Chronic high-level multidrug-resistant Campylobacter coli enterocolitis in an agammaglobulinemia patient: Oral gentamicin efficacy

BackgroundCampylobacter is the most common cause of infectious diarrhea in agammaglobulinemia patients. These infections can be severe, prolonged, and recurrent in such patients.Patient and methodsWe report a 29-year-old male patient with X-linked agammaglobulinemia with Campylobacter coli enterocolitis that persisted for nine months despite multiple 10- to 14-day courses of oral ciprofloxacin and azithromycin.ResultsThe isolate was highly resistant to ciprofloxacin, erythromycin, tetracycline, and fosfomycin. The patient failed to respond to intravenous ertapenem, 1.0 g/day for two weeks, to which the pathogen was susceptible. He was finally cured with oral gentamicin, 80 mg four times daily, and stool cultures remained negative during the seven-month follow-up.ConclusionOral aminoglycoside might be the most appropriate choice for eradication of persistent Campylobacter in the intestinal tract for macrolide- and fluoroquinolone-resistant isolate in agammaglobulinemia patients with chronic diarrhea or relapsing systemic infections.     

The jejunum is the key factor in insulin resistance

BackgroundBiliopancreatic diversion (BPD) is more effective than Roux-en-Y gastric bypass (RYGB) on both insulin resistance and diabetes.ObjectivesBecause the major difference between the 2 procedures resides in the length of jejunal bypass, we investigated the role of the jejunum in insulin resistance.SettingUniversity hospital in Italy.MethodsInsulin sensitivity (IS) and secretion were measured before and 4 weeks after RYGB or BPD in 16 patients. A translational study was also conducted in 6 pigs, by isolating a jejunal loop with its vascular and nerve supply (Thiry-Vella loop [TVL]). TVL was doubly stomatized and bowel continuity restored by a side-to-side jejuno-jejunostomy. At baseline and 4 weeks postoperatively a glucose bolus was injected either in the stomach or in the TVL. Whole-body IS and jejunal heat shock proteins (HSPs) were measured. Primary porcine hepatocyte cultures were incubated with plasma or individual HSPs.ResultsWhole-body IS increased from 353.5 ± 26.7 to 442.0 ± 37.4 (P < .05) after RYGB and from 312.4 ± 14.9 to 441.2 ± 15.9 mL/m⁻²/min⁻¹ (P < .001) after BPD. Hepatic IS was unchanged after RYGB, while it increased from .3 ± .01 to .4 ± .1 (μM/pM) – 1 (P < .01) after BPD. Total insulin secretion rate remained unchanged after RYGB but decreased (from 58.3 ± 23.6 to 33.1 ± 7.8 nmol/m⁻², P < .05) after BPD. Jejunectomy in pigs enhanced IS (.3 ± .01 versus .2 ± .01 mM/pM, P < .001), while injection of glucose into TVL reduced it (.1 ± .01 versus .3 ± .01 mM/pM, P < .0001). The jejunum secreted HSPs, Hsp70, and GRP78, which impaired insulin signaling in hepatocyte cultures.ConclusionsThis study shows that jejunal bypass in both humans and pigs improves IS. Injection of glucose into the TVL in pigs determines insulin resistance. In response to glucose, the jejunum secretes HSPs that impair insulin signaling.     

Human metabolism: pathways and clinical aspects

Metabolism describes the series of chemical reactions that are concerned with the provision of energy to biological systems. They may be divided into reactions involved in energy yield (catabolism: demand exceeds supply), and energy storage (anabolism: supply exceeds demand). Regulation of these pathways is critical for homeostasis, and derangements in metabolism are seen in a wide variety of pathological processes. Understanding metabolism is key to the treatment of many diseases, notably diabetes, as well as underpinning clinical nutritional support.     

Phenotypic and Genotypic Characterization of Streptococcus mutans Strains Isolated from Endodontic Infections

Streptococcus mutans plays an important role in caries etiology and eventually in systemic infections. However, it is often found in infected root canals, but the pathophysiological characteristics of strains residing in this site are largely unknown. Here, we characterized strains of S. mutans isolated from root canals of primary (PI) and secondary/persistent (SI) endodontic infections in relation to serotype and genotype; presence of genes coding for collagen binding proteins (CBPs); collagen binding activity and biofilm formation capacity; ability to withstand environmental stresses; systemic virulence in Galleria mellonella; and invasion of human coronary artery endothelial cells and human dental pupal fibroblasts. Samples from 10 patients with PI and 10 patients with SI were collected, and a total of 14 S. mutans isolates, belonging to 3 genotypes, were obtained. Of these, 13 were serotype c, and 1 was serotype k. When compared with the reference strains, the clinical isolates were hypersensitive to hydrogen peroxide. Remarkably, all 14 strains harbored and expressed the CBP-encoding gene cbm, showing increased binding to collagen, enhanced systemic virulence in G. mellonella, and ability to invade human coronary artery endothelial cells and human dental pupal fibroblasts when compared with CBP-negative strains. Whole genome sequence analysis of PI and SI isolates revealed that these strains are phylogenetically related but genetically distinct from each other. Our findings highlight the importance of CBPs in facilitating colonization and persistence of S. mutans in collagenous substrates such as root canals and their potential role in the pathogenesis of endodontic infections.     

