The structural and functional workings of KEOPS.

KEOPS (Kinase, Endopeptidase and Other Proteins of Small size) is a five-subunit protein complex that is highly conserved in eukaryotes and archaea and is essential for the fitness of cells and for animal development. In humans, mutations in KEOPS genes underlie Galloway-Mowat syndrome, which manifests in severe microcephaly and renal dysfunction that lead to childhood death. The Kae1 subunit of KEOPS catalyzes the universal and essential tRNA modification N6-threonylcarbamoyl adenosine (t6A), while the auxiliary subunits Cgi121, the kinase/ATPase Bud32, Pcc1 and Gon7 play a supporting role. Kae1 orthologs are also present in bacteria and mitochondria but function in distinct complexes with proteins that are not related in structure or function to the auxiliary subunits of KEOPS. Over the past 15 years since its discovery, extensive study in the KEOPS field has provided many answers towards understanding the roles that KEOPS plays in cells and in human disease and how KEOPS carries out these functions. In this review, we provide an overview into recent advances in the study of KEOPS and illuminate exciting future directions.

Disruption of pathways regulated by Integrator complex in Galloway-Mowat syndrome due to WDR73 mutations.

Several studies have reported WDR73 mutations to be causative of Galloway-Mowat syndrome, a rare disorder characterised by the association of neurological defects and renal-glomerular disease. In this study, we demonstrate interaction of WDR73 with the INTS9 and INTS11 components of Integrator, a large multiprotein complex with various roles in RNA metabolism and transcriptional control. We implicate WDR73 in two Integrator-regulated cellular pathways; namely, the processing of uridylate-rich small nuclear RNAs (UsnRNA), and mediating the transcriptional response to epidermal growth factor stimulation. We also show that WDR73 suppression leads to altered expression of genes encoding cell cycle regulatory proteins. Altogether, our results suggest that a range of cellular pathways are perturbed by WDR73 loss-of-function, and support the consensus that proper regulation of UsnRNA maturation, transcription initiation and cell cycle control are all critical in maintaining the health of post-mitotic cells such as glomerular podocytes and neurons, and preventing degenerative disease.

Association between Increased Gastric Juice Acidity and Sliding Hiatal Hernia Development in Humans.

OBJECTIVES: Several clinical factors; overweight, male gender and increasing age, have been implicated as the etiology of hiatal hernia. Esophageal shortening due to acid perfusion in the lower esophagus has been suggested as the etiological mechanism. However, little is known about the correlation between gastric acidity and sliding hiatus hernia formation. This study examined whether increased gastric acid secretion is associated with an endoscopic diagnosis of hiatal hernia. METHODS: A total of 286 consecutive asymptomatic patients (64 were diagnosed as having a hiatal hernia) who underwent upper gastrointestinal endoscopy were studied. Clinical findings including fasting gastric juice pH as an indicator of acid secretion, age, sex, body mass index, and Helicobacter pylori infection status determined by both Helicobacter pylori serology and pepsinogen status, were evaluated to identify predictors in subjects with hiatal hernia. RESULTS: Male gender, obesity with a body mass index >25, and fasting gastric juice pH were significantly different between subjects with and without hiatal hernia. The cut-off point of fasting gastric juice pH determined by receiver operating curve analysis was 2.1. Multivariate regression analyses using these variables, and age, which is known to be associated with hiatal hernia, revealed that increased gastric acid secretion with fasting gastric juice pH <2.1 (OR = 2.60, 95% CI: 1.38-4.90) was independently associated with hiatal hernia. Moreover, previously reported risk factors including male gender (OR = 2.32, 95% CI: 1.23-4.35), body mass index >25 (OR = 3.49, 95% CI: 1.77-6.91) and age >65 years (OR = 1.86, 95% CI: 1.00-3.45), were also significantly associated with hiatal hernia. CONCLUSIONS: This study suggests that increased gastric acid secretion independently induces the development of hiatal hernia in humans. These results are in accordance with the previously reported hypothesis that high gastric acid itself induces hiatal hernia development.

Benign glycogenic acanthosis lesions of the esophagus.

