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U Bengtsson

Publications and source records attributed to U Bengtsson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Efforts toward understanding the molecular basis of facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a frequency of 1 in 20,000. The report in 1992 of a DNA polymorphism that occurred both in familial and sporadic cases led to the pronouncement that the FSHD defect had been identified. Unfortunately, 2 years have passed without the isolation of a gene or definitive proof of the mutation. Over this time it has become clear that the region of the human genome containing the FSHD gene is a complex assemblage of mildly repetitive sequences that includes the suspected polymorphic fragment. We have employed molecular and cytogenetic techniques to initiate the structural analysis of terminal 4q35 in an effort to facilitate the isolation of the gene responsible for FSHD. As a result of these efforts and our inability to identify expressed sequences unique to 4q35 we have begun to consider alternate hypotheses for a molecular mechanism resulting in FSHD other than a simple coding sequence disruption.

Chromosome Mapping↗
PubMed1994

High-resolution physical mapping of human 5q31-q33 using three methods: radiation hybrid mapping, interphase fluorescence in situ hybridization, and pulsed-field gel electrophoresis.

Three physical mapping methods, radiation hybrid (RH) mapping, pulsed-field gel electrophoresis (PFGE), and fluorescence in situ hybridization (FISH) of interphase nuclei, were used to determine the order and relative distances between 12 loci in the q31-q33 region of human chromosome 5. The information obtained by each of the methods was compared to determine whether they gave consistent results. Based upon a combination of data, the predicted order of the 12 loci is cen-ADRB2-PDEA-CSF1R-RPS14-ANX6-SPARC++ +-GLRA1-GLUR1-ADRA1B-IL12- GABRG2-GABRA1-tel. Over the 5-Mb region spanned by these loci, we determined that an RH mapping unit (centiray, cR6500) is equivalent to 21 kb, in good agreement with previous estimates of 27-34 kb/cR6500 using the same set of radiation hybrids to map other regions. Of the three methods, RH mapping was by far the easiest and most efficient method for determining both order and distances. In addition, the range of resolution of RH mapping was the broadest, ranging from approximately 200 kb to several megabasepairs. Interphase FISH was the most informative method for clarifying the order of closely linked markers. The FISH distances obtained in this study will be useful as an internal reference for high-resolution mapping studies of other regions on the long arm of human chromosome 5. In contrast to RH mapping and FISH, PFGE was the least reliable of the three methods, producing some data that were inconsistent with the distances determined by the other two methods.

Chromosome Mapping↗
PubMed1994

[Segmental intestinal perfusion. A "new" technique for human studies].

Intestinal release of inflammatory mediators and permeation of macromolecules were studied in patients suffering from Crohn's disease, celiac disease and food intolerance with the use of a system for segmental intestinal perfusion. Drug absorption and ion and bicarbonate transport were also studied in healthy subjects. Patients with Crohn's disease of the distal ileum revealed an increased release of inflammatory agents into the lumen of the proximal jejunum. Luminal provocation with different antigens in cases of celiac disease and food intolerance not only activated cells in the intestinal mucosa but also increased the leakage from plasma and lymph. Studies of drug absorption elucidated the kinetics of drug transport from intestine to plasma, and basal neurologic effects on ion and bicarbonate transport were determined.

Celiac Disease↗
PubMed1994

The DNA rearrangement associated with facioscapulohumeral muscular dystrophy involves a heterochromatin-associated repetitive element: implications for a role of chromatin structure in the pathogenesis of the disease.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant form of muscular dystrophy. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. Recently, a probe was identified that detects an EcoRI fragment length polymorphism which segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. In several familial cases and four independent sporadic FSHD mutations, the variation in size of the EcoRI fragment was due to a decrease in copy number of the 3.2 kb repeats. To gain further insight into the relationship between the tandem array and FSHD, a single 3.2 kb repeat unit was characterized. Fluorescence in situ hybridization (FISH) demonstrates that the 3.2 kb repeat cross-hybridizes to several regions of heterochromatin in the human genome. In addition, DNA sequence analysis of the repeat reveals a region which is highly homologous to a previously identified family of heterochromatic repeats, LSau. FISH on interphase chromosomes demonstrates that the tandem array of 3.2 kb repeats lies within 215 kb of the 4q telomere. Together, these results suggest that the tandem array of 3.2 kb repeats, tightly linked to the FSHD locus, is contained in heterochromatin adjacent to the telomere. In addition, they are consistent with the hypothesis that the gene responsible for FSHD may be subjected to position effect variegation because of its proximity to telomeric heterochromatin.

