Induction of Mutant Sik3Sleepy Allele in Neurons in Late Infancy Increases Sleep Need

Sleep is regulated in a homeostatic manner. Sleep deprivation increases sleep need, which is compensated mainly by increased EEG δ power during non-rapid eye movement sleep (NREMS) and, to a lesser extent, by increased sleep amount. Although genetic factors determine the constitutive level of sleep need and sleep amount in mice and humans, the molecular entity behind sleep need remains unknown. Recently, we found that a gain-of-function Sleepy (Slp) mutation in the salt-inducible kinase 3 (Sik3) gene, which produces the mutant SIK3(SLP) protein, leads to an increase in NREMS EEG δ power and sleep amount. Since Sik3^Slp mice express SIK3(SLP) in various types of cells in the brain as well as multiple peripheral tissues from the embryonic stage, the cell type and developmental stage responsible for the sleep phenotype in Sik3^Slp mice remain to be elucidated. Here, we generated two mouse lines, synapsin1^CreERT2 and Sik3^ex13flox mice, which enable inducible Cre-mediated, conditional expression of SIK3(SLP) in neurons on tamoxifen administration. Administration of tamoxifen to synapsin1^CreERT2 mice during late infancy resulted in higher recombination efficiency than administration during adolescence. SIK3(SLP) expression after late infancy increased NREMS and NREMS δ power in male synapsin1^CreERT2; Sik3^ex13flox/+ mice. The expression of SIK3(SLP) after adolescence led to a higher NREMS δ power without a significant change in NREMS amounts. Thus, neuron-specific expression of SIK3(SLP) after late infancy is sufficient to increase sleep.SIGNIFICANCE STATEMENT The propensity to accumulate sleep need during wakefulness and to dissipate it during sleep underlies the homeostatic regulation of sleep. However, little is known about the developmental stage and cell types involved in determining the homeostatic regulation of sleep. Here, we show that Sik3^Slp allele induction in mature neurons in late infancy is sufficient to increase non-rapid eye movement sleep amount and non-rapid eye movement sleep δ power. SIK3 signaling in neurons constitutes an intracellular mechanism to increase sleep.     

Epilepsy in patients with advanced Fukuyama congenital muscular dystrophy

BackgroundRecent advances in respiratory management have improved survival for patients with Fukuyama congenital muscular dystrophy (FCMD), characterized by congenital muscular dystrophy and brain malformation. Previous studies reported that more than half of patients exhibit seizures in childhood. However, little is known about epilepsy after childhood.MethodsTo elucidate the long-term clinical course of epilepsy, we retrospectively reviewed all medical records in nine patients (6 males, mean age 20.7 years) with FCMD diagnosed between 1981 and 2019.ResultsThe follow-up periods ranged from 6 to 30 years (mean 18.4 years). A total of 75 EEG recordings were available from nine patients. In some patients, EEGs were normal during early childhood but tended to show paroxysmal discharges with age. Overall, epileptic seizures were observed in six patients. Except for one presenting with afebrile seizure at one year of age, the remaining five patients developed epilepsy between 13 and 22 years of age. The most common seizure type was focal impaired awareness seizure. After adolescence, four patients exhibited status epilepticus. Their convulsive movements of the seizures became less prominent with progression of the disease. At the last evaluation, most patients (5/6) had uncontrolled seizures.ConclusionsDespite presence of distinct brain malformation, epileptic seizures may develop after childhood in FCMD patients. Our experience suggests that clinicians should be careful not to overlook epileptic seizures, especially in advanced-stage patients who had profound muscle weakness.     

Crown-Rump Length Measured in the Early First Trimester as a Predictor of Low Birth Weight

The aim of this study is to assess the association between crown-rump length (CRL) measured before the 10th gestational week and birth weight. Results from 316 transvaginal ultrasonography scans at the 46th, 53rd, 60th, 67th, and 74th days of pregnancy were compared in low birth weight (LBW) versus normal birth weight groups. A positive correlation between CRL and birth weight was observed when CRL was measured at days 60, 67, and 74. CRL measured on the 67th day of pregnancy was significantly smaller in the LBW group than in the normal birth weight group. A cut-off value of CRL=26.5 mm measured at day 67 has the highest power to predict LBW.     

