Biomedical subjects
K Kruger
Publications and source records attributed to K Kruger.
Predictive value of fetal scalp blood lactate concentration and pH as markers of neurologic disability.
OBJECTIVES: We aimed to analyze the predictive value of the fetal scalp blood lactate concentration and pH, especially in regard to outcome variables that are strong predictors of impaired long-term outcome. An additional aim was to establish cutoff lactate levels in fetal scalp blood. STUDY DESIGN: We conducted a retrospective study of all patients who had fetal scalp blood sampling performed because of an ominous fetal heart rate pattern at Huddinge University Hospital from October 1993 to October 1998. Fetal scalp blood sampling was performed in 1709 patients. The pH and the lactate concentration were determined in fetal scalp blood of 1221 and 814 of these patients, respectively. Outcome variables included pH <7.0 in umbilical artery blood; base deficit >16.0 mmol/L in umbilical artery blood; Apgar scores <7 at 1 minute, <7 at 5 minutes, and <4 at 5 minutes; and hypoxic-ischemic encephalopathy. RESULTS: Sensitivity and specificity were generally higher in the lactate group than in the pH group, particularly in relation to an Apgar score <4 at 5 minutes and moderate to severe hypoxic-ischemic encephalopathy. In 326 patients the scalp blood lactate concentration and pH value had been obtained at the same time, thus allowing a comparison between these methods. The areas under the receiver operating characteristic curves were significantly higher for the lactate concentration than for the pH value with 2 outcome variables: Apgar score <4 at 5 minutes (P =.033) and moderate to severe hypoxic-ischemic encephalopathy (P =.015). CONCLUSIONS: Our findings suggest that determination of the lactate concentration in fetal scalp blood is a more sensitive diagnostic tool than is determination of the pH value for predicting either an Apgar score <4 at 5 minutes or moderate to severe hypoxic-ischemic encephalopathy. In previous studies we also showed lactate measurements to be more often successful than pH analysis. Therefore we consider the measurement of lactate in fetal scalp blood to be an attractive alternative to pH analysis, and determination of the lactate concentration in fetal scalp blood seems to be a useful tool for monitoring the condition of the fetus. A suitable cutoff limit for fetal scalp blood lactate concentration as an indicator of fetal asphyxia could be 4.8 mmol/L.
Role of lactate measurements during labor.
Lactate can safely and easily be determined in fetal scalp and umbilical artery blood with a new microvolume (5 microliters) lactate meter. Comparison between lactate and pH in scalp blood revealed a significant correlation (r = -0.43; P < .001). In a management trial where scalp lactate was compared to scalp pH, the lactate group underwent significantly more successful blood sampling procedures and fewer number of scalp incisions per blood sampling attempt. The mode of delivery and neonatal outcome were similar in patients managed with lactate and those using pH. Lactate concentration in umbilical artery blood had the same predictive properties as pH or base deficit in relation to poor neonatal outcome. Our data suggest that this method for lactate determination is robust and feasible and is suitable as a tool for fetal monitoring. Additional clinical management trials will be required to define the clinical usefulness of this method and how it should be combined with other modalities for fetal monitoring.
Randomized retinal ganglion cell axon routing at the optic chiasm of GAP-43-deficient mice: association with midline recrossing and lack of normal ipsilateral axon turning.
During mammalian development, retinal ganglion cell (RGC) axons from nasal retina cross the optic chiasm midline, whereas temporal retina axons do not and grow ipsilaterally, resulting in a projection of part of the visual world onto one side of the brain while the remaining part is represented on the opposite side. Previous studies have shown that RGC axons in GAP-43-deficient mice initially fail to grow from the optic chiasm to form optic tracts and are delayed temporarily in the midline region. Here we show that this delayed RGC axon exit from the chiasm is characterized by abnormal randomized axon routing into the ipsilateral and contralateral optic tracts, leading to duplicated representations of the visual world in both sides of the brain. Within the chiasm, individual contralaterally projecting axons grow in unusual semicircular trajectories, and the normal ipsilateral turning of ventral temporal axons is absent. These effects on both axon populations suggest that GAP-43 does not mediate pathfinding specifically for one or the other axon population but is more consistent with a model in which the initial pathfinding defect at the chiasm/tract transition zone leads to axons backing up into the chiasm, resulting in circular trajectories and eventual random axon exit into one or the other optic tract. Unusual RGC axon trajectories include chiasm midline recrossing similar to abnormal CNS midline recrossing in invertebrate "roundabout" mutants and Drosophila with altered calmodulin function. This resemblance and the fact that GAP-43 also has been proposed to regulate calmodulin availability raise the possibility that calmodulin function is involved in CNS midline axon guidance in both vertebrates and invertebrates.
