An Elderly Patient Developed Ulcerative Colitis after SARS-CoV-2 mRNA Vaccination: A Case Report and Review of the Literature.

An 86-year-old man presented to our hospital with symptoms of diarrhea and bloody stool, which had manifested two weeks after receiving his third severe acute respiratory syndrome coronavirus 2 mRNA vaccination. Colonoscopy revealed diffuse, rough-surfaced mucosa extending from the ascending colon to the rectum. Despite attempting probiotic treatment, the patient's condition did not improve, leading to admission. Endoscopic findings at admission worsened. Based on endoscopic and histopathological findings, the patient was diagnosed with ulcerative colitis. Corticosteroids and 5-aminosalicylic acid were administered, and the clinical symptoms improved. Subsequently, the disease worsened during steroid tapering, and filgotinib was added, leading to steroid-free remission.

Importance of beating rate control for the analysis of drug effects on contractility in human induced pluripotent stem cell-derived cardiomyocytes.

Cardiac contractility evaluation using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) has recently attracted much attention as a clinical cardiotoxicity predictive model. Most studies on this were conducted under spontaneous beating conditions and involved video-based analyses. Cardiac contractility is known to be influenced by beating rates; accordingly, beating rate control is recommended to accurately analyze the effects of drugs on cardiac contractility. Therefore, we investigated the relationship between contraction parameters and beating rates of cardiac cell sheet tissues by directly measuring the contraction force and compared the effects of ion channel drugs (mexiletine, ranolazine, and dofetilide) on contraction parameters under spontaneous beating conditions with those under pacing (1 Hz) conditions. To characterize the contraction/relaxation kinetics, we introduced a novel analysis tool, called a "C-V loop," a plot of contraction force versus force-changing rate ("velocity"). When we increased the beating rate, the contraction force, force-changing rate, and relaxation time markedly decreased. The occurrence frequencies of beating arrest and irregular beats at high concentration ranges of mexiletine and ranolazine were more suppressed in paced samples than in spontaneously beating ones. We also found that relaxation time increased by treatment with dofetilide and contraction amplitude decreased in a concentration-dependent manner by mexiletine treatment only in the samples under pacing. These drug responses were consistent with the previous reports using human samples. These results indicated that beating rate control is necessary to stably evaluate the effects of drugs on contractility and that tests under 1-Hz pacing are more relevant to clinical settings.

Prognostic outcomes after direct percutaneous endoscopic jejunostomy in elderly patients: comparison with percutaneous endoscopic gastrostomy.

BACKGROUND AND AIMS: Direct percutaneous endoscopic jejunostomy (DPEJ) is an alternative method of enteral feeding to percutaneous endoscopic gastrostomy (PEG). Although long-term outcomes of PEG have been reported, little is known regarding the outcomes of DPEJ. METHODS: A retrospective cohort study was conducted including 115 and 651 consecutive attempts of DPEJ and PEG, respectively, in a total of 766 elderly patients between April 2004 and March 2019. Patients' clinical background, procedural and long-term outcomes, survival analysis, and cause of death were analyzed. RESULTS: Successful placement rates were 93.9% and 97.1% for DPEJ and PEG, respectively. There was no significant difference in procedure-related adverse events (AEs) between the DPEJ and PEG groups. Rates of pneumonia, vomiting, and upper GI bleeding were significantly lower, whereas those of fistula enlargement and ileus were significantly higher in the DPEJ group as long-term AEs. The median survival periods were 694 and 734 days for DPEJ and PEG, respectively, with no significant differences between the 2 groups. Multivariate analysis revealed that age 80 years old or older, C-reactive protein level of 1.0 mg/dL or higher, and the presence of diabetes were independent risk factors for mortality after DPEJ. Respiratory tract infection was the primary cause of death in both groups. CONCLUSIONS: DPEJ is considered a safe and feasible method of access for enteral feeding as well as PEG. Although the survival period after DPEJ may be expected to be as long as that with PEG, DPEJ-specific AEs should be kept in mind on long-term feeding.

