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Background Cow's milk protein allergy (CMPA) is commonly seen in children. There have been no reports of the true prevalence of CMPA in Chinese infants. The aim of this population-based study is to determine the prevalence, clinical characteristics, and outcome of CMPA in Chinese infants. Methods We carried out a prospective survey in 7 participating hospitals throughout southern China. We included infants ≤12 months of age during the survey. For those suspected of CMPA, oral food challenge with cow's milk protein (CMP) was performed. A follow-up telephone interview was conducted at 12 months after the diagnosis to assess the clinical outcome of CMPA. Results A total of 9910 questionnaire surveys were distributed and 7364 (74.3%) were returned. The eligible survey number of surveys was 6768 (91.9%). A total of 182 infants was confirmed with CMPA, including 13 with anaphylactic reactions, 28 with clinical symptoms and serum immunoglobulin E (sIgE) >3.5 IU/mL, and 141 with positive CMP challenge test. The prevalence of CMPA was 2.69%. Infants with confirmed CMPA had significantly stronger family history of either 1 or both parents with food allergy, higher Cesarean section rate, and lower rate of breastfeeding, compared with those without CMPA. At 12-month telephone follow-up of 176 CMPA infants, 136 infants (77.3%) had become tolerant to CMP. Conclusions The prevalence of CMPA was 2.69%. CMPA infants had a strong family history of food allergy and atopy. Both Cesarean delivery and formula feeding were risk factors for CMPA. At 12-month follow-up, the majority of CMPA infants had become tolerant to CMP.

Acetaminophen overdose is the most common cause of acute liver injury (ALI) or acute liver failure in the United States. Its pathogenetic mechanisms are incompletely understood. Additional studies are warranted to identify new genetic risk factors for more mechanistic insights and new therapeutic target discoveries. The objective of this study was to explore the role and mechanisms of nicotinamide phosphoribosyltransferase (NAMPT) in acetaminophen-induced ALI. C57BL/6 Nampt gene wild-type (Nampt(+/+)), heterozygous knockout (Nampt(+/−)), and overexpression (Nampt(OE)) mice were treated with overdose of acetaminophen, followed by histologic, biochemical, and transcriptomic evaluation of liver injury. The mechanism of Nampt in acetaminophen-induced hepatocytic toxicity was also explored in cultured primary hepatocytes. Three lines of evidence have convergently demonstrated that acetaminophen overdose triggers the most severe oxidative stress and necrosis, and the highest expression of key necrosis driving genes in Nampt(+/−) mice, whereas the effects in Nampt(OE) mice were least severe relative to Nampt(+/+) mice. Treatment of P7C3-A20, a small chemical molecule up-regulator of Nampt, ameliorated acetaminophen-induced mouse ALI over the reagent control. These findings support the fact that NAMPT protects against acetaminophen-induced ALI.

BACKGROUND: Both type 2 diabetes (T2D) and Alzheimer’s disease (AD) occur commonly in the aging populations and T2D has been considered as an important risk factor for AD. The heritability of both diseases is estimated to be over 50%. However, common pleiotropic single-nucleotide polymorphisms (SNPs)/loci have not been well-defined. The aim of this study is to analyze two large public accessible GWAS datasets to identify novel common genetic loci for T2D and/or AD. METHODS AND MATERIALS: The recently developed novel conditional false discovery rate (cFDR) approach was used to analyze the summary GWAS datasets from International Genomics of Alzheimer’s Project (IGAP) and Diabetes Genetics Replication And Meta-analysis (DIAGRAM) to identify novel susceptibility genes for AD and T2D. RESULTS: We identified 78 SNPs (including 58 novel SNPs) that were associated with AD in Europeans conditional on T2D (cFDR < 0.05). 66 T2D SNPs (including 40 novel SNPs) were identified by conditioning on SNPs association with AD (cFDR < 0.05). A conjunction-cFDR (ccFDR) analysis detected 8 pleiotropic SNPs with a significance threshold of ccFDR < 0.05 for both AD and T2D, of which 5 SNPs (rs6982393, rs4734295, rs7812465, rs10510109, rs2421016) were novel findings. Furthermore, among the 8 SNPs annotated at 6 different genes, 3 corresponding genes TP53INP1, TOMM40 and C8orf38 were related to mitochondrial dysfunction, critically involved in oxidative stress, which potentially contribute to the etiology of both AD and T2D. CONCLUSION: Our study provided evidence for shared genetic loci between T2D and AD in European subjects by using cFDR and ccFDR analyses. These results may provide novel insight into the etiology and potential therapeutic targets of T2D and/or AD.

