The Prognostic Significance of Protein-energy Malnutrition in Geriatric Patients

Although it has been shown that protein-energy malnutrition is a predictor of adverse outcome in geriatric patients, it is unclear whether this is due to underlying disease or disability, or whether malnutrition is an independent outcome predictor. To clarify the predictive role of malnutrition, we analysed the 4.5-year mortality and living location follow-ups of 219 geriatric patients admitted to a geriatric assessment unit. Prevalence of anthropometric and serological malnutrition indicators were between 13.7% and 39.8% at hospital admission. In bivariate models, prealbumin, subnormal arm muscle area, and subnormal body weight were predictors of mortality and survival at home. On the other hand, albumin, transferrin, and triceps skin-fold thickness did not predict these outcomes. In multivariate models the hazard ratio (HR) of 4.5-year mortality remained significant with an HR of 1.8 (95% CI 1.3−2.6) for subnormal arm muscle area, and 1.6 (95% CI 1.3−2.6) for subnormal body weight. Prealbumin was the strongest serological outcome predictor (multivariate mortality HR 1.9, 95% CI, 1.3−2.8). In these models, subnormal cognitive function, impaired physical function, and creatinine clearance < 30 ml/min were also associated with increased mortality. Malnutrition did not predict hospital discharge location, but among patients discharged home, those with initial malnutrition had a decreased length of survival at home. Our findings indicate that certain protein-energy malnutrition indicators are independent risk factors predicting decreased length of overall survival and survival at home in geriatric patients. Physicians should screen actively for this often unrecognized problem and initiate appropriate treatment strategie

The CXCR4/CXCR7/CXCL12 Axis Is Involved in a Secondary but Complex Control of Neuroblastoma Metastatic Cell Homing.

Neuroblastoma (NB) is one of the most deadly solid tumors of the young child, for which new efficient and targeted therapies are strongly needed. The CXCR4/CXCR7/CXCL12 chemokine axis has been involved in the progression and organ-specific dissemination of various cancers. In NB, CXCR4 expression was shown to be associated to highly aggressive undifferentiated tumors, while CXCR7 expression was detected in more differentiated and mature neuroblastic tumors. As investigated in vivo, using an orthotopic model of tumor cell implantation of chemokine receptor-overexpressing NB cells (IGR-NB8), the CXCR4/CXCR7/CXCL12 axis was shown to regulate NB primary and secondary growth, although without any apparent influence on organ selective metastasis. In the present study, we addressed the selective role of CXCR4 and CXCR7 receptors in the homing phase of metastatic dissemination using an intravenous model of tumor cell implantation. Tail vein injection into NOD-scid-gamma mice of transduced IGR-NB8 cells overexpressing CXCR4, CXCR7, or both receptors revealed that all transduced cell variants preferentially invaded the adrenal gland and typical NB metastatic target organs, such as the liver and the bone marrow. However, CXCR4 expression favored NB cell dissemination to the liver and the lungs, while CXCR7 was able to strongly promote NB cell homing to the adrenal gland and the liver. Finally, coexpression of CXCR4 and CXCR7 receptors significantly and selectively increased NB dissemination toward the bone marrow. In conclusion, CXCR4 and CXCR7 receptors may be involved in a complex and organ-dependent control of NB growth and selective homing, making these receptors and their inhibitors potential new therapeutic targets

The Clacton Spear: the last one hundred years

In 1911 an eminent amateur prehistorian pulled the broken end of a pointed wooden shaft from Palaeolithic-age sediments at a seaside town in Essex. This artefact, still the earliest worked wood to be discovered in the world, became known as the Clacton Spear. Over the past 100 years it has variously been interpreted as a projectile weapon, a stave, a digging stick, a snow probe, a lance, a game stake and a prod to ward off rival scavengers. These perspectives have followed academic fashions, as the popular views of early hominins have altered. Since discovery the Clacton spear has also been replicated twice, has undergone physical transformations due to preservation treatments, and has featured in two public exhibitions. Within this article the changing context of the spear, its parallels, and all previous conservation treatments and their impacts are assessed.© 2015 Royal Archaeological Institute. This is an Accepted Manuscript of an article published by Taylor & Francis in The Archaeological Journal on 3rd March 2015, available online: http://www.tandfonline.com/doi.org/10.1080/00665983.2015.1008839.The attached document is the author(’s’) final accepted/submitted version of the journal article. You are advised to consult the publisher’s version if you wish to cite from it

Autochthonous Case of Pulmonary Histoplasmosis, Switzerland.