Retinal ganglion cell axon progression from the optic chiasm to initiate optic tract development requires cell autonomous function of GAP-43.
Pathfinding mechanisms underlying retinal ganglion cell (RGC) axon growth from the optic chiasm into the optic tract are unknown. Previous work has shown that mouse embryos deficient in GAP-43 have an enlarged optic chiasm within which RGC axons were reportedly stalled. Here we have found that the enlarged chiasm of GAP-43 null mouse embryos appears subsequent to a failure of the earliest RGC axons to progress laterally through the chiasm-tract transition zone to form the optic tract. Previous work has shown that ventral diencephalon CD44/stage-specific embryonic antigen (SSEA) neurons provide guidance information for RGC axons during chiasm formation. Here we found that in the chiasm-tract transition zone, axons of CD44/SSEA neurons precede RGC axons into the lateral diencephalic wall and like RGC axons also express GAP-43. However unlike RGC axons, CD44/SSEA axon trajectories are unaffected in GAP-43 null embryos, indicating that GAP-43-dependent guidance at this site is RGC axon specific or occurs only at specific developmental times. To determine whether the phenotype results from loss of GAP-43 in RGCs or in diencephalon components such as CD44/SSEA axons, wild-type, heterozygous, or homozygous GAP-43 null donor retinal tissues were grafted onto host diencephalons of all three genotypes, and graft axon growth into the optic tract region was assessed. Results show that optic tract development requires cell autonomous GAP-43 function in RGC axons and not in cellular elements of the ventral diencephalon or transition zone.
Investigative methods of congenital complete heart block.
Congenital heart block (CHB) has been described for a century and related to the presence of maternal autoimmune disease for three decades, but little is understood about its mechanism. To explore the pathophysiology of CHB, technologies in both basic and clinical electrophysiology are being developed and applied. Human fetal rhythm is currently inferred from cardiac mechanical events by using fetal ultrasound, allowing for the detection of second and third-degree heart block. Fetal electrocardiography is being explored to assess its feasibility as a clinical tool to detect fetal first-degree block in the mid trimester. Sequential composite digital recordings from the maternal abdomen are made every 4 weeks from pregnancies at risk for congenital heart block. Filtering and averaging techniques are used to enhance the fetal signal. So far, these techniques have produced a fetal QRS complex trigger signal for use in three-dimensional fetal echocardiography. Because the human fetus cannot be studied directly, a Langendorff rabbit model of CHB has been developed. With 5-10 mL of human serum in 150-300 mL of Krebs solution, prolongation of the Wenckebach second-degree atrioventricular block cycle length occurred. This was reproduced by using serum from seven of eight CHB mothers as compared with none of six controls mothers.
Lactate compared with pH analysis at fetal scalp blood sampling: a prospective randomised study.
OBJECTIVE: Fetal scalp blood sampling is a widely used method for assessing fetal condition in the event of ominous fetal heart rate patterns. The purpose of this randomised trial was to compare the value of fetal scalp blood lactate and pH management in cases of abnormal intrapartum fetal heart rate tracings. METHODS: Of 341 cases of ominous fetal heart rate patterns, 169 were randomly assigned to pH analysis, and 172 to lactate measurements. Lactate was measured using a lactate card requiring 5 microL of blood and yielding the result within 60 seconds. pH analysis was performed with an ABL 510 acid-base analyser requiring 35 microL of blood and yielding the results within 47 seconds. RESULTS: Unsuccessful fetal blood sampling procedures (no result or an unreliable result) occurred significantly more often in the pH subgroup than in the lactate subgroup (OR 16.1 with 95% CI 5.8-44.7). In the pH subgroup the failure rate was inversely related to the degree of cervical dilatation. Compared with the pH subgroup, the lactate subgroup was characterised by fewer fetal scalp incisions per blood sampling attempt (median 1.0 [interquartile range (IQR) 1-1] vs 2.0 [IQR 1-2]), and significantly less time required for the sampling procedure (median 120 s [IQR 90-147] vs 230 s [IQR 180-300]). The groups did not differ in mode of delivery, neonatal outcome and umbilical artery acid-base balance and lactate levels. CONCLUSION: This trial showed the levels of lactate and pH in fetal scalp blood to be comparable in predicting perinatal outcome, but the procedure to measuring lactate was more successful than that for pH. Owing to its simplicity of performance, lactate analysis is an attractive alternative for intrapartum fetal monitoring.
