Identification of Small Proteins and Peptides in the Differentiation of Patients with Intraductal Mucinous Neoplasms of the Pancreas,Chronic Pancreatitis and Pancreatic Adenocarcinoma

Background

There are a limited number of studies investigating the type of serum proteins capable of differentiating intraductal papillary mucinous neoplasms from benign or malignant diseases of the pancreas.

Aims

To select proteins able to differentiate intraductal papillary mucinous neoplasms from benign and malignant pancreatic disease using semiquantitative proteomics.

Methods

Serum samples were obtained from 74 patients (19 with type II intraductal papillary mucinous neoplasms, 8 with type I/III intraductal papillary mucinous neoplasms, 24 with chronic pancreatitis, 23 with pancreatic ductal adenocarcinomas) and 21 healthy subjects. Small proteins and peptides were assayed by matrix-assisted laser desorption/ionization for the detection of differentially abundant species possibly related to tumor onset. Serum pancreatic amylase, lipase, carcinoembryonic antigen and carbohydrate antigen 19-9 (CA 19-9) were also assayed.

Results

Twenty-six of 84 peaks detected were dysregulated (7 more abundant and 19 less abundant in the type II intraductal papillary mucinous neoplasms, p < 0.05). Of the differentially abundant peaks, 17 were commonly dysregulated (3 peaks more abundant and 13 less abundant in type II intraductal papillary mucinous neoplasms, and one at  m/z = 9961 at variance), indicating a protein fingerprint shared by types I/III and type II intraductal papillary mucinous neoplasms and pancreatic ductal adenocarcinomas.

Conclusions

These results suggest that our approach can be used to differentiate type II intraductal papillary mucinous neoplasms from type I/III neoplasms, and type II intraductal papillary mucinous neoplasms from pancreatic ductal adenocarcinomas.

     

Disseminated nocardiosis caused by <Emphasis Type="Italic">Nocardia elegans</Emphasis>: a case report and review of the literature

Background

Disseminated nocardiosis is a rare disease mostly occurring in immunocompromised patients.

Methods

We report a case of disseminated nocardiosis in a diabetic patient with both pulmonary and cutaneous involvement. Nocardia elegans was isolated and identified using the 16s ribosomal RNA gene sequence data.

Results

Clinical improvement was observed within 3 months after initiation of antimicrobial treatment with oral doxycycline, trimethoprim-sulfamethoxazole and intravenous penicillin, but the patient died 5 months later after arbitrary discontinuation of the treatment.

Conclusions

This is the first case report of disseminated nocardiosis caused by Nocardia elegans in China.

     

Were all carbapenemases created equal? Treatment of NDM-producing extensively drug-resistant <Emphasis Type="Italic">Enterobacteriaceae</Emphasis>: a case report and literature review

Purpose

There is currently a paucity of published literature focused on the treatment of infections caused by NDM-producing organisms.

Methods

We describe a case of a bacteraemia caused by an extensively drug-resistant (XDR) New Delhi metallo-β-lactamase (NDM)-producing Serratia marcescens and review the treatment options for XDR NDM-producing Enterobacteriaceae.

Results

Infections caused by New Delhi beta-lactamase (NDM)-producing Enterobacteriaceae are becoming increasingly prevalent worldwide. The presence of the enzyme results in multidrug-resistant and extensively drug-resistant phenotypes which often pose a treatment challenge. Despite this challenge, case reports and series have demonstrated good clinical outcomes with numerous treatment options in comparison to infections due to KPC-producing Enterobacteriaceae.

Conclusions

Further good-quality research focused on the treatment of NDM-producing Enterobacteriaceae is warranted.

     

Gastric adenocarcinoma in a patient re-infected with <Emphasis Type="Italic">H. pylori</Emphasis> after regression of MALT lymphoma with successful anti-<Emphasis Type="Italic">H. pylori</Emphasis>therapy and gastric resection: a case report

Background

Helicobacter pylori (H. pylori) has been etiologically linked with primary gastric lymphoma (PGL) and gastric carcinoma (GC). There are a few reports of occurrence of both diseases in the same patient with H. pylori infection.