Background Congenital chloride diarrhea (CCD) in a newborn is a rare autosomal recessive disorder with life-threatening complications, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. SLC26A3 rs386833481 (c.392C>G; p.P131R) gene polymorphism is an important genetic determinant of CCD. Here, we report the influence of the non-synonymous SLC26A3 variant rs386833481 gene polymorphism on the function of the epithelial barrier and the potential mechanisms of these effects. Results We found that P131R-SLC26A3 increased dysfunction of the epithelial barrier compared with wild type SLC26A3 in human colonic Caco-2 and mouse colonic CMT-93 cells. When P131R-SLC26A3 was subsequently reverted to wild type, the epithelial barrier function was restored similar to wild type cells. Further study demonstrated that variant P131R-SLC26A3 disrupts function of epithelial barrier through two distinct molecular mechanisms: (a) decreasing SLC26A3 expression through a ubiquitination pathway and (b) disrupting a key interaction with its partner ZO-1/CFTR, thereby increasing the epithelial permeability. Conclusion Our study provides an important insight of SLC26A3 SNPs in the regulation of the epithelial permeability and indicates that SLC26A3 rs386833481 is likely a causative mutation in the dysfunction of epithelial barrier of CCD, and correction of this SNP or increasing SLC26A3 function could be therapeutically beneficial for chronic diarrhea diseases.

Calcium is an important integrative component of the human body and critical for human health. It has been well established that calcium intake is helpful in the prevention and treatment of osteoporosis, which has become one of the most serious public health problems across the world. However, community-dwelling adults with and without osteoporosis are rarely concerned or even not aware of the potential side effects of high or inappropriate doses of calcium intake. Some recent studies have revealed that excessive calcium intake might increase the risks of cardiovascular diseases. The purpose of this article was to review the health benefits, costs, and consequences of calcium supplementation on osteoporosis/osteoporotic fractures, cardiovascular events, kidney stones, gastrointestinal diseases, and other important diseases. In the end, we suggest that calcium supplementation should be prescribed and taken cautiously, accounting for individual patients' risks and benefits. Clearly, further studies are needed to examine the health effects of calcium supplementation to make any solid recommendations for people of different genders, ages, and ethnicities.

The treatment of intrahepatic cholestasis has been limited, and development of an effective drug is needed. Clinical studies have shown that Yinzhihuang (YZH), a traditional Chinese decoction, enhances bilirubin clearance. The goal of this study was to determine the protective effect of YZH on experimental intrahepatic cholestasis in young rats and to explore its underlying molecular mechanisms. Intrahepatic cholestasis in rats was induced by α-naphthylisothiocyanate (ANIT) on days 1 and 8. The rats received YZH, ursodeoxycholic acid (UDCA), or vehicle for 9 d and were killed on either day 3 or day 10. Serum biomarkers, liver histology, and the distribution of protein and mRNA expression of Mrp2 and Bsep were analyzed. YZH treatment resulted in decreased levels of serum biomarkers except γ-glutamyl transpeptidase, attenuated liver histological injuries, increased protein expressions of Mrp2 and Bsep, and upregulated expressions of Mrp2 and Bsep mRNAs. The effects of YZH on serum biomarkers (aminotransferase, alanine aminotransferase, and direct bilirubin), liver histology, and Mrp2 mRNA expressions were significantly greater and earlier than those of UDCA. Our results suggest that YZH has protective effect against ANIT-induced intrahepatic cholestasis in rats, through upregulation of Mrp2 and Bsep expressions.