Use of a Low-carbohydrate Enteral Nutrition Formula with Effective Inhibition of Hypoglycemia and Post-infusion Hyperglycemia in Non-diabetic Patients Fed via a Jejunostomy Tube.

Objective As direct jejunal feeding often causes great fluctuation in glucose levels, continuous or slow infusion is recommended for jejunal tube-fed patients. However, continuous feeding results in prolonged immobility and the loss of activities of daily living. We investigated whether or not intermittent feeding of a low-carbohydrate high-monounsaturated fatty acid (LC/HM) nutrient formula reduces glucose fluctuation in patients who have undergone jejunotomy. Methods Ten bed-ridden non-diabetic patients receiving enteral feeding via a jejunostomy tube were enrolled in this study. LC/HM formula and standard control formula were infused in cross-over order for each patient at a speed of 160 kcal/h. Blood glucose levels were monitored by a continuous glucose monitoring system during the investigation period. Results The mean and standard deviation of the glucose concentrations and mean amplitude of glucose excursion (MAGE) were markedly lower while receiving LC/HM formula than while receiving control standard formula (104 vs. 136 mg/dL, 18.1 vs. 58.1 mg/dL, 50.8 vs. 160 mg/dL, respectively). The post-infusion hyperglycemia [area under the curve (AUC) >140 mg/dL] and peak value of the glucose level were also significantly lower in patients fed LC/HM than the control (25.7 vs. 880 mg・h/dL and 153 vs. 272 mg/dL, respectively). Reactive hypoglycemia (AUC <70 mg/dL) was also significantly lower (0.63 vs. 16.7 mg・h/dL) and the minimum value of the glucose level higher (78.4 vs. 61.8 mg/dL) in patients fed LC/HM than the control. Conclusion The LC/HM formula is considered to markedly inhibit glycemic spikes and prevent rebound hypoglycemia in patients who receive enteral feeding after jejunostomy.

Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists.

The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Olfactory Sensory Neurons Control Dendritic Complexity of Mitral Cells via Notch Signaling.

Mitral cells (MCs) of the mammalian olfactory bulb have a single primary dendrite extending into a single glomerulus, where they receive odor information from olfactory sensory neurons (OSNs). Molecular mechanisms for controlling dendritic arbors of MCs, which dynamically change during development, are largely unknown. Here we found that MCs displayed more complex dendritic morphologies in mouse mutants of Maml1, a crucial gene in Notch signaling. Similar phenotypes were observed by conditionally misexpressing a dominant negative form of MAML1 (dnMAML1) in MCs after their migration. Conversely, conditional misexpression of a constitutively active form of Notch reduced their dendritic complexity. Furthermore, the intracellular domain of Notch1 (NICD1) was localized to nuclei of MCs. These findings suggest that Notch signaling at embryonic stages is involved in the dendritic complexity of MCs. After the embryonic misexpression of dnMAML1, many MCs aberrantly extended dendrites to more than one glomerulus at postnatal stages, suggesting that Notch signaling is essential for proper formation of olfactory circuits. Moreover, dendrites in cultured MCs were shortened by Jag1-expressing cells. Finally, blocking the activity of Notch ligands in OSNs led to an increase in dendritic complexity as well as a decrease in NICD1 signals in MCs. These results demonstrate that the dendritic complexity of MCs is controlled by their presynaptic partners, OSNs.

Ampicillin- and ampicillin/sulbactam-resistant Escherichia coli infection in a neonatal intensive care unit in Japan.

The incidence of ampicillin (ABPC)-resistant Escherichia coli (E. coli) infection in very low-birthweight infants has been increasing. The rate of ABPC/sulbactam (ABPC/SBT)-resistant E. coli in this population, however, is currently unknown. We encountered two cases of severe infection due to resistant E. coli and retrospectively studied the prevalence of ABPC- and ABPC/SBT-resistant E. coli in regular surveillance cultures obtained from all neonatal intensive care unit (NICU) patients between 2000 and 2013. The overall prevalence of ABPC-resistant E. coli was 39% (47/120), accounting for 63% of cases (32/51) between 2007 and 2013, compared with 22% (15/69) between 2000 and 2006. The prevalence of ABPC/SBT resistance was 17% (20/120), which was similar in both periods (16%, 8/51 vs 17%, 12/69). According to these results, not only ABPC, but also ABPC/SBT-resistant E. coli must be considered in the NICU.

