Clinically significant findings in patients with focal incidental colorectal abnormalities on positron emission tomography-CT scans.

INTRODUCTION: The aim of this study was to determine the clinical significance of focal incidentally detected colorectal abnormalities on 18 F- Fluoro-2-Deoxy-D-Glucose (FDG) PET-CT scans. METHODS: Retrospective audit of PET-CT scans performed at our institution between 2009 and 2014. Demographic and clinical details were retrieved from electronic patient records. An advanced adenoma was defined as: ≥1 cm in size, tubullo-villous histology, or displaying high grade dysplasia. A high-risk lesion (HRL) was defined as an advanced adenoma or colorectal cancer (CRC). RESULTS: Of the 1911 PET-CT eligible scans, focal incidental colorectal FDG uptake was detected in 99 (5.2%) patients. Colonoscopy was undertaken in 43 (43.4%) patients and 45 FDG-avid sites were evaluated. The commonest site of abnormal FDG uptake was the rectosigmoid region, with 34 (75.6%) of the 45 foci being located in this area. Overall, 23 (53.5%) of these patients had clinically significant pathology. Of the 45 focal PET-CT abnormalities evaluated, 17 (37.8%) were adenomas, of which 11 (24.4%) were advanced adenomas, and six (13.3%) were cancers, with a total of 17 (37.8%) HRLs. Five of the six patients with CRC underwent surgical resection, whilst one had endoscopic resection. The overall survival for the entire cohort was 18 months (range 1-72 months) with those that underwent colonoscopy having higher overall survival compared to those that did not (38 vs. 13.5 months). CONCLUSION: Incidental colorectal abnormalities on PET-CT scans are often clinically significant. However, careful selection for colonoscopy is important due to the poor survival in these patients related to the underlying primary malignancy.

Indian consensus on gastroesophageal reflux disease in adults: A position statement of the Indian Society of Gastroenterology.

The Indian Society of Gastroenterology developed this evidence-based practice guideline for management of gastroesophageal reflux disease (GERD) in adults. A modified Delphi process was used to develop this consensus containing 58 statements, which were generated by electronic voting iteration as well as face-to-face meeting and review of the supporting literature primarily from India. These statements include 10 on epidemiology, 8 on clinical presentation, 10 on investigations, 23 on treatment (including medical, endoscopic, and surgical modalities), and 7 on complications of GERD. When the proportion of those who voted either to accept completely or with minor reservation was 80% or higher, the statement was regarded as accepted. The prevalence of GERD in India ranges from 7.6% to 30%, being < 10% in most population studies, and higher in cohort studies. The dietary factors associated with GERD include use of spices and non-vegetarian food. Helicobacter pylori is thought to have a negative relation with GERD; H. pylori negative patients have higher grade of symptoms of GERD and esophagitis. Less than 10% of GERD patients in India have erosive esophagitis. In patients with occasional or mild symptoms, antacids and histamine H2 receptor blockers (H2RAs) may be used, and proton pump inhibitors (PPI) should be used in patients with frequent or severe symptoms. Prokinetics have limited proven role in management of GERD.

Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis.

Many eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains that are receptors for inositol pyrophosphates (PP-InsP), suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that deletion of two diphosphoinositol pentakisphosphate kinases VIH1/2 impairs plant growth and leads to constitutive Pi starvation responses. Deletion of phosphate starvation response transcription factors partially rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases in plant Pi signal transduction cascades. VIH1/2 are bifunctional enzymes able to generate and break-down PP-InsPs. Mutations in the kinase active site lead to increased Pi levels and constitutive Pi starvation responses. ATP levels change significantly in different Pi growth conditions. ATP-Mg2+ concentrations shift the relative kinase and phosphatase activities of diphosphoinositol pentakisphosphate kinases in vitro. Pi inhibits the phosphatase activity of the enzyme. Thus, VIH1 and VIH2 relay changes in cellular ATP and Pi concentrations to changes in PP-InsP levels, allowing plants to maintain sufficient Pi levels.

Inositol polyphosphates promote T cell-independent humoral immunity via the regulation of Bruton's tyrosine kinase.

