Substance P and neprilysin in chronic pancreatitis

Background/Aims: We aimed to analyze substance P (SP) and neprilysin (NEP), the membrane metallopeptidase that degrades SP, in chronic pancreatitis (CP). Methods: SP and NEP mRNA levels were analyzed by qRT-PCR in tissue samples from 30 patients with CP and 8 organ donors. In addition, SP serum levels were determined before and after surgery in the same patients, by means of a competitive ELISA assay. Genetic and epigenetic analyses of the NEP gene were also performed. Results: SP mRNA expression levels were higher in CP tissues compared to controls (p =0.0152), while NEP mRNA showed no significant differences between CP and healthy subjects (p = 0.2102). In CP patients, SP serum levels correlated with those in tissue, and after surgical resection SP serum levels were reduced compared to the preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR-128a overexpression (p = 0.02), rather than with mutations in the NEP coding region or the presence of hypermethylation sites in the NEP promoter region. Conclusion: Tissue and serum levels of SP were increased in CP, while NEP levels remained unaltered. In an SP/NEP-mediated pathway, it would appear that NEP fails to provide adequate surveillance of SP levels. Failure of NEP to overexpress could be associated with miRNA regulation. Copyright © 2012 S.Karger AG, Base

Substance P and neprilysin in chronic pancreatitis

Background/Aims: We aimed to analyze substance P (SP) and neprilysin (NEP), the membrane metallopeptidase that degrades SP, in chronic pancreatitis (CP). Methods: SP and NEP mRNA levels were analyzed by qRT-PCR in tissue samples from 30 patients with CP and 8 organ donors. In addition, SP serum levels were determined before and after surgery in the same patients, by means of a competitive ELISA assay. Genetic and epigenetic analyses of the NEP gene were also performed. Results: SP mRNA expression levels were higher in CP tissues compared to controls (p =0.0152), while NEP mRNA showed no significant differences between CP and healthy subjects (p = 0.2102). In CP patients, SP serum levels correlated with those in tissue, and after surgical resection SP serum levels were reduced compared to the preoperative values. Failure of NEP to overexpress in CP tissues was associated with significant miR-128a overexpression (p = 0.02), rather than with mutations in the NEP coding region or the presence of hypermethylation sites in the NEP promoter region. Conclusion: Tissue and serum levels of SP were increased in CP, while NEP levels remained unaltered. In an SP/NEP-mediated pathway, it would appear that NEP fails to provide adequate surveillance of SP levels. Failure of NEP to overexpress could be associated with miRNA regulation. Copyright © 2012 S.Karger AG, Base

Malignant PEComa: a case report with emphasis on clinical and morphological criteria

<p>Abstract</p> <p>Background</p> <p>Malignant perivascular epitheliod cell tumor (PEComa) is a very rare entity composed of distinctive perivascular epitheliod cells with variable immunoreactivity for melanocytic and muscle markers. At present this neoplasm does not have a known normal cellular counterpart and the natural history is often unpredictable. Up to now, few cases of PEComa have been described and treatment modalities are still controversial, particularly in advanced conditions.</p> <p>Case presentation</p> <p>We handled the case of a 42-year-old man with unresectable PEComa of the abdomen. A 7 cm hepatic hypodense lesion between segment V and VIII of the liver and diffuse intraperitoneal nodules of 0,3-3,5 cm along the right subcapsular hepatic region, were documented by a CT scan. Radiological images showed abnormal lymph nodes of the right internal mammary chain and anterior mediastinum. The patient underwent an explorative laparotomy for uncontrolled intrabdominal hemorrhage without a well-defined preoperative tumor diagnosis. At surgery, multiple lobulated nodules containing hemorrhagic fluid on the liver surface, peritoneum and omentum were confirmed. The procedure had a palliative intent and consisted of hemostasis, hematomas evacuation and omentectomy. The diagnosis of PEComa was made after surgery on the basis of morphological and immunohystochemical criteria. Radiological and intra operative findings suggest that the mass has an hepatic origin with diffuse involvement of hepatic capsule and suspensory ligaments. The patient received medical support care with blood and plasma transfusions. In our experience, PEComa was clinically malignant, leading to a fatal outcome 25 days after hospital admission of patient.</p> <p>Conclusions</p> <p>Here we report and discuss the peculiar clinical, radiological and morphological presentation of unresectable PEComa. Although in the majority of the reported series, PEComas show a more better prognosis, our case presents with a particular aggressive biological behaviour. The importance of a correct preoperative diagnosis, the need for more effective targeted therapies based on tumor molecular knowledge and evidence-based clinical studies are emphasized together with a revision of the concerning scientific literature.</p

