A Newly Developed Method-Based Xanthine Oxidoreductase Activities in Various Human Liver Diseases.

Studies evaluating xanthine oxidoreductase (XOR) activities in comprehensive liver diseases are scarce, and different etiologies have previously been combined in groups for comparison. To accurately evaluate XOR activities in liver diseases, the plasma XOR activities in etiology-based comprehensive liver diseases were measured using a novel, sensitive, and accurate assay that is a combination of liquid chromatography and triple quadrupole mass spectrometry to detect [13C2, 15N2]uric acid using [13C2, 15N2]xanthine as a substrate. We also mainly evaluated the association between the plasma XOR activities and parameters of liver tests, purine metabolism-associated markers, oxidative stress markers, and an inflammation marker. In total, 329 patients and 32 controls were enrolled in our study. Plasma XOR activities were generally increased in liver diseases, especially in the active phase, such as in patients with hepatitis C virus RNA positivity, those with abnormal alanine transaminase (ALT) levels in autoimmune liver diseases, and uncured hepatocellular carcinoma patients. Plasma XOR activities were numerically highest in patients with acute hepatitis B. Plasma XOR activities were closely correlated with parameters of liver tests, especially serum ALT levels, regardless of etiology and plasma xanthine levels. Our results indicated that plasma XOR activity might reflect the active phase in various liver diseases.

Analysis of the effect of brexpiprazole on sleep architecture in patients with schizophrenia: A preliminary study.

BACKGROUND: Brexpiprazole is an atypical antipsychotic drug widely used in Japan for the treatment of schizophrenia. Previous studies have investigated the therapeutic effects of some antipsychotics on sleep variables; however, to our knowledge, the effects of brexpiprazole on sleep architecture have not been examined in patients with schizophrenia. Therefore, we aimed to exploratorily investigate the effect of brexpiprazole on sleep variables measured by polysomnography in patients with schizophrenia. METHODS: This study included 10 patients with schizophrenia who were originally treated with haloperidol alone. Sleep variables of the participants were measured using polysomnography. After excluding those who did not meet the study criteria, seven patients (five men and two women; mean age [SD], 59.0 [10.0] years) were eligible for further analysis. Polysomnography was repeated at 4 weeks after the participants were prescribed brexpiprazole in addition to haloperidol. We compared the sleep architecture of the participants, measured using polysomnography, before and after taking brexpiprazole. RESULTS: Add-on brexpiprazole significantly prolonged rapid eye movement latency, increased the duration and percentage of stage N2 and stage N3 sleep (min, %), and decreased the duration and percentage of stage rapid eye movement sleep (min, %) at a significance level of nominal p < 0.05. CONCLUSION: Although not significant after correcting for multiple comparisons, the present results showed that add-on brexpiprazole could alter the sleep architecture of patients with schizophrenia. Future studies are warranted to replicate these findings and to further investigate the beneficial influence of brexpiprazole on sleep.

Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice.

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and ß subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.

Inherited PD-1 deficiency underlies tuberculosis and autoimmunity in a child.

The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-γ upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-γ production who are vulnerable to TB. This phenotype resulted from a combined depletion of Vδ2+ γδ T, mucosal-associated invariant T and CD56bright natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and RORγT+ CD4-CD8- double-negative αß T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of RORγT by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

Critical role of the CD44lowCD62Llow CD8+ T cell subset in restoring antitumor immunity in aged mice.