Case presentation

We report a patient with PGL in whom the tumor regressed after surgical resection combined with eradication of H. pylori infection. However, he developed GC on follow up; this was temporally associated with recrudescence / re-infection of H. pylori. This is perhaps first report of such occurrence.

Conclusions

Possible cause and effect relationship between H. pylori infection and both PGL and GC is discussed. This case also documents a unique problem in management of PGL in tropical countries where re-infection with H. pylori is supposed to be high.

     

First case of <Emphasis Type="Italic">E. meningoseptica</Emphasis> in Italy in a patient with necrotic hemorrhagic pancreatitis

Introduction

Elizabethkingia meningoseptica can frequently colonizes the respiratory tract, but its pathogenetic role and its clinical significance are frequently questioned. However, recent data reported E. meningoseptica outbreaks in particular settings, as hospitalized patients.

Case Report

We report here the first case of Elizabethkingia meningoseptica infection in Italy in a patient with necrotic-hemorrhagic pancreatitis. E. meningoseptica was isolated from respiratory tract and treated with combination antibiotic therapy.

Conclusion

We discuss here the role of isolation of E. meningoseptica in hospitalized patients as a sign of patient’s frailty.

     

Illnesses Associated with Freshwater Recreation During International Travel

Purpose of Review

International travel, adventure travel, and eco-tourism are increasing over the past few decades. This review aims to summarize the spectrum of infections associated with recreational freshwater activities and international travel.

Recent Findings

Recreational water activities can be associated with a wide range of infections. Acute febrile illnesses due to leptospirosis and schistosomiasis are not uncommon in travelers following extensive freshwater exposure. Aeromonas and other water-associated pathogens are important to consider in a traveler presenting with a skin and soft tissue infection. Recreational water activities are often associated with diarrheal illnesses, especially in children, and the range of enteric pathogens includes bacterial pathogens such as Escherichia coli O157:H7 and Shigella species and the protozoan parasites Cryptosporidium and Giardia duodenalis. Infections due to free-living amebas though rare can lead to fulminant central nervous system infections.

Summary

A diverse range of infections may be associated with freshwater exposure, and it is important that these entities are considered in a returning traveler presenting with an acute illness.

     

Tracing the origins and signatures of selection of antifolate resistance in island populations of <Emphasis Type="Italic">Plasmodium falciparum</Emphasis>

Background

Resistance of the malaria parasite Plasmodium falciparum to sulfadoxine-pyrimethamine (SP) has evolved worldwide. In the archipelago of São Tomé and Principe (STP), West Africa, although SP resistance is highly prevalent the drug is still in use in particular circumstances. To address the evolutionary origins of SP resistance in these islands, we genotyped point mutations at P. falciparum dhfr and dhps genes and analysed microsatellites flanking those genes.

Methods

Blood samples were collected in July and December 2004 in three localities of São Tomé Island and one in Principe Island. Species-specific nested-PCR was used to identify P. falciparum infected samples. Subsequently, SNPs at the dhfr and dhps genes were identified through PCR-RFLP. Isolates were also analysed for three microsatellite loci flanking the dhfr gene, three loci flanking dhps and four loci located at putative neutral genomic regions.

Results

An increase of resistance-associated mutations at dhfr and dhps was observed, in particular for the dhfr/dhps quintuple mutant, associated with clinical SP failure. Analysis of flanking microsatellites suggests multiple independent introductions for dhfr and dhps mutant haplotypes, possibly from West Africa. A reduced genetic diversity and increased differentiation at flanking microsatellites when compared to neutral loci is consistent with a selective sweep for resistant alleles at both loci.

Conclusions

This study provides additional evidence for the crucial role of gene flow and drug selective pressures in the rapid spread of SP resistance in P. falciparum populations, from only a few mutation events giving rise to resistance-associated mutants. It also highlights the importance of human migration in the spread of drug resistant malaria parasites, as the distance between the islands and mainland is not consistent with mosquito-mediated parasite dispersal.