The effects of acute Methylene Blue administration on cerebral blood flow and metabolism in humans and rats

Methylene Blue (MB) is a brain-penetrating drug with putative neuroprotective, antioxidant and metabolic enhancing effects. In vitro studies suggest that MB enhances mitochondrial complexes activity. However, no study has directly assessed the metabolic effects of MB in the human brain. We used in vivo neuroimaging to measure the effect of MB on cerebral blood flow (CBF) and brain metabolism in humans and in rats. Two doses of MB (0.5 and 1 mg/kg in humans; 2 and 4 mg/kg in rats; iv) induced reductions in global cerebral blood flow (CBF) in humans (F(1.74, 12.17)5.82, p = 0.02) and rats (F(1,5)26.04, p = 0.0038). Human cerebral metabolic rate of oxygen (CMRO2) was also significantly reduced (F(1.26, 8.84)8.01, p = 0.016), as was the rat cerebral metabolic rate of glucose (CMRglu) (t = 2.6(16) p = 0.018). This was contrary to our hypothesis that MB will increase CBF and energy metrics. Nevertheless, our results were reproducible across species and dose dependent. One possible explanation is that the concentrations used, although clinically relevant, reflect MB’s hormetic effects, i.e., higher concentrations produce inhibitory rather than augmentation effects on metabolism. Additionally, here we used healthy volunteers and healthy rats with normal cerebral metabolism where MB’s ability to enhance cerebral metabolism might be limited

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Contrasting styles of (U)HP rock exhumation along the Cenozoic Adria-Europe plate boundary (Western Alps, Calabria, Corsica)

Since the first discovery of ultrahigh pressure (UHP) rocks 30 years ago in the Western Alps, the mechanisms for exhumation of (U)HP terranes worldwide are still debated. In the western Mediterranean, the presently accepted model of synconvergent exhumation (e.g., the channel-flow model) is in conflict with parts of the geologic record. We synthesize regional geologic data and present alternative exhumation mechanisms that consider the role of divergence within subduction zones. These mechanisms, i.e., (i) the motion of the upper plate away from the trench and (ii) the rollback of the lower plate, are discussed in detail with particular reference to the Cenozoic Adria-Europe plate boundary, and along three different transects (Western Alps, Calabria-Sardinia, and Corsica-Northern Apennines). In the Western Alps, (U)HP rocks were exhumed from the greatest depth at the rear of the accretionary wedge during motion of the upper plate away from the trench. Exhumation was extremely fast, and associated with very low geothermal gradients. In Calabria, HP rocks were exhumed from shallower depths and at lower rates during rollback of the Adriatic plate, with repeated exhumation pulses progressively younging toward the foreland. Both mechanisms were active to create boundary divergence along the Corsica-Northern Apennines transect, where European southeastward subduction was progressively replaced along strike by Adriatic northwestward subduction. The tectonic scenario depicted for the Western Alps trench during Eocene exhumation of (U)HP rocks correlates well with present-day eastern Papua New Guinea, which is presented as a modern analog of the Paleogene Adria-Europe plate boundary

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Towards a muon collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work

Towards a Muon Collider

A muon collider would enable the big jump ahead in energy reach that is needed for a fruitful exploration of fundamental interactions. The challenges of producing muon collisions at high luminosity and 10 TeV centre of mass energy are being investigated by the recently-formed International Muon Collider Collaboration. This Review summarises the status and the recent advances on muon colliders design, physics and detector studies. The aim is to provide a global perspective of the field and to outline directions for future work.Comment: 118 pages, 103 figure