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Background: Our understanding of the pathophysiology of gastro-oesophageal reflux disease (GERD) in man is limited. The aim of the present study was to establish a long-term (>1 year) animal model for reflux oesophagitis which would allow us to study various aspects of the development of chronic reflux oesophagitis. Methods: Myotomy was carried out in the gastro-oesophageal junction in eight cats; seven other cats were sham-operated. Before the operation, and every 2 months thereafter, oesophagoscopy was carried out, biopsies were taken for histology, and manometry was performed to determine the lower oesophageal sphincter pressure (LESP). The cats were killed 1 year after the operation. Results: The myotomy operation resulted in a significantly decreased LESP. In oesophageal biopsies from these cats, there was a varying degree of oesophagitis starting already 2 months after surgery. In six of the eight myotomized cats there was hyperplasia of the stratum basale, and cardiac type metaplasia was observed in two cats. The control cats showed no significant changes in LESP or in the histology of the oesophagus. Conclusions: In cats followed for more than a year, myotomy in the gastro-oesophageal junction results in reflux oesophagitis similar to that seen in patients with chronic gastro-oesophageal reflux. [ABSTRACT FROM AUTHOR]

Background: Our aim was to infect rats with Helicobacter pylori and to study the effects of the infection on the gastric mucosa in normal and in ulcer-operated rats. Methods: A mouse-adapted H. pylori (cagA, VacA) strain was inoculated into 23 rats. Another 20 uninfected rats served as controls. Two months later a gastric ulcer was induced in some rats. The animals were killed 3, 6, or 15 days after the ulcer operation. Tissues were taken for histology and for culture of H. pylori. Serum antibodies were determined. Results: All inoculated rats were infected by H. pylori after 2 months, mainly in the antrum. In these rats a mild to moderate chronic inflammation and a significantly increased frequency of apoptotic cells were observed in the antrum and in the ulcer margin, the ulcer healing was delayed, and the serum level of H. pylori-specific Ig was increased. Conclusions: H. pylori infection in rats was successful and was accompanied by a mild to moderate mucosal inflammation. Gastric ulcer healing was delayed in infected rats, probably due to the inflammation and the increased apoptosis in epithelium. [ABSTRACT FROM AUTHOR]

Pieces of rabbit gallbladders were incubated in vitro for 1 hr in Ringer's solution at 37° ('transporting epithelium'), or in Ringer's containing 1 mm ouabain ('inhibited epithelium'). The tissues were fixed in 2% glutaraldehyde, postfixed in OsO and embedded in Epon. Stereological analysis was carried out on electron micrographs; with this type of analysis it is possible to obtain quantitative data for the three-dimensional structure of the tissue. The following data were obtained for crest transporting epithelium (crypt epithelium in parentheses): Epithelial height, 28 (18) μm; nucleus, 16.9 (18.7) % of cell volume; mitochondria, 18.7 (14.1) % of cytoplasmic volume; paracellular channels, 28.3 (11.0)% of epithelial volume; lateral plasma membrane, 4.1 (2.9) m/cm, and apical membrane, 0.5 (0.6) m/cm of cell volume. The paracellular channels appeared as interconnected tissue sheets of a highly varying width. They were broader in the basal portion of the epithelium than in the apical portion; however, immediately above the basement membrane the channels became very narrow. The arithmetic mean width of the channels was 0.9 (0.2) μm and their length was in the range of 40-120 μm. Our stereological data seem compatible with the standing gradient model for water transport. The ouabain inhibited cells were swollen with collapsed paracellular channels. It cannot be ruled out that volume changes occurred in the cells and the paracellular channels during the processing of the tissue. However, qualitatively the same morphology was observed by light microscopy of transporting and inhibited gallbladder epithelium fixed by freeze-drying and embedded in Epon. This constitutes a strong indication of the presence of such channels in the living, in vitro transporting rabbit gallbladder epithelium. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate responses from the gastric mucosa of rats during long-term H. pylori infection. Twenty-four Sprague-Dawley rats were inoculated with a mouse-adapted strain of human H. pylori (vacA+, cagA+), 16 uninfected rats served as controls. Three to six rats from each group were killed two weeks or two, six, or 12 months later. At sacrifice, blood was sampled and the gastric mucosa was taken for bacterial culture, histology, immunocytochemistry and in situ hybridization. H. pylori colonized the antrum in 23/24 inoculated rats; with time the density of bacteria increased. The inflammation in the antral mucosa was mild to moderate and was dominated by infiltration of lymphocytes and macrophages. Serum H. pylori-specific IgG2a was significantly increased in the infected rats. The frequency of epithelial cell apoptosis was significantly increased in the early months of infection. The mucosal expression of trefoil peptide mRNA remained unchanged. We conclude that after one year of H. pylori infection in rats, the mucosal responses were rather mild, indicating that the animals may adapt to the infection by mechanisms which remain to be identified. [ABSTRACT FROM AUTHOR]