Metformin suppresses diethylnitrosamine-induced liver tumorigenesis in obese and diabetic C57BL/KsJ-+Leprdb/+Leprdb mice.

Obesity and related metabolic disorders, such as diabetes mellitus, raise the risk of liver carcinogenesis. Metformin, which is widely used in the treatment of diabetes, ameliorates insulin sensitivity. Metformin is also thought to have antineoplastic activities and to reduce cancer risk. The present study examined the preventive effect of metformin on the development of diethylnitrosamine (DEN)-induced liver tumorigenesis in C57BL/KsJ-+Leprdb/+Leprdb (db/db) obese and diabetic mice. The mice were given a single injection of DEN at 2 weeks of age and subsequently received drinking water containing metformin for 20 weeks. Metformin administration significantly reduced the multiplicity of hepatic premalignant lesions and inhibited liver cell neoplasms. Metformin also markedly decreased serum levels of insulin and reduced insulin resistance, and inhibited phosphorylation of Akt, mammalian target of rapamycin (mTOR), and p70S6 in the liver. Furthermore, serum levels of leptin were decreased, while those of adiponectin were increased by metformin. These findings suggest that metformin prevents liver tumorigenesis by ameliorating insulin sensitivity, inhibiting the activation of Akt/mTOR/p70S6 signaling, and improving adipokine imbalance. Therefore, metformin may be a potent candidate for chemoprevention of liver tumorigenesis in patients with obesity or diabetes.

Exfoliative toxin A staphylococcal scalded skin syndrome in preterm infants.

UNLABELLED: Staphylococcal scalded skin syndrome (SSSS) demonstrates dermal symptoms due to exfoliative toxin (ET) A or ETB produced by Staphylococcus aureus. We examined the association between anti-ETA antibodies and SSSS onset in neonates. Three preterm infants carried an ETA-producing strain of S. aureus, manifesting as either SSSS or bullous impetigo; a full-term infant carrying the same strain was asymptomatic. The infants (n=106) were categorized into three groups according to their gestational age (GA) as follows: <30 weeks, 30-37 weeks, and >37 weeks. The measured levels of anti-ETA antibody in the three infants displaying SSSS were low before the onset of dermal symptoms; only the asymptomatic full-term infant displayed a high antibody level. Anti-ETA antibody levels in the preterm group with a GA of <30 weeks were statistically lower than those in the term infant group; the prevalences of anti-ETA antibodies above a cutoff value in the three groups of neonates were 55 % (18/33) among preterm infants with a GA <30 weeks, 73 % (25/34) among those with a GA of 30-37 weeks, and 90 % (35/39) among infants with a GA >37 weeks. CONCLUSION: The presence of anti-ETA antibodies below a particular cutoff level might be associated with SSSS onset in preterm infants.

Preventive effects of the angiotensin-converting enzyme inhibitor, captopril, on the development of azoxymethane-induced colonic preneoplastic lesions in diabetic and hypertensive rats.