BACKGROUND/AIMS: Glycogenic acanthosis is described as benign thickening of the esophageal squamous epithelium of unknown etiology. Although its etiology is unknown, it has been reported that glycogenic acanthosis may be related to gastroesophageal reflux and hiatal hernia. The aim of the present study was to review the patients who were diagnosed with glycogenic acanthosis on upper gastrointestinal endoscopy and to determine whether there is any association between glycogenic acanthosis and gastroesophageal reflux and hiatal hernia. MATERIAL AND METHODS: A total of 504 patients who underwent upper gastrointestinal endoscopy for evaluation of non-ulcer dyspepsia were reviewed retrospectively. RESULTS: Glycogenic acanthosis was detected in 143 (28.3%) of those 504 patients. Of the 143 patients, 82 (57.3%) were male and 61 (42.7%) were female. Patients with glycogenic acanthosis were aged 20-83 years. Gastroesophageal reflux was detected in 50 (34.9%) cases with glycogenic acanthosis, while hiatal hernia was detected in 30 (20.9%) cases. Gastroesophageal reflux was detected in 102 (28.2%) control subjects, while hiatal hernia was detected in 50 (13.8%). Hiatal hernia was significantly higher in glycogenic acanthosis patients than in controls subjects (p<0.05). Glycogenic acanthosis patients had higher gastroesophageal reflux than seen in controls subjects, but the difference between groups was not statistically significant (p>0.05). CONCLUSIONS: Our results suggest that glycogenic acanthosis is primarily an age-related disease. We demonstrated that glycogenic acanthosis may be associated with gastroesophageal reflux and hiatal hernia. Further studies are necessary to confirm these findings.

Collagen type I:III ratio of the gastroesophageal junction in patients with paraesophageal hernias.

BACKGROUND: The purpose of this study was to examine the biological environment of the esophageal hiatus through analysis of the collagen content within the gastrohepatic ligament (GHL), gastrophrenic ligament (GPL), and phrenoesophageal ligament (PEL) in patients with type I hiatal hernias (HH) and type III paraesophageal hernias (PEH). METHODS: A control group (N=10) and patients with type I HH (N=10) and type III PEH (N=10) were included in the analysis. Specimens of the GHL, PEL, and GPL were collected intraoperatively. Slides stained with sirius red/fast green were created and ten photos at 400×magnification were taken of each specimen. Axiovision 4.7 (Zeiss) photo analysis software was employed for quantification of collagen I (red) and III (green) by calculating color area (µm2). Statistical significance (p<0.05) was determined using a one-way ANOVA and Fisher's LSD post-test. RESULTS: Cross-polarization microscopy revealed that the collagen I content was similar in the three study groups for the GHL, greater in the type III PEH group and in the control group compared to the type I HH group for the PEL, and greater in the type III PEH group compared to control group for the GPL. Collagen III quantity was greater in the control group than in the type I HH group for each ligament, and greater in the GHL and PEL when compared to the type III PEH group. Type III PEH patients had greater collagen III quantity than did type I HH patients for each ligament. Collagen type I:III ratio of the GHL was greater in both hernia groups compared to the control group. Type III PEH patients contained a higher I:III ratio than both the control and type I HH groups with respect to the PEL. There was no difference in the ratio with evaluation of the GPL for the three groups. CONCLUSION: Evaluation of the esophageal hiatus revealed that patients with PEH have a different biological environment with regard to collagen content compared to control patients. The collagen I:III ratio of the study groups was equal to or greater than the control group. Collagen deficiency in the GE junction supporting ligaments does not appear to be an etiology of PEH formation.

Differential regulation of MMP-2 in the gastrohepatic ligament of the gastroesophageal junction.

INTRODUCTION: Ligamentous attachments maintain the normal anatomic position of the gastroesophageal (GE) junction. Failure of these elastic ligaments through an alteration in collagen synthesis, deposition, and metabolism may be a primary etiology of hiatal hernia formation. Differential expression of zinc-dependent matrix metalloproteinases (MMPs) is largely responsible for collagen remodeling. The purpose of this study was to survey baseline levels of MMPs in supporting ligaments of the GE junction from patients without hiatal hernia. METHODS: Following an institutional review board-approved protocol, plasma and tissue biopsies of the gastrohepatic ligament (GHL), gastrophrenic ligament (GPL), and phrenoesophageal ligament (PEL) were obtained in six patients without a hiatal hernia during laparoscopic anterior esophageal myotomy for achalasia. Total protein extracts from tissue biopsies were analyzed for elastases MMP-2, -9, and -12 and collagenases MMP-1, -3, -7, -8, and -13 using a multiplex profiling kit (R&D Systems, Minneapolis, MN). Data are reported as mean +/- standard deviation. Statistical significance (p < 0.05) was determined using Tukey's test and analysis of variance. RESULTS: In control patients without hiatal hernias, increased levels of MMP-2 (p < 0.02) were detected in the GHL compared with the GPL and PEL, respectively. Tissue levels of MMP-1, -12, and -13 were not detectable. CONCLUSIONS: Gelatinase-A (MMP-2) is present in the GHL and plasma of control patients. The GHL may provide the primary GE junction supporting ligament to compare tissue from patients with type I (sliding) and type III (paraesophageal) hiatal hernias to examine the role of altered collagen metabolism in hiatal hernia formation.

