Babesiosis is an emerging health risk in several parts of the world. However, little is known about the prevalence of Babesia in malaria-endemic countries. The area along the China-Myanmar border in Yunnan is a main endemic area of malaria in P.R. China, however, human infection with Babesia microti (B. microti) is not recognized in this region, and its profile of co-infection is not yet clear.
To understand its profile of co-infections with B. microti, our investigation was undertaken in the malaria-endemic area along the China-Myanmar border in Yunnan between April 2012 and June 2013. Four parasite species, including B. microti, Plasmodium falciparum (P. falciparum), P. vivax, and P. malariae, were identified among 449 suspected febrile persons detected by nested polymerase chain reaction (PCR) assay based on small subunit ribosomal ribonucleic acid (RNA) genes of B. microti and Plasmodium spp.
Of all the collected samples from febrile patients, mono-infection with B. microti, P. vivax, P. falciparum, and P. malariae accounted for 1.8% (8/449), 9.8% (44/449), 2.9% (13/449), and 0.2% (1/449), respectively. The rate of mixed infections of B. microti with P. falciparum or P. vivax are both 0.2% (1/449), and mixed infections of P. falciparum and P. vivax accounted for 1.1% (5/449).
This report supports the hypothesis that babesiosis caused by B. microti is emerging along the China-Myanmar border in the Yunnan province, P.R. China, but it was ignored because of low parasitemia or mixed infection with Plasmodium spp. More sensitive and specific diagnosis methods are needed to find the rapid response mechanism of emergency for babesiosis and malaria co-prevalence areas.
Babesia; Plasmodium; Co-infection; China-Myanmar border
The integrin family of cell adhesion receptors mediates bi-directional signaling: “inside-out” signaling activates the ligand binding function of integrins and “outside-in” signaling mediates cellular responses induced by ligand binding to integrins leading to cell spreading, retraction, migration, and proliferation. Integrin signaling requires both heterotrimeric G proteins and monomeric small G proteins. This review focuses on recent development in the roles of G proteins in integrin outside-in signaling. The finding of direct interaction between the heterotrimeric G protein subunit Gα13 and integrin β subunits reveals a new mechanism for integrin signaling, and also uncovers a crosstalk between the signaling pathways initiated by G protein-coupled receptors (GPCRs) and integrins. This crosstalk, which may be referred to as “inside-outside-in” signaling, dynamically regulates contractility and greatly promotes integrin outside-in signaling
α-Oxy amides are prepared through enantioselective synthesis using a sequence beginning with a Henry addition of bromonitromethane to aldehydes, and finishing with Umpolung Amide Synthesis (UmAS). Key to high enantioselection is the finding that ortho-iodo benzoic acid salts of the chiral copper(II) bis(oxazoline) catalyst deliver both diastereomers of the Henry adduct with high enantiomeric excess, homochiral at the oxygen-bearing carbon. Overall, this approach to α-oxy amides provides an innovative complement to alternatives that focus almost entirely on the enantioselective synthesis of α-oxy carboxylic acids.
Mixed epithelial and stromal tumor of the kidney (MESTK) is the term given to a class of uncommon biphasic tumors of the kidney, with few reported cases. We describe eight cases of MESTK with detailed clinicopathological data and follow-up information. With this report, we hope to increase clinical awareness that MESTK should be considered as one of the possible diagnoses for cystic renal mass, especially in peri-menopausal women or those who receive hormone therapy. In addition, regular follow-up is necessary for the any cases with malignant potential.