Metabolic syndrome (Mets), including diabetes and hypertension, increases the risk of colorectal cancer via the induction of chronic inflammation, acceleration of oxidative stress, and activation of the renin-angiotensin system. The present study examined the possible inhibitory effects of captopril, an angiotensin-converting enzyme (ACE) inhibitor and antihypertensive drug, on the development of azoxymethane (AOM)-induced colonic premalignant lesions, aberrant crypt foci (ACF), in SHRSP.Z-Leprfa /IzmDmcr (SHRSP-ZF) diabetic and hypertensive rats. Male 6-week-old SHRSP-ZF rats were administered two, weekly intraperitoneal injections of AOM (20 mg/kg body weight). Following the second injection, the rats received drinking water containing captopril (8 mg/kg/day) for two weeks. At sacrifice, captopril administration significantly lowered the blood pressure and reduced the total number and size of ACF compared with those observed in the untreated group. The serum levels of angiotensin-II and the expression levels of ACE and angiotensin-II type 1 receptor mRNA on the colonic mucosa decreased following captopril treatment. Captopril also reduced the urinary 8-hydroxy-2'-deoxyguanosine levels and the serum derivatives of reactive oxygen metabolites levels, both of which are oxidative stress markers, but increased the mRNA levels of catalase, an antioxidant enzyme, in the colonic epithelium. Moreover, the expression levels of tumor necrosis factor-α, interleukin-18, monocyte chemoattractant protein-1, inducible nitric oxide synthase, vascular endothelial growth factor and proliferating cell nuclear antigen mRNA in the colonic epithelium were decreased significantly following captopril administration. These observations suggested that captopril prevents the development of ACF by inhibiting renin-angiotensin system activation and attenuating inflammation and oxidative stress in SHRSP-ZF rats. Therefore, targeting Mets-related pathophysiological conditions, including renin-angiotensin system activation, may be an effective strategy to prevent colorectal carcinogenesis in patients with Mets, particularly those with hypertension.

Cleavage within Reelin repeat 3 regulates the duration and range of the signaling activity of Reelin protein.

Reelin is a secreted glycoprotein that plays essential roles in the brain. Reelin is specifically cleaved at two distinct sites, called N-t and C-t, with the former being the major one. N-t cleavage can occur both in the extracellular space and in the endosomes, although the physiological importance of endosomal N-t cleavage has not been investigated. In this study, we first determined the exact N-t cleavage site catalyzed by a protease secreted by cerebral cortical neurons. Cleavage occurred between Pro-1244 and Ala-1245 within Reelin repeat 3. A Reelin mutant in which Pro-1244 was replaced with aspartate (Reelin-PD) was resistant to a protease secreted by cultured cerebral cortical neurons, and its biological activity stayed active longer than that of wild-type Reelin. Interestingly, Reelin-PD remained in the intracellular compartments longer than wild-type Reelin and persistently activated downstream signaling. Therefore, N-t cleavage of Reelin is required for halting the signaling machinery in the extracellular space as well as within endosomes of target neurons. We established a monoclonal antibody specific to uncleaved Reelin protein and found that it is localized in the vicinity of Reelin-producing cells, whereas the N-terminal fragment diffuses, or is transported, to distant regions. These data demonstrate that N-t cleavage of Reelin plays critical roles in regulating the duration and range of Reelin functions both in the extracellular milieu and in the intracellular compartments.

Combination of bevacizumab and acyclic retinoid inhibits the growth of hepatocellular carcinoma xenografts.

The prognosis of patients with hepatocellular carcinoma (HCC) is poor and the development of effective treatments for this malignancy, including combination chemotherapy, is required. This study examined the possible combined inhibitory effects of bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, and acyclic retinoid (ACR), which can prevent the development of HCC, on the growth of Huh7 human HCC cells. Xenograft tumors were produced by subcutaneously injecting Huh7 cells into nude mice. Starting 1 wk after the tumor cell injection, the mice were treated with bevacizumab alone (5 mg/kg body weight, subcutaneous injection, twice a week), ACR alone (given in a diet containing 0.03%), or their combination for 6 wk, and the effects of these regimens on xenograft growth were examined. Combined treatment with bevacizumab plus ACR significantly suppressed the growth of Huh7 xenografts. The combination of these agents significantly inhibited the phosphorylation of the Akt protein in tumor tissues. With combination therapy, the population of Ki-67-positive cells in xenografts decreased, while that of TUNEL-positive cells increased. The combination of bevacizumab and ACR exerts growth-suppressing effects on HCC cells by inhibiting cell proliferation and inducing apoptosis. This combination might be an effective regimen for the treatment of HCC.

Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions.

