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Biomedical subjects

G Ragnarsson

Publications and source records attributed to G Ragnarsson.

17 recordsLinked to original sources

[Irritable bowel syndrome. Survey of definitions, differential diagnosis and pathogenesis].

Abdominal pain/discomfort, bloating, need to rush to the toilet, straining, feeling of incomplete bowel emptying and alternating periods of diarrhea and constipation is the clinical definition of the irritable bowel syndrome. The internationally used syndrome definition is based on expert opinions and answers to patient questionnaires. When symptoms are registered prospectively, abdominal pain starts or worsens after meals and is not relieved by defecation. As in the general population patients with the syndrome define diarrhea as loose stools and constipation as hard stools regardless of stool frequencies. Variation in defecatory symptoms and discrepancies between these symptoms and stool consistency are the hallmarks of the syndrome, and the degree of variation per fortnight is relatively stable in the individual patient. Fermentation of carbohydrates by colonic bacteria, increased sensitivity to bowel distention by gas, gas-producing food, increased secretion of cholecystokinin after fatty meals and/or increased sympathetic nerve tone at stress can give rise to symptoms. Symptoms can start after a single period of bacterial gastroenteritis. Although patients seeking medical care for the syndrome are more often anxious, the syndrome itself is not psychosomatic. Symptoms are possibly mediated through partial degranulation of mast cells in bowel mucosa, but this does not make it an allergic disease. If bowel dysmotility can be measured, early stage or a mild case of intestinal pseudoobstruction should be considered. Hyperreactivity in the enteric nervous system and/or in the brain is the likely main cause of the symptoms. More widespread activity in the brain after exposure to stimuli originating from bowel nerves or less inhibition of this stimulation in the brain are possible mechanisms.

Abdominal Pain↗

Abdominal symptoms and anorectal function in health and irritable bowel syndrome.

BACKGROUND: It is unclear how the quality and quantity of abdominal symptoms and anorectal function differ between irritable bowel syndrome (IBS) patients and healthy controls, and whether different anorectal function in patients is associated with abdominal symptoms in IBS. METHODS: Fifty-two outpatients with IBS and 12 healthy controls kept daily symptom records over 1 week. At the end of the week, anorectal function was assessed by manovolumetry before and after a standard fatty meal. Patients were divided into symptom and manovolumetric subgroups using a cluster analysis and also into those below (hypersensitive) and those within (normosensitive) the 95% confidence interval of the controls' mean for maximal tolerable distension (MTD). RESULTS: Regardless of subgroup, the patients were distinguished from the controls by pain, bloating, straining and incomplete evacuation. Compared with controls, MTD was lower in the pain/bloating subgroup characterized by considerable pain and the bowel habit subgroup characterized by hard stools, variable stool consistency and heavily disturbed stool passage. Preprandial rectal hypersensitivity was highly prevalent in this bowel habit subgroup. No similar association with the pain/bloating subgroup was found. Patients and controls showed a significant and similar postprandial decrease in MTD. CONCLUSIONS: IBS is distinguished from health by pain, bloating, straining and a feeling of incomplete evacuation. Baseline rectal hypersensitivity is associated with constipation-like bowel habit. Increased rectal sensitivity after a meal and/or preceding distension is a normal reaction unimportant in the genesis of symptoms in IBS.

Abdominal Pain↗

Chromosome 8p alterations in sporadic and BRCA2 999del5 linked breast cancer.