The position of the acid pocket as a major risk factor for acidic reflux in healthy subjects and patients with GORD.

INTRODUCTION: Gastro-oesophageal reflux occurs twice as much during transient lower oesophageal sphincter relaxations (TLOSRs) in patients with gastro-oesophageal reflux disease (GORD) compared to healthy volunteers (HVs). Our aim was to assess whether the localisation of the postprandial acid pocket and its interaction with a hiatal hernia (HH) play a role in the occurrence of acidic reflux during TLOSRs. METHODS: Ten HVs and 22 patients with GORD (12 with HH<3 cm (s-HH), 10 with HH > or =3 cm (l-HH)) were studied. The squamocolumnar junction and diaphragmatic impression were marked with a radioactively labelled clip. To visualise the acid pocket, (99m)Tc-pertechnetate was injected intravenously and images were acquired up to 2 h postprandial. Concurrently, combined manometry/impedance and four-channel pH-metry were performed, with pH pull-through at multiple time-points. RESULTS: The rate of TLOSRs and the per cent associated with reflux was comparable between all groups. However, acidic reflux was significantly increased in patients, especially in patients with l-HH. Acid pocket length was significantly enlarged in patients. Moreover, immediately before a TLOSR, the acid pocket was more frequently located within the hiatus or above the diaphragm in patients with GORD (s-HH, 54%; l-HH, 77%) compared to HVs (22% of TLOSRs). Acidic reflux was significantly increased when the acid pocket was located above the diaphragm in all groups compared to a sub-diaphragmatic localisation. CONCLUSION: The position of the acid pocket is largely determined by the presence of a HH. Entrapment of the pocket above the diaphragm, especially in patients with l-HH, is a major risk factor underlying the increased occurrence of acidic reflux during a TLOSR in patients with GORD.

Collagen metabolism and recurrent hiatal hernia: cause and effect?

Hiatus hernia (HH) is a condition characterized by herniation of the intra-abdominal organs into the thorax. Of the several types that have been identified, the most common is type I (sliding) HH. Congenital predisposition and acquired factors, for example trauma and iatrogeny, have been identified as causative factors. There is a strong association between gastroesophageal reflux disease and HH-the prevalence of reflux in HH may reach 94%. Many methods have been used to treat reflux disease and HH, among which are laparoscopic techniques, which gained popularity as a safe method of treatment. Primary crural repair without mesh application was found to have a recurrence rate of up to 42%. This led to the introduction of mesh in HH repair, which was associated with a significant decrease in recurrence rate. Collagen and its relation to hernia have been investigated for several decades. Collagen has mechanical properties sufficient to enable it to support healed scars and other tissues. Nineteen distinct types of collagen have been recognized, the most common of which are types I and III. Type III collagen is the major constituent of early granulation tissue whereas type I predominates as healing proceeds. Collagen fibers are imbedded in extracellular matrix (ECM), which is in continuous process of synthesis and degradation under the action of matrix metalloproteinases. Many authors have studied the role of collagen in ventral hernia and have even defined hernia as a disease of the ECM. The relationship between collagen and HH, and its recurrence, is not fully understood and needs further investigation.

Effect of hiatal hernia on proximal oesophageal acid clearance in gastro-oesophageal reflux disease patients.

BACKGROUND: Proximal acid reflux is common in gastro-oesophageal reflux disease and is a determinant of symptoms. Patients with hiatal hernia complain of more symptoms than those without and are less responsive to proton-pump inhibitors. AIM: To evaluate the role of hiatal hernia on spatiotemporal characteristics of acid reflux. METHODS: Thirty seven consecutive gastro-oesophageal reflux disease patients underwent endoscopy, videofluoroscopy, manometry and multichannel 24-h pH test. Data were compared with those of 15 asymptomatic controls. Multivariate linear regression was used for statistical analysis. RESULTS: At videofluoroscopy, hiatal hernia was found in 16 of 37 patients. The mean size of hiatal hernia was 3.4 cm. Patients showed significantly prolonged acid clearance time, both at proximal and distal oesophagus, compared with controls. Hiatal hernia patients showed a significantly delayed acid clearance, along the oesophageal body, compared with non-hiatal hernia patients. The prolonged acid exposure was maintained during upright and supine position. The presence of hiatal hernia significantly predicted acid clearance delay in the distal and proximal oesophagus [at 10 cm below upper oesophageal sphincter: Delta + 2.5 min (95% confidence interval: 0.4-4.5); P < 0.02]. CONCLUSIONS: The presence of hiatal hernia is a strong predictor of more prolonged proximal oesophageal acid exposure and clearance. Hiatal hernia is likely to play a role in the pathophysiology of gastro-oesophageal reflux disease symptoms, and should be taken into greater consideration in the treatment strategies of the disease.