Non-alcoholic steatohepatitis (NASH), which involves hepatic inflammation and fibrosis, is associated with liver carcinogenesis. The activation of the renin-angiotensin system (RAS), which plays a key role in blood pressure regulation, promotes hepatic fibrogenesis. In this study, we investigated the effects of (-)-epigallocatechin-3-gallate (EGCG), a major component of green tea catechins, on the development of glutathione S-transferase placental form (GST-P)-positive (GST-P(+)) foci, a hepatic preneoplastic lesion, in SHRSP.Z-Lepr(fa)/IzmDmcr (SHRSP-ZF) obese and hypertensive rats. Male 7-week-old SHRSP-ZF rats and control non-obese and normotensive WKY rats were fed a high fat diet and received intraperitoneal injections of carbon tetrachloride twice a week for 8weeks. The rats were also provided tap water containing 0.1% EGCG during the experiment. SHRSP-ZF rats presented with obesity, insulin resistance, dyslipidemia, an imbalance of adipokines in the serum, and hepatic steatosis. The development of GST-P(+) foci and liver fibrosis was markedly accelerated in SHRSP-ZF rats compared to that in control rats. Additionally, in SHRSP-ZF rats, RAS was activated and inflammation and oxidative stress were induced. Administration of EGCG, however, inhibited the development of hepatic premalignant lesions by improving liver fibrosis, inhibiting RAS activation, and attenuating inflammation and oxidative stress in SHRSP-ZF rats. In conclusion, obese and hypertensive SHRSP-ZF rats treated with a high fat diet and carbon tetrachloride displayed the histopathological and pathophysiological characteristics of NASH and developed GST-P(+) foci hepatic premalignant lesions, suggesting the model might be useful for the evaluation of NASH-related liver tumorigenesis. EGCG might also be able to prevent NASH-related liver fibrosis and tumorigenesis.

Synergistic growth inhibition by acyclic retinoid and phosphatidylinositol 3-kinase inhibitor in human hepatoma cells.

BACKGROUND: A malfunction of RXRα due to phosphorylation is associated with liver carcinogenesis, and acyclic retinoid (ACR), which targets RXRα, can prevent the development of hepatocellular carcinoma (HCC). Activation of PI3K/Akt signaling plays a critical role in the proliferation and survival of HCC cells. The present study examined the possible combined effects of ACR and LY294002, a PI3K inhibitor, on the growth of human HCC cells. METHODS: This study examined the effects of the combination of ACR plus LY294002 on the growth of HLF human HCC cells. RESULTS: ACR and LY294002 preferentially inhibited the growth of HLF cells in comparison with Hc normal hepatocytes. The combination of 1 µM ACR and 5 µM LY294002, in which the concentrations used are less than the IC50 values of these agents, synergistically inhibited the growth of HLF, Hep3B, and Huh7 human HCC cells. These agents when administered in combination acted cooperatively to induce apoptosis in HLF cells. The phosphorylation of RXRα, Akt, and ERK proteins in HLF cells were markedly inhibited by treatment with ACR plus LY294002. Moreover, this combination also increased RXRE promoter activity and the cellular levels of RARß and p21(CIP1), while decreasing the levels of cyclin D1. CONCLUSION: ACR and LY294002 cooperatively increase the expression of RARß, while inhibiting the phosphorylation of RXRα, and that these effects are associated with the induction of apoptosis and the inhibition of cell growth in human HCC cells. This combination might therefore be effective for the chemoprevention and chemotherapy of HCC.

Enhanced development of azoxymethane-induced colonic preneoplastic lesions in hypertensive rats.