Objectives The present study aims to identify the genotype-phenotype correlation in children with Peutz-Jeghers Syndrome (PJS) through the analysis of STK11 gene mutations in the context of clinical and pathological characteristics. Method In this observational cohort study, the clinical characteristics of 18 families diagnosed with pediatric PJS were collected. Genomic DNA from the peripheral blood of affected children and their family members was collected. The coding region of STK11 was amplified by PCR and screened for mutation by Sanger sequencing. The families that were negative for STK11 mutation were further assessed by multiplex ligation-dependent probe amplification (MLPA). Result Initial presentation in affected children was at 1.6 to 14.2 years and included anemia in 8 patients whereas 6 presented for screening by virtue of family history. All patients underwent endoscopy, colonoscopy, and polypectomy. Polyps were distributed throughout the gastrointestinal (GI) tract, including the small intestine, stomach, colon, and rectum.In the 18 pediatric PJS families, STK11 mutations were detected in 8 families by Sanger sequencing, and large deletions were detected in 3 by MLPA, respectively. Nine of the 11 STK11 mutations were de novo, 3 were novel (c.419T>C:p.L140P, c.314T>G:p.L105X), and (c.488_489insACGG p.L164fs). Conclusions Although the main clinical features of pediatric PJS were similar to those of PJS cases in adults, a high frequency of STK11 de novo mutations were encountered in our population of patients with PJS.

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn's disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD.

Background. Nontyphoidal Salmonella infection is a common cause for acute bacterial gastroenteritis in children in China. There have been no reports of the prevalence of lactose intolerance or food allergies in children with nontyphoidal Salmonella infection. The aim of this study was to characterize nontyphoidal Salmonella gastroenteritis in a tertiary children’s hospital and evaluate clinical presentation, lactose intolerance, and food allergies in children with prolonged nontyphoidal Salmonella gastroenteritis. Methods. A retrospective case-series analysis was carried out in a tertiary children’s hospital in Guangzhou, China. We included all infants and children who were diagnosed with nontyphoidal Salmonella gastroenteritis between 1 January 2014 and 31 December 2016. Patients’ clinical features, feeding patterns, laboratory tests, and treatment outcomes were reviewed. Results. A total of 142 infants and children were diagnosed with nontyphoidal Salmonella gastroenteritis. 52.1% of cases occurred in infants ≤ 12 months of age and the majority (89.4%) in children younger than 3 years old. The most common symptoms were diarrhea (100%), fever (62%), and vomiting (18.3%). Salmonella Typhimurium was the predominant serotype, accounting for 82.4%. 91.5% of patients were treated with antibiotics. Forty-one (28.9%) and 9 (6.3%) children improved with a lactose-free diet and hypoallergenic formula, respectively, when diarrhea persisted for more than a week. Conclusions. Salmonella Typhimurium was the predominant serotype. Most patients with nontyphoidal Salmonella gastroenteritis were younger than 3 years old. Lactose intolerance occurred frequently in children with nontyphoidal Salmonella gastroenteritis and dietary modification should be considered when diarrhea is persistent and prolonged.

Caustic esophageal stricture (CES) in children still occurs frequently in developing countries. We aimed to evaluate the long-term outcomes of endoscopic balloon dilatation (EBD) in treating CES in children and the influencing factors associated with outcome. We retrospectively reviewed the data of all patients who had a diagnosis of CES and underwent EBD from August 1, 2005, to December 31, 2014. The primary outcome was EBD success, which was defined as the maintenance of dysphagia-free status for at least 12 months after the last EBD. The secondary outcome was to analyze influencing factors associated with EBD success. Forty-three patients were included for analysis (29 males; mean age at first dilatation 44 months with range 121 months). 26 (60.5%) patients had long segment (>2 cm) stricture. A total of 168 EBD procedures were performed. Twenty-six (60.5%) patients were considered EBD success. Seventeen (39.5%) patients failed EBD and required stent placement and/or surgery. Patients in the EBD success group had significantly shorter stricture segments when compared to the EBD failure group (t=2.398, P=0.018, OR=3.206, 95% OR: 1.228–8.371). Seven (4.4%) esophageal perforations occurred in 6 patients after EBD. Stents were placed in 5 patients, and gastric tube esophagoplasty was performed in 14 patients. In conclusion, 26 (60.5%) of 43 children with CES had EBD success. Length of stricture was the main influencing factor associated with EBD treatment outcome.