Abstract Background The role of the renin-angiotensin system in gastric physiology and disease has as yet been sparsely explored. The first aim of the study was to investigate the baseline presence and location of angiotensin II receptors (AT1R and AT2R) in the stomach of the Mongolian gerbil. A second aim was to elucidate whether the presence of H. pylori infection is associated with changes in the expression of these receptors. Methods H. pylori-negative and H. pylori-infected (strain SS1 or TN2GF4) male Mongolian gerbils were investigated. The stomachs were examined at six or 12 months after inoculation by the use of immunohistochemistry, western blot and microscopic morphometry. Results AT1R and AT2R were located in a variety of cells in the gerbil gastric wall, including a subpopulation of endocrine cells in the antral mucosa and inflammatory cells infiltrating H. pylori-infected stomachs. Gerbils infected with the SS1 strain showed a significantly increased antral AT1R protein expression and an increased number of infiltrating polymorphonuclear leucocytes (PMNs) at 12 months. The AT1R protein expression correlated with the number of PMNs and the antral expression of myeloperoxidase. Conclusions Angiotensin II receptors are present in a variety of cells in the gastric wall of the Mongolian gerbil. The results indicate an influence dependent on the H. pylori strain on the gastric AT1R expression and a relationship between gastric AT1R expression and mucosal PMNs infiltration.

Intellectual disability (ID) is a common disorder, yet there is a wide spectrum of impairment from mild to profoundly affected individuals. Mild ID is seen as the low extreme of the general distribution of intelligence, while severe ID is often seen as a monogenic disorder caused by rare, pathogenic, highly penetrant variants. To investigate the genetic factors influencing mild and severe ID, we evaluated rare and common variation in the Northern Finland Intellectual Disability cohort (n = 1096 ID patients), a cohort with a high percentage of mild ID (n = 550) and from a population bottleneck enriched in rare, damaging variation. Despite this enrichment, we found only a small percentage of ID was due to recessive Finnish-enriched variants (0.5%). A larger proportion was linked to dominant variation, with a significant burden of rare, damaging variation in both mild and severe ID. This rare variant burden was enriched in more severe ID (p = 2.4e-4), patients without a relative with ID (p = 4.76e-4), and in those with features associated with monogenic disorders. We also found a significant burden of common variants associated with decreased cognitive function, with no difference between mild and more severe ID. When we included common and rare variants in a joint model, the rare and common variants had additive effects in both mild and severe ID. A multimodel inference approach also found that common and rare variants together best explained ID status (ΔAIC = 16.8, ΔBIC = 10.2). Overall, we report evidence for the additivity of rare and common variant burden throughout the spectrum of intellectual disability., (© 2024. The Author(s).)

Objective: Paediatric movement disorder patients can benefit from deep brain stimulation (DBS) treatment and it should be offered in a timely manner. In this paper we describe our experience establishing a DBS service for paediatric patients., Methods: We set out to establish a paediatric DBS (pDBS) procedure in Oulu University Hospital in northern Finland, where up to this point DBS treatment for movement disorders had been available for adult patients. Collaboration with experienced centres aided in the process., Results: A multidisciplinary team was assembled and a systematic protocol for patient evaluation and treatment was created, with attention to special features of the regional health care system. All of our first paediatric patients had very severe movement disorders, which is typical for a new DBS centre. The patients benefitted from pDBS treatment despite variable aetiologies of movement disorders, which included cerebral palsy and rare genetic disorders with variants in PDE10A, TPK1 and ARX. We also present our high-quality paediatric MR-imaging protocol with tractography., Conclusions: Establishment of a pDBS centre requires expertise in classification of paediatric movement disorders, longstanding experience in adult DBS and a committed multidisciplinary team. Besides high-quality imaging and a skilled neurosurgery team, careful patient selection, realistic treatment goals and experience in rehabilitation are imperative in pDBS treatment., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: There are limited data on the pathogen-related and host-related factors in the pathogenesis of febrile seizures (FS). We designed a controlled study to compare the role of different respiratory viruses and febrile response in FS., Methods: In a prospective cohort study of 1899 pediatric emergency room patients aged 6 months-6 years with a positive respiratory virus multiplex PCR, we identified 225 patients with FSs. We first compared the distribution of respiratory viruses in age-stratified patients with FSs with that in other patients. In an embedded case-control study, we compared the febrile response in patients with FSs with that in the controls matched for age, season and the same respiratory virus., Results: The relative risk for FS was the highest for coronavirus OC43, 229E, and NL63 infections [RR: 3.2, 95 % confidence interval (CI): 1.4-7.2) and influenza A and B [RR: 2.5, 95 % CI: 1.4-4.7] as compared to those with other respiratory viral infections. The patients with FSs had a stronger febrile response of 39.2 °C (difference: 0.8 °C, 95 % CI: 0.5-1.2) later during hospitalization after acute care than the controls matched for the same respiratory virus., Conclusions: Influenza and coronaviruses caused relatively more FS-related emergency room visits than other respiratory viruses. Furthermore, the febrile response was stronger in the patients with FSs than in the controls matched for the same respiratory virus. The results suggest that the pathomechanism of FSs includes modifiable pathogen-related and host-related factors with possible potential in the prevention of FSs., (Copyright © 2020 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The contribution of de novo variants in severe intellectual disability (ID) has been extensively studied whereas the genetics of mild ID has been less characterized. To elucidate the genetics of milder ID we studied 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. Using exome sequencing, we show that rare damaging variants in known ID genes are observed significantly more often in severe (27%) than in mild ID (13%) patients. We further observe a significant enrichment of functional variants in genes not yet associated with ID (OR: 2.1). We show that a common variant polygenic risk significantly contributes to ID. The heritability explained by polygenic risk score is the highest for educational attainment (EDU) in mild ID (2.2%) but lower for more severe ID (0.6%). Finally, we identify a Finland enriched homozygote variant in the CRADD ID associated gene.