Kidney; Mixed epithelial and stromal tumor
In non-climacteric fruits, the respiratory increase is absent and no phytohormone is appearing to be critical for their ripening process. They must remain on the parent plant to enable full ripening and be picked at or near the fully ripe stage to obtain the best eating quality. However, huge losses often occur for their quick post-harvest senescence. To understanding the complex mechanism of non-climacteric fruits post-harvest senescence, we constructed two small RNA libraries and one degradome from strawberry fruit stored at 20°C for 0 and 24 h. A total of 88 known and 1224 new candidatemiRNAs, and 103 targets cleaved by 19 known miRNAs families and 55 new candidatemiRNAs were obtained. These targets were associated with development, metabolism, defense response, signaling transduction and transcriptional regulation. Among them, 14 targets, including NAC transcription factor, Auxin response factors (ARF) and Myb transcription factors, cleaved by 6 known miRNA families and 6 predicted candidates, were found to be involved in regulating fruit senescence. The present study provided valuable information for understanding the quick senescence of strawberry fruit, and offered a foundation for studying the miRNA-mediated senescence of non-climacteric fruits.
The prophenoloxidase subunit A3 (proPOA3) gene was cloned from Culex pipiens pallens, which had an open reading frame of 2,061 bp encoding a putative 686 amino acid protein. The deduced amino acid sequence shares 98% with proPOA3 from Cx. quinquefasciatus. ProPOA3 is expressed at all developmental stages of Cx. pipiens pallens. Significant negative correlation was observed between proPOA3 expression and deltamethrin resistance in resistant Cx. pipiens pallens. Furthermore, proPOA3 expression levels were significantly lower in deltamethrin-resistant mosquitoes than in susceptible mosquitoes collected at four locations in Eastern China. However, we did not find any substantial change in proPOA3 expression in field-collected resistant Anopheles mosquitoes. Moreover, overexpressing proPOA3 in C6/36 cells led to more sensitivity to deltamethrin treatment. In laboratory and field-collected resistant Cx. pipiens pallens, a valine to isoleucine mutation (769G>A) and two synonymous mutations (1116G>C and 1116G>A) were identified in proPOA3. In addition, the mutation frequency of 769G>A and 1116G>C increased gradually, which corresponded with raised deltamethrin resistance levels. Taken together, our study provides the first evidence that proPOA3 may play a role in the regulation of deltamethrin-resistance in Cx. pipiens pallens.
Culex pipiens pallens; deltamethrin resistance; prophenoloxidase; mutation
Deltamethrin (DM) insecticides are currently being promoted worldwide for mosquito control, because of the high efficacy, low mammalian toxicity and less environmental impact. Widespread and improper use of insecticides induced resistance, which has become a major obstacle for the insect-borne disease management. Resistance development is a complex and dynamic process involving many genes. To better understand the possible molecular mechanisms involved in DM resistance, a proteomic approach was employed for screening of differentially expressed proteins in DM-susceptible and -resistant mosquito cells. Twenty-seven differentially expressed proteins were identified by two-dimensional electrophoresis (2-DE) and mass spectrometry (MS). Four members of the ubiquitin-proteasome system were significantly elevated in DM-resistant cells, suggesting that the ubiquitin-proteasome pathway may play an important role in DM resistance. Proteasome subunit beta type 6 (PSMB6) is a member of 20S proteasomal subunit family, which forms the proteolytic core of 26S proteasome. We used pharmaceutical inhibitor and molecular approaches to study the contributions of PSMB6 in DM resistance: the proteasome inhibitor MG-132 and bortezomib were used to suppress the proteasomal activity and siRNA was designed to block the function of PSMB6. The results revealed that both MG-132 and bortezomib increased the susceptibility in DM-resistant cells and resistance larvae. Moreover, PSMB6 knockdown decreased cellular viability under DM treatment. Taken together, our study indicated that PSMB6 is associated with DM resistance in mosquitoes and that proteasome inhibitors such as MG-132 or bortezomib are suitable for use as a DM synergist for vector control.