Eosinophilic colitis is a well recognized clinical entity mainly associated with food allergies. Empiric treatment options include dietary allergen exclusion (extensively hydrolyzed protein formula and elimination diet), anti-allergy medications (antihistamines and leukotriene receptor antagonists) and corticosteroids. We evaluated the effectiveness of dietary antigen exclusion on clinical remission of eosinophilic colitis in infants and young children. We retrospectively reviewed charts of all infants and children ≤3 years of age who were diagnosed with eosinophilic colitis (defined as mucosal eosinophilia ≥20 hpf−1) from 1 January 2011 to 31 December 2013 at a tertiary children’s hospital in China. Forty-nine children were identified with eosinophilic colitis. Elemental formula, simple elimination diet or combination therapy resulted in clinical improvement in 75%, 88.2% and 80% of patients, respectively. In conclusion, eosinophilic colitis in infants and children ≤3 years of age responded well to dietary allergen exclusion.

Aim Astragalus membranaceus is a Chinese medicinal herb and has been shown to improve hapten-induced experimental colitis. One of its major components is polysaccharides. We investigated the effect of Astragalus polysaccharides (APS) on expression of TNF-α, IL-1β and NFATc4 in a rat model of experimental colitis. Methods The experimental colitis model was induced by TNBS. Forty five rats were divided into five groups ( n = 9): Normal control group, receiving ethanol vehicle with no TNBS during induction and IP saline injection during treatment; TNBS colitis model group (TNBS + IP saline), receiving only IP saline vehicle treatment; APS low dose group (TNBS + L-APS), receiving APS 100 mg/kg; APS high dose group (TNBS + H-APS), receiving APS 200 mg/kg; and positive control group (TNBS + Dexm), receiving dexamethasone 0.3 mg/kg. The clinical features, macroscopic and microscopic scores were assessed. The expressions of TNF-α, IL-1β and NFATc4 were measured by real-time PCR and ELISA assays. Results Compared to normal control rats, TNBS + IP saline had significant weight loss, increased macroscopic and microscopic scores, higher disease activity index (DAI) up-regulation of TNF-α, IL-1β and NFATc4 mRNA expression and up-regulation of TNF-α and IL-1β protein expression. Compared to TNBS + IP saline, treatment with APS or dexamethasone significantly reduced DAI, partially but significantly prevented TNBS colitis-induced weight loss and improved both macroscopic and microscopic scores; high dose APS or dexamethasone significantly down-regulated TNF-α and IL-1β expressions (both mRNA and protein) and up-regulated NFATc4 mRNA and protein expression. The effect of high dose APS and dexamethasone is comparable. Conclusions APS significantly improved experimental TNBS-induced colitis in rats through regulation of TNF-α, IL-1β and NFATc4 expression.

With increasing prevalence of childhood obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common cause of liver disease among children and adolescents in industrialized countries. It is generally recognized that both genetic and environmental risk factors contribute to the pathogenesis of NAFLD. Recently, there has been a growing body of evidence to implicate altered gut microbiota in the development of NAFLD through the gut-liver axis. The first line of prevention and treatment of NAFLD in children should be intensive lifestyle interventions such as changes in diet and physical activity. Recent advances have been focused on limitation of dietary fructose and supplementation of antioxidants, omega-3 fatty acids, and prebiotics/probiotics. Convincing evidences from both animal models and human studies have shown that reduction of dietary fructose and supplement of vitamin E, omega-3 fatty acids, and prebiotics/probiotics improve NAFLD.

Rotavirus diarrhea is a major worldwide cause of infantile gastroenteritis; however, the mechanism responsible for intestinal fluid loss remains unclear. Water transfer across the intestinal epithelial membrane seems to occur because of aquaporins (AQPs). Accumulating evidence indicates that alterations in AQPs may play an important role in pathogenesis. Here, we focus on changes in AQPs in a mouse model of rotavirus diarrhea. In the present study, 32 of 35 mice developed diarrhea and mild dehydration within 24 hours after infection with rotavirus strain SA11. Intestinal epithelial cells demonstrated cytoplasmic vacuolation, malaligned villi, and atrophy. AQP1 expression was significantly attenuated in the ileum and colon in comparison with controls; likewise, AQP4 and -8 protein expression were significantly decreased in the colon of rotavirus diarrhea-infected mice. In contrast, AQP3 protein expression was significantly increased in the colon of rotavirus-infected mice in comparison with controls. These results indicate that rotavirus diarrhea is associated with the downregulation of AQP1, -4, and -8 expression. Therefore, AQPs play an important role in rotavirus diarrhea.