Base Sequence↗
PubMed1994

High resolution fluorescence in situ hybridization to linearly extended DNA visually maps a tandem repeat associated with facioscapulohumeral muscular dystrophy immediately adjacent to the telomere of 4q.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder. The FSHD locus has been linked to the most distal genetic markers on the long arm of chromosome 4. An EcoRI fragment length polymorphism segregates with the disease in most FSHD families. Within the EcoRI fragment lies a tandem array of 3.2 kb repeats. Deletions of integral copies of this repeat have been associated with the disease. The 3.2 kbp repeat has recently been shown to cross-hybridize to several regions of heterochromatin in the human genome and DNA sequence analysis reveals strong homology to a class of heterochromatin repeats, LSau. In this report, we demonstrate that the 3.2 kbp tandem repeat lies adjacent to a subtelomeric sequence, which is within 5-14 kb of the telomeric repeat (TTAGGG)n. Direct visual fluorescence hybridization to linearly extended strands of DNA enabled the visualization of this subtelomeric sequence as a short string of signals at the end of a longer string of signals from the differentially labeled 3.2 kbp tandem repeat. Furthermore, in support of our data showing that the 3.2 kbp repeat lies in close proximity to the telomere of 4q, we demonstrated the lack of hybridization of total human DNA to this same region. Our results indicate that the tandem array of 3.2 kbp repeats, disrupted in FSHD, lies immediately adjacent to the telomere of 4q and that the gene responsible for FSHD is likely located proximal to the tandem repeat.

Animals↗
PubMed1994

Molecular and phenotypic mapping of the short arm of chromosome 5: sublocalization of the critical region for the cri-du-chat syndrome.

Forty-nine individuals have been identified with deletions or translocations involving the short arm of chromosome 5. While most display the classical phenotype of the cri-du-chat syndrome, several of the patients do not have the syndrome or have only a subset of the clinical features. Somatic cell hybrids containing the deleted chromosome 5 were derived from each patient. Each somatic cell hybrid was analyzed at the DNA level using 136 chromosome 5p-specific DNA fragments. It was possible to unambiguously order most of the chromosomal breakpoints present in the somatic cell hybrids based on the hybridization patterns of Southern blots. Further comparisons between the deletions present in the patients and their clinical features identified several chromosomal regions that were involved in specific clinical features. A critical chromosomal region involved the high-pitched cry mapped to 5p15.3, while the chromosomal region involved in the remaining features of the cri-du-chat syndrome mapped to a small region within 5p15.2. Deletions that did not include these two chromosomal regions presented varying clinical phenotypes from severe mental retardation and microcephaly to a clinically normal phenotype. These results demonstrate the need for careful characterization of a 5p deletion in prenatal cases before clinical predictions are made.

Animals↗
PubMed1994

Genes encoding adrenergic receptors are not clustered on the long arm of human chromosome 5.

The distal portion of the long arm of chromosome 5 (5q) contains a large number of genes encoding membrane receptors belonging to various gene families, including G protein-coupled adrenergic receptors. Previous reports indicated that the genes for two of the adrenergic receptors, ADRB2 and ADRA1B, were within 300 kb of one another on 5q. In an effort to determine if a third adrenergic receptor assigned to 5q, ADRA1A, was physically close to the genes encoding the other adrenergic receptors, we attempted to place all three loci on a radiation hybrid map of 5q. The results conflicted with previous mapping results in two ways. First, ADRA1B is on 5q but is several million bases, rather than a few hundred thousand bases, from ADRB2. Second, ADRA1A is not on chromosome 5, but rather on chromosome 20. Thus, even though 5q contains an extraordinary number of genes encoding receptors for various hormones, growth factors, and neurotransmitters, there is no particular clustering of genes encoding adrenergic receptors in this region.

Animals↗
PubMed1993

Identification of a cryptic t(5;7) reciprocal translocation by fluorescent in situ hybridization.

Fluorescent in situ hybridization (FISH) identified a cryptic balanced reciprocal translocation in the mother of an infant with the cri-duchat syndrome. A biotinylated probe from a flow-sorted chromosome 5 cosmid library was used to show the distal deletion of 5p15.2 in the propositus and a translocation of this segment to the distal end of 7 at 7p21 in his mother. In a subsequent pregnancy, the fetus was shown to have normal chromosomes using the same 5 cosmid library probe and a locus-specific probe derived from the 5p15.3 region. The importance of incorporating FISH into the routine diagnostic laboratory is discussed.