Competing Interests: Conflict of Interest: None.

Objective We conducted a randomized controlled trial to evaluate whether a combination of repeated botulinum toxin A (BTX-A) and conservative treatment is more effective in decreasing toe-walking than conservative treatment alone at 24 months follow-up. Patients and Methods Children between 2 and 9 years of age were randomized either into the conservative (CO) or botulinum treatment (BTX) group. The treatment in the CO group consisted of firm shoes, night splints, a home stretching program and physiotherapy. The BTX arm had all the same conservative treatments added with calf muscle BTX-A injections repeated in 6 months intervals if needed. Change in toe-walking pattern, ankle range of movement (ROM), and overall function were assessed at baseline and 6, 12, 18, and 24 months posttreatment. Results A total of 30 toe-walkers participated: 14 in CO and 16 in BTX group. At 24 months, all children in the BTX group and 85% in the CO group evaluated by the blinded physiotherapist (p = 0.065), 75% in the BTX group and 70% in the CO group graded by the research physiotherapist (p = 0.730), and 50% in the BTX group and 54% in the CO group reported by the parents ceased toe-walking (p = 0.837). The most prominent change was noted during the 1st year. The BTX group seemed to reach the goal earlier. No significant differences between the treatment groups in function or in ankle ROM ensued. Conclusion Adding BTX injections did not significantly enhance the goal to walk either flat foot or with heel strike at 24 months posttreatment., (Georg Thieme Verlag KG Stuttgart · New York.)

We have investigated the induction of the CYP2C12 and IGF-I genes by rGH and a "binding site 2 mutant", G118RrGH, in primary hepatocytes derived from male and female rats. Both the basal and the induced levels of CYP2C12, but not of IGF-I, were markedly lower in male derived than in female derived hepatocytes. A lower degree of receptor occupancy appears needed to elicit the CYP2C12 than the IGF-I response in cells obtained from both gender. At 7h of GH exposure high doses of rGH caused a bell-shaped induction of IGF-1 and a plateau was reached for CYP2C12 in female derived cells. G118RrGH did not antagonize the rGH effect; in contrast G118RrGH had an agonistic effect on CYP2C12 induction in female derived cells that in dose-response experiments was bell-shaped. The difficulty in achieving bell-shaped dose-response curves with rGH, together with the lack of an antagonistic effect of G118RrGH, suggests that both binding sites of rGH have similar affinity for the rGHR. The agonistic and bell-shaped dose-related effect of G118RrGH on CYP2C12 expression indicates that G118RrGH interacts with two receptors. The results could also imply that rGH, via its site 2, can interact with other receptor molecules than rGHR.

Background: Hypergastrinaemia stimulates cell proliferation in the oesophageal epithelium of the rat. In the present study, we tested whether hypergastrinaemia also affected cell turnover time and structure of the oesophageal epithelium., Methods: Seventy-two female adult Sprague-Dawley rats, divided into 12 equal groups, were given 3H-thymidine by infusion/injection. Groups 1-6 were control rats, groups 7-9 were provided with a minipump releasing synthetic rat gastrin-17, and groups 10-12 were given injections of omeprazole twice daily. The rats in the control groups were killed after 1 h, and after 1, 6, 9, 17 or 25 days. The rats given gastrin or omeprazole were killed after 1, 6 or 9 days. Tissue samples of oesophagus were processed for light microscopic autoradiography and the labelling index (LI) was calculated. Morphometric data of the oesophageal epithelium were also obtained, as well as plasma gastrin concentrations., Results: LI in the control rats increased continuously up to 9 days when about 90% of the cells were labelled. Extrapolation indicates a mean cell turnover time of 10.4 +/- 0.58 days. Plasma gastrin levels were significantly elevated in the rats given gastrin or omeprazole. In these animals, average cell turnover times were reduced to 9.1 +/- 0.11 and 9.4 +/- 0.18 days, respectively, and the epithelium was almost 20% thinner than in the controls. Moreover, in the gastrin-treated rats the number of epithelial cells/mm was decreased by almost 20%., Conclusion: Hypergastrinaemia reduces cell turnover time in rat oesophageal epithelium. This is independent of stimulation of acid secretion. The concomitant epithelial hypotrophy may be explained by a premature shedding of the epithelial cells or by acceleration of cell maturation.