In Europe, pulmonary histoplasmosis is rarely diagnosed except in travelers. We report a probable autochthonous case of severe chronic pulmonary histoplasmosis in an immunocompetent man in Switzerland without travel history outside of Europe. Diagnosis was achieved by histopathology, fungal culture, and serology, but the source of the infection remains speculative

Expression of the Neuroblastoma-Associated ALK-F1174L Activating Mutation During Embryogenesis Impairs the Differentiation of Neural Crest Progenitors in Sympathetic Ganglia.

Neuroblastoma (NB) is an embryonal malignancy derived from the abnormal differentiation of the sympathetic nervous system. The Anaplastic Lymphoma Kinase (ALK) gene is frequently altered in NB, through copy number alterations and activating mutations, and represents a predisposition in NB-genesis when mutated. Our previously published data suggested that ALK activating mutations may impair the differentiation potential of neural crest (NC) progenitor cells. Here, we demonstrated that the expression of the endogenous ALK gene starts at E10.5 in the developing sympathetic ganglia (SG). To decipher the impact of deregulated ALK signaling during embryogenesis on the formation and differentiation of sympathetic neuroblasts, Sox10-Cre;LSL-ALK-F1174L embryos were produced to restrict the expression of the human ALK-F1174L transgene to migrating NC cells (NCCs). First, ALK-F1174L mediated an embryonic lethality at mid-gestation and an enlargement of SG with a disorganized architecture in Sox10-Cre;LSL-ALK-F1174L embryos at E10.5 and E11.5. Second, early sympathetic differentiation was severely impaired in Sox10-Cre;LSL-ALK-F1174L embryos. Indeed, their SG displayed a marked increase in the proportion of NCCs and a decrease of sympathetic neuroblasts at both embryonic stages. Third, neuronal and noradrenergic differentiations were blocked in Sox10-Cre;LSL-ALK-F1174L SG, as a reduced proportion of Phox2b &lt;sup&gt;+&lt;/sup&gt; sympathoblasts expressed βIII-tubulin and almost none were Tyrosine Hydroxylase (TH) positive. Finally, at E10.5, ALK-F1174L mediated an important increase in the proliferation of Phox2b &lt;sup&gt;+&lt;/sup&gt; progenitors, affecting the transient cell cycle exit observed in normal SG at this embryonic stage. Altogether, we report for the first time that the expression of the human ALK-F1174L mutation in NCCs during embryonic development profoundly disturbs early sympathetic progenitor differentiation, in addition to increasing their proliferation, both mechanisms being potential crucial events in NB oncogenesis

Clinical Aureobasidium Isolates Are More Fungicide Sensitive than Many Agricultural Isolates.

Fungicide applications in agriculture and medicine can promote the evolution of resistant, pathogenic fungi, which is a growing problem for disease management in both settings. Nonpathogenic mycobiota are also exposed to fungicides, may become tolerant, and could turn into agricultural or medical problems, for example, due to climate change or in immunocompromised individuals. However, quantitative data about fungicide sensitivity of environmental fungi is mostly lacking. Aureobasidium species are widely distributed and frequently isolated yeast-like fungi. One species, A. pullulans, is used as a biocontrol agent, but is also encountered in clinical samples, regularly. Here, we compared 16 clinical and 30 agricultural Aureobasidium isolates based on whole-genome data and by sensitivity testing with the 3 fungicides captan, cyprodinil, and difenoconazole. Our phylogenetic analyses determined that 7 of the 16 clinical isolates did not belong to the species A. pullulans. These isolates clustered with other Aureobasidium species, including A. melanogenum, a recently separated species that expresses virulence traits that are mostly lacking in A. pullulans. Interestingly, the clinical Aureobasidium isolates were significantly more fungicide sensitive than many isolates from agricultural samples, which implies selection for fungicide tolerance of non-target fungi in agricultural ecosystems. IMPORTANCE Environmental microbiota are regularly found in clinical samples and can cause disease, in particular, in immunocompromised individuals. Organisms of the genus Aureobasidium belonging to this group are highly abundant, and some species are even described as pathogens. Many A. pullulans isolates from agricultural samples are tolerant to different fungicides, and it seems inevitable that such strains will eventually appear in the clinics. Selection for fungicide tolerance would be particularly worrisome for species A. melanogenum, which is also found in the environment and exhibits virulence traits. Based on our observation and the strains tested here, clinical Aureobasidium isolates are still fungicide sensitive. We, therefore, suggest monitoring fungicide sensitivity in species, such as A. pullulans and A. melanogenum, and to consider the development of fungicide tolerance in the evaluation process of fungicides