Adult↗
PubMed1993

Intestinal reactivity in allergic and nonallergic patients: an approach to determine the complexity of the mucosal reaction.

BACKGROUND: To determine whether inflammatory markers and mediators were released in response to different intestinal antigens, studies were performed in atopic patients allergic to birch, patients allergic to psyllium powder (ispaghula), and patients intolerant to milk. METHODS: Allergy to birch and psyllium powder was documented by the presence of circulating IgE antibodies and positive skin tests. Patients intolerant to milk had negative outcomes of radioallergosorbent tests and skin tests but positive results of double-blind, placebo-controlled tests. Challenge of the intestine with different antigens was achieved by perfusion of a jejunal segment occluded between balloons. Basal and antigen-activated release of mast cell/basophil and eosinophil products and of substances emanating from the plasma and interstitial fluid was compared in perfusate fluid from patients (n = 8) and matched healthy controls (n = 8). RESULTS: Perfusate levels of albumin and hyaluronan (previous name hyaluronic acid) were increased threefold to fivefold by antigen in all patients, but not in controls. Eosinophilic cationic protein increased in patients but also in ispaghula controls. Histamine was released in response to milk, but not in patients allergic to birch or ispaghula. Prostaglandin E2 increased in milk- and birch-sensitive patients. In response to ispaghula, however, it was released in both patients and controls. CONCLUSIONS: We conclude that subclinical intestinal challenge with antigen induces an increase in the appearance rate of albumin and hyaluronan in the intestinal lumen both in atopic patients (with target organs such as the lungs or nose and eyes) and in patients with intestinal intolerance to milk. These changes in permeation are similar to those reported from other organs such as the lung. They may reflect a common response in early phase I reactions that are either IgE-mediated or occur in response to food antigens without any obvious involvement of an IgE-mediated mechanism. Subclinical provocation with intestinal antigens should prove useful for further elucidation of mechanisms underlying intestinal mucosal reactions to exogenous stimuli.

Antigens↗
PubMed1993

High resolution physical map of the region surrounding the spinal muscular atrophy gene.

Spinal muscular atrophy (SMA) is the second most common lethal, autosomal recessive disease in Caucasians, second only to cystic fibrosis. In an effort to identify the causative gene in SMA, we have used radiation hybrid (RH) mapping to prepare a high resolution physical map of the proximal region of chromosome 5 (5q11-13) which contains the SMA gene. The map of the SMA region, which spans approximately 4 Mb, contains 19 loci including 9 polymorphic DNA markers, 8 monomorphic sequence tagged sites (STS) and two genes. Based upon the RH map the two polymorphic loci which most closely flank the SMA locus were estimated to be separated by approximately 750 kb. Using two different directional cloning schemes, several new clones between the genetic markers which most closely flank SMA were isolated. These new clones within the SMA candidate region, together with cosmid clones prepared from one RH hybrid which retains an approximately 1 Mb segment spanning the SMA region as its only human DNA, will greatly facilitate efforts to identify the gene for SMA. In addition, analysis of cloned DNA segments from within the SMA candidate region has identified the presence of a novel, chromosome 5-specific, low copy repeated sequence which is distributed throughout the region containing the SMA gene as well as in at least four other regions of chromosome 5. Whether or not these novel repeated sequences throughout the SMA region are involved in the disease remains to be determined.

Animals↗
PubMed1993

Scintigraphic detection of gastro-pulmonary aspiration in patients with respiratory disorders.

The scintigraphic detection of small nocturnal aspirations of radio-labelled gastric contents is difficult in the presence of high remaining activity in the abdomen, causing a non-uniform background activity. This problem was examined in phantom experiments and a technique for interpolative background correction was further developed. The accuracy of this technique was found to be influenced by the distance between the lung and the abdominal source of activity, and the minimum detectable 'aspirated' activity was determined as 0.1 MBq at a distance of 15 cm and 1 MBq at 5 cm. The interpolative technique for background correction was evaluated on healthy volunteers and laryngectomized patients, examined 10 h after intragastric instillation of 200 MBq of 99Tcm-pertechnetate. After background subtraction, their calculated pulmonary mean net count value was comparable to that registered before the radioactive tracer was administered. No localized accumulation of activity was found in any of these controls. The technique was then applied clinically to 55 patients with chronic respiratory disorders and symptoms of gastroesophageal reflux. Aspiration was detected in 11 patients (20%). Five aspirators had asthma, two a chronic cough of unknown origin, two recurrent pulmonary infections, and one chronic bronchitis and chronic laryngitis respectively. Aspiration was detected among patients with and without demonstrated pathological gastroesophageal reflux.