The expression level of CC-chemokine receptor 5 (CCR5) is enhanced post inflammatory stimulations and might play a crucial role on inflammatory cells infiltration post myocardial ischemia. The purpose of this study was to evaluate the role of CCR5 on myocardial ischemia–reperfusion (I/R) injury in rats. Adult male rats were randomized to sham group, I/R group (I/R, 30 min coronary artery occlusion followed by 2-h reperfusion), ischemic preconditioning (I/R + Pre), CCR5 antibody group [I/R + CCR5Ab (0.2 mg/kg)], and CCR5 agonist group [I/R + CCR5Ago, RNATES (0.1 mg/kg)], n = 12 each group. The serum level of creatine kinase (CK) and tumor necrosis factor α (TNF-α) were measured by ELISA. Myocardial infarction size and myeloperoxidase (MPO) activity were determined. Myocardial protein expression of CCR5 and intercellular adhesion molecule-1 (ICAM-1) were evaluated by Western blotting and immunohistochemistry staining, respectively. Myocardial nuclear factor-kappa B (NF-κB) activity was assayed by electrophoretic mobility shift assay. Myocardial CCR5 protein expression was significantly reduced in I/R + Pre group (P < 0.05 vs. I/R) and further reduced in I/R + CCR5Ab group (P < 0.05 vs. I/R + Pre). LVSP and ±dP/dtmax were significantly lower while serum CK and TNF-α as well as myocardial MPO activity, ICAM-1 expression, and NF-κB activity were significantly higher in I/R group than in sham group (all P < 0.05), which were significantly reversed by I/R + Pre (all P < 0.05 vs. I/R) and I/R + CCR5Ab (all P < 0.05 vs. I/R + Pre) while aggravated by I/R + CCR5Ago (all P < 0.05 vs. I/R). Our results suggest that blocking CCR5 attenuates while enhancing CCR5 aggravates myocardial I/R injury through modulating inflammatory responses in rat heart.
Ischemia–reperfusion injury; CC-chemokine receptor 5; Antibody; Agonist; Nuclear factor-kappa B
Polymorphisms in the nicotinic acetylcholine receptor subunit CHRNA5 gene have been associated with lung cancer positive susceptibility in European and American populations. In the present hospital-based, case-control study, we determined whether polymorphism in rs503464 of CHRNA5 is associated with lung cancer risk in Chinese individuals. A single nucleotide polymorphism in CHRNA5 rs503464, c.-166T>A (hereafter T>A), was identified using TaqMan-MGB probes with sequencing via PCR in 600 lung cancer cases and 600 healthy individuals. Genotype frequencies for rs503464 (T>A) were in Hardy-Weinberg equilibrium for the control population. However, genotype frequencies were significantly different between cases and controls (P < 0.05), while allele frequencies were not significantly different between groups. Compared to homozygous genotypes (TT or AA), the risk of lung cancer in those with the heterozygous genotype (TA) was significantly lower (OR = 0.611, 95%CI = 0.486-0.768, P = 0.001). Using genotype AA as a reference, the risk of lung cancer for those with genotype TA was increased 1.5 times (OR = 1.496, 95%CI = 1.120-1.997, P = 0.006). However, no difference in risk was observed between T allele carriers and A allele carriers (OR = 0.914, 95%CI = 0.779-1.073, P = 0.270). Stratification analysis showed that the protective effect of TA was more pronounced in those younger than 60 years, nonsmokers, or those without a family history of cancer, as well as in patients with adenocarcinoma or squamous cell carcinoma in clinical stages III or IV (P < 0.05). Therefore, the heterozygous genotype c.-166T>A at rs503464 of CHRNA5 may be associated with reduced risk of lung cancer, thus representing a susceptibility allele in Chinese individuals.
Lung cancer; Nicotinic acetylcholine receptors; CHRNA5 gene; Single nucleotide polymorphisms
We report an unusual case of retrovesical ectopic prostate tissue in a 73-year-old man with primary prostate cancer. The man’s prostate-specific antigen was 24.66 ng/ml.Transabdominal ultrasonography, pelvic computed tomography,and pelvic magnetic resonance imaging demonstrated a heterogeneous 8.5 × 8.0 × 7.0 cm mass in contact with the posterior wall of the urinary bladder. The patient underwent a retropubic radical prostatectomy and resection of tumor. Pathological examination of prostate revealed a prostatic adenocarcinoma, Gleason score of 4 + 5 = 9, and the retrovesical tumor was confirmed to be a benign prostate tissue.