On the evolution of the tymbalian tymbal organ: Comment on “Planthopper bugs use a fast, cyclic elastic recoil mechanism for effective vibrational communication at small body size” by Davranoglou et al. 2019

In ihrer kürzlich erschienenen Arbeit (Davranoglou et al. 2019) untersuchten die Autoren an lebenden Exemplaren von Agalmatium bilobium (Issidae) mit modernsten Methoden (microCT) die Interaktionen zwischen Muskulatur und bestimmten Anteilen des Exoskeletts zur Vibrationserzeugung und beschreiben deren biomechanische Grundlage. Auf der Basis des morphologischen Vergleichs mit Museumsmaterial von Vertretern der meisten Taxa der Fulgoromorpha (Spitzkopfzikaden) im Familienrang postulieren Davranoglou et al. (2019), ein „neues und bisher übersehenes“ Organ entdeckt zu haben, das sie als „snapping organ“ bezeichnen und als charakteristisch für die Fulgoromorpha (mit Ausnahme der Delphacidae) interpretieren. Wir sehen diese Ergebnisse aus folgenden Gründen kritisch: 1. In ihrer umfassenden Übersicht zu den vibrationserzeugenden Organen der Hemiptera stellten Wessel et al. (2014) die Hypothese auf, dass sich alle bisher bekannten Strukturen zur Schall- und Vibrationserzeugung auf ein Organ zurückführen lassen, das mit hoher Wahrscheinlichkeit bei der Stammart aller Hemipteren oberhalb der Sternorrhyncha vorhanden war, und eine Synapomorphie dieses Taxons, der sog. Tymbalia (Wessel et al. 2014), darstellt. Da aufgrund der morphologischen Disparität des Organs in den einzelnen Taxa die Homologieverhältnisse schwierig zu beurteilen sind, stellten Wessel et al. (2014) Kriterien für das „Tymbal der Tymbalia“ auf. Das sogenannte „snapping organ“ erfüllt alle Kriterien dieses Tymbal-Organes. Die Einführung eines neuen Begriffes für eine bestimmte Struktur in einer langen und komplexen Kette evolutionärer Transformationen ist daher unnötig, wenn nicht sogar irreführend. Wir empfehlen daher dringend, in zukünftigen Arbeiten den Begriff „tymbalian tymbal organ with a snapping mechanism“ zu verwenden. 2. Die Grundannahme von Davranoglou et al. (2019), dass – im Gegensatz zum neu entdeckten „snapping organ“ der Fulgoromorpha – allen Cicadomorpha ein „tymbal-ähnliches Or-gan“ gemeinsam sei, ist zu stark vereinfacht und vernachlässigt die enorme Vielfalt der Ausprägungen des Tymbals bei Nicht-Singzikaden innerhalb der Cicadomorpha. In Anbetracht der verfügbaren Studien scheint es daher zweifelhaft, dass sich die vibrationserzeugenden Strukturen dreimal unabhängig voneinander entwickelt haben sollen, wie es die phylogenetische Interpretation bei Davranoglou et al. (2019: Abb. 3) suggeriert

Wild-type ALK and activating ALK-R1275Q and ALK-F1174L mutations upregulate Myc and initiate tumor formation in murine neural crest progenitor cells.

