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Von Hippel–Lindau disease (VHL) is a multineoplasm inherited disease manifesting with hemangioblastoma of the central nervous system and retina, adrenal pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors and cysts, and neoplasms/cysts of the ear, broad ligament, and testicles. During 2018-2020, the VHL Alliance gathered several committees of experts in the various clinical manifestations of VHL to review the literature, gather the available evidence on VHL, and develop recommendations for patient management. The current report details the results of the discussion of a group of experts in the pancreatic manifestations of VHL along with their proposed recommendations for the clinical surveillance and management of patients with VHL. The recommendations subcommittee performed a comprehensive systematic review of the literature and conducted panel discussions to reach the current recommendations. The level of evidence was defined according to the Shekelle variation of the Grading of Recommendations, Assessment, Development, and Evaluation grading system. The National Comprehensive Cancer Network Categories of Evidence and Consensus defined the committee members' interpretation of the evidence and degree of consensus. The recommendations encompass the main aspects of VHL-related pancreatic manifestations and their clinical management. They are presented in a clinical orientation, including general planning of screening and surveillance for pancreatic neuroendocrine tumors, utility of biochemical biomarkers, the optimal choice for imaging modality, indirect risk stratification, indications for tissue sampling of VHL-related pancreatic neuroendocrine tumors, and interventions. These recommendations are designed to serve as the reference for all aspects of the screening, surveillance, and management of VHL-related pancreatic manifestations.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of desmoplastic small round cell tumor, breast, and gastrointestinal stromal tumor specifically related to peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for palliative care specifically related to peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, gynecologic oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of neuroendocrine tumors specifically related to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

BACKGROUND Nonfunctioning pancreatic neuroendocrine tumors (NFPanNETs) may be sporadic or inherited because of germline mutations associated with von Hippel-Lindau disease (VHL) or multiple endocrine neoplasia type 1 (MEN1). The clinical behavior of NFPanNETs is difficult to predict, even in tumors of the same stage and grade. The authors analyzed genotype-specific patterns of transcriptional messenger RNA (mRNA) levels of NFPanNETs to understand the molecular features that determine PanNET phenotype. METHODS Thirty-two samples were included for genome-wide mRNA gene expression analysis (9 VHL-associated, 10 MEN1-associated, and 9 sporadic NFPanNETs and 4 purified normal islet cell [NIC] samples). Validation of genes was performed by real-time polymerase chain reaction analysis and immunohistochemistry. Gene expression profiles were analyzed by tumor genotype, and pathway analysis was curated. RESULTS Consensus clustering of mRNA expression revealed separate clustering of NICs, VHL-associated NFPanNETs, and MEN1-associated NFPanNETs; whereas some sporadic tumors clustered with MEN1. Four of 5 MEN1-like sporadic PanNET subtypes had loss of heterozygosity at the MEN1 gene locus. Pathway analysis demonstrated subtype-specific pathway activation, comprising angiogenesis and immune response in VHL; neuronal development in MEN1; protein ubiquitination in the new MEN1/sporadic subtype; and cytokinesis and cilium/microtubule development in sporadic NFPanNETs. Among many genes, platelet-derived growth factor receptor β (PDGFRB), lymphoid enhancer-binding factor-1 (Lef-1), cyclin-dependent kinase 4 (CDK4), and CDK6 were upregulated in VHL or MEN1 NFPanNETs, providing potential subtype-specific treatment targets. CONCLUSIONS Distinct mRNA expression patterns were identified in sporadic-associated, VHL-associated, and MEN1-associated NFPanNETs. The current results uncover new pathways involved in NFPanNETs that are subtype-specific and provide potential new diagnostic or therapeutic targets based on tumor subtype. Cancer 2018;124:636-47. © 2017 American Cancer Society.