Ectopic prostate; Retrovesical space; Prostate cancer
Continuous and excessive application of insecticides has resulted in the rapid development of insecticide resistance in several mosquito species, including Culex pipiens pallens. Previous studies in our laboratory found that arrestin gene expression was higher in the deltamethrin-resistant (DR) strain than in the deltamethrin-susceptible (DS) strain of Cx. pipiens pallens. Similarly, other studies reported that arrestin was highly expressed in permethrin-resistant Cx. quinquefasciatus and in dichlorodiphenyltrichloroethane (DDT)-resistant Drosophila melanogaster.
Full-length cDNAs of an arrestin gene were cloned from Cx. pipiens pallens via polymerase chain reaction (PCR) and rapid amplification of cDNA end (RACE). The mRNA levels of the arrestin gene in the whole life cycle of DR and DS strains of Cx. pipiens pallens were investigated via quantitative real-time PCR. In addition, the relationship between arrestin and deltamethrin (DM) resistance were identified using genetic overexpression strategies and arrestin RNAi in mosquito cells. Cell viability was analyzed with cholecystokinin octapeptide after DM treatment. Moreover, the mRNA levels of cytochrome P450 6A1 (CYP6A1) and opsin in the transfected cells and controls were analyzed.
Complete arrestin gene sequence was cloned and expressed throughout the life cycle of Cx. pipiens pallens. Moreover, arrestin was significantly upregulated in the DR strain, compared with that in the DS strain at the egg, pupae, and adult stages. Arrestin overexpression comparably increased the mosquito cell viability, whereas arrestin knockdown by siRNA decreased mosquito cell viability with deltamethrin (DM) treatment. Meanwhile, the mRNA levels of CYP6A1 and opsin were upregulated in mosquito cells transfected with arrestin and downregulated in mosquito cells with arrestin knockdown.
This study presented the first evidence that arrestin might be associated with insecticide resistance in Cx. pipiens pallens.
Insecticide resistance; Arrestin; Gene cloning; Transfection; SiRNA; Cell viability
The aim of the study was to review the clinical features and treatments of 10 (9 males and 1 female; age range, 61–73 years; median age, 67 years) upper urinary tract inverted papilloma (IP) cases between 1995 and 2010. The clinical syndromes, diagnostic procedures, treatments and results of the follow-up were evaluated. The results showed that the site of tumor development was the ureter in 6 cases and the renal pelvis in 4 cases. It was also identified that 7 tumors developed on the left side and 3 developed on the right side of the ureter and renal pelvis, respectively. A nephroureterectomy was performed in the first 6 cases, while a partial ureterectomy was performed in 3 cases and a local resection was performed endoscopically in 1 case. All but 2 tumors were solitary, ranging from 5 to 30 mm in diameter. Occurrence in association with transitional cell carcinoma was identified in one case. All 10 patients were subject to follow-up (range, 19–120 months; median, 59 months), during which no recurrence was found. Local excision is considered as adequate treatment when upper urinary tract IP is diagnosed according to strictly defined criteria.
upper urinary tract; inverted papilloma; prognosis; excision
Ileal pouch-anal anastomosis (IPAA) following total proctocolectomy has become the surgical treatment of choice for ulcerative colitis patients who have medically refractory disease or neoplasia. Unfortunately, various metabolic complications have been reported with this surgical procedure, including anemia, vitamin B12 deficiency, bile salt and fat malabsorption, vitamin D deficiency, bone loss, and nephrolithiasis. Recognition and early diagnosis of these complications are important when managing IPAA patients.