The transcription factors signal transducer and activator of transcription (Stat)5a and Stat5b have been implicated in the GH regulation of CYP2C genes in rodent liver. In addition to full-length Stat5 isoforms, truncated Stat5 proteins (Stat5beta), lacking the transactivating domain, have been demonstrated. In this study we found that Stat5beta can be formed by proteolytic cleavage in rat liver nuclei and that the activity of the protease is independent of GH. The GH regulation of the female-specific CYP2C12 gene has recently been shown to be conveyed by two adjacent Stat5-binding elements in the 5'-upstream region. We found that binding of Stat5 in liver nuclear extracts to this site involved simultaneous binding of two Stat5 dimers, most likely both Stat5b homodimers and Stat5a/Stat5b heterodimers. We also investigated Stat5 binding to a potential composite Stat5 element in the 3'-untranslated region (UTR) of CYP2C12. Several Stat5 complexes were formed on this element including Stat5beta-containing complexes. In transient transfection experiments we could demonstrate that the 3'-UTR element reduced GH activation of a CYP2C12-luciferase reporter construct harboring the 5'-Stat5 elements. We speculate that binding of Stat5beta to the 3'-UTR element could be of relevance for the GH-dependent and sex-specific expression of CYP2C12.

A large number of the population, especially the elderly, suffers from dry mouth. The aim of the present investigation was to stimulate the minor salivary glands by the topical application of the cholinesterase inhibitor physostigmine. In eight healthy subjects. 100 microl of the substance, in the concentration interval 2-8 mg/ml, was applied locally to the inside of the lower lip for 1 min. In a separate study comprising 12 dry-mouth patients. 10 ml of 0.4 1.6 mg/ml physostigmine was administered as a mouth rinse solution for 2 min. Secretion from the labial glands. assessed using the Periotron method, increased in a dose-dependent manner in response to physostigmine in both groups. Average peak secretion exceeded baseline by more than 50% throughout the 30- to 45-min observation period; from 1.71 to 2.62 microl cm(-2) min(-1) among the healthy subjects and from 1.17 to 1.84 microl cm 2 min among the dry mouth patients. No systemic effects were registered as reflected by ECG, heart rate or blood pressure. It is assumed that intraorally applied physostigmine diffuses through the oral mucosa and acts by preserving acetylcholine released from the cholinergic, parasympathetic nerves that innervate the minor salivary glands. The topical application of physostigmine to the oral mucosa may, therefore, be an interesting approach for the treatment of dry mouth.

An H+-K+-ATPase contributes to hydrogen secretion and potassium reabsorption by the rat and rabbit collecting ducts. Transport of these ions appears to be accomplished by one or both of two isoforms of the H+-K+-ATPase, HKalpha(1) and HKalpha(2,) because both isoforms are found in the collecting ducts and transport of hydrogen and potassium is attenuated by exposure to inhibitors of these transport proteins. To evaluate whether an H+-K+-ATPase is present in the human kidney, immunohistochemical studies were performed using normal human renal tissue probed with antibodies directed against epitopes of three of the known isoforms of the H+-K+-ATPase , HKalpha(1), HKalpha(2), and HKalpha(4), and the V-type H+-ATPase. Cortical and medullary tissue probed with antibodies against HKalpha(1) showed cytoplasmic staining of intercalated cells that was less intense than that observed in the parietal cells of normal rat stomach stained with the same antibody. Also, weak immunoreactivity was detected in principal cells of the human collecting ducts. Cortical and medullary tissue probed with antibodies directed against HKalpha(4) revealed weak, diffuse staining of intercalated cells of the collecting ducts and occasional light staining of principal cells. Cortical and medullary tissue probed with antibodies directed against the H+-ATPase revealed staining of intercalated cells of the collecting ducts and some cells of the proximal convoluted tubules. By contrast, no discernible staining was noted with the use of the antibody against HKalpha(2). These data indicate that HKalpha(1) and HKalpha(4) are present in the collecting ducts of the human kidney. In this location, these isoforms might contribute to hydrogen and potassium transport by the kidney.