CD8+ T cells play a central role in antitumor immune responses that kill cancer cells directly. In aged individuals, CD8+ T cell immunity is strongly suppressed, which is associated with cancer and other age-related diseases. The mechanism underlying this age-related decrease in immune function remains largely unknown. This study investigated the role of T cell function in age-related unresponsiveness to PD-1 blockade cancer therapy. We found inefficient generation of CD44lowCD62Llow CD8+ T cell subset (P4) in draining lymph nodes of tumor-bearing aged mice. In vitro stimulation of naive CD8+ T cells first generated P4 cells, followed by effector/memory T cells. The P4 cells contained a unique set of genes related to enzymes involved in one-carbon (1C) metabolism, which is critical to antigen-specific T cell activation and mitochondrial function. Consistent with this finding, 1C-metabolism-related gene expression and mitochondrial respiration were down-regulated in aged CD8+ T cells compared with young CD8+ T cells. In aged OVA-specific T cell receptor (TCR) transgenic mice, ZAP-70 was not activated, even after inoculation with OVA-expressing tumor cells. The attenuation of TCR signaling appeared to be due to elevated expression of CD45RB phosphatase in aged CD8+ T cells. Surprisingly, strong stimulation by nonself cell injection into aged PD-1-deficient mice restored normal levels of CD45RB and ameliorated the emergence of P4 cells and 1C metabolic enzyme expression in CD8+ T cells, and antitumor activity. These findings indicate that impaired induction of the P4 subset may be responsible for the age-related resistance to PD-1 blockade, which can be rescued by strong TCR stimulation.

Computational screening of cryoprotective agents for regenerative medical products using quantum chemistry and molecular dynamics simulations.

Cryoprotective agents (CPAs) are essential for the cryopreservation of cells. Thus far, dimethyl sulfoxide (DMSO) has been widely used as a CPA; however, DMSO is known to be toxic to cells. The damaged cells by the toxicity can present abnormal conditions, and should not be used for regenerative medical products because the cells/products are implanted directly into human bodies. With the aim of searching for an alternative CPA to DMSO, this work presents a computational screening of CPA candidate compounds using quantum chemistry and molecular dynamics (MD) simulations. Forty compounds were evaluated in regard to the solvation free energy and partition coefficient by quantum chemistry simulation and the root mean square deviation (RMSD) of a phospholipid bilayer which composes a cell membrane by MD simulation. The solvation free energy, partition coefficient, and RMSD were defined as indicators of osmoregulatory ability, affinity with a cell membrane, and ability to spread a cell membrane, respectively. The quantum chemistry simulation elucidated that the six compounds of trimethylglycine, formamide, urea, thiourea, diethylene glycol, and dulcitol were better than DMSO in either or both of the physical properties considered. This finding is based on the inherent physical property and is thus case-independent. Further characterization with the MD simulation suggested that formamide, thiourea, and urea should be the first candidates to investigate, although the result was valid only in the simulated condition. This work serves as the first step of multi-faceted computational evaluation of multiple compounds in the search for an effective CPA compound after DMSO.

Nucleomethylin deficiency impairs embryonic erythropoiesis.

Nucleomethylin (NML) has been shown to contribute to ribosome formation through regulating transcription and post-transcriptional modification of rRNA. Based on the observation that NML-/- mice are frequently embryonic lethal, we analyzed NML-/- embryos to clarify the role of NML in embryogenesis. We found that NML deficiency leads to lethality at the time point between E10.5 and E12.5. Most of E10.5 NML-/- embryos exhibited growth retardation and/or malformation with marked impairment of erythropoiesis. Consistent with a previous study, the m1A in 28S rRNA was dramatically reduced in NML-/- foetal liver (FL) cells. Because the previous study demonstrated p53-dependent apoptosis of NML-knockdown cells, and because we observed upregulation of p21, one of the p53 target genes, in NML-/- FL cells, we tested whether p53 disruption cancelled the NML-deficient phenotypes. Contrary to our expectation, suppression of p53 did not rescue the lethality or impaired erythropoiesis of NML-/- embryos, suggesting that p53-independent mechanisms underlie the NML-deficient phenotypes. These results clarify an essential role of NML during embryogenesis, particularly in erythropoiesis. We surmise that embryonic erythropoiesis is particularly sensitive to impaired protein synthesis, which is caused by the defective methylation of rRNA and consequent failure of ribosome formation.

Comparing the Effect of Animal-Rearing Education in Japan with Conventional Animal-Assisted Education.