     

Genome characterization of bile-isolated <Emphasis Type="Italic">Shewanella algae</Emphasis> ACCC

Background

Shewanella algae has been recognized as an emerging human pathogen. However, not much is known about the mechanism of its pathogenesis and its adaptation to a special niche such as the hepatobiliary tract.

Results

In this study, we isolated the S. algae ACCC strain from human bile and performed whole genome sequencing. S. algae ACCC consists of a circular 4,743,354-bp chromosome with a GC content of 53.08%, within 4080 protein coding sequences. The genome of strain ACCC contains a number of candidate genes which have been reported to be associated with bile adaption, including htpB, exbBD, wecA, galU, adeFGH and phoPQ regulon.

Conclusions

Our results highlight the association of S. algae with a rare disease profile. Further studies are needed to shed light on the evolution of pathogenesis and the niche adaptation of S. algae.

     

Differences Between the Intestinal Lumen Microbiota of Aberrant Crypt Foci (ACF)-Bearing and Non-bearing Rats

Background

Multiple factors including host–microbiota interaction could contribute to the conversion of healthy mucosa to sporadic precancerous lesions. An imbalance of the gut microbiota may be a cause or consequence of this process.

Aim

The goal was to investigate and analyze the composition of gut microbiota during the genesis of precancerous lesions of colorectal cancer.

Methods

To analyze the composition of gut microbiota in the genesis of precancerous lesions, a rat model of 1, 2-dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) was established. The feces of these rats and healthy rats were collected for 16S rRNA sequencing.

Results

The diversity and density of the rat intestinal microbiota were significantly different between ACF-bearing and non-bearing group. ACF were induced in rats treated with DMH and showed increased expression of the inflammatory cytokines IL-6, IL-8, and TNF-α. Firmicutes was the most predominant phylum in both ACF-bearing and non-bearing group, followed by Bacteroidetes. Interestingly, although the density of Bacteroidetes decreased from the fifth week to the 17th week in both groups, it was significantly reduced in ACF-bearing group at the 13th week (P?<?0.01). At the genus level, no significant difference was observed in the most predominant genus, Lactobacillus. Instead, Bacteroides and Prevotella were significantly less abundant (P?<?0.01), while Akkermansia was significantly more abundant (P?<?0.05) in ACF-bearing group at the 13th week.

Conclusion

Imbalance of the intestinal microbiota existed between ACF-bearing and non-bearing rats, which could be used as biomarker to predict the genesis of precancerous lesions in the gut.

     

Germline mutations of aryl hydrocarbon receptor-interacting protein (<Emphasis Type="Italic">AIP</Emphasis>) gene and somatostatin receptor 1–5 and <Emphasis Type="Italic">AIP</Emphasis> immunostaining in patients with sporadic acromegaly with poor versus good response to somatostatin analogues

Objective

To determine aryl hydrocarbon interacting protein (AIP) gene variations and AIP and somatostatin receptor (SSTR) 1–5 immunostaining in patients with apparently sporadic acromegaly with poor versus good response to somatostatin analogues (SRLs).

Methods

A total of 94 patients (66 with poor and 28 with good response to SRLs) were screened for the AIP gene variations using Sanger sequencing. Immunostaining was performed in 60 tumors.

Results

Several variations, albeit some with undetermined significance, were detected, especially in poor responder patients. The prevalence of AIP mutation was 2.1% in the whole group and 1.5% in patients with poor response to SRLs. AIP, SSTR2A, and SSTR2B immunostainings were decreased in patients with poor response (p?<?0.05 for all), and other SSTRs did not differ between the groups (p?>?0.05 for all). Patients with low AIP had decreased levels of SSTR2A and SSTR3 (p?<?0.05 for all). AIP and SSTR2A immunostainings were positively correlated to the treatment response and age at diagnosis was negatively correlated (p?<?0.05 for all). In poor responder patients with high SSTR2A immunostaining, SSTR2B immunostaining and preoperative tumor size were positively and negatively correlated, respectively, to SRL response (p?<?0.05 for all).