T cell-independent (TI) B cell response is critical for the early protection against pathogen invasion. The regulation and activation of Bruton's tyrosine kinase (Btk) is known as a pivotal step of B cell antigen receptor (BCR) signaling in TI humoral immunity, as observed in patients with X-linked agammaglobulinemia (XLA) experiencing a high incidence of encapsulated bacterial infections. However, key questions remain as to whether a well-established canonical BCR signaling pathway is sufficient to regulate the activity of Btk. Here, we find that inositol hexakisphosphate (InsP6) acts as a physiological regulator of Btk in BCR signaling. Absence of higher order inositol phosphates (InsPs), inositol polyphosphates, leads to an inability to mount immune response against TI antigens. Interestingly, the significance of InsP6-mediated Btk regulation is more prominent in IgM+ plasma cells. Hence, the present study identifies higher order InsPs as principal components of B cell activation upon TI antigen stimulation and presents a mechanism for InsP-mediated regulation of the BCR signaling.

5-Diphosphoinositol pentakisphosphate (5-IP7) regulates phosphate release from acidocalcisomes and yeast vacuoles.

Acidocalcisomes of Trypanosoma brucei and the acidocalcisome-like vacuoles of Saccharomyces cerevisiae are acidic calcium compartments that store polyphosphate (polyP). Both organelles possess a phosphate-sodium symporter (TbPho91 and Pho91p in T. brucei and yeast, respectively), but the roles of these transporters in growth and orthophosphate (Pi) transport are unclear. We found here that Tbpho91-/- trypanosomes have a lower growth rate under phosphate starvation and contain larger acidocalcisomes that have increased Pi content. Heterologous expression of TbPHO91 in Xenopus oocytes followed by two-electrode voltage clamp recordings disclosed that myo-inositol polyphosphates stimulate both sodium-dependent depolarization of the oocyte membrane potential and Pi conductance. Deletion of the SPX domain in TbPho91 abolished this stimulation. Inositol pyrophosphates such as 5-diphosphoinositol pentakisphosphate generated outward currents in Na+/Pi-loaded giant vacuoles prepared from WT or from TbPHO91-expressing pho91Δ strains but not from the pho91Δ yeast strains or from the pho91Δ strains expressing PHO91 or TbPHO91 with mutated SPX domains. Our results indicate that TbPho91 and Pho91p are responsible for vacuolar Pi and Na+ efflux and that myo-inositol polyphosphates stimulate the Na+/Pi symporter activities through their SPX domains.

Exploring current status of Helicobacter pylori infection in different age groups of patients with dyspepsia.

Recent data from Asian countries including India has shown a significant decline in the frequency of peptic ulcer disease (PUD) compared to the past. H. pylori is considered the most important risk factor for PUD, and we aimed to explore the current frequency of H. pylori infection in different age groups of patients with dyspepsia. Patients >15 years of age with dyspeptic symptoms were prospectively recruited in this study from 2010 to 2014 after obtaining informed consent. Patients were divided into three age groups: 15-30 years, 31-50 years, and >50 years, and the minimum sample size required in the three groups with a power of 90% was 259, 256, and 188, respectively. All patients underwent upper gastrointestinal endoscopy; rapid urease test was done on gastric mucosal biopsy to detect H. pylori. The clinical, demographic features and socioeconomic status were recorded. The institute review board approved the study. We included 1000 patients with dyspepsia during the study period. Their mean age was 40.0+13.3 years, and 69.3% were males. Infection with H. pylori was detected in 419 (41.9%) patients. Among men, H. pylori was present in 45.7% while the frequency of infection in women was lower at 33.2% (p < 0.001). In the 15-30 years age group (n = 303), the frequency of infection was 42.6% while it was 48.3% in the 31-50 years group (n = 350) and 34.9% in the above 50 years group (n = 347). Male sex was a significant risk factor for H. pylori infection (p < 0.001). H. pylori infection, an important risk factor for PUD, was detected in less than half of the dyspeptic patients in the current study.

Chemokine CXCL1 mediated neutrophil recruitment: Role of glycosaminoglycan interactions.

