Study of the genetic association between selected 3q29 region genes and schizophrenia and autism spectrum disorder in the Japanese population.

Psychiatric disorders are highly inheritable, and most psychiatric disorders exhibit genetic overlap. Recent studies associated the 3q29 recurrent deletion with schizophrenia (SCZ) and autism spectrum disorder (ASD). In this study, we investigated the association of genes in the 3q29 region with SCZ and ASD. TM4SF19 and PAK2 were chosen as candidate genes for this study based on evidence from previous research. We sequenced TM4SF19 and PAK2 in 437 SCZ cases, 187 ASD cases and 524 controls in the Japanese population. Through targeted sequencing, we identified 6 missense variants among the cases (ASD & SCZ), 3 missense variants among controls, and 1 variant common to both cases and controls; however, no loss-of-function variants were identified. Fisher's exact test showed a significant association of variants in TM4SF19 among cases (p=0.0160). These results suggest TM4SF19 variants affect the etiology of SCZ and ASD in the Japanese population. Further research examining 3q29 region genes and their association with SCZ and ASD is thus needed.

Investigation of OLIG2 as a candidate gene for schizophrenia and autism spectrum disorder.

A number of genomic mutations that are thought to be strongly involved in the development of schizophrenia (SCZ) and autism spectrum disorder (ASD) have been identified. Abnormalities involving oligodendrocytes have been reported in SCZ, and as a related gene, oligodendrocyte lineage transcription factor 2 (OLIG2) has been reported to be strongly associated with SCZ. In this study, based on the common disease-rare variant hypothesis, target sequencing of candidate genes was performed to identify rare mutations with a high effect size and the possibility that the identified mutations may increase the risks of SCZ and ASD in the Japanese population. In this study, the exon region of OLIG2 was targeted; 370 patients with SCZ and 192 with ASD were subjected to next-generation sequencing. As a result, one rare missense mutation (A33T) was detected. We used the Sanger method to validate this missense mutation with a low frequency (<1%), and then carried out a genetic association analysis involving 3299 unrelated individuals (1447 with SCZ, 380 with ASD, and 1472 healthy controls) to clarify whether A33T was associated with SCZ or ASD. A33T was not found in either case group, and in only one control. We did not find evidence that p.A33T is involved in the onset of ASD or SCZ; however, associations with this variant need to be evaluated in larger samples to confirm our results.

Cross-Disorder Analysis of Genic and Regulatory Copy Number Variations in Bipolar Disorder, Schizophrenia, and Autism Spectrum Disorder.

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (<100 kb) exonic deletions in BD, which contrasted with the highest burden of larger (>500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25-0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD.

Gastric Perforation: A Rare Presentation of Malignant Gastric Outlet Obstruction.

Mechanical gastric outlet obstruction (GOO) due to malignancy can occur with cancers in the stomach and duodenum. GOO can cause perforation of the stomach or the esophagus. We present a 65-year-old female with newly diagnosed metastatic pancreatic cancer who presented with acute onset abdominal pain. She was taken for emergent exploratory laparotomy where she was found to have gastric perforation and duodenal obstruction from an invasive large pancreatic head mass. This is a rare case report of gastric perforation due to a malignant gastric outlet obstruction secondary to invasive pancreatic cancer.

Cookiecutter Shark-Related Injuries: A New Threat to Swimming Across the Ka'iwi Channel.