This work illustrates the practicality of investigating sinkholes integrating data gathered by ground penetrating radar (GPR), electrical resistivity imaging (ERI) and trenching or direct logging of the subsidence-affected sediments in combination with retrodeformation analysis. This mutidisciplinary approach has been tested in a large paleosinkhole developed during the deposition of a Quaternary terrace on salt-bearing evaporites. The subsidence structure, exposed in an artificial excavation, is located next to Puilatos, a village that was abandoned in the 1970s due to severe subsidence damage. Detailed logging of the exposure revealed that the subsidence structure corresponds to an asymmetric sagging and collapse paleosinkhole with no clear evidence of recent activity. The sedimentological and structural relationships together with the retrodeformation analysis indicate that synsedimentary subsidence controlled channel location, the development of a palustrine environment and local changes in the channel pattern. GPR profiles were acquired using an array of systems with different antenna frequencies, including some recently developed shielded antennas with improved vertical resolution and penetration depth. Although radargrams imaged the faulted sagging structure and provided valuable data on fault throw, they did not satisfactorily image the complex architecture of the fluvial deposit. ERI showed lower resolution but higher penetration depth when compared to GPR, roughly capturing the subsidence structure and yielding information on the thickness of the high-resistivity alluvium and the nature of the underlying low-resistivity karstic residue developed on top of the halite-bearing evaporitic bedrock. Data comparison allows the assessment of the advantages and limitations of these complementary techniques, highly useful for site-specific sinkhole risk management. This article is protected by copyright. All rights reserved.

Lakes developed in the inner depressions of tufa mounds are rare geomorphic features and still poorly understood. Sedimentation in this unusual type of endorheic lake with a very restricted catchment area is highly sensitive to environmental and hydrological changes. The Isona tufa mound complex, north-eastern Iberian Peninsula, is associated with the discharge zone of a confined artesian aquifer and comprises 11 tufa mounds consisting of an annular rimstone enclosing a central depression filled with lake deposits. Data gathered from trenches excavated in four palaeolakes located within three different morphostratigraphic units permitted a precise analysis of the geometrical characteristics and stratigraphic relationships of the deposits and provided a sedimentation model for the Late Quaternary infilling of the spring-fed lakes. The work illustrates that trenches allow a precise characterization of the stratigraphic arrangements, lateral facies changes and deformation structures, which are not apparent in studies relying solely on borehole records, and facilitate sampling for dating and geochemical analyses. The five sedimentary facies described represent different evolutionary stages of the lakes, including: (i) carbonate-rich palustrine deposits probably related to periods with strong hydrological seasonality; (ii) massive highly bioturbated organic ooze; (iii) banded organic carbonate-rich facies associated with an increase in the regional effective moisture; (iv) finegrained quartz-rich aeolian/slope-wash sediments; and (v) colluvial facies deposited following the desiccation of the lakes located at higher altitudes. Geochemical and sedimentological analyses of the lacustrine sequences provided information on the palaeohydrological evolution of the Isona tufa mound complex and the palaeoenvironmental conditions of the area over the last 28 ka. Radiometric dating suggests that deposition occurred simultaneously at ca 22 ka in palaeolakes situated at different elevations. A drop in the piezometric level prompted by the opening of springs at lower altitudes probably caused the deactivation of the upper springs and the desiccation of the lakes. Arid conditions prevailed in the area during the Late Glacial and the early Holocene (28·0 to 8·5 ka BP). More humid conditions recorded from 8·5 to 4·2 ka and again since 1·7 ka are in accordance with palaeoenvironmental reconstructions available in the Western Mediterranean since the Last Glacial Maximum.

OBJECTIVE: While psychotic experiences (PEs) are known to be associated with a range of mental and general medical disorders, little is known about the association between PEs and measures of disability. We aimed to investigate this question using the World Mental Health surveys. METHOD: Lifetime occurrences of six types of PEs were assessed along with 21 mental disorders and 14 general medical conditions. Disability was assessed with a modified version of the WHO Disability Assessment Schedule. Descriptive statistics and logistic regression models were used to investigate the association between PEs and high disability scores (top quartile) with various adjustments. RESULTS: Respondents with PEs were more likely to have top quartile scores on global disability than respondents without PEs (19.1% vs. 7.5%; χ2 = 190.1, P < 0.001) as well as greater likelihood of cognitive, social, and role impairment. Relationships persisted in each adjusted model. A significant dose-response relationship was also found for the PE type measures with most of these outcomes. CONCLUSIONS: Psychotic experiences are associated with disability measures with a dose-response relationship. These results are consistent with the view that PEs are associated with disability regardless of the presence of comorbid mental or general medical disorders. This study was funded by the International Center (R03 TW006481‐01), anonymous private donations to IDRAAC, Lebanon, and unrestricted grants from, Algorithm, AstraZeneca, Benta, Bella Pharma, Eli Lilly, Glaxo Smith Kline, Lundbeck, Novartis, Servier, Phenicia, UPO. The Mexican National Comorbidity Survey (MNCS) is supported by The National Institute of Psychiatry Ramon de la Fuente (INPRFMDIES 4280) and by the National Council on Science and Technology (CONACyT‐G30544‐H). The São Paulo Megacity Mental Health Survey is supported by the State of São Paulo Research Foundation (FAPESP) Thematic Project Grant 03/00204‐3. The US National Comorbidity Survey Replication (NCS‐R) is supported by the National Institute of Mental Health (NIMH; U01‐MH60220) with supplemental support from the National Institute of Drug Abuse (NIDA), the Substance Abuse and Mental Health Services Administration (SAMHSA), the Robert Wood Johnson Foundation (RWJF; Grant 044708), and the John W. Alden Trust. John McGrath received John Cade Fellowship APP1056929 from the National Health and Medical Research Council and Niels Bohr Professorship from the Danish National Research Foundation