The chemokine CXCL1/MGSA plays a pivotal role in the host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. CXCL1 exists reversibly as monomers and dimers, and mediates its function by binding glycosaminoglycans (GAG) and CXCR2 receptor. We recently showed that both monomers and dimers are potent CXCR2 agonists, the dimer is the high-affinity GAG ligand, lysine and arginine residues located in two non-overlapping domains mediate GAG interactions, and there is extensive overlap between GAG and receptor-binding domains. To understand how these structural properties influence in vivo function, we characterized peritoneal neutrophil recruitment of a trapped monomer and trapped dimer and a panel of WT lysine/arginine to alanine mutants. Monomers and dimers were active, but WT was more active indicating synergistic interactions promote recruitment. Mutants from both domains showed reduced GAG heparin binding affinities and reduced neutrophil recruitment, providing compelling evidence that both GAG-binding domains mediate in vivo trafficking. Further, mutant of a residue that is involved in both GAG binding and receptor signaling showed the highest reduction in recruitment. We conclude that GAG interactions and receptor activity of CXCL1 monomers and dimers are fine-tuned to regulate neutrophil trafficking for successful resolution of tissue injury.

Head mass in chronic pancreatitis: Inflammatory or malignant.

Chronic pancreatitis increases the risk of developing pancreatic cancer. This often presents as a mass lesion in the head of pancreas. Mass lesion in the head of pancreas can also occur secondary to an inflammatory lesion. Recognising this is crucial to avoid unnecessary surgery. This is sometimes difficult as there is an overlap in clinical presentation and conventional computed tomography (CT) abdomen findings in inflammatory and malignant mass. Advances in imaging technologies like endoscopic ultrasound in conjunction with techniques like fine needle aspiration, contrast enhancement and elastography as well as multidetector row CT, magnetic resonance imaging and positron emission tomography scanning have been shown to help in distinguishing inflammatory and malignant mass. Research is ongoing to develop molecular techniques to help characterise focal pancreatic mass lesions. This paper reviews the current status of imaging and molecular techniques in differentiating a benign mass lesion in chronic pancreatitis and from malignancy.

Colonic mucosa-associated lymphoid tissue lymphoma.

Colonic mucosa-associated lymphoid tissue (MALT) lymphomas are rare and a definitive treatment has not been established. Solitary or multiple, elevated or polypoid lesions are the usual appearances of MALT lymphoma in the colon and sometimes the surface may reveal abnormal vascularity. In this paper we report our experience with four cases of colonic MALT lymphoma and review the relevant literature. The first patient had a smooth elevated lesion in the rectum and histopathologic examination of the biopsy from the lesion showed centrocyte-like cells infiltrating the lamina propria. Endoscopic ultrasonography (EUS) revealed thickening of the submucosa and muscularis propria. The patient underwent radiation therapy, and 9 months later a repeat colonoscopy showed complete resolution of the lesion. In case 2, colonoscopy showed a polyp in the cecum; the biopsy was diagnostic of MALT lymphoma. EUS detected a hypoechoic lesion confined to the mucosal layer of the colonic wall. The patient underwent endoscopic mucosal resection of the lesion and after 6 years of follow-up there was no evidence of recurrence. The third patient had a sessile elevated lesion in the sigmoid colon for which she underwent sigmoidectomy. Pathological examination of the surgical specimen was suggestive of MALT lymphoma. The last patient had a smooth elevated lesion in the rectum and magnification endoscopy showed irregular vascular pattern. The patient underwent endoscopic submucosal dissection, and biopsy examination showed the tumor to be MALT lymphoma. Although rare, awareness of MALT lymphoma of the colon is important to evaluate the patient appropriately and to plan further management.

Unusual Manifestation of Gastric Helicobacter pylori Infection.

Infection with Helicobacter pylori (HP) is common in many parts of the world. While most patients are asymptomatic, it causes peptic ulcer disease and malignancy in some of them. Other rare conditions have occasionally been reported in association with this infection. We report a case of hypertrophic gastropathy caused by HP in a 52-year-old asymptomatic patient. He was found to have marked enlargement of the gastric mucosal folds on radiological imaging and endoscopy. A gastric mucosal biopsy showed HP colonization associated with neutrophilic inflammation. After exclusion of neoplasia, other infections and infiltrative disorders, HP was thought to be the cause of the gastric fold hypertrophy. The patient responded well to HP eradication therapy, with normalization of the gastric mucosal folds. HP infection should be considered in the differential diagnosis of hypertrophic gastropathy and treated accordingly.