Hiatal hernia in iodine-131 scintigraphy: a potential cause of false-positive midline thoracic uptake.

There are occasional reports of a hiatal hernia demonstrating thoracic uptake on I-131 scintigraphy. This is a cause of a potential false-positive appearance mimicking a pulmonary or mediastinal metastasis. Hiatal hernia is 1 of a number of causes of false-positive I-131 whole-body scans. Although previous case reports have demonstrated uptake to lie to the left of the midline, this case is slightly unusual in view of the midline appearance of the uptake. Although this appearance could be seen with mediastinal, pulmonary, or prevertebral metastases, hiatal hernia should be considered in the differential diagnosis of uptake in the thoracic midline on I-131 scintigraphy.

Incomplete intestinal metaplasia in the diagnosis of columnar lined esophagus (Barrett's esophagus).

To investigate the distribution and specificity of intestinal metaplasia (IM) in columnar lined esophagus (CLE), the authors reviewed biopsies of the hiatal hernia pouch (HHP) and esophagus from 17 patients with CLE (84 biopsies) and 10 controls (25 biopsies). The proximal margin of the gastric folds was used as an endoscopic landmark, corresponding to the gastroesophageal muscular junction (GEMJ). No biopsies obtained above the GEMJ in control patients showed columnar mucosa. No goblet cell metaplasia was seen in 21 biopsies of the HHP from patients with CLE or in 13 corresponding biopsies from controls. In contrast, alcian blue (AB) stains showed diffuse acid mucins in 3 of 21 biopsies of the HHP from patients with CLE and in 10 of 13 corresponding biopsies from controls, demonstrating that goblet cell metaplasia clearly distinguishes biopsies of CLE from the HHP (P less than 0.01), whereas small amounts of diffuse acid mucin on AB stains do not. IM evidenced by goblet cell metaplasia was frequently seen in biopsies only 2-3 cm above the GEMJ, and CLE was limited to that area in three patients, suggesting that the distal esophagus cannot be dismissed as a site for metaplastic and possibly premalignant mucosa. Adenocarcinoma was diagnosed during the course of the study in one patient with only 5 cm of columnar mucosa above the GEMJ.

Distribution and content of neuropeptide Y in the human lower esophageal sphincter.

The occurrence and distribution of neuropeptide Y (NPY) was studied in smooth-muscle specimens from the human lower esophageal sphincter region by immunocytochemistry and immunochemistry. Normal individuals and patients suffering from achalasia or hiatus hernia with severe gastroesophageal reflux were examined. NPY fibers were found within and around smooth-muscle bundles of the longitudinal and the circular muscle layers and within the myenteric ganglia. Smooth-muscle specimens from patients with hiatus hernia and gastroesophageal reflux displayed numerous NPY fibers and an increased content of NPY. Specimens from patients with achalasia contained only few NPY fibers and had a decreased content of NPY as compared to specimens from control patients. Conceivably, NPY may play a role in the regulation of the lower esophageal sphincter.

An evaluation of the bile acid binding and antacid properties of hydrotalcite in hiatus hernia and peptic ulceration.

The bile acid binding and antacid properties of hydrotalcite were studied in 25 patients with hiatus hernia or peptic ulceration. Hydrotalcite was found to have significant bile acid binding properties in the presence of free acid in the stomach. There was a definite antacid effect in both pathological entities. These results suggest that hydrotalcite may be an effective therapeutic agent in upper gastro-intestinal ulceration, warranting further investigation in lesions which are thought to involve both hydrochloric acid and bile acids in their pathogenesis.

Evidence for an association between cholelithiasis and hiatus hernia.

A prospective, controlled study was carried out to determine if there was an association between hiatus hernia and cholelithiasis. The prevalence of gallstones was calculated in 100 patients (50 men and 50 women) with radiological evidence of hiatus hernia. 100 subjects (50 men and 50 women) without hiatus hernia, matched for age, body-weight, and number of pregnancies, acted as controls. Gallstones were twice as common in the former group (34%) as in the control group (17%) (P less than 0.01). Moreover, a comparison of the lipid composition of the gallbladder bile in 15 subjects operated on for hiatus hernia with that in 17 patients operated on for another digestive disease showed that the molar percentage of choelsterol in the bile and the cholesterol saturation index were significantly higher in the patients with hiatus hernia (9.3 +/- 1.1, mean +/- S.E.M., 1.41) than in the control subjects (5.9 +/- 0.5; 0.97) (P less than 0.01). These results suggest an association between hiatus hernia and cholelithiasis. It is likely that common factors, probably related to a low-residue diet, predispose to the two diseases.