Alternative, established models for the deglaciation of the midlands of Ireland are tested against an interpretation of a suite of deglacial sediments covering an area of 600 km2 in the east central midland area. Interpretation of the sediments is based on geomorphological mapping, lithostratigraphic characterization of exposures and geotechnical data supported by electrical resistivity tomography (ERT) and ground penetrating radar (GPR). GPR depicted small-scale sedimentological and deformational structures within low-conductivity soft sediments, such as cross-bedding, planar bedding, channel-like features and faulting planes, and revealed the internal architecture of eskers, glaciodeltas, subaqueous fans and raised bogs. ERT data permitted the detection of depth to bedrock and the lithological characterization of unconsolidated sediments. The ten sites presented were surveyed by traditional mapping methods and/or geophysical techniques. This allowed the construction of a local model of the deglaciation of the area which recognized five main stages. An ice sheet covering most of Ireland withdrew as a single body as far as the midlands. At this stage, two main directions of ice retreat are identified from the spatial distribution of meltwater/overflow channels, esker and morainic ridges, and ice-marginal glaciolacustrine deposits. A pattern of deglacial sedimentation into an expanding ice-marginal glacial lake is depicted. The glacial lake was dammed to the west by two ice dome fronts, one decaying to the north-west and another to the south-west, and by the Shannon Basin watershed to the east. Glacial lake outlets identified along the watershed and the altitude of the topset/foreset interface zone depicted in glaciodeltaic deposits allowed the identification of three lake water levels. The highest level is at 87–89 m Ordnance Datum (OD), the second lake level at 84 m OD and the third at 78 m OD. Copyright © 2012 John Wiley & Sons, Ltd.

It is estimated that at least one out of three children with recurrent wheezing is atopic. Reliable diagnostic tools are needed in primary care that allow for adequate identification of these children. The purpose of this study was to assess the value of ImmunoCAP ® Rapid (ICR) Wheeze-Rhinitis Child in the identification of atopy with the use of 10 selected allergens in children with recurrent episodes of wheezing. A multicenter population study is based on primary care. It included children managed consecutively at the health center, who had three or more episodes of wheezing, at least one of them in the last 12 months. Each child completed a physical examination, an epidemiological survey, one capillary blood sampling (110 μl) for ICR, and one venous blood sampling for determination of Phadiatop Infant, total IgE and 10 specific IgE measurements. The children were identified as atopic, based on their clinical signs and symptoms and at least one positive specific IgE (0.35 kU A /l or higher), before knowing the results of ICR, Phadiatop Infant and total IgE. ICR was read by two independent observers. Six classes were evaluated, negative without any color and five positive degrees of pink-red color. Two hundred and fifteen children aged between 1 and 14 years were studied (138 boys); 50.7% were identified as atopic, 39.1 % were sensitized only to inhalant allergens, 6.5% to food allergens and 5.1 % to both. The predominant allergen was the dust mite (39.3%). For ICR, there were 2134 valid double observations. The Kappa index, comparing the negative results vs. any positive result, was 0.91 (95% CI: 0.88-0.94). The intraclass correlation coefficient was 0.98 (95% CI: 0.98-0.99). In the identification of a child as atopic, the positive post-test probability of ICR depended on the color degrees considered: 88.4% for any positive and 97.6% for the most intense tones. The positive post-test probability of Phadiatop Infant and total IgE was 95.6% and 68.2% respectively. ICR showed good reliability for the most prevalent allergen, the dust mite, with a sensitivity of 90.5% (95% CI: 82.1-95.8) and specificity of 88.5% (95% CI: 81.7-93.4). The analysis of the other allergens was limited by the small number of sensitized children. The analysis of receiver operating characteristic curves revealed an area under the curve of 0.84 (95% CI 0.80-0.88) for the cut-off point of specific IgE of 0.35 kU A /1 and of 0.94(CI 0.91-0.97) for 2 kU A /1. A greater intensity of color of the lines of ICR was related to higher levels of specific IgE in blood. ICR is a reliable test for the identification of atopy in children, which identifies most children as atopic, and shows a good correlation in allergen-by-allergen identification. This suggests that it should be regarded as a first-rate tool, in the primary care clinic, for the evaluation of children with recurrent wheezing.