Molecular and Epidemiological Characterization of Carbapenem-Resistant Acinetobacter baumannii in Non-Tertiary Korean Hospitals

Purpose

The increasing prevalence and global spread of carbapenem-resistant Acinetobacter baumannii (A. baumannii) has become a serious problem. The aim of this study was to investigate molecular and epidemiological characteristics of carbapenem-resistant A. baumannii isolates collected from Korean non-tertiary hospitals.

Materials and Methods

Thirty six non-duplicated carbapenem-resistant A. baumannii isolates were collected from 17 non-tertiary hospitals in Korea between 2004 and 2006. Isolates were typed by multilocus sequence typing and repetitive-sequence-based PCR (rep-PCR). Detection of genes encoding OXA carbapenemase and their relationship with ISAba1 was performed by PCR.

Results

Two clones were prevalent among 36 isolates: ST69 (17 isolates, 47.2%) and ST92 (19 isolates, 52.8%). Rep-PCR patterns were diverse and revealed that all isolates were clustered into eight band patterns. The ISAba1-activated blaOXA-23-like and ISAba1-activated blaOXA-51-like genes were prevalent among the carbapenem-resistant A. baumannii isolates.

Conclusion

The class D β-lactamase genes of A. baumannii were distributed nationwide in non-tertiary Korean hospitals.     

Clinical Implications and Risk Factors of Acute Pancreatitis after Cardiac Valve Surgery

Purpose

Acute pancreatitis is one of the potentially lethal complications that occurs after cardiac surgery. We tried to identify risk factors for and the prognosis of acute pancreatitis after cardiac valve surgery with cardiopulmonary bypass.

Materials and Methods

We retrospectively analyzed a database of consecutive patients who underwent cardiac valve surgery with cardiopulmonary bypass between January 2005 and April 2010 at our institution. Patients were classified as having acute pancreatitis based on serum lipase concentration and clinical symptoms (lipase ≥180 U/L or ≥60 U/L with relevant symptoms).

Results

Of the 986 patients who underwent cardiac valve surgery with cardiopulmonary bypass, 58 (5.9%) patients developed post-operative pancreatitis. Post-operative hospital stay was significantly longer (29.7±45.6 days vs. 12.4±10.7 days, p=0.005) and in-hospital mortality rate was higher (15.5% vs. 2.0%, p<0.001) in patients with post-operative pancreatitis than those without. Hypertension, chronic kidney disease, and peri-operative use of norepinephrine were identified as independent risk factors for developing pancreatitis after cardiac valve surgery.

Conclusion

We found that acute pancreatitis after cardiac valve surgery requires longer hospitalization and increases the in-hospital mortality rate. Clinicians should be aware that patients could develop pancreatitis after cardiac valve surgery, especially in patients with hypertension and chronic kidney disease treated with norepinephrine.     

Gastric Autoantigenic Proteins in Helicobacter Pylori Infection

Purpose

This study tried to identify novel gastric autoimmune antigens that might be involved in aggravating the atrophic gastritis among patients with Helicobacter pylori infection using two-dimensional immunoblotting analysis.

Materials and Methods

Proteins from gastric mucosal antrectomy specimens and AGS cells (gastric adenocarcinoma cell lines derived from a Caucasian patient who had received no prior therapy) were 2-dimensionally immunoblotted separately with a pool of 300 sera from H. pylroi-infected patients at Gyeongsang National University Hospital.