The anaplastic lymphoma kinase (ALK) gene is overexpressed, mutated or amplified in most neuroblastoma (NB), a pediatric neural crest-derived embryonal tumor. The two most frequent mutations, ALK-F1174L and ALK-R1275Q, contribute to NB tumorigenesis in mouse models, and cooperate with MYCN in the oncogenic process. However, the precise role of activating ALK mutations or ALK-wt overexpression in NB tumor initiation needs further clarification. Human ALK-wt, ALK-F1174L, or ALK-R1275Q were stably expressed in murine neural crest progenitor cells (NCPC), MONC-1 or JoMa1, immortalized with v-Myc or Tamoxifen-inducible Myc-ERT, respectively. While orthotopic implantations of MONC-1 parental cells in nude mice generated various tumor types, such as NB, osteo/chondrosarcoma, and undifferentiated tumors, due to v-Myc oncogenic activity, MONC-1-ALK-F1174L cells only produced undifferentiated tumors. Furthermore, our data represent the first demonstration of ALK-wt transforming capacity, as ALK-wt expression in JoMa1 cells, likewise ALK-F1174L, or ALK-R1275Q, in absence of exogenous Myc-ERT activity, was sufficient to induce the formation of aggressive and undifferentiated neural crest cell-derived tumors, but not to drive NB development. Interestingly, JoMa1-ALK tumors and their derived cell lines upregulated Myc endogenous expression, resulting from ALK activation, and both ALK and Myc activities were necessary to confer tumorigenic properties on tumor-derived JoMa1 cells in vitro

Low number of neurosecretory vesicles in neuroblastoma impairs massive catecholamine release and prevents hypertension.

Neuroblastoma (NB) is a pediatric cancer of the developing sympathetic nervous system. It produces and releases metanephrines, which are used as biomarkers for diagnosis in plasma and urine. However, plasma catecholamine concentrations remain generally normal in children with NB. Thus, unlike pheochromocytoma and paraganglioma (PHEO/PGL), two other non-epithelial neuroendocrine tumors, hypertension is not part of the usual clinical picture of patients with NB. This suggests that the mode of production and secretion of catecholamines and metanephrines in NB is different from that in PHEO/PGL, but little is known about these discrepancies. Here we aim to provide a detailed comparison of the biosynthesis, metabolism and storage of catecholamines and metanephrines between patients with NB and PHEO. Catecholamines and metanephrines were quantified in NB and PHEO/PGL patients from plasma and tumor tissues by ultra-high pressure liquid chromatography tandem mass spectrometry. Electron microscopy was used to quantify neurosecretory vesicles within cells derived from PHEO tumor biopsies, NB-PDX and NB cell lines. Chromaffin markers were detected by qPCR, IHC and/or immunoblotting. Plasma levels of metanephrines were comparable between NB and PHEO patients, while catecholamines were 3.5-fold lower in NB vs PHEO affected individuals. However, we observed that intratumoral concentrations of metanephrines and catecholamines measured in NB were several orders of magnitude lower than in PHEO. Cellular and molecular analyses revealed that NB cell lines, primary cells dissociated from human tumor biopsies as well as cells from patient-derived xenograft tumors (NB-PDX) stored a very low amount of intracellular catecholamines, and contained only rare neurosecretory vesicles relative to PHEO cells. In addition, primary NB expressed reduced levels of numerous chromaffin markers, as compared to PHEO/PGL, except catechol O-methyltransferase and monoamine oxidase A. Furthermore, functional assays through induction of chromaffin differentiation of the IMR32 NB cell line with Bt2cAMP led to an increase of neurosecretory vesicles able to secrete catecholamines after KCl or nicotine stimulation. The low amount of neurosecretory vesicles in NB cytoplasm prevents catecholamine storage and lead to their rapid transformation by catechol O-methyltransferase into metanephrines that diffuse in blood. Hence, in contrast to PHEO/PGL, catecholamines are not secreted massively in the blood, which explains why systemic hypertension is not observed in most patients with NB

Rocking Promotes Sleep in Mice through Rhythmic Stimulation of the Vestibular System.

Rocking has long been known to promote sleep in infants and, more recently, also in adults, increasing NREM sleep stage N2 and enhancing EEG slow waves and spindles. Nevertheless, whether rocking