Inflammatory bowel disease; ileal pouch—anal anastomosis; metabolic consequences; anemia; vitamin B12 deficiency; vitamin D deficiency
The perioperative management of patients with inflammatory bowel disease is challenging given the altered immune system that results from a variety of biologic and immunomodulator therapies. Clinicians are often faced with challenges and complicated equations when deciding on the type and dose of medication. To understand the effect of these medications and review the evidence regarding the management of these medications in the perioperative setting, a PubMed-based literature search (January 1, 1960, through April 1, 2011) was conducted using the following search terms: perioperative management, risk, outcome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, aminosalicylates, glucocorticoids, purine analogues, cyclosporine, methotrexate, biologic therapy, infliximab, and thromboembolism. The 414 articles identified were manually sorted to exclude those that did not address perioperative risk, outcomes, and medications in the abstracts, yielding 84 articles for review. Additional references were obtained from the citations within the retrieved articles. This review surveys the findings of the selected articles and presents guidelines and resources for perioperative medication management for patients with inflammatory bowel disease undergoing surgery.
Ulcerative colitis (UC) is a chronic inflammatory disease characterized by diffuse mucosal inflammation limited to the colon and rectum. Although a complete medical cure may not be possible, UC can be treated with medications that induce and maintain remission. The medical management of this disease continues to evolve with a goal to avoid colectomy and ultimately alter the natural history of UC. Emergence of antitumor necrosis factor-α (TNF-α) agents has expanded the medical armamentarium. 5-Aminosalicylates continue to be used in mild to moderate UC and corticosteroids are mainly used for induction of remission with immunomodulators (6-mercaptopurine/azathiopurine/methotrexate) being applied as steroid-sparing agents for maintenance therapy. Infliximab has been approved by the U.S. Food and Drug Administration and used in the treatment of moderate to severe UC; nevertheless, its use may be associated with significant adverse effects and have a negative impact on the postoperative course should the patients undergo restorative proctocolectomy. In addition, there is always a concern about patients' compliance to medical therapy, cost of medications, and risk for UC-associated dysplasia. The authors discuss the pros and cons of medications used in the treatment of UC.
Inflammatory bowel disease; ulcerative colitis; medical treatment; risks and benefits
Although restorative proctocolectomy with ileal pouch-anal anastomosis (IPAA) has become the surgical treatment of choice for patients with refractory ulcerative colitis (UC) or UC with dysplasia, surgical, inflammatory, and noninflammatory adverse sequelae are common. Pouchitis, representing a spectrum of disease phenotypes, is the most common long-term complication of IPAA. De novo Crohn disease (CD) of the pouch can occur in patients with a preoperative diagnosis of UC. Differential diagnosis between fibrostenotic or fistulizing CD and surgery-associated strictures, sinuses, and fistulas often requires a combined assessment of symptom, endoscopy, histology, radiography, and examination under anesthesia. There is a role for endoscopic therapy for stricturing complications of IPAA. Chronic antibiotic-refractory pouchitis, refractory cuffitis, as well as fibrostenotic or fistulizing CD of the pouch are the leading late-onset causes for pouch failure.
Complication; ileal pouch; inflammatory bowel disease; restorative proctocolectomy
Autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high titers of autoantibodies or antigen-specific T cells, and derive from genetic variants of the innate immune system. This study characterized a cohort of patients with similar phenotypes and nucleotide oligomerization domain 2 (NOD2) gene mutations.
Diagnostically challenging patients with the following clinical and genetic characteristics were prospectively studied between January 2009 and April 2011: periodic fever, dermatitis, polyarthritis, serositis, negative serum autoantibodies and additional positive NOD2 IVS8+158 gene mutation. Genetic testing for gene mutations of NOD2, tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS) and familial Mediterranean fever (FMF) was performed.
All seven patients with the disease were Caucasians, with four being male. The mean age at disease onset was 40.7 years and disease duration was 3.2 years. These patients characteristically presented with periodic fever, dermatitis and inflammatory polyarthritis. There were gastrointestinal symptoms in three patients, granulomas of the skin and gut in two, and recurrent chest pain in two, with one having pleuritis and pericarditis. Three patients had sicca-like symptoms. Five patients had increased acute phase reactants. All seven patients had negative tests for autoantibodies but carried the NOD2 gene mutation IVS8+158 with four having concurrent R702W mutation.