The thrombogenicity of membrane oxygenators as well as clotting parameters profiles, using standard human clotting tests, was analyzed in calves and pigs during 6 h perfusion. Three calves and 3 pigs were connected to extracorporeal circulation with standard heparinization. Blood samples were taken for coagulation variables throughout perfusion, and oxygenators were examined for clot deposits at the end of the experiment. Two out of 3 oxygenators of the calf group presented clot deposits while none in the pig group did. Baseline coagulation variables of pigs showed values similar to those of humans while neither extrinsic nor intrinsic pathways could be activated in calves with standard human coagulation tests. The calf model, in conclusion, was confirmed to be a difficult model for the testing of extracorporeal circulation device resistance to thrombus formation, which is, however, not reflected by standard human coagulation tests. The pig model is a better model in which both coagulation pathways could be activated with standard human coagulation tests.

BACKGROUND The replacement of Sandimmun by Neoral in 1995 was thought to cause subsequent renal function deterioration due to the better bioavailability of the new drug. We prospectively analyzed the effect of a dose-to-dose drug replacement on renal function over 12 months. METHODS AND RESULTS The renal function of 47 consecutive heart transplanted patients was prospectively evaluated before (T0), at 1 (T1), 3 (T3), and 12 (T12) months after drug replacement. Mean serum creatinine was not significantly different at T0 and T12 (142 +/- 55 and 154 +/- 60 micromol/L, p = 0.1). We were able to reduce cyclosporine total and weight-indexed doses by, respectively, 11% and 14% between T0 and T12 (274 +/- 86 to 244 +/- 72 mg/d, p = 0.0003; and 3.7 +/- 1.4 to 3.2 +/- 1.2 mg/kg/d, respectively, p = 0.0005). CONCLUSIONS This study demonstrates that the dose-to-dose replacement of Sandimmun by Neoral is feasible, with no direct influence on renal function over a 1-yr follow-up.

In a calf model, 3 standard and 3 heparin coated intraaortic balloons (IAB) were inserted and left deflated in the descending aorta during 20 min to simulate balloon rupture. At the end of the experiment, the IAB were examined, and 3 samples of each were collected for scanning electron microscopy (SEM) analysis. None of the heparin coated IAB showed any sign of clot or deposit whereas all 3 standard IAB exhibited clots. SEM revealed no deposit on the heparin coated samples while 8 of the 9 standard samples disclosed deposits (p < 0.001). Morphometrically, 16.1+/-21.4% of the surfaces of the standard samples were covered with deposits whereas all the heparin coated samples were free (p = 0.004). The presence of clots on every standard IAB supports the hypothesis that other than local factors of the insertion site can play a role in the vascular complications of IAB. The absence of clots and deposits on the heparin coated IAB suggests a promising role of such devices in circumventing the tendency of clot formation on deflated balloons while avoiding the drawback of systemic anticoagulation.