In a 5-month period in 2019, 3 long-distance swimmers sustained cookiecutter shark-related injuries while attempting to cross the Ka'iwi Channel between the Hawaiian Islands of O'ahu and Moloka'i. This report is the first case series of cookiecutter shark bites on live humans. A retrospective review of the State of Hawai'i Division of Aquatic Resources Shark Incidents List was conducted between March 1, 2019, and July 31, 2019. Trauma registry data and medical records were reviewed in patients treated for cookiecutter shark bites at The Queen's Medical Center in Honolulu, Hawai'i. All 3 patients sustained nonfatal cookiecutter shark bite circular wounds measuring between 8-13 cm in diameter. They were injured swimming over waters with depths of greater than 2000 feet at night. Patients had prolonged transport times to the emergency department (ED), averaging 73 minutes, due to their injuries occurring on the open water. All were hemodynamically stable upon ED arrival and did not require blood products. Tetanus toxoid was updated, and prophylactic antibiotic coverage, including doxycycline for Vibrio spp., was administered. Two of 3 patients were treated with operative management. Open water swimmers crossing the deep waters between the Hawaiian Islands at night are most at risk for cookiecutter shark bites. Wounds may penetrate down to and through the fascial level. Immediate life-saving hemorrhage control administered by personnel accompanying the swimmers on the open water is important for preventing morbidity and mortality. Antibiotic prophylaxis for marine bacteria is recommended.

Rare single-nucleotide DAB1 variants and their contribution to Schizophrenia and autism spectrum disorder susceptibility.

Disabled 1 (DAB1) is an intracellular adaptor protein in the Reelin signaling pathway and plays an essential role in correct neuronal migration and layer formation in the developing brain. DAB1 has been repeatedly reported to be associated with neurodevelopmental disorders including schizophrenia (SCZ) and autism spectrum disorders (ASD) in genetic, animal, and postmortem studies. Recently, increasing attention has been given to rare single-nucleotide variants (SNVs) found by deep sequencing of candidate genes. In this study, we performed exon-targeted resequencing of DAB1 in 370 SCZ and 192 ASD patients using next-generation sequencing technology to identify rare SNVs with a minor allele frequency <1%. We detected two rare missense mutations (G382C, V129I) and then performed a genetic association study in a sample comprising 1763 SCZ, 380 ASD, and 2190 healthy control subjects. Although no statistically significant association with the detected mutations was observed for either SCZ or ASD, G382C was found only in the case group, and in silico analyses and in vitro functional assays suggested that G382C alters the function of the DAB1 protein. The rare variants of DAB1 found in the present study should be studied further to elucidate their potential functional relevance to the pathophysiology of SCZ and ASD.

Rare genetic variants in the gene encoding histone lysine demethylase 4C (KDM4C) and their contributions to susceptibility to schizophrenia and autism spectrum disorder.

Dysregulation of epigenetic processes involving histone methylation induces neurodevelopmental impairments and has been implicated in schizophrenia (SCZ) and autism spectrum disorder (ASD). Variants in the gene encoding lysine demethylase 4C (KDM4C) have been suggested to confer a risk for such disorders. However, rare genetic variants in KDM4C have not been fully evaluated, and the functional impact of the variants has not been studied using patient-derived cells. In this study, we conducted copy number variant (CNV) analysis in a Japanese sample set (2605 SCZ and 1141 ASD cases, and 2310 controls). We found evidence for significant associations between CNVs in KDM4C and SCZ (p = 0.003) and ASD (p = 0.04). We also observed a significant association between deletions in KDM4C and SCZ (corrected p = 0.04). Next, to explore the contribution of single nucleotide variants in KDM4C, we sequenced the coding exons in a second sample set (370 SCZ and 192 ASD cases) and detected 18 rare missense variants, including p.D160N within the JmjC domain of KDM4C. We, then, performed association analysis for p.D160N in a third sample set (1751 SCZ and 377 ASD cases, and 2276 controls), but did not find a statistical association with these disorders. Immunoblotting analysis using lymphoblastoid cell lines from a case with KDM4C deletion revealed reduced KDM4C protein expression and altered histone methylation patterns. In conclusion, this study strengthens the evidence for associations between KDM4C CNVs and these two disorders and for their potential functional effect on histone methylation patterns.

Shark-related injuries in Hawai'i treated at a level 1 trauma center.