Our cohort may represent a new disease category of autoinflammatory disease with characteristic clinical phenotypes and genotypes. It may somewhat resemble pediatric Blau's syndrome.
Kallistatin is a plasma protein with anti-inflammatory properties. In this study, we investigated the role and mechanisms of kallistatin in inhibiting endothelial inflammation through its heparin-binding domain. We showed that recombinant wild-type kallistatin dose-dependently competed with tumor necrosis factor (TNF)-α binding to TNF-α receptor in endothelial cells, whereas kallistatin mutant at the heparin-binding domain had no effect. Kallistatin, but not kallistatin mutant at the heparin-binding domain, abrogated TNF-α-induced endothelial cell activation as evidenced by inhibition of TNF-α receptor/TRADD activation, IκB-α degradation, nuclear factor-κB translocation and p38MAPK phosphorylation, as well as cell adhesion molecule and cytokine expression. Moreover, kallistatin, but not kallistatin mutant at the heparin-binding domain, inhibited TNF-α-induced THP-1 monocyte adhesion to endothelial cells, and prevented vascular endothelial growth factor-induced endothelial permeability. In mice, kallistatin gene delivery prevented vascular leakage provoked by complement factor C5a, whereas delivery of kallistatin heparin mutant gene had no effect. Similarly, gene transfer of kallistatin, but not the kallistatin heparin mutant, inhibited collagen/adjuvant-induced arthritis in rats. These results indicate that kallistatin's heparin–binding site plays an essential role in preventing TNF-α–mediated endothelial activation and reducing vascular endothelial growth factor-induced vascular permeability, resulting in attenuation of vascular inflammation in cultured endothelial cells and animal models. This study identifies a protective role of kallistatin in vascular injury, thereby implicating therapeutic potential of kallistatin for vascular and inflammatory diseases.
kallistatin; tumor necrosis factor-α; vascular endothelial growth factor; nuclear factor κB; inflammation; vascular permeability
Our earlier study demonstrated the induction of PKC isoforms (beta II, PKC-alpha/beta, PKC-theta) by ionizing radiation induced bystander response in human cells. In this study, we extended our investigation to yet another important member of PKC family, PKC epsilon (PKCε). PKCε functions both as an anti-apoptotic and pro-apoptotic protein and it is the only PKC isozyme implicated in oncogenesis. Given the importance of PKCε in oncogenesis, we wished to determine whether or not PKCε is involved in bystander response. Gene expression array analysis demonstrated a 2-3 fold increase in PKCε expression in the bystander human primary fibroblast cells that were co-cultured in double sided Mylar dishes for 3 h with human primary fibroblast cells irradiated with 5 Gy of α-particles. The elevated PKCε expression in bystander cells was verified by quantitative real time PCR. Suppression of PKCε expression by small molecule inhibitor Bisindolylmaleimide IX (Ro 31-8220) considerably reduced the frequency of micronuclei (MN) induced both by 5 Gy of γ-rays (low LET) and α-particles (high LET) in bystander cells. Similar cytoprotective effects were observed in bystander cells after siRNA mediated silencing of PKCε suggestive of its critical role in mediating some of the bystander effects (BE). Our novel study suggests the possibility that PKC signaling pathway may be a critical molecular target for suppression of ionizing radiation induced biological effects in bystander cells.
bystander effects; protein kinase Cε; ionizing radiation; signal transduction pathway
The amide functional group is one of Nature’s key functional and structural elements, most notably within peptides. Amides are also key intermediates in the preparation of a diverse range of therapeutic small molecules. Its construction using available methods focuses principally upon dehydrative approaches, although oxidative and radical-based methods are representative alternatives. During the carbon-nitrogen bond forming step in most every example, the carbon and nitrogen bear electrophilic and nucleophilic character, respectively. Here we show that activation of amines and nitroalkanes with an electrophilic iodine source in wet THF can lead directly to amide products. Preliminary observations support a mechanistic construct in which reactant polarity is reversed (umpolung) during C-N bond formation relative to traditional approaches. The use of nitroalkanes as acyl anion equivalents provides a conceptually innovative approach to amide and peptide synthesis, and one that might ultimately provide for efficient peptide synthesis that is fully reliant on enantioselective methods.