Background and Objective The morphological evolution of transmyocardial laser channels was analyzed in a pig model. Materials and Methods Five channels were created in the lateral wall of the left ventricle of 12 animals, using a Ho:YAG laser. In half of the animals, an additional infarction was induced in the same area. Animals were sacrificed at one-week intervals until week 5 and the critical regions of the left ventricular wall were subjected to microscopic computed morphometrical analysis. Results There was no clearly patent lumen at any stage. Cross-sectional area of the channels fell from 8.5 ± 1.2 mm2 at day 0 to 2.1 ± 0.1 mm2 at day 35. From day 7 onward, the channel area was gradually replaced by granulation tissue and the proportion of the channel occupied by granulation scar tissue increased from 37 ± 2% at day 7 to 100% at day 28. In the subgroup with concomitant infarction, granulation tissue of both channel and infarction became indistinguishable from day 14 onward. Conclusions These results suggest strongly that channel patency is not the mechanism of angina relief after transmyocardial laser revascularization with Ho:YAG laser. Lasers Surg. Med. 25:79–87, 1999. © 1999 Wiley-Liss, Inc.

Talus flatirons are debris-covered relict slopes, disconnected from the source area, which are relatively common in arid and semi-arid areas. Talus flatiron sequences record the alternation of accumulation and incision phases. These chronosequences may be used for infer temporal changes in the morphogenetic processes acting on the slopes as well as information on the local paleoclimatic history. Talus flatiron sequences developed in the Tremp Depression, eastern Spanish Pyrenees, are analysed from the geomorphological, chronological and paleoenvironmental perspective. The two groups of relict slopes differentiated by means of detailed geomorphological mapping have been dated by optically stimulated luminescence (OSL) and radiocarbon dating at 25–20 kyr (S3) and 5·4–1·7 cal kyr (S2). The talus flatiron group S3 is correlated with a fluvial terrace of the Noguera Pallaresa River (c. 23 kyr bp). The comparison of the ages obtained in the Tremp Depression with chronologies published for talus flatiron sequences in semi-arid areas and other paleoclimatic proxies suggests that the aggradation phases in the slopes occurred during periods with higher humidity and vegetation cover. The chronological differences observed between semi-arid Spain and the Tremp Depression may be partly related to the more humid climate of the latter mountain area. Copyright © 2013 John Wiley & Sons, Ltd.

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The AB-180 is a new implantable centrifugal pump with a low volume dome (10 ml) and a local heparin delivery system which avoids systemic heparinization. This study focuses on its hemodynamic performance. We analyzed 3 anesthetized calves (71.0 +/- 2.5 kg), equipped with arterial pressure (AP), and Swan-Ganz and left atrial pressure (LAP) catheters. The AB-180 pump was installed through a left thoracotomy, with a transmitral left ventricular (LV) inflow cannula inserted via the left appendage and an outflow tract sutured to the descending aorta. LAP, AP, and blood flow across the pump were recorded for various pump speed and in different preload conditions (right atrial pressure = 4, 7, and 10 mm Hg, respectively). The pump significantly unloaded the left heart cavities and was able to increase the mean AP. For an RAP of 10 mm Hg, running the pump at 4,500 rpm decreased the LAP from 11.0 +/- 0.8 mm Hg to 3.0 +/- 0.8 mm Hg (p < 0.001) and augmented the mean AP from 48.2 +/- 6.4 mm Hg to 80.8 +/- 12.1 mm Hg (p < 0.001). A maximal pump flow of 5.6 +/- 0.2 L/min was obtained under these conditions. In addition to the advantage of its particular design, the AB-180 can be considered as an efficient left ventricular assist device (LVAD). It significantly unloads the left heart cavities and ensures efficient systemic AP and blood flow.

Racemic 4-[(N-allyl-cis-3-methyl-4-piperidinyl)phenylamino]-N,N-diethylbenzamide (3a) was synthesized and found to have good affinity and selectivity for the δ receptor. these compounds can be viewed as an analog of BW373U86 and SNC-80 where an internal piperazine nitrogen has been transposed with a benzylic carbon. Functionally, 3a behaves as an agonist at the δ receptor with no measurable stimulation of either the μ or k receptor subtypes and was found to be devoid of any measurable amount of antagonist activity for any opioid receptor. A comparison of 3a to SNC-80 and DPDPE in the [35S]GTPγS functional assay suggests that 3a may be more like the peptide DPDPE.

This work summarizes studies on the preparation, structure, and reactivity of a new heterocyclic system containing phosphorus and nitrogen: 2,8-disubstituted-2,5,8-triaza-1 u 5 -phosphabicyclo[3.3.0]octane 1-oxide (and 1-sulfide).