authorities and domiciliary work undertaken by experienced community physiotherapists. MAIN OUTCOME MEASURES: Barthel index, functional ambulatory categories, Motor Club assessment, Frenchay activities index, and Nottingham health profile were used. Carers' stress was indicated by the general health questionnaire. Treatment given and community care provided were recorded. RESULTS: Of 124 patients recruited, 108 were available for reassessment at six months. Both treatment groups had significantly improved in functional abilities between discharge and six months. The improvements were significantly greater for patients treated at home (Mann-Whitney test; Barthel index, median difference 2 (95% confidence interval 0 to 3) p = 0.01; Motor Club assessment, median difference 2 (1 to 5), p = 0.01). The home treated patients received less treatment (median difference 16 (11 to 21) treatments, p less than 0.001). More than a third of patients in both groups showed depressed mood, and a quarter of care givers were emotionally distressed. CONCLUSIONS: Home physiotherapy seems to be slightly more effective and more resource efficient than day hospital attendance and should be the preferred rehabilitation method for aftercare of stroke patients. New strategies are needed to address psychosocial function for both patients and care givers.

Activities of Daily Living↗
PubMed1992

[Ambulatory surgery. Attitude of patients].

Whilst day care surgery is well developed in English-speaking countries for its medical, social and economic advantages, for ill-defined reasons a small proportion of ambulatory operations is performed in Switzerland. The purpose of this study was to determine the patients' attitude towards day care surgery in order to inform the general population concerning the development of this type of surgery. One hundred and ten hospitalized patients about to undergo unilateral repair of inguinal hernia were questioned: 58 percent were unfavourable, 22 percent were favourable and 20 percent would be favourable if a home care system was organized. The factors responsible for this negative attitude towards day care surgery are analysed, and proposals are made to overcome the patients, reluctance.

Adolescent↗