Double-blind comparison of the efficacy of diclofenac/misoprostol and diclofenac in the treatment of rheumatoid arthritis.
A double-blind, randomised, parallel-group study was conducted in eight countries to compare the efficacy of a fixed combination of diclofenac sodium (50 mg) and misoprostol (200 mcg) with a fixed combination of diclofenac sodium (50 mg) and placebo in treating the signs and symptoms of rheumatoid arthritis (RA). A total of 346 patients with RA who had been stabilised on diclofenac for at least 30 days were randomly assigned to receive either diclofenac/misoprostol BID or TID (n = 177) or diclofenac/placebo BID or TID (n = 169) for 12 weeks. Primary analyses of efficacy, made upon admission and at 4-week intervals, consisted of physician's global assessment of the arthritic condition, patient's global assessment of the arthritic condition, patient's global assessment of joint tenderness/pain, and physician's assessment of joint swelling. In this study, the fixed combination tablet of diclofenac sodium 50 mg/misoprostol 200 mcg administered BID or TID demonstrated no statistically significant difference in efficacy in the treatment of the signs and symptoms of RA compared with diclofenac sodium 50 mg/placebo administered BID or TID.
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Molecular basis of heavy-chain class switching and switch region deletion in an Abelson virus-transformed cell line.
We demonstrated that a subclone of an Abelson murine leukemia virus-transformed B-lymphoid cell line switched from mu to gamma 2b expression in vitro, by the classical recombination-deletion mechanism. In this line, the expressed VHDJH region and the C gamma 2b constant region gene were juxtaposed by a recombination event which linked the highly repetitive portions of the S mu and S gama 2b regions and resulted in the loss of the C mu gene from the intervening region. An additional recombination event in this subclone involved an internal deletion in the S mu region of the expressed (switched) allele. One end of this deletion occurred very close to the switch recombination point. Despite the recombination-deletion mechanism of switching, the gamma 2b-producing line retained two copies of the C mu gene and two copies of the sequence just 5' to the S gamma 2b recombination point. The possible significance of the retention of these sequences to the mechanism of class switching is discussed.
Self-splicing RNA: autoexcision and autocyclization of the ribosomal RNA intervening sequence of Tetrahymena.
In the macronuclear rRNA genes of Tetrahymena thermophila, a 413 bp intervening sequence (IVS) interrupts the 26S rRNA-coding region. A restriction fragment of the rDNA containing the IVS and portions of the adjacent rRNA sequences (exons) was inserted downstream from the lac UV5 promoter in a recombinant plasmid. Transcription of this template by purified Escherichia coli RNA polymerase in vitro produced a shortened version of the pre-rRNA, which was then deproteinized. When incubated with monovalent and divalent cations and a guanosine factor, this RNA underwent splicing. The reactions that were characterized included the precise excision of the IVS, attachment of guanosine to the 5' end of the IVS, covalent cyclization of the IVS and ligation of the exons. We conclude that splicing activity is intrinsic to the structure of the RNA, and that enzymes, small nuclear RNAs and folding of the pre-rRNA into an RNP are unnecessary for these reactions. We propose that the IVS portion of the RNA has several enzyme-like properties that enable it to break and reform phosphodiester bonds. The finding of autocatalytic rearrangements of RNA molecules has implications for the mechanism and the evolution of other reactions that involve RNA.
Tumor induction by Agrobacterium tumefaciens: analysis of the boundaries of T-DNA.