Adult↗
PubMed1991

IgE-positive duodenal mast cells in patients with food-related diarrhea.

Thirty-seven consecutive adult patients with a history of adverse reactions to foods, manifested mainly as diarrhea, were investigated with skin prick test (SPT), IgE levels in serum, and the presence of IgE bound to mast cells in duodenal biopsy specimens. Nineteen percent had increased serum IgE levels indicating the presence of atopic disease and in 35% positive SPTs for one or several allergens related to their gastrointestinal symptoms were found. In 92% of the patients with positive SPTs to food, IgE-positive mast cells in duodenal biopsy specimens were found, twice as many as in patients with negative SPTs (47%). Forty-two percent of normal individuals without any adverse reactions to foods had IgE-bearing mast cells in their intestinal mucosa. The results showed that 'arming' of mast cells with IgE locally was relatively prominent but not consistent in the gut of patients with food-related diarrhea suggested to be allergic by positive SPT. Intestinal IgE-mediated hypersensitivity reactions could be of pathogenetic significance in most of these patients. However, since also half of the normal individuals were found to have IgE-positive intestinal mast cells, this phenomenon presumably also reflects a normal physiological defence mechanism.

Adult↗
PubMed1991

Molecular confirmation of Wolf-Hirschhorn syndrome with a subtle translocation of chromosome 4.

Wolf-Hirschhorn syndrome is a clinically recognizable, multiple congenital anomaly syndrome usually associated with terminal deletion of the short arm of chromosome 4. A girl with clinical features of Wolf-Hirschhorn syndrome did not show an obvious deletion of chromosome 4, and a molecular defect was suspected. RFLPs of genomic DNA from the proband and her parents were studied using DNA probes from the distal region of chromosome 4p. Fluorescence in situ hybridization using a cosmid p847.351 containing the fragment 847 E-C was performed to investigate the possibility of a subtle translocation. Cytogenetic analyses done on the child and on both parents did not conclusively reveal abnormalities of chromosome 4. Molecular studies using two probes mapped to distal 4p showed the absence of the maternal haplotype in the child. These findings are thus consistent with a molecular deletion of 4p and confirm the diagnosis of Wolf-Hirschhorn syndrome. Cytogenetic experiments involving fluorescence in situ hybridization showed that the mother carried a subtle translocation between chromosomes 4 and 19, 46,XX,t(4,19)(p16.3; p13.3), which resulted in an unbalanced form in the child. Chorionic villus sampling for prenatal diagnosis in a subsequent pregnancy showed the fetus to be unaffected. This provides the first evidence, in chromosome 4p, of a molecular deletion due to a subtle, inherited translocation leading to the Wolf-Hirschhorn phenotype. Such subtle translocations may become an important mechanism for some recurrent genetic defects.

Adult↗
PubMed1990

Felodipine in the treatment of patients with severe hypertension and impaired renal function.

Twenty-three patients with severe hypertension and impaired renal function were included in an open study of the efficacy and tolerance of felodipine treatment over 6 months. All patients were previously treated with a diuretic, a beta blocker, and a vasodilator, and eight of them also received an ACE inhibitor. At the start of felodipine treatment the previously used vasodilator was withdrawn. In nine patients the concomitant antihypertensive treatment was reduced during the study. The glomerular filtration rate (GFR), as 51Cr EDTA clearance, was determined before and at the end of the study. The blood pressure (BP) and heart rate (HR) were recorded at all clinical visits in the morning 12 hours after the evening dose of felodipine and 2 hours after the morning dose. Plasma concentrations of felodipine were measured at every visit before the morning dose and 2 hours after dose. The BP was reduced after felodipine was substituted for the previously used vasodilator. A significant additional anti-hypertensive effect was recorded 2 hours after the dose and amounted to -37 +/- 22/-15 +/- 12 mmHg (p = 0.0001/p = 0.0002) at 6 months. The effect measured 12 hours after the dose was less pronounced and was -11 +/- 28/-6 +/- 10 mmHg (p = 0.15/p = 0.03). Mean GFR was unchanged during the study, 38 +/- 19 versus 38 +/- 19 ml/min (n = 16). There was a sixfold interindividual variation in the trough plasma concentrations at steady state at the same drug dosage. Higher plasma concentrations seemed to be required to achieve the same antihypertensive effects as in patients with less severe hypertension and normal renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