Clostridium difficile (C. difficile) infection (CDI) is the leading identifiable cause of antibiotic-associated diarrhea. While there is an alarming trend of increasing incidence and severity of CDI in the United States and Europe, superimposed CDI in patients with inflammatory bowel disease (IBD) has drawn considerable attention in the gastrointestinal community. The majority of IBD patients appear to contract CDI as outpatients. C. difficile affects disease course of IBD in several ways, including triggering disease flares, sustaining activity, and in some cases, acting as an “innocent” bystander. Despite its wide spectrum of presentations, CDI has been reported to be associated with a longer duration of hospitalization and a higher mortality in IBD patients. IBD patients with restorative proctocolectomy or with diverting ileostomy are not immune to CDI of the small bowel or ileal pouch. Whether immunomodulator or corticosteroid therapy for IBD should be continued in patients with superimposed CDI is controversial. It appears that more adverse outcomes was observed among patients treated by a combination of immunomodulators and antibiotics than those treated by antibiotics alone. The use of biologic agents does not appear to increase the risk of acquisition of CDI. For CDI in the setting of underlying IBD, vancomycin appears to be more efficacious than metronidazole. Randomized controlled trials are required to clearly define the appropriate management for CDI in patients with IBD.
Clostridium difficile; Inflammatory bowel disease; Antibiotics; Colectomy
Crohn’s disease (CD) of the pouch can occur in patients with restorative proctocolectomy and ileal pouch-anal anastomosis originally performed for a pre-operative diagnosis of ulcerative colitis (UC). CD of the pouch was often observed in patients with a family history of CD.
To determine whether the family history of CD increased the risk for CD of the pouch in patients who underwent restorative proctocolectomy.
A total of 558 eligible patients seen in the Pouchitis Clinic were enrolled, including 116 patients with CD of the pouch and 442 patients with a normal pouch or other pouch disorders. Demographic and clinical variables were included in the study. Multivariable logistic regression analyses were performed.
The adjusted multivariable logistic analyses revealed that the risk for CD of the pouch was increased in patients with a family history of CD with odds ratio (OR) of 3.22 (95%CI 1.56–6.67), or with a first-degree relative with CD (OR=4.18, 95%CI 1.48–11.8), or with a greater number of family members with CD (OR=2.00 per family member, 95% CI 1.19–3.37), adjusting for age, gender, smoking status, duration of IBD, duration of having a pouch, and a pre-op diagnosis of indeterminate colitis or CD. In addition, patients with a younger age and longer duration of having a pouch had a higher risk for CD of the pouch. A diagnosis of CD of the pouch was associated with a poor outcome with a greater than 5-fold estimated increased odds of pouch failure (OR=5.58 and 95% CI, 2.74 – 11.4).
The presence of a family history of CD is associated with an increased risk for CD of the pouch, which in turn has a high risk for pouch failure.