An increasing number of teachers are introducing animals into their class so that pupils foster cognitive, physiological, and social skills through their interaction with animals. Along with such an educational style termed animal-assisted education (AAE), Japanese formal education has also utilized animals for education. Japanese animal-rearing education is unique regarding the following two points: (1) it takes the form of "education through assisting animals" rather than "animals assisting education" and (2) animal rearing is embedded in formal education. While conventional AAE expects the benefit from the social support of animals, Japanese animal-rearing education expects benefit from nurturing and caring for animals. The present study aims to identify effective methods for using animals for education by highlighting the benefits of Japanese animal-rearing education. An overview of Japanese animal-rearing education is followed by a critical review of empirical studies of conventional AAE and Japanese animal-rearing education. Despite the differences in the educational styles, it was found that both systems commonly help children adapt to school. Additionally, conventional AAE were effective in enhancing cognitive and athletic ability of students and foster social skills, while Japanese animal-rearing education enhanced academic knowledge and skills and cultivated sympathy for animals and other people. Furthermore, it was demonstrated that the experience of raising animals affects children's development for a long time even after children stop raising animals. In order to determine the effect of animal presence at school, however, more empirical studies with various viewpoints are necessary for both styles of education. Concerning Japanese animal-rearing education, the effects of the differences such as the amount of exposure to animals, developmental stage or character of individual children, the types of animals need to be controlled for a more sophisticated examination. Empirical studies show that preadolescence is one of the periods in which animal rearing has the greatest impact on children's development. It is suggested that through the program of raising school animals, conventional AAE obtains more a variety of effects in their interaction with animals.

BNIP3 upregulation via stimulation of ERK and JNK activity is required for the protection of keratinocytes from UVB-induced apoptosis.

The human skin has an important role in barrier function. Ultraviolet rays (UV) from sunlight exposure can cause cell apoptosis in the skin epidermis, resulting in the disruption of the barrier. Previously, we have demonstrated that BNIP3 stimulates autophagy in epidermal keratinocytes and has a protective effect in these cells upon UVB irradiation. In this study, we found that the accumulation of reactive oxygen species (ROS) by UVB irradiation was sufficient to trigger the activation of JNK and ERK mitogen-activated protein kinase (MAPK) in human primary epidermal keratinocytes. In turn, activated JNK and ERK MAPK mediated the upregulation of BNIP3 expression. Treatment with an antioxidant reagent or a specific inhibitor of MAPK, U0126, and a JNK inhibitor significantly attenuated the expression of BNIP3 triggered by UVB, followed by the induction of cell death by apoptosis. Furthermore, UVB-induced apoptosis was significantly stimulated by chloroquine or bafilomycin A1, an inhibitor of autophagy. Moreover, BNIP3 was required for the degradation of dysfunctional mitochondria upon UVB irradiation. These data clearly indicated that BNIP3-induced autophagy, which occurs via UVB-generated ROS-mediated JNK and ERK MAPK activation, has a crucial role in the protection of the skin epidermis against UVB irradiation.

Beneficial Effects of the Genus Aloe on Wound Healing, Cell Proliferation, and Differentiation of Epidermal Keratinocytes.

Aloe has been used as a folk medicine because it has several important therapeutic properties. These include wound and burn healing, and Aloe is now used in a variety of commercially available topical medications for wound healing and skin care. However, its effects on epidermal keratinocytes remain largely unclear. Our data indicated that both Aloe vera gel (AVG) and Cape aloe extract (CAE) significantly improved wound healing in human primary epidermal keratinocytes (HPEKs) and a human skin equivalent model. In addition, flow cytometry analysis revealed that cell surface expressions of ß1-, α6-, ß4-integrin, and E-cadherin increased in HPEKs treated with AVG and CAE. These increases may contribute to cell migration and wound healing. Treatment with Aloe also resulted in significant changes in cell-cycle progression and in increases in cell number. Aloe increased gene expression of differentiation markers in HPEKs, suggesting roles for AVG and CAE in the improvement of keratinocyte function. Furthermore, human skin epidermal equivalents developed from HPEKs with medium containing Aloe were thicker than control equivalents, indicating the effectiveness of Aloe on enhancing epidermal development. Based on these results, both AVG and CAE have benefits in wound healing and in treatment of rough skin.