Conclusions

Lack of response to SRLs does not necessarily increase the risk of harboring AIP mutations. The finding of decreased AIP, SSTR2A, and SSTR2B immunostaining in patients with poor response to SRLs and decreased SSTR2A and SSTR3 level in those with low AIP immunostaining suggests a possible interaction between AIP and some SSTR subtypes that might alter SRL sensitivity.

     

A type 1 diabetes genetic risk score can discriminate monogenic autoimmunity with diabetes from early-onset clustering of polygenic autoimmunity with diabetes

Aims/hypothesis

Identifying individuals suitable for monogenic autoimmunity testing and gene discovery studies is challenging: early-onset type 1 diabetes mellitus can cluster with additional autoimmune diseases due to shared polygenic risk and islet- and other organ-specific autoantibodies are present in both monogenic and polygenic aetiologies. We aimed to assess whether a type 1 diabetes genetic risk score (GRS) could identify monogenic autoimmune diabetes and be useful to prioritise individuals for gene discovery studies.

Methods

We studied 79 individuals with diabetes and at least one additional autoimmune disease diagnosed before the age of 5 years. We screened all participants for the seven genes known to cause monogenic autoimmunity that can include diabetes (AIRE, IL2RA, FOXP3, LRBA, STAT1, STAT3, STAT5B). We genotyped the top ten risk alleles for type 1 diabetes, including HLA and non-HLA loci, to generate a type 1 diabetes GRS.

Results

Of the 79 individuals studied, 37 (47%) had mutations in the monogenic autoimmunity genes. The type 1 diabetes GRS was lower in these individuals than in those without mutations in these genes (median 9th vs 49th centile of type 1 diabetes controls, p?<?0.0001). Age of diabetes diagnosis and type 1 diabetes GRS combined to be highly discriminatory of monogenic autoimmunity (receiver operating characteristic AUC: 0.88). Most individuals without a mutation in a known gene had a high type 1 diabetes GRS, suggesting that they have polygenic clustering of type 1 diabetes and additional autoimmunity and should not be included in gene discovery studies.

Conclusions/interpretation

We have shown that the type 1 diabetes GRS can identify individuals likely to have monogenic autoimmunity, helping both diagnostic testing and novel monogenic autoimmunity gene discovery. Individuals with monogenic autoimmunity have a different clinical course to those with polygenic type 1 diabetes and can respond well to therapies targeting the underlying genetic defect.

     

The influence of gender on symptoms associated with obstructive sleep apnea

Background

It has been reported that the clinical expression of obstructive sleep apnea (OSA) may differ in women and men.

Objective

The objective of this study was to evaluate the influence of gender on reported OSA-related symptoms in a large clinical population of patients.

Methods

The database from the sleep laboratory of a tertiary care center was examined. Adult patients who had undergone a diagnostic polysomnography and completed the Berlin questionnaire, a sleep questionnaire, and the Epworth sleepiness scale were selected. Multiple logistic regression analysis was performed to assess the relationship between OSA-associated symptoms and different potential explanatory variables.

Results

The study sample included 1084 patients, median age was 53 years, 46.5% (504) were women, 72.7% (788) had OSA (apnea/hypopnea index ≥?5), and 31.2% were obese. After adjusting for age, body mass index, and apnea/hypopnea index, men were more likely to report snoring (OR 4.06, p?<?0.001), habitual or loud snoring (OR 2.34, p?<?0.001; 2.14, p?<?0.001, respectively) and apneas (OR 2.44, p?<?0.001), than women. After controlling for multiple variables, female gender was an independent predictive factor for reported tiredness (OR 0.57, p 0.001), sleep onset insomnia (OR 0.59, p 0.0035), and morning headaches (OR 0.32, p?<?0.001). Reports of excessive daytime sleepiness, nocturia, midnight insomnia, and subjective cognitive complaints were not significantly associated with gender.