Cow's milk is the most common cause of food-protein-induced enterocolitis syndrome (FPIES). The aim of this study was to examine the clinical features and treatment outcomes of infants with severe FPIES to cow's milk. We reviewed all infants ≤ 12 months of age who were hospitalized and diagnosed with severe FPIES to cow's milk between 1 January 2011 and 31 August 2014 in a tertiary Children's Medical Center in China. Patients' clinical features, feeding patterns, laboratory tests, and treatment outcomes were reviewed. A total of 12 infants met the inclusion criteria. All infants presented with diarrhea, edema, and hypoalbuminemia. Other main clinical manifestations included regurgitation/vomiting, skin rashes, low-grade fever, bloody and/or mucous stools, abdominal distention, and failure to thrive. They had clinical remission with resolution of diarrhea and significant increase of serum albumin after elimination of cow's milk protein (CMP) from the diet. The majority of infants developed tolerance to the CMP challenge test after 12 months of avoidance. In conclusion, we reported the clinical experience of 12 infants with severe FPIES to cow's milk, which resulted in malnutrition, hypoproteinemia, and failure to thrive. Prompt treatment with CMP-free formula is effective and leads to clinical remission of FPIES in infants.

Obesity is a serious health problem with strong genetic determination. Copy number variation (CNV) is a common type of genomic variant associated with some complex human diseases. However, it is not clear how CNVs contribute to the etiology of obesity. In this study, we examined 1,000 unrelated US whites to search for CNVs that may predispose to obesity. We focused our analyses on the Prader–Willi syndrome (PWS) critical region (chromosome 15q11–q13), because the PWS region is a hotspot for CNV generation and obesity is one of the major clinical manifestations for chromosome abnormalities at this region. We constructed a map containing 39 CNVs at the PWS critical region with CNV occurrence rates higher than 1%. Among them, three CNVs were significantly associated with body fat mass (P < 0.05), with a higher copy number (CN) associated with an increase of 5.08–9.77 kg in body fat mass. These three CNVs are close to two known PWS genes, NDN (necdin homolog) and C15orf2 (chromosome 15 open reading frame 2), and partially overlap with another obesity gene PWRN1 (Prader–Willi region nonprotein-coding RNA 1). Interestingly, our recently published whole genome association scan study using the same sample by examining single-nucleotide polymorphisms (SNPs) did not find any significant associations at these CNV regions, suggesting the importance of examining both CNVs and SNPs for better understanding of genetic basis of obesity. Further studies are warranted to validate these CNVs and their importance to obesity.

Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.

There are co-morbidity between osteoporosis (OP) and rheumatoid arthritis (RA). Some genetic risk factors have been identified for these two phenotypes respectively in previous research; however, they accounted for only a small portion of the underlying total genetic variances. Here, we sought to identify additional common genetic loci associated with OP and/or RA. The conditional false discovery rate (cFDR) approach allows detection of additional genetic factors (those respective ones as well as common pleiotropic ones) for the two associated phenotypes. We collected and analyzed summary statistics provided by large, multi-center GWAS studies of FNK (femoral neck) BMD (a major risk factor for osteoporosis) (n = 53,236) and RA (n = 80,799). The conditional quantile-quantile (Q-Q) plots can assess the enrichment of SNPs related to FNK BMD and RA, respectively. Furthermore, we identified shared loci between FNK BMD and RA using conjunction cFDR (ccFDR). We found strong enrichment of p-values in FNK BMD when conditional Q-Q was done on RA and vice versa. We identified 30 novel OP-RA associated pleiotropic loci that have not been reported in previous OP or RA GWAS, 18 of which located in the MHC (major histocompatibility complex) region previously reported to play an important role in immune system and bone health. We identified some specific novel polygenic factors for OP and RA respectively, and identified 30 novel OP-RA associated pleiotropic loci. These discovery findings may offer novel pathobiological insights, and suggest new targets and pathways for drug development in OP and RA patients.