Chromosomal losses involving the short arm of chromosome 8 are frequent in a variety of tumour types, including breast cancer, suggesting the presence of one or more tumour suppressor genes in this region. In this study, we have used 11 microsatellite markers to analyse loss of heterozygosity (LOH) at chromosome 8p in 151 sporadic breast tumours and 50 tumours from subjects carrying the BRCA2 999del5 mutation. Fifty percent of sporadic tumours compared to 78% of BRCA2 linked tumours exhibit LOH at one or more markers at 8p showing that chromosome 8p alterations in breast tumours from BRCA2 999del5 carriers are more pronounced than in sporadic breast tumours. The pattern of LOH is different in the two groups and a higher proportion of BRCA2 tumours have LOH in a large region of chromosome 8p. In the total patient material, LOH of 8p is associated with LOH at other chromosome regions, for example, 1p, 3p, 6q, 7q, 9p, 11p, 13q, 17p, and 20q, but no association is found between LOH at 8p and chromosome regions 11q, 16q, 17q, and 18q. Furthermore, an association is detected between LOH at 8p and positive node status, large tumour size, aneuploidy, and high S phase fraction. Breast cancer patients with LOH at chromosome 8p have a worse prognosis than patients without this defect. Multivariate analysis suggests that LOH at 8p is an independent prognostic factor. We conclude that chromosome 8p carries a tumour suppressor gene or genes, the loss of which results in growth advantage of breast tumour cells, especially in carriers of the BRCA2 999del5 mutation.

BRCA2 Protein↗

Loss of heterozygosity at chromosome 1p in different solid human tumours: association with survival.

The distal half of chromosome 1p was analysed with 15 polymorphic microsatellite markers in 683 human solid tumours at different locations. Loss of heterozygosity (LOH) was observed at least at one site in 369 cases or 54% of the tumours. LOHs detected ranged from 30-64%, depending on tumour location. The major results regarding LOH at different tumour locations were as follows: stomach, 20/38 (53%); colon and rectum, 60/109 (55%); lung, 38/63 (60%); breast, 145/238 (61%); endometrium, 18/25 (72%); ovary, 17/31 (55%); testis, 11/30 (37%); kidney, 22/73 (30%); thyroid, 4/14 (29%); and sarcomas, 9/14 (64%). High percentages of LOH were seen in the 1p36.3, 1p36.1, 1p35-p34.3, 1p32 and 1p31 regions, suggesting the presence of tumour-suppressor genes. All these regions on chromosome 1p show high LOH in more than one tumour type. However, distinct patterns of LOH were detected at different tumour locations. There was a significant separation of survival curves, with and without LOH at chromosome 1p, in the breast cancer patients. Multivariate analysis showed that LOH at 1p in breast tumours is a better indicator for prognosis than the other variables tested in our model, including nodal metastasis.

Analysis of Variance↗

Abdominal symptoms are not related to anorectal function in the irritable bowel syndrome.

BACKGROUND: The pathophysiologic significance of altered intestinal motility and perception in irritable bowel syndrome (IBS) is unclear, as a consistent association with abdominal symptoms has not been proved. Our aim was to investigate the association between abdominal symptoms and anorectal function in IBS. METHODS: Fifty-two patients recorded their symptoms daily for I week. At the end of the week anorectal function was investigated by manovolumetry before and after a standardized fatty meal. Cluster analysis of daily recorded symptoms and both pre- and postprandial manovolumetric data was performed to identify symptom and physiologic subgroups. RESULTS: Symptom subgroups did not differ with regard to anorectal function. Physiologic subgroups did not differ with regard to daily recorded symptoms. Postprandially, the thresholds eliciting maximal tolerable distention were decreased in 22 of the patients. This increase in rectal sensitivity was not related to symptoms and may have been caused by the preprandial anorectal measurement, since thresholds for maximal tolerable distention decreased significantly in nine patients retested without an intervening meal. CONCLUSIONS: Abdominal symptoms and anorectal function are not related in IBS.

Adult↗

Division of the irritable bowel syndrome into subgroups on the basis of daily recorded symptoms in two outpatients samples.