Conclusion

Women with OSA were more likely to report tiredness, initial insomnia, and morning headaches, and less likely to complain of typical OSA symptoms (snoring, apneas) than men.

     

Enhanced Expression of CXCL13 in Human <Emphasis Type="Italic">Helicobacter pylori</Emphasis>-Associated Gastritis

Background and Aims

Chemokine CXC ligand 13 (CXCL13) and CXC receptor type 5 (CXCR5) are constitutively expressed in tertiary lymphoid follicles where the CXCL13/CXCR5 system regulates B lymphocytes homing. In this study, we sought to examine CXCL13 expression in the H. pylori-infected and -uninfected gastric mucosa and to elucidate the implication in the pathogenesis of HAG in humans.

Methods

Using endoscopic biopsies taken from the gastric antrum of 29 subjects infected with Helicobacter pylori and 22 uninfected subjects, mucosal CXCL13 mRNA and protein levels were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively.

Results

The CXCL13 expression levels were significantly more elevated in H. pylori-positive patients than uninfected ones. The CXCL13 expression levels correlated with the degree of chronic gastritis and bacterial colonization. Immunohistochemistry and in vitro infection assay showed that CXCL13 was not produced by the gastric epithelium, but the α-smooth muscle antigen expressing mesenchymal cells were the possible source of CXCL13 within H. pylori-infected gastric mucosa. CXCR5 immunostaining was seen in the CD20-positive lymphoid aggregates.

Conclusions

The enhanced induction of CXCL13 may be involved in the pathogenesis of H. pylori-associated gastritis.

     

Insurance Coverage Predicts Mortality in Patients Transferred Between Hospitals: a Cross-Sectional Study

Background

Patients transferred between hospitals are at high risk of adverse events and mortality. The relationship between insurance status, transfer practices, and outcomes has not been definitively characterized.

Objective

To identify the association between insurance coverage and mortality of patients transferred between hospitals.

Design

We conducted a single-institution observational study, and validated results using a national administrative database of inter-hospital transfers.

Setting

Three ICUs at an academic tertiary care center validated by a nationally representative sample of inter-hospital transfers.

Patients

The single-institution analysis included 652 consecutive patients transferred from 57 hospitals between 2011 and 2012. The administrative database included 353,018 patients transferred between 437 hospitals.

Measurements

Adjusted inpatient mortality and 24-h mortality, stratified by insurance status.

Results

Of 652 consecutive transfers to three ICUs, we observed that uninsured patients had higher adjusted inpatient mortality (OR 2.67, p?=?0.021) when controlling for age, race, gender, Apache-II, and whether the patient was transferred from an ED. Uninsured were more likely to be transferred from ED (OR 2.3, p?=?0.026), and earlier in their hospital course (3.9 vs 2.0 days, p?=?0.002). Using an administrative dataset, we validated these observations, finding that the uninsured had higher adjusted inpatient mortality (OR 1.24, 95% CI 1.13–1.36, p?<?0.001) and higher mortality within 24 h (OR 1.33 95% CI 1.11–1.60, p?<?0.002). The increase in mortality was independent of patient demographics, referral patterns, or diagnoses.

Limitations

This is an observational study where transfer appropriateness cannot be directly assessed.

Conclusions

Uninsured patients are more likely to be transferred from an ED and have higher mortality. These data suggest factors that drive inter-hospital transfer of uninsured patients have the potential to exacerbate outcome disparities.

     

Teaching Medical Students to Help Patients Quit Smoking: Outcomes of a 10-School Randomized Controlled Trial

Background

Early in medical education, physicians must develop competencies needed for tobacco dependence treatment.

Objective

To assess the effect of a multi-modal tobacco dependence treatment curriculum on medical students’ counseling skills.

Design

A group-randomized controlled trial (2010–2014) included ten U.S. medical schools that were randomized to receive either multi-modal tobacco treatment education (MME) or traditional tobacco treatment education (TE).