NML-mediated rRNA base methylation links ribosomal subunit formation to cell proliferation in a p53-dependent manner.

Ribosomal RNAs (rRNAs) act as scaffolds and ribozymes in ribosomes, and these functions are modulated by post-transcriptional modifications. However, the biological role of base methylation, a well-conserved modification of rRNA, is poorly understood. Here, we demonstrate that a nucleolar factor, nucleomethylin (NML; also known as RRP8), is required for the N(1)-methyladenosine (m(1)A) modification in 28S rRNAs of human and mouse cells. NML also contributes to 60S ribosomal subunit formation. Intriguingly, NML depletion increases 60S ribosomal protein L11 (RPL11) levels in the ribosome-free fraction and protein levels of p53 through an RPL11-MDM2 complex, which activates the p53 pathway. Consequently, the growth of NML-depleted cells is suppressed in a p53-dependent manner. These observations reveal a new biological function of rRNA base methylation, which links ribosomal subunit formation to p53-dependent inhibition of cell proliferation in mammalian cells.

Estrogen Exhibits a Biphasic Effect on Prostate Tumor Growth through the Estrogen Receptor ß-KLF5 Pathway.

Estrogens are effective in the treatment of prostate cancer; however, the effects of estrogens on prostate cancer are enigmatic. In this study, we demonstrated that estrogen (17ß-estradiol [E2]) has biphasic effects on prostate tumor growth. A lower dose of E2 increased tumor growth in mouse xenograft models using DU145 and PC-3 human prostate cancer cells, whereas a higher dose significantly decreased tumor growth. We found that anchorage-independent apoptosis in these cells was inhibited by E2 treatment. Similarly, in vivo angiogenesis was suppressed by E2. Interestingly, these effects of E2 were abolished by knockdown of either estrogen receptor ß (ERß) or Krüppel-like zinc finger transcription factor 5 (KLF5). Ιn addition, E2 suppressed KLF5-mediated transcription through ERß, which inhibits proapoptotic FOXO1 and proangiogenic PDGFA expression. Furthermore, we revealed that a nonagonistic ER ligand GS-1405 inhibited FOXO1 and PDGFA expression through the ERß-KLF5 pathway and regulated prostate tumor growth without ERß transactivation. Therefore, these results suggest that E2 biphasically modulates prostate tumor formation by regulating KLF5-dependent transcription through ERß and provide a new strategy for designing ER modulators, which will be able to regulate prostate cancer progression with minimal adverse effects due to ER transactivation.

2-(4-Hydroxy-3-methoxyphenyl)-benzothiazole suppresses tumor progression and metastatic potential of breast cancer cells by inducing ubiquitin ligase CHIP.

Breast cancer is the most common malignancy among women and has poor survival and high recurrence rates for aggressive metastatic disease. Notably, triple-negative breast cancer (TNBC) is a highly aggressive cancer and there is no preferred agent for TNBC therapy. In this study, we show that a novel agent, 2-(4-hydroxy-3-methoxyphenyl)-benzothiazole (YL-109), has ability to inhibit breast cancer cell growth and invasiveness in vitro and in vivo. In addition, YL-109 repressed the sphere-forming ability and the expression of stem cell markers in MDA-MB-231 mammosphere cultures. YL-109 increased the expression of carboxyl terminus of Hsp70-interacting protein (CHIP), which suppresses tumorigenic and metastatic potential of breast cancer cells by inhibiting the oncogenic pathway. YL-109 induced CHIP transcription because of the recruitment of the aryl hydrocarbon receptor (AhR) to upstream of CHIP gene in MDA-MB-231 cells. Consistently, the antitumor effects of YL-109 were depressed by CHIP or AhR knockdown in MDA-MB-231 cells. Taken together, our findings indicate that a novel agent YL-109 inhibits cell growth and metastatic potential by inducing CHIP expression through AhR signaling and reduces cancer stem cell properties in MDA-MB-231 cells. It suggests that YL-109 is a potential candidate for breast cancer therapy.