BACKGROUND: Although rare, human-shark interactions can result in a wide spectrum of injuries. This is the first study to characterize shark-related injuries (SRIs) in Hawai'i. METHODS: This is a retrospective review of the State of Hawai'i Division of Aquatic Resources Shark Incidents List between January 1, 2009 and December 31, 2019. Trauma registry data and medical records of patients treated for SRIs at the only level 1 trauma center in Hawai'i were reviewed. RESULTS: Sixty-one patients sustained SRIs in the Hawaiian Islands: 25 in Maui, 16 in O'ahu, 12 in Hawai'i, and 8 in Kaua'i. In cases where the shark species could be identified, tiger sharks were the most frequent (25, 41%). Four cases were fatal-all died on scene in Maui with the shark species unknown. Forty-five survivors (79%) received definitive care at regional facilities. Twelve (21%) were treated at the level 1 trauma center, of which two were transferred in for higher level of care. Of the 12 patients, 11 (92%) had extremity injuries, with 3 lower extremity amputations (25%), 2 with vascular injuries (17%), and 5 with nerve injuries (42%). One had an injury to the abdomen. All patients had local bleeding control in the prehospital setting, with 9 (75%) tourniquets and 3 (25%) hemostatic/pressure dressings applied for truncal or proximal extremity injuries. The mean time from injury to emergency department arrival was 63 minutes. DISCUSSION: Most SRIs are managed at regional facilities, rather than at a level 1 trauma center. Prehospital hemorrhage control is an important survival skill as time to definitive care may be prolonged. For cases treated at the level 1 trauma center, nerve injuries were common and should be suspected even in the absence of major vascular injury. Correlating shark behavior with observed injury patterns may help improve public awareness and ocean safety. LEVEL OF EVIDENCE: Level V, epidemiological.

Decline of Plasma Concentrations of Interleukin-18 in Severely Malnourished Patients with Anorexia Nervosa: Exploratory Analysis.

Multiple studies on the dynamics of inflammatory cytokines in patients with anorexia nervosa (AN) have been published, although results are not consistent among reports. Thus the pathophysiologic roles of these cytokines are not clear. We performed an exploratory analysis that included (1) comparisons of plasma interleukin-18 (IL-18) concentrations between patients with AN (n = 21) and healthy controls (n = 39), and (2) correlations between body mass index (BMI) and IL-18 concentrations in both groups, exploring the relationship between malnourishment and IL-18. Plasma IL-18 levels were significantly decreased in patients with AN compared with controls. Plasma IL-18 levels correlated to BMI in controls, but not in patients with AN. These results suggest that a decline in plasma IL-18 levels in patients with AN is not only due to malnourishment, but other pathophysiologic changes as well. IL-18 has a role in the brain's reaction to sadness and chronic stress. Therefore, decreased levels of IL-18 may commonly occur in patients with chronic AN.

Blood volume measured by ultrasound and radioisotope dilution in critically ill subjects.

BACKGROUND: Accurate bedside assessment of circulating blood volume (BV) continues to challenge clinicians in their attempt to implement goal-directed therapy in the critically ill subject. The aim of this investigation was to comparatively evaluate BV measurements obtained by ultrasound and radioisotope dilution methodologies in adult subjects admitted to a surgical intensive care unit. MATERIALS AND METHODS: Fifty subjects with concurrent central venous catheters and peripheral arterial lines underwent measurement of BV using both ultrasound and radioisotope dilution (BV-RD) methods. The ultrasound dilution method was performed using a 30-mL injectate (BV-UD30) and a 60-mL injectate (BV-UD60) of isotonic saline. RESULTS: There were 24 paired data points for the BV-UD30 and 40 paired data points for the BV-UD60 measurements. Spearman's rank-order correlation demonstrated a positive relationship comparing both the BV-UD30 (r = 0.46, P = 0.0249) and the BV-UD60 (r = 0.80, P < 0.0001) to values obtained by radioisotope measurements. Bland-Altman analysis showed a mean bias of 1329 mL with limits of agreement (LOA) ± 2559 mL comparing BV-RD and BV-UD30, and a mean bias of 62 mL with LOA ±1353 mL for BV-RD and BV-UD60. CONCLUSIONS: This preliminary investigation shows that the BV-UD60 had better agreement with BV-RD, compared with the BV-UD30, but its utility appears limited by a large LOA. As this technology continues to evolve, the ultrasound dilution approach may potentially become a feasible means to calculate BV in critically ill surgical subjects.