Background: Refractory esophageal stricture (RES) may be attributed to food allergy. Its etiology and pathogenesis are not fully understood. Identification of novel genetic variants associated with this disease by exome sequencing (exome-seq) may provide new mechanistic insights and new therapeutic targets. Methods: To identify new and novel disease-associating variants, whole-exome sequencing was performed on an Illumina NGS platform in three children with RES as well as food allergy. Results: A total of 91,024 variants were identified. By filtering out ‘normal variants’ against those of the 1000 Genomes Project, we identified 12,741 remaining variants which are potentially associated with RES plus food allergy. Among these variants, there are 11,539 single nucleotide polymorphisms (SNPs), 627 deletions, 551 insertions and 24 mixture variants. These variants are located in 1370 genes. They are enriched in biological processes or pathways such as cell adhesion, digestion, receptor metabolic process, bile acid transport and the neurological system. By the PubMatrix analysis, 50 out of the top 100 genes, which contain most variants, have not been previously associated with any of the 17 allergy-associated diseases. These 50 genes represent newly identified allergy-associated genes. Those variants of 627 deletions and 551 insertions have also not been reported before in RES with food allergy. Conclusions: Exome-seq is potentially a powerful tool to identify potential new biomarkers for RES with food allergy. This study has identified a number of novel genetic variants, opening new avenues of research in RES plus food allergy. Additional validation in larger and different patient populations and further exploration of the underlying molecular mechanisms are warranted.

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt−/−) resulted in lethality at an early stage of mouse embryonic development and death within 5–10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of NamptF/F × Cre mice. These results substantiate that Nampt is an essential gene for life. In Nampt−/− mice versusNampt+/+ mice, biochemical assays indicated that liver and intestinal tissue NAD levels were decreased significantly; histological examination showed that mouse intestinal villi were atrophic and disrupted, and visceral fat was depleted; mass spectrometry detected unusual higher serum polyunsaturated fatty acid containing triglycerides. RNA-seq analyses of both mouse and human pediatric liver transcriptomes have convergently revealed that NAMPT is involved in key basic cellular functions such as transcription, translation, cell signaling, and fundamental metabolism. Notably, the expression of all eight enzymes in the tricarboxylic acid cycle were decreased significantly in the Nampt−/− mice. These findings prompt us to posit that adult Nampt−/− mouse lethality is a result of a short supply of ATP from compromised intestinal absorption of nutrients from digested food, which leads to the exhaustion of body fat stores.

Nonalcoholic fatty liver disease (NAFLD) is a major clinical consequence for people with obesity and metabolic syndrome and is also associated with enteral and parenteral nutrition. Early studies suggested that altered gut microbiota might contribute to obesity by affecting energy harvest from the diet and energy storage in the host. Recent evidence in humans as well as in animal models has linked gut microbiota to the development of NAFLD through the gut-liver axis. With bacterial overgrowth and increased intestinal permeability observed in patients with NAFLD and in animal models, gut-derived bacterial products such as endotoxin (lipopolysaccharide) and bacterial DNA are being delivered to the liver through the portal vein and then activate Toll-like receptors (TLRs), mainly TLR4 and TLR9, and their downstream cytokines and chemokines, leading to the development and progression of NAFLD. Given the limited data in humans, the role of gut microbiota in the pathogenesis of NAFLD is still open to discussion. Prebiotics and probiotics have been attempted to modify the microbiota as preventive or therapeutic strategies on this pathological condition. Their beneficial effects on NALFD have been demonstrated in animal models and limited human studies. However, prospective, appropriately powered, randomized, controlled clinical trials are needed to determine whether prebiotics and probiotics and other integrated strategies to modify intestinal microbiota are efficacious therapeutic modalities to treat NALFD.