Molecular cloning has been used to isolate the ends of that portion of the tumor-inducing (Ti) plasmid of Agrobacterium tumefaciens which has been designated T-DNA and which has been transferred to the genome of tobacco crown gall tumor cells. Analysis of the DNA sequences of the plant border clones compared with the corresponding sequences of the Ti plasmid suggests that the mechanism of transferred DNA integration and subsequent stabilization is precise at the right border and imprecise on the left. The T-DNA junction occurs within a variation of a single base pair (bp) on the right but varies over at least 70 bp on the left. In addition, there are several sequences which are repeated near the ends of the T-DNA region in the Ti plasmid. Seemingly, there is no specificity with regard to the site of integration in the plant genome.
Tumor DNA structure in plant cells transformed by A. tumefaciens.
Crown gall tumors are induced in plants by infection with the soil bacterium Agrobacterium tumefaciens. Because the tumor induction involves transfer of a portion of the tumor-inducing (Ti) plasmid DNA from the bacterium to the plant cells, this system is of interest for the study of genetic exchange as well as tumor induction. The boundaries of the transferred DNA (T-DNA) have been cloned from transformed plant cells of tobacco. Detailed mapping with restriction enzymes and nucleotide sequence analysis of two independent clones were used to study the molecular structure of the ends of the T-DNA. One clone contains the two ends of the T-DNA joined together; the other contains one end of the T-DNA joined to repetitive plant DNA sequences. These studies provide direct evidence that the T-DNA can be integrated into the plant genome. In addition, the data suggest that in the plant, T-DNA can be tandemly repeated. Sequence analysis of the junction of crown gall clone 1 reveals several direct repeats as well as an inverted repeat; these structures may be involved in the transfer of the DNA from Agrobacterium to plant cells.
Volume dependence of instantaneous time constants derived from the maximal expiratory flow-volume curve. A new approach to the analysis of forced expiration.
A simple expansion of the information in the maximal expiratory flow-volume curve was used to measure the convexity to the volume axis of maximal expiratory flow-volume curves produced by 11 asymptomatic smokers and 11 asymptomatic nonsmokers. The ratio of remaining volume to maximal flow was equal to the product of upstream resistance and chord compliance. This "instantaneous time constant" increased more near residual volume in the smokers. Using this method, plethysmographically obtained maximal expiratory flow-volume curves were more sensitive than spirometrically obtained maximal expiratory flow-volume curves. This method compared favorably with moment analysis and helium response of maximal expiratory flow as a separator of asymptomatic smokers and nonsmokers.
Transit time analysis of the forced expiratory spirogram in growth.
In the search for more sensitive indicators of airway obstruction Fish et al. (Am. Rev. Respirat. Diseases 109: 700, 1974) have proposed a transit time analysis of the forced expiratory spirogram. In this method the forced vital capacity (FVC) is divided into volumes of air and each volume is assigned a transit time; the nature of the FVC can be described by the transit times' mean, standard deviation, and index of skewness. In a group of 48 healthy nonsmoking subjects between the ages of 9 and 22 yr we found that all three quantities decreased with increasing age. This demonstrates an improvement in the function of the peripheral airways with lung growth. In contrast to the increase in flow rates with lung growth, none of this improved function can be attributed to increased lung volume.
Transit time analysis of the forced expiratory vital capacity in cystic fibrosis.
Transit time analysis of the forced expiratory vital capacity maneuver was applied to 37 patients with cystic fibrosis 8 to 22 years of age. This analysis divides the vital capacity into segments of air and assigns a transit time to each segment. The characteristics of the distribution of these transit times are used as measurements of pulmonary function. The quantities were compared with the forced vital capacity, 1-sec forced expiratory volume, ratio of 1-sec forced expiratory volume to vital capacity, peak flow, forced expiratory flow during the middle half of the forced vital capacity, maximal expiratory flow at 25 per cent of the vital capacity, specific airway conductance, and arterial PO2 of these patients. The standard deviation of the transit times was the most frequently abnormal. The mean transit time had the largest range of values in terms of its own standard deviation, and it was the best single estimate of over-all lung function because it correlated almost equally with large and small airway function. The coefficient of cariance of transit times was specific in detecting abnormality of small airways and was as sensitive in the detection of minimal lung disease as the standard deviation of transit times.
Measurement of respiratory resistance in children by forced oscillations.
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