Ubiquitin ligase CHIP suppresses cancer stem cell properties in a population of breast cancer cells.

Cancer stem cells (CSCs) have several distinctive characteristics, including high metastatic potential, tumor-initiating potential, and properties that resemble normal stem cells such as self-renewal, differentiation, and drug efflux. Because of these characteristics, CSC is regarded to be responsible for cancer progression and patient prognosis. In our previous study, we showed that a ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein (CHIP) suppressed breast cancer malignancy. Moreover, a recent clinical study reported that CHIP expression levels were associated with favorable prognostic parameters of patients with breast cancer. Here we show that CHIP suppresses CSC properties in a population of breast cancer cells. CHIP depletion resulted in an increased proportion of CSCs among breast cancers when using several assays to assess CSC properties. From our results, we propose that inhibition of CSC properties may be one of the functions of CHIP as a suppressor of cancer progression.

Identification of a Novel Compound That Suppresses Breast Cancer Invasiveness by Inhibiting Transforming Growth Factor-ß Signaling via Estrogen Receptor α.

Breast cancer is the most frequently diagnosed cancer and the leading cause of death by cancer among females worldwide. An overwhelming majority of these deaths is because of metastasis. Estrogen stimulates and promotes growth of breast tumors, whereas transforming growth factor-beta (TGF-ß) signaling promotes invasion and metastasis. We previously reported that estrogen and estrogen receptor alpha (ERα) suppressed breast cancer metastasis by inhibiting TGF-ß signaling, whereas antiestrogens that suppress breast cancer growth, such as the selective ER modulator tamoxifen (TAM) or the pure antiestrogen fulvestrant (ICI 182,780), cannot suppress TGF-ß signaling or breast cancer invasiveness. Therefore, we predicted that a compound that inhibits TGF-ß signaling but does not facilitate ERα signaling would be ideal for suppressing breast cancer invasiveness and growth. In the present study, we identified an ideal candidate compound, N-23. Like estrogen, N-23 strongly decreased expression of TGF-ß/Smad target gene plasminogen activator inhibitor-1 (PAI-1), but it did not increase the expression of ERα target gene pS2. While estrogen decreased the levels of phosphorylated Smad2 and Smad3, N-23 had no effect. In addition, TGF-ß-dependent recruitment of Smad3 to the PAI-1 gene promoter was inhibited in the presence of estrogen or N-23. We also investigated the effects of N-23 on proliferation, migration, and invasion of breast cancer cells. In contrast to estrogen, N-23 inhibited the cellular proliferation of breast cancer cells. Moreover, we showed that N-23 suppressed the migration and invasion of breast cancer cells to the same extent as by estrogen. Taken together, our findings indicate that N-23 may be a candidate compound that is effective in inhibiting breast cancer progression.

Hepatic rRNA transcription regulates high-fat-diet-induced obesity.

Ribosome biosynthesis is a major intracellular energy-consuming process. We previously identified a nucleolar factor, nucleomethylin (NML), which regulates intracellular energy consumption by limiting rRNA transcription. Here, we show that, in livers of obese mice, the recruitment of NML to rRNA gene loci is increased to repress rRNA transcription. To clarify the relationship between obesity and rRNA transcription, we generated NML-null (NML-KO) mice. NML-KO mice show elevated rRNA level, reduced ATP concentration, and reduced lipid accumulation in the liver. Furthermore, in high-fat-diet (HFD)-fed NML-KO mice, hepatic rRNA levels are not decreased. Both weight gain and fat accumulation in HFD-fed NML-KO mice are significantly lower than those in HFD-fed wild-type mice. These findings indicate that rRNA transcriptional activation promotes hepatic energy consumption, which alters hepatic lipid metabolism. Namely, hepatic rRNA transcriptional repression by HFD feeding is essential for energy storage.

Estrogen receptor ligands ameliorate fatty liver through a nonclassical estrogen receptor/Liver X receptor pathway in mice.