Knockdown of KDM1B inhibits cell proliferation and induces apoptosis of pancreatic cancer cells

Pancreatic cancer (PC) is one of the common malignant tumors in digestive tract with a high fatality rate. The oncogenic role of lysine-specific demethylase1 (LSD1/KDM1?A) has been well recognized in PC. While, the role of its homolog LSD2 (KDM1B) in regulating PC progression is poorly understood. In this study, we attempted to evaluate the functional role of KDM1B in PC cells. The expression of KDM1B was detected by immunohistochemistry and immunoblotting in PC tissues and cells. Lentivirus-mediated shRNA was applied to silence KDM1B in PANC-1 and SW1990 cells. Cell proliferation was measured by MTT and Celigo assay. Cell apoptosis was determined by both Caspase-Glo^®3/7 assay and Flow cytometry. Intracellular signaling molecules were detected using a PathScan intracellular signaling array kit. In this study, we found KDM1B was highly expressed in PC tissues compared to paracancerous tissues. Moreover, elevated expression of KDM1B was detected in PC cell lines (BxPC-3, CFPAC-1, PANC-1 and SW1990) as compared with a normal human pancreatic duct epithelial cell line (HPDE6-C7). Further investigations revealed that KDM1B knockdown significantly inhibited PC cell proliferation. Furthermore, the apoptosis of PANC-1 and SW1990 cells was significantly increased after KDM1B knockdown. Notably, the activations of p-ERK1/2, p-Smad2, p-p53, cleaved PARP, cleaved Caspase-3, cleaved Caspase-7, p-eIF2a and Survivin were promoted by KDM1B knockdown, while IkBa was suppressed. Taken together, our findings provided new insights into the critical and multifaceted roles of KDM1B in the regulation of cell proliferation and apoptosis, and offered a potentially novel target in preventing the progression of PC.     

A review of approaches to 18F radiolabelling affinity peptides and proteins

Affinity peptide and protein‐ (APP) based radiotracers are an increasingly popular class of radiotracer in positron emission tomography (PET), which was once dominated by the use of small molecule radiotracers. Radiolabelled monoclonal antibodies (mAbs) are important examples of APPs, yet a preference for smaller APPs, which exhibit fast pharmacokinetics and permit rapid PET aided diagnosis, has become apparent. ¹⁸F exhibits favourable physical characteristics for APP radiolabelling and has been described as an ideal PET radionuclide. Notwithstanding, ¹⁸F radiolabelling of APP is challenging, and this is echoed in the literature where a number of diverse approaches have been adopted. This review seeks to assess and compare the approaches taken to ¹⁸F APP radiolabelling with the intention of highlighting trends within this expanding field. Generic themes have emerged in the literature, namely the use of mild radiolabelling conditions, a preference of site‐specific methodologies with an impetus for short, automated procedures which produce high‐yielding [¹⁸F]APPs.     

Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

An update in pathologic diagnosis of uterine mesenchymal tumours

Recent discovery of new disease-defining molecular alterations and development of novel targeted therapies has dramatically changed the classification and management of uterine mesenchymal neoplasms. This review discusses diagnostic updates in endometrial stromal sarcoma, PEComa, uterine tumor resembling ovarian sex cord tumor (UTROSCT), inflammatory myofibroblastic tumor, NTRK fusion uterine sarcoma, COL1A1-PDGFB fusion sarcoma, and SMARC-deficient uterine sarcoma. Key clinical, morphologic, immunophenotypic, and molecular features are reviewed, with emphasis on common differential diagnoses and pitfalls, and their impact on prognosis or management. Where applicable, the role of novel targeted therapies is discussed. A stepwise approach to uterine mesenchymal neoplasms can achieve a proper diagnosis and guide appropriate clinical management in most cases. Nonetheless, given the rarity of these tumors, their overlapping pathologic features, and rapid evolution in their classification and management, we advocate a low threshold for diagnostic consultation.     

The role of the computerized tomography scanner in the cross-transmission of carbapenem-resistant Acinetobacter baumannii between hospitalized patients

ObjectiveTo assess the role of the computerized tomography (CT) scanner in cross-transmission of carbapenem-resistant Acinetobacter baumannii between hospitalized patients undergoing CT scan.MethodsA single-centre retrospective observational analysis of inpatients undergoing CT scans. Patient-unique CT scans were defined as ‘index cases’ (patients undergoing CT scan with carbapenem-resistant Acinetobacter baumannii (CRAB) colonization documented during the previous 60 days), ‘incident cases’ (patients found colonized with CRAB within 14 days following CT scan), and ‘negative cases’ (negative for CRAB before and after CT scan). CRAB acquisition was analysed by time interval between CT scan and CT scan of the prior index-case patient.ResultsAmongst 73 047 CT scans performed over 5 years, 4834 scans were performed within 12 hours of an index case. CRAB acquisition was detected in 20 patients (incident cases), including 16/2725 (5.8/1000 scans) who underwent CT scan within 6 hours of an index-case CT scan and 4/2109 (1.9/1000 scans) who had their CT scan 7–12 hours after the CT scan of an index-case patient (p 0.033, risk ratio 3.1, 95%CI 1.03–9.25). Patient characteristics for the two time periods were similar. While not the only significant predictor of CRAB acquisition (others included age and length of hospital stay prior to the CT scan), the time elapsed from an index case remained a significant predictor for CRAB acquisition on multivariate analysis (OR 0.84, 95%CI 0.74–0.95, p 0.007).ConclusionsPerforming a CT scan within 6 hours of a CT scan performed in a CRAB-positive patient was an independent predictor of CRAB acquisition, approximately tripling the risk. This probably reflects poor infection control practice in the CT suite.