Metabolic syndrome is associated with an increased risk of colorectal cancer. This study investigated the impact of hypertension, a component of metabolic syndrome, on azoxymethane (AOM)-induced colorectal carcinogenesis using SHRSP/Izm (SHRSP) non-diabetic/hypertensive rats and SHRSP.Z-Leprfa/IzmDmcr (SHRSP-ZF) diabetic/hypertensive rats. Male 6-week-old SHRSP, SHRSP-ZF, and control non-diabetic/normotensive Wister Kyoto/Izm (WKY) rats were given 2 weekly intraperitoneal injections of AOM (20 mg/kg body weight). Two weeks after the last injection of AOM, the SHRSP and SHRSP-ZF rats became hypertensive compared to the control WKY rats. Serum levels of angiotensin-II, the active product of the renin-angiotensin system, were elevated in both SHRSP and SHRSP-ZF rats, but only the SHRSP-ZF rats developed insulin resistance, dyslipidemia, and hyperleptinemia and exhibited an increase in adipose tissue. The development of AOM-induced colonic preneoplastic lesions and aberrant crypts foci, was significantly accelerated in both SHRSP and SHRSP-ZF hypertensive rats, compared to WKY normotensive rats. Furthermore, induction of oxidative stress and exacerbation of inflammation were observed in the colonic mucosa and systemically in SHRSP and SHRSP-ZF rats. Our findings suggest that hypertension plays a role in the early stage of colorectal carcinogenesis by inducing oxidative stress and chronic inflammation, which might be associated with activation of the renin-angiotensin system.

Extremely low flow tracheal gas insufflation of helium-oxygen mixture improves gas exchange in a rabbit model of piston-type high-frequency oscillatory ventilation.

OBJECTIVE: The purpose of this study was to show the effects of the tracheal gas insufflation (TGI) technique on gas exchange using helium-oxygen mixtures during high-frequency oscillatory ventilation (HFOV). We hypothesized that a helium-oxygen mixture delivered into the trachea using the TGI technique (0.3 L/min) would enhance gas exchange during HFOV. METHODS: Three rabbits were prepared and ventilated by HFOV with carrier 70% helium/oxygen or 70% nitrogen/oxygen gas mixture with TGI in a crossover study. Changing the gas mixture from nitrogen70% to helium70% and back was performed three times per animal with constant ventilation parameters. RESULTS: Compared with the nitrogen-oxygen mixture, the helium-oxygen mixture of TGI reduced PaCO2 by 7.6 mmHg (p < 0.01) and improved PaO2 by 14 mmHg (p < 0.01). Amplitude during TGI was significantly lower with the helium-oxygen mixture than with the nitrogen-oxygen mixture (p < 0.01) and did not significantly affect mean airway pressure. CONCLUSIONS: This study demonstrated that a helium-oxygen mixture delivered into the trachea using the TGI technique would enhance CO2 elimination and improve oxygenation during HFOV.

Preventive effects of branched-chain amino acid supplementation on the spontaneous development of hepatic preneoplastic lesions in C57BL/KsJ-db/db obese mice.

Obesity and its associated disorders, such as non-alcoholic steatohepatitis, increase the risk of hepatocellular carcinoma. Branched-chain amino acids (BCAA), which improve protein malnutrition in patients with liver cirrhosis, reduce the risk of hepatocellular carcinoma in these patients with obesity. In the present study, the effects of BCAA supplementation on the spontaneous development of hepatic premalignant lesions, foci of cellular alteration, in db/db obese mice were examined. Male db/db mice were given a basal diet containing 3.0% of either BCAA or casein, a nitrogen-content-matched control of BCAA, for 36 weeks. On killing the mice, supplementation with BCAA significantly inhibited the development of foci of cellular alteration when compared with casein supplementation by inhibiting cell proliferation, but inducing apoptosis. BCAA supplementation increased the expression levels of peroxisome proliferator-activated receptor-γ, p21(CIP1) and p27(KIP1) messenger RNA and decreased the levels of c-fos and cyclin D1 mRNA in the liver. BCAA supplementation also reduced both the amount of hepatic triglyceride accumulation and the expression of interleukin (IL)-6, IL-1ß, IL-18 and tumor necrosis factor-α mRNA in the liver. Increased macrophage infiltration was inhibited and the expression of IL-6, TNF-α, and monocyte chemoattractant protein-1 mRNA in the white adipose tissue were each decreased by BCAA supplementation. BCAA supplementation also reduced adipocyte size while increasing the expression of peroxisome proliferator-activated receptor-α, peroxisome proliferator-activated receptor-γ and adiponectin mRNA in the white adipose tissue compared with casein supplementation. These findings indicate that BCAA supplementation inhibits the early phase of obesity-related liver tumorigenesis by attenuating chronic inflammation in both the liver and white adipose tissue. BCAA supplementation may be useful in the chemoprevention of liver tumorigenesis in obese individuals.