Divergent roles of SPINK1 and PRSS2 variants in tropical calcific pancreatitis.

BACKGROUND/AIMS: Tropical calcific pancreatitis (TCP) refers to a type of idiopathic pancreatitis prevalent in Asia. The trypsin inhibitor (SPINK1) N34S variant partially explains the genetic susceptibility to TCP. As anionic trypsinogen (PRSS2) G191R protects against chronic pancreatitis in Europeans, we investigated whether this variant protects from TCP in Indians. METHODS: We enrolled 174 patients and 794 controls from two Indian tertiary care referral hospitals. We analyzed PRSS2 and SPINK1 variants by melting curve analysis, allele-specific discrimination assay, and sequencing. RESULTS: G191R was detected in 1 TCP patient (0.6%) compared to 13 controls (1.6%; OR 0.27, 95% CI 0.03-2.1; p = 0.33). SPINK1 N34S was enriched in the TCP population 67/174 (38.5%) compared to controls 10/234 (4.3%; OR 14, 95% CI 6.9-28.3; p < 0.001). CONCLUSION: G191R PRSS2 is a rare allele in the Indian population and the data suggest a nonsignificant trend towards a protective effect. N34S SPINK1 represents the major genetic risk factor in TCP.

Viscoelastic properties of adsorbed and cross-linked polypeptide and protein layers at a solid-liquid interface.

The real-time changes in viscoelasticity of adsorbed poly(L-lysine) (PLL) and adsorbed histone (lysine rich fraction) due to cross-linking by glutaraldehyde and corresponding release of associated water were investigated using a quartz crystal microbalance with dissipation monitoring (QCM-D) and attenuated total reflection Fourier transform infrared spectroscopy (ATR/FTIR). The kinetics of PLL and histone adsorption were measured through changes in mass adsorbed onto a gold-coated quartz surface from changes in frequency and dissipation and using the Voigt viscoelastic model. Prior to cross-linking, the shear viscosity and shear modulus of the adsorbed PLL layer were approximately 3.0 x 10(-3) Pas and approximately 2.5 x 10(5) Pa, respectively, while after cross-linking, they increased to approximately 17.5 x 10(-3) Pas and approximately 2.5 x 10(6) Pa, respectively. For the adsorbed histone layer, shear viscosity and shear modulus increased modestly from approximately 1.3 x 10(-3) to approximately 2.0 x 10(-3) Pas and from approximately 1.2 x 10(4) to approximately 1.6 x 10(4) Pa, respectively. The adsorbed mass estimated from the Sauerbrey equation (perfectly elastic) and the Voigt viscoelastic model differ appreciably prior to cross-linking whereas after cross-linking they converged. This is because trapped water molecules were released during cross-linking. This was confirmed experimentally via ATR/FTIR measurements. The variation in viscoelastic properties increased substantially after cross-linking presumably due to fluctuation of the randomly cross-linked network structure. An increase in fluctuation of the viscoelastic properties and the loss of imbibed water could be used as a signature of the formation of a cross-linked network and the amount of cross-linking, respectively.

Surface-enhanced nucleation of insulin amyloid fibrillation.

Proteins can interact with biological surfaces such as cell membrane, chaperones, cornea, bone, arteries, veins, and heart cavities of the cardiovascular system and also with non-biological surfaces including dialysis membranes and tubing, catheters, invasive surgical instruments, needles, and artificial implants. Fibrillation of amyloid proteins is implicated in many human diseases, including Alzheimer's, Parkinson's, and type II diabetes. Here, we show that heterogeneous surfaces accelerate the human insulin nucleation process that is the rate-determining step during amyloid fibril formation. The observed shorter lag (nucleation) phase correlates both with surface wettability and surface roughness. Surfaces promote faster nucleation possibly by increasing the local concentration of protein molecules. A composite parameter combining both surface wettability and roughness suggests that the ideal surface for slower nucleation should be hydrophilic and smooth. These findings provide a basis for designing suitable biomaterials and biomedical devices, especially those to resist amyloidosis.