Results

Thirty-eight autoantigenic proteins including alcohol dehydrogenase [NADP+], alpha enolase, gastrokine-1, gastric triacylglycerol lipase, heat shock 70 kDa protein 1, and peroxiredoxin-2 were identified in the gastric mucosal tissue. Fourteen autoantigenic proteins including programmed cell death 6-interacting protein, serum albumin and T-complex protein 1 subunit gamma were identified in the AGS cells. Albumin, alpha-enolase, annexin A3, cytoplasmic actin 1, heat shock cognate 71 kDa protein and leukocyte elastase inhibitor were commonly observed autoantigenic proteins in both gastric mucosal tissue and AGS cells. Alpha-enolase, glutathione S-transferase P, heat shock cognate 71 kDa protein, heat shock 70 kDa protein 1, human mitochondrial adenosine triphosphate synthase (ATP) subunit beta, mitochondrial 60 kDa heat shock protein, peroxiredoxin-2, 78 kDa glucose-regulated protein precursor, tyrosine-protein phosphatase non-receptor type 11 and Tryptophan-Aspartic acid (WD) repeat-containing protein 1 showed 60% or higher amino acid positivity.

Conclusion

These newly identified gastric autoimmune antigens might be useful in the control and prevention of gastroduodenal disorders, and might be valuable in breaking the vicious circle that exists in gastroduodenal disorders if their pathophysiological roles could be understood in the progress of chronic atrophic gastritis, gastroduodenal ulcers, intestinal metaplasia, and gastric carcinogenesis.     

The Role of One-Year Endoscopic Follow-Up for the Esophageal Remnant and Gastric Conduit after Esophagectomy with Gastric Reconstruction for Esophageal Squamous Cell Carcinoma

Purpose

After esophagectomy and gastric reconstruction for esophageal cancer, patients suffer from various symptoms that can detract from quality of life. Endoscopy is a useful diagnostic tool for evaluating patients after esophagectomy. This observational study was performed to investigate the correlation between symptoms and endoscopic findings one year after esophageal surgery and to assess the clinical usefulness of one-year endoscopic follow-up.

Materials and Methods

From 2001 to 2008, 162 patients who underwent esophagectomy with gastric reconstruction were endoscopically examined one year after operation.

Results

Patients suffered from the following symptoms: nocturnal cough (n=10), regurgitation (n=7), cervical heartburn (n=3), lump sensation (n=2), dysphagia (n=20) and odynophagia (n=22). Eighty-five (52.5%) patients had abnormal findings on endoscopic examination. Twelve (7.4%) patients had reflux esophagitis, and 37 (22.8%) patients had an anastomotic stricture. Only stricture-related symptoms were correlated with the finding of anastomotic strictures (p<0.001). Two patients had recurrences at the anastomotic sites, and four patients had regional lymph node recurrences with gastric conduit invasion visualized by endoscopy. Newly-developed malignancies in the esophageal remnant or hypopharynx that were not detected by clinical symptoms and imaging studies were reported in two patients.

Conclusion

One year after esophagectomy, endoscopic findings were not correlated with clinical symptoms, except those related to stricture. Routine endoscopic follow-up is a useful tool for identifying latent functional and oncological lesions.     

Dipeptidyl Peptidase 10, a Novel Prognostic Marker in Colorectal Cancer

Purpose

The dipeptidyl peptidase IV (DPPIV) gene family exhibits multiple functions and is involved in the pathogenesis of various diseases. It has attracted pharmaceutical interest in the areas of metabolic disorders as well as cancer. However, clinicopathologic significance of DPPIV family in colorectal cancer is not fully understood.

Materials and Methods

The clinical relevance of DPPIV and DPP10 expression was determined by immunohistochemical staining, and by assessing its clinicopathologic correlation in 383 colorectal cancer patients with known clinical outcomes.

Results

DPPIV was not expressed in normal colon mucosa, but it showed luminal expression in 52 of the 383 colorectal cancers (13.5%). DPPIV expression in tumors was associated with right-sided location of the colon (p=0.010) and more advanced tumor stage (p=0.045). DPP10 was expressed in normal colonic mucosa, but its expression varied in primary colorectal cancer tissues. Loss of DPP10 expression was found in 11 colorectal cancers (CRCs) (2.9%), and multivariate analysis showed that loss of DPP10 expression was an independent factor for poor patient prognosis (p=0.008).

Conclusion

DPP10 may play a role in disease progression of colorectal cancer and loss of DPP10 expression in primary CRC is significantly associated with poor survival outcomes.