UNLABELLED: Liver X receptor (LXR) activation stimulates triglyceride (TG) accumulation in the liver. Several lines of evidence indicate that estradiol-17ß (E2) reduces TG levels in the liver; however, the molecular mechanism underlying the E2 effect remains unclear. Here, we show that administration of E2 attenuated sterol regulatory element-binding protein (SREBP)-1 expression and TG accumulation induced by LXR activation in mouse liver. In estrogen receptor alpha (ERα) knockout (KO) and liver-specific ERα KO mice, E2 did not affect SREBP-1 expression or TG levels. Molecular analysis revealed that ERα is recruited to the SREBP-1c promoter through direct binding to LXR and inhibits coactivator recruitment to LXR in an E2-dependent manner. Our findings demonstrate the existence of a novel liver-dependent mechanism controlling TG accumulation through the nonclassical ER/LXR pathway. To confirm that a nonclassical ER/LXR pathway regulates ERα-dependent inhibition of LXR activation, we screened ERα ligands that were able to repress LXR activation without enhancing ERα transcriptional activity, and, as a result, we identified the phytoestrogen, phloretin. In mice, phloretin showed no estrogenic activity; however, it did reduce SREBP-1 expression and TG levels in liver of mice fed a high-fat diet to an extent similar to that of E2. CONCLUSION: We propose that ER ligands reduce TG levels in the liver by inhibiting LXR activation through a nonclassical pathway. Our results also indicate that the effects of ER on TG accumulation can be distinguished from its estrogenic effects by a specific ER ligand.

A nonclassical vitamin D receptor pathway suppresses renal fibrosis.

The TGF-ß superfamily comprises pleiotropic cytokines that regulate SMAD and non-SMAD signaling. TGF-ß-SMAD signal transduction is known to be involved in tissue fibrosis, including renal fibrosis. Here, we found that 1,25-dihydroxyvitamin D3-bound [1,25(OH)2D3-bound] vitamin D receptor (VDR) specifically inhibits TGF-ß-SMAD signal transduction through direct interaction with SMAD3. In mouse models of tissue fibrosis, 1,25(OH)2D3 treatment prevented renal fibrosis through the suppression of TGF-ß-SMAD signal transduction. Based on the structure of the VDR-ligand complex, we generated 2 synthetic ligands. These ligands selectively inhibited TGF-ß-SMAD signal transduction without activating VDR-mediated transcription and significantly attenuated renal fibrosis in mice. These results indicate that 1,25(OH)2D3-dependent suppression of TGF-ß-SMAD signal transduction is independent of VDR-mediated transcriptional activity. In addition, these ligands did not cause hypercalcemia resulting from stimulation of the transcriptional activity of the VDR. Thus, our study provides a new strategy for generating chemical compounds that specifically inhibit TGF-ß-SMAD signal transduction. Since TGF-ß-SMAD signal transduction is reportedly involved in several disorders, our results will aid in the development of new drugs that do not cause detectable adverse effects, such as hypercalcemia.

Successful treatment of a 14-year-old patient with intestinal malrotation with laparoscopic Ladd procedure: case report and literature review.

Midgut malrotation is an anomaly of intestinal rotation that occurs during fetal development and usually presents in the neonatal period. We present a rare case of malrotation in a 14-year-old patient who presented with cramping, generalized right abdominal pain, and vomiting for a duration of one day. A computed tomography abdominal scan and upper gastrointestinal contrast studies showed malrotation of the small bowel without volvulus. Laparoscopy revealed typical Ladd's bands and a distended flabby third and fourth duodenal portion extrinsically obstructing the misplaced duodeno-jejunal junction. The Ladd procedure, including widening of the mesenteric base and appendectomy, was performed. Symptoms completely resolved in a half-year follow up period. Patients with midgut malrotation may present with vague abdominal pain, intestinal obstruction, or intestinal ischemia. The laparoscopic Ladd procedure is feasible and safe, and it appears to be as effective as the standard open Ladd procedure in the diagnosis and treatment of teenage or adult patients with intestinal malrotation.