The word sepsis was derived from the Greek word: sepsis, which means the state of putrefaction or decay. Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state, called a systemic inflammatory response syndrome, and the presence of a known or suspected infection. The more critical subsets of sepsis are severe sepsis with acute organ dysfunction, hypoperfusion, or hypotension and septic shock with refractory arterial hypotension despite adequate fluid resuscitation [1, 2]. Because the molecular pathogenesis of sepsis is incompletely understood and its specific and effective therapies are lacking, sepsis is still a major cause of death in intensive-care units worldwide, with mortality rates that range from 20% for sepsis, through 40% for severe sepsis, to over 60% for septic shock [3, 4]. More knowledge of the pathophysiology of sepsis is needed if we are to develop better, more effective interventions to sepsis. It has been increasingly recognized that genetic factors influence individual susceptibility, severity and outcome in sepsis [5, 6]. Identification of new genetic factors in sepsis may hold promise for new mechanistic insights and new therapeutic modalities.

Compressive strength index (CSI) of the femoral neck is a parameter that integrates the information of bone mineral density (BMD), femoral neck width (FNW), and body weight. CSI is considered to have the potential to improve the performance of assessment for hip fracture risk. However, studies on CSI have been rare. In particular, few studies have evaluated the performance of CSI, in comparison with BMD, FNW, and bending geometry, for assessment of hip fracture risk. We studied two large populations, including 1683 unrelated U.S. Caucasians and 2758 unrelated Chinese adults. For all the study subjects, CSI, femoral neck BMD (FN_BMD), FNW, and bending geometry (section modulus [Z]) of the samples were obtained from dual-energy X-ray absorptiometry scans. We investigated the age-related trends of these bone phenotypes and potential sex and ethnic differences. We further evaluated the performance of these four phenotypes for assessment of hip fracture risk by logistic regression models. Chinese had significantly lower FN_BMD, FNW, and Z, but higher CSI than sex-matched Caucasians. Logistic regression analysis showed that higher CSI was significantly associated with lower risk of hip fracture, and the significance remained after adjusting for covariates of age, sex, and height. Each standard deviation (SD) increment in CSI was associated with odds ratios of 0.765 (95% confidence interval, 0.634, 0.992) and 0.724 (95% confidence interval, 0.569, 0.921) for hip fracture risk in Caucasians and Chinese, respectively. The higher CSI in Chinese may partially help explain the lower incidence of hip fractures in this population compared to Caucasians. Further studies in larger cohorts and/or longitudinal observations are necessary to confirm our findings.

Background/Purpose Inflammation has been implicated in functional gastrointestinal disorders, including functional dyspepsia and irritable bowel syndrome. This study was undertaken to evaluate gallbladder wall inflammatory cells in children with abdominal pain related to gallstones and biliary dyskinesia to determine the candidate cell types that may be contributing to the pathophysiology of these entities. Methods Gallbladder specimens from 20 patients with cholelithiasis, 20 biliary patients with dyskinesia, and 12 autopsy controls were evaluated in a blinded fashion. Eosinophil, tryptase-positive, and CD3+ cell densities were determined for the lamina propria and muscularis mucosa layers and compared between groups. Results Patients with biliary dyskinesia and cholelithiasis had a 9- to 12-fold increase in mean and peak mast cell densities, respectively, in both layers as compared with controls. Peak (13.7 vs 8.4) and mean (9.2 vs 5.2) CD3+ cell densities were increased in the muscularis mucosae of cholelithiasis specimens as compared with biliary dyskinesia specimens. Conclusion Gallbladder wall inflammatory cell densities, particularly mast cells, differ between children with cholelithiasis, children with biliary dyskinesia, and controls. Future studies are warranted to define the roles for specific inflammatory cell types.

Background Congenital sucrase-isomaltase deficiency (CSID) is a rare genetic disorder. The prevalence of CSID in Chinese population is unknown and no single case has been reported. Methods Sucrose tolerance tests were performed in three children suspected of CSID. Glucose tolerance tests were performed to exclude glucose malabsorption. Blood glucose was measured at fasting and at 30 min, 60 min, 120 min, and 180 min of the study. Gastrointestinal symptoms were recorded up to 4 hours after the study. Results From December 2008 to June 2011, three children, ranging from 16 to 19 months old, were referred to our tertiary children’s hospital due to chronic watery diarrhea and failure to thrive. Laboratory investigations including complete blood counts, ESR, CRP, and serum immunoglobulins were normal. Routine stool culture for bacteria and exam for parasites were negative. Upper endoscopy, colonoscopy and histology were unremarkable. All children failed lactose-free and amino acid-based formulas. All three children had flat sucrose tolerance tests and began to have watery stool 2–4 hours after feeding sucrose test solution. The glucose tolerance tests were normal and no children developed watery stools up to 4 hours after feeding glucose test solution. Conclusions This is the first case series of CSID in Chinese children. The diagnosis of CSID can be made based on clinical suspicion and sucrose tolerance test. CSID is probably an under-diagnosed or misdiagnosed disease in Chinese children and should be considered in children with chronic watery diarrhea.