BACKGROUND: If subgroups exist in a sample of patients with irritable bowel syndrome (IBS), they may represent different etiologic and pathophysiologic entities. Our aim was to identify subgroups on the basis of symptoms in IBS. METHODS: Two independent groups of 56 (sample I) and 52 (sample II) outpatients recorded their abdominal symptoms daily for 6 weeks and 1 week, respectively. The daily records were assessed by using cluster analysis. RESULTS: Similar subgroups appeared in both samples. Three bowel habit subgroups were identified. The first was distinguished by hard stools, varying stool consistency, and highly disturbed stool passage, the second by loose stools and urgency, and the third by normal stools and the least disturbed stool passage. Two pain/bloating subgroups were identified, one distinguished by little and the other by considerable pain and bloating. No relation was found between pain/bloating and bowel habit subgroup membership. Most patients had stool frequency within the normal range regardless of subgroup. In sample I the subgroups had stable symptoms during the study, and subgroup placement was not related to the presence of dyspepsia, smoking habits, or use of bulk agent and/or sporadic intake of loperamide. The degree of pain and bloating was inversely related to illness duration. CONCLUSIONS: Subgroups exist in IBS. Division of IBS into bowel habit subgroups should be based on stool consistency, not frequency. Mechanisms mediating pain and bloating may be different from those mediating symptoms at defecation.

Abdominal Pain↗

High incidence of loss of heterozygosity in breast tumors from carriers of the BRCA2 999del5 mutation.

Germ-line mutation in the BRCA2 gene confers an increased risk of breast cancer. An elevation of additional genetic defects in tumors of patients with germ-line mutation in the BRCA2 gene compared with sporadic breast tumors has been reported. To evaluate the nature of the difference, we did detailed mapping of chromosomes 1p, 3p, 6q, 11, 13q, 16q, 17, and 20q, using microsatellite markers. We found that the frequency of loss of heterozygosity was similar at some chromosomal regions in the BRCA2 999del5 and sporadic tumors but significantly different at others. These others include chromosomal arms 3p, 6q, 11p, 11q, 13q, and 17p. Loss of heterozygosity mapping suggests that the same chromosome regions are involved in both tumor groups but at elevated frequencies in BRCA2 999del5 tumors. This higher frequency of genetic aberrations could pinpoint genes that selectively promote tumor progression in individuals predisposed to breast cancer due to the BRCA2 999del5 germ-line mutation. Accumulation of somatic genetic changes during tumor progression may follow a specific and more aggressive pathway of chromosome damage in these individuals.

BRCA2 Protein↗

Pain is temporally related to eating but not to defaecation in the irritable bowel syndrome (IBS). Patients' description of diarrhea, constipation and symptom variation during a prospective 6-week study.

OBJECTIVES: To study the intensity and variation of pain and its temporal relation to eating and defaecation. Furthermore, what irritable bowel (IBS) patients mean by constipation and diarrhea and how bowel symptoms vary. DESIGN: Prospective daily symptom recording over 6 weeks. SETTING: The primary catchment area of University Hospital of Linköping. PARTICIPANTS: Eighty consecutive patients fulfilling the Rome criteria; 63 finished the study. RESULTS: Fifty-nine of 63 patients recorded an average of 29 pain periods and 24 days with pain during the 6 weeks. Over-all pain burden decreased slightly over the study period. At inclusion 38 (64%) patients claimed that pain was relieved by defaecation. However, on average, only 10% of each patient's recorded pain periods were relieved by defaecation. At inclusion 29 (49%) patients claimed postprandial worsening of pain. On average, 50% of each patient's recorded pain periods worsened postprandially. The patients defined constipation as hard stools and diarrhea as loose stools and urgency. Stool frequency did not differ. Bowel symptoms varied within, but not between, fortnightly periods. CONCLUSIONS: Postprandial worsening of pain should be included as a criterion in the clinical definition of IBS while the criterion 'pain relieved by defaecation' should be re-evaluated. IBS patients can probably be divided into subgroups based on stool consistency, not frequency. Daily records are superior to structured clinical interviews or questionnaires for a detailed study of symptoms in IBS.

Abdominal Pain↗

Review article: Targeted drug delivery in treatment of intestinal diseases.

Topical therapy within the treatment of intestinal diseases presents realistic formulation challenges for targeted drug delivery. Some relevant oral formulation concepts are reviewed. The basic principles employed are based mainly on differences in pH and metabolic activity between the different parts of the gastrointestinal tract. A successful example of targeted drug delivery within the treatment of Crohn's disease is presented. Topical therapy for the treatment of ulcerative colitis is also discussed. Physiological variations and influence of the disease and disease status present major challenges when deciding upon a suitable formulation principle.