Setting/Participants

Students from the classes of 2012 and 2014 at ten medical schools participated. Students from the class of 2012 (N?=?1345) completed objective structured clinical examinations (OSCEs), and 50 % (N?=?660) were randomly selected for pre-intervention evaluation. A total of 72.9 % of eligible students (N?=?1096) from the class of 2014 completed an OSCE and 69.7 % (N?=?1047) completed pre and post surveys.

Interventions

The MME included a Web-based course, a role-play classroom demonstration, and a clerkship booster session. Clerkship preceptors in MME schools participated in an academic detailing module and were encouraged to be role models for third-year students.

Measurements

The primary outcome was student tobacco treatment skills using the 5As measured by an objective structured clinical examination (OSCE) scored on a 33-item behavior checklist. Secondary outcomes were student self-reported skills for performing 5As and pharmacotherapy counseling.

Results

Although the difference was not statistically significant, MME students completed more tobacco counseling behaviors on the OSCE checklist (mean 8.7 [SE 0.6] vs. mean?8.0 [SE 0.6], p?=?0.52) than TE students. Several of the individual Assist and Arrange items were significantly more likely to have been completed by MME students, including suggesting behavioral strategies (11.8 % vs. 4.5 %, p?<?0.001) and providing information regarding quitline (21.0 % vs. 3.8 %, p?<?0.001). MME students reported higher self-efficacy for Assist, Arrange, and Pharmacotherapy counseling items (ps?≤0.05).

Limitations

Inclusion of only ten schools limits generalizability.

Conclusions

Subsequent interventions should incorporate lessons learned from this first randomized controlled trial of a multi-modal longitudinal tobacco treatment curriculum in multiple U.S. medical schools.NIH Trial Registry Number: NCT01905618

     

The Emerging Threat of Antifungal Resistance in Transplant Infectious Diseases

Purpose of Review

The global emergence of antifungal resistance among Candida spp. and Aspergillus spp. will disproportionately affect transplantation recipients, who are prone to invasive fungal disease.

Recent Findings

Invasive candidiasis is increasingly caused by non-albicans Candida species with reduced susceptibility to first-line antifungals. Echinocandin resistance in Candida glabrata is increasing in some settings. Candida auris has rapidly emerged as a global concern due to multidrug resistance and efficient nosocomial spread in healthcare settings. Azole-resistant Aspergillus fumigatus is already an important concern in some European countries and is increasingly reported elsewhere, possibly driven by agricultural use of triazole fungicides.

Summary

Antifungal resistance is anticipated to expand among these and other common fungal pathogens. Culture-independent detection methods will become more important for rapid diagnosis and to guide empiric therapy. Antifungal stewardship is of critical importance to conserve our limited antifungal armamentarium for transplantation recipients and other vulnerable patients.

     

The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus

Aims/hypothesis

We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes.

Methods

A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain.

Results

The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI?=?0.51–0.80, p?=?0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51–0.88, p?=?0.009).

Conclusions/interpretation

The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.

     

A novel <Emphasis Type="Italic">SLC12A3</Emphasis> homozygous c2039delG mutation in Gitelman syndrome with hypocalcemia

Background

Gitelman syndrome (GS) is a rare autosomal recessive renal tubular disease, caused by mutations in the SLC12A3 gene, which encodes the renal thiazide-sensitive Na/Cl cotransporter (NCCT) in the distal renal tubule.

Case presentation

A 23-year-old woman was admitted with limb numbness, recurrent tetany and palpitation. Laboratory tests showed hypokalemic alkalosis, hypomagnesemia, hypocalcemia and secondary hyperaldosteronism, as well as hypocalciuria and transient decreased PTH. Next-generation sequencing detected a novel homozygous mutations c.2039delG in the SLC12A3 gene, and her father and children were all heterozygous carriers.

Conclusion

We reported a case of GS with a novel homozygous frame-shift mutation of SLC12A3, and reviewed recent literatures about diagnosis, differential diagnosis and treatments. Hypocalcemia in Gitelman syndrome is rare, and may be related to inhibited PTH secretion induced by hypomagnesemia.