Crohn’s disease; Inflammatory Bowel Disease; Family History; Ileal Pouch; Pouchitis; Restorative Proctocolectomy; Ulcerative Colitis
Integrins mediate cell adhesion to the extracellular matrix and transmit signals within the cell that stimulate cell spreading, retraction, migration, and proliferation. The mechanism of integrin outside-in signaling has been unclear. We found that the heterotrimeric guanine nucleotide-binding protein (G protein), Gα13, directly bound to the integrin β3 cytoplasmic domain, and that Gα13-integrin interaction was promoted by ligand binding to the integrin αIIbβ3 and by guanosine triphosphate (GTP)-loading of Gα13. Interference of Gα13 expression or a myristoylated fragment of Gα13 that inhibited interaction of αIIbβ3 with Gα13 diminished activation of protein kinase c-Src and stimulated the small GTPase RhoA, consequently inhibiting cell spreading and accelerating cell retraction. We conclude that integrins are non-canonical Gα13-coupled receptors that provide a mechanism for dynamic regulation of RhoA.
We investigated the role of the Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of tissue kallikrein on myocardial injury by promoting angiogenesis and blood flow in rats after myocardial infarction (MI).
Methods and results
Human tissue kallikrein gene in an adenoviral vector, with or without co-administration of dominant-negative Akt (Ad.DN-Akt) or constitutively active GSK-3β (Ad.GSK-3βS9A), was injected into rat myocardium after MI. The expression of recombinant human kallikrein in rat heart significantly improved cardiac function and reduced infarct size 10 days after gene delivery. Kallikrein administration significantly increased myocardial blood flow as well as capillary and arteriole densities in the infarcted myocardium. Kallikrein increased cardiac Akt and GSK-3β phosphorylation in conjunction with decreased GSK-3β activity and the upregulation of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2). All of kallikrein’s effects on the myocardium were abrogated by Ad.DN-Akt and Ad.GSK-3βS9A. Moreover, in cultured human aortic endothelial cells, tissue kallikrein stimulated capillary tube formation and promoted cell migration; however, these effects were blocked by Ad.DN-Akt, Ad.GSK-3βS9A, icatibant (a kinin B2 receptor antagonist), Tki (a VEGF receptor tyrosine kinase inhibitor), and a neutralizing VEGF antibody. In addition, tissue kallikrein decreased GSK-3β activity via the phosphatidylinositol 3-kinase-Akt pathway and enhanced VEGF and VEGFR-2 expression in endothelial cells.
These data provide the first direct evidence that tissue kallikrein protects against acute-phase MI by promoting neovascularization, restoring regional blood flow and improving cardiac function through the kinin B2 receptor-Akt-GSK-3β and VEGF signalling pathways.
Tissue kallikrein; Angiogenesis; Myocardial infarction; GSK-3β; VEGF
Mesenchymal stem cells (MSCs) migrate to sites of tissue injury and serve as an ideal vehicle for cellular gene transfer. As tissue kallikrein has pleiotropic effects in protection against oxidative organ damage, we investigated the potential of kallikrein-modified MSCs (TK-MSCs) in healing injured kidney after acute ischemia/reperfusion (I/R). TK-MSCs secreted recombinant human kallikrein with elevated vascular endothelial growth factor levels in culture medium, and were more resistant to oxidative stress-induced apoptosis than control MSCs. Expression of human kallikrein was identified in rat glomeruli after I/R injury and systemic TK-MSC injection. Engrafted TK-MSCs exhibited advanced protection against renal injury by reducing blood urea nitrogen, serum creatinine levels and tubular injury. At 6 hours after I/R, TK-MSC implantation significantly reduced renal cell apoptosis in association with decreased inducible nitric oxide synthase expression and nitric oxide levels. At 48 hours after I/R, TK-MSCs inhibited interstitial neutrophil and monocyte/macrophage infiltration and decreased myeloperoxidase activity, superoxide formation, p38 mitogen-activated protein kinase phosphorylation, and expression of tumor necrosis factor-α, monocyte chemoattractant protein-1 and intercellular adhesion molecule-1. Additionally, tissue kallikrein and kinin significantly inhibited H2O2-induced apoptosis and increased Akt phosphorylation and cell viability in cultured proximal tubular cells. These results indicate that implantation of kallikrein-modified MSCs in the kidney provides advanced benefits in protection against ischemia-induced kidney injury by suppression of apoptosis and inflammation.