Administration, Oral↗

Design of a new multiple-unit controlled-release formulation of metoprolol--metoprolol CR.

A new controlled-release (CR) formulation of the beta 1-selective adrenoceptor antagonist metoprolol has been developed, aiming at an even 24-h pharmacological effect. In order to achieve this, using a once-daily dose, factors such as absorption characteristics, physicochemical properties, and technological aspects had to be considered. The new formulation, called metoprolol CR, is a disintegrating tablet consisting of several hundred coated pellets of metoprolol succinate, each pellet being its own CR delivery unit. In vitro testing and in vivo studies in healthy volunteers show that the new CR formulation gives continuous delivery of metoprolol throughout the day, resulting in smooth plasma concentration profiles, without peaks and troughs. The release of the drug is independent of pH and other physiological variables, such as food intake, which do not seem to alter the biopharmaceutical properties of the formulation.

Delayed-Action Preparations↗

Force-displacement measurements in tableting.

The influence of particle interaction, i.e. friction and bonding, on the net work (NETW) during compaction and on Heckel plots was tested by varying the particle size, the lubrication or the moisture content. The NETW was found to be significantly affected by particle interaction. The yield pressure, calculated from Heckel plots, was far less dependent on particle interaction and appears to be more useful for the evaluation of the deformation properties of materials. The NETW may be useful as a test of inter-lot variations in compaction behaviour of materials, due to its high sensitivity to both inter- and intraparticle properties, good reproducibility and low dependence upon die wall conditions. However, it appears to be a poor measure of the plastic properties of the substance.

Chemistry, Pharmaceutical↗

Work of friction and net work during compaction.

Series of tablets were compressed in a reciprocating tablet machine with a gradually increasing die wall friction. The force needed on the upper punch to maintain the tablet dimensions constant increased with the die wall friction while the lower punch force decreased. The change in punch forces due to differences in die wall friction had no effect on the tablet strength. The net work of compaction should be constant under these circumstances. The net work calculated by subtracting the work of friction and the expansion work from the gross work input was constant when the frictional work was calculated according to one of the two equations proposed in the literature (Järvinen & Juslin 1974) while the other appears to give an overestimation of the work of friction.

Tablets↗

Replication error in colorectal carcinoma: association with loss of heterozygosity at mismatch repair loci and clinicopathological variables.

Instability of microsatellite DNA or replication error (RER) is characteristic of tumours caused by mismatch repair (MMR) deficiency. Germline mutations in MMR genes are associated with Hereditary non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in these genes are also found in a substantial fraction of colorectal cancers (CRC). In this study we concurrently screened colorectal tumours for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) tumours. RER was more commonly detected in young patients (< 50 years) and in tumours located in the proximal colon. RER was positively associated with LOH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the younger patients (< 50 years). RER was not associated with clinicopathological parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indicates that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patients.

Adaptor Proteins, Signal Transducing↗

Loss of heterozygosity at chromosome 7q in human breast cancer: association with clinical variables.

In this study 238 human primary breast cancers were analysed with 9 polymorphic microsatellite markers specific to region 7q21-q35 on chromosome 7. LOH was observed at one or more marker in 82 cases or (34%). The deletions were evenly distributed throughout the region. Patients were divided into two groups according to whether LOH was observed in their tumours or not, and tested for association with overall survival, the clinicopathological features: steroid receptor content, tumour size, node status, DNA ploidy and S-phase fraction, and LOH at other chromosomal regions. An association was found between 7q LOH and high S-phase fraction. An association was found between LOH at 7q and LOH at 1p, 3p, 9p, 13q and 17q. These results suggest the location of a putative tumour suppressor gene at chromosome 7q21-q35 that, in combination with other deletions, might enhance tumour growth.

Breast Neoplasms↗