Recessive RYR1 mutations in a patient with severe congenital nemaline myopathy with ophthalomoplegia identified through massively parallel sequencing.

Nemaline myopathy (NM) is a group of congenital myopathies, characterized by the presence of distinct rod-like inclusions "nemaline bodies" in the sarcoplasm of skeletal muscle fibers. To date, ACTA1, NEB, TPM3, TPM2, TNNT1, and CFL2 have been found to cause NM. We have identified recessive RYR1 mutations in a patient with severe congenital NM, through high-throughput screening of congenital myopathy/muscular dystrophy-related genes using massively parallel sequencing with target gene capture. The patient manifested fetal akinesia, neonatal severe hypotonia with muscle weakness, respiratory insufficiency, swallowing disturbance, and ophthalomoplegia. Skeletal muscle histology demonstrated nemaline bodies and small type 1 fibers, but without central cores or minicores. Congenital myopathies, a molecularly, histopathologically, and clinically heterogeneous group of disorders are considered to be a good candidate for massively parallel sequencing.

Differential localization of sphingomyelin synthase isoforms in neurons regulates sphingomyelin cluster formation.

Sphingomyelin (SM) plays important roles in regulating structure and function of plasma membrane, but how intracellular localization of SM is regulated in neuronal cells is not understood. Here we show that two isoforms of SM synthase (SMS) are differentially expressed in neuronal subtypes and that only SMS2 proteins localize in neurites of hippocampal neurons. Moreover, SMS proteins induce Lysenin-binding SM clusters exclusively in their vicinity although neurons hardly contain such cluster under control condition. These findings indicate three important notions about SM metabolism in neurons. First, the activity of SMS is the rate-limiting step of SM cluster formation. Second, the SM content or clustering can be modulated by SMS activity. Third, SMS1 and SMS2 play distinct roles in regulating local SM clustering. Particularly, SMS2, rather than SMS1, is likely to be the major enzyme that is important for SM synthesis in the long neurites and its tip, the growth cone.

Preventive effects of curcumin on the development of azoxymethane-induced colonic preneoplastic lesions in male C57BL/KsJ-db/db obese mice.

Obesity-related metabolic abnormalities include a state of chronic inflammation and adipocytokine imbalance, which increase the risk of colon cancer. Curcumin, a component of turmeric, exerts both cancer preventive and antiinflammatory properties. Curcumin is also expected to have the ability to reverse obesity-related metabolic derangements. The present study examined the effects of curcumin on the development of azoxymethane (AOM)-induced colonic premalignant lesions in C57BL/KsJ-db/db (db/db) obese mice. Feeding with a diet containing 0.2% and 2.0% curcumin caused a significant reduction in the total number of colonic premalignant lesions compared with basal diet-fed mice. The expression levels of tumor necrosis factor-α, interleukin-6, and cyclooxygenase-2 (COX-2) mRNAs on the colonic mucosa of AOM-treated mice were significantly decreased by curcumin administration. Dietary feeding with curcumin markedly activated AMP-activated kinase, decreased the expression of COX-2 protein, and inhibited nuclear factor-κB activity on the colonic mucosa of AOM-treated mice. Curcumin also increased the serum levels of adiponectin while conversely decreasing the serum levels of leptin and the weights of fat. In conclusion, curcumin inhibits the development of colonic premalignant lesions in an obesity-related colorectal carcinogenesis model, at least in part, by attenuating chronic inflammation and improving adipocytokine imbalance. Curcumin may be useful in the chemoprevention of colorectal carcinogenesis in obese individuals.