Introduction Duodenal duplication is a rare congenital malformation and has been reported as a rare cause of recurrent acute pancreatitis. Hemorrhagic ascites has been reported in only one case of duodenal duplication. Case presentation An 11-year-old Chinese girl presented with abdominal pain, hematemesis and dark stools. On admission, an abdominal examination revealed a moderately distended abdomen with diffuse tenderness. Biochemical investigations showed increased serum levels of amylase, lipase, and urine amylase. An abdominal computed tomography scan and magnetic resonance imaging scan revealed an enlarged and heterogeneous pancreas with poorly delineated borders. There was a cystic lesion measuring 25mm × 48mm × 28mm, located between the descending portion of her duodenum and the head of her pancreas. There were massive effusion signals in her abdominal cavity. An exploratory laparotomy was performed. A tubular cyst measuring 32mm × 52mm × 30mm was found in the second part of the duodenum, next to the head of her pancreas. The anterior wall of the duplication cyst was resected and anastomosis of the remaining cyst to the duodenum was performed for drainage. Histopathological examination of the excised cyst wall showed duodenal mucosa, submucosa and muscle coats, indicative of a duodenal duplication. Conclusions It is important to be aware of duodenal duplication when evaluating a patient with recurrent acute pancreatitis accompanied by massive hemorrhagic ascites.

Background The current study was undertaken to determine the degree of activation of gallbladder mucosal mast cells, whether mast cell (MC) density or activation differ between patients with and without a positive clinical response to cholecystectomy, and whether either density or activation correlate with gallbladder emptying. Results Fifteen biliary dyskinesia (BD) and 13 symptomatic cholelithiasis (CL) patients undergoing cholecystectomy were prospectively enrolled. Gallbladder wall MC density (by immunohistochemistry) and activation (by electron microscopy) were determined. Clinical response was evaluated 30 days post-cholecystectomy on a 5-point Likert-type scale. A complete or nearly complete clinical response was seen in 100% of CL and in 87% of BD patients. The overall degranulation indices were 49.4 ± 18.7% for CL patients and 44.2 ± 16.8% for BD patients. Neither MC density nor activation correlated with the gallbladder ejection fraction. A complete clinical response was associated with lower epithelial MC density. Conclusion Cholecystectomy is efficacious in relieving pain in both CL and BD patients. BD and CL are associated not only with increased MC density but a moderate to high degree of MC activation. A possible relationship between MC density and outcome for BD warrants further investigation.

Background Numerous diagnostic tests are available to detect Helicobactor pylori (H. pylori). There has been no single test available to detect H. pylori infection reliably. We evaluated the accuracy of a new fluorescence quantitative PCR (fqPCR) for H. pylori detection in children. Methods Gastric biopsy specimens from 138 children with gastritis were sent for routine histology exam, rapid urease test (RUT) and fqPCR. 13C-urea breath test (13C-UBT) was carried out prior to endoscopic procedure. Gastric fluids and dental plaques were also collected for fqPCR analysis. Results 38 children (27.5%) were considered positive for H. pylori infection by gold standard (concordant positive results on 2 or more tests). The remaining 100 children (72.5%) were considered negative for H. pylori. Gastric mucosa fqPCR not only detected all 38 H. pylori positive patients but also detected 8 (8%) of the 100 gold standard-negative children or 11 (10.7%) of the 103 routine histology-negative samples. Therefore, gastric mucosa fqPCR identified 46 children (33.3%) with H. pylori infection, significantly higher than gold standard or routine histology (P Conclusions Gastric mucosa fqPCR was more sensitive than routine histology, RUT, 13C-UBT alone or in combination to detect H. pylori infection in children with chronic gastritis. Either gastric fluid or dental plaque PCR is as reliable as 13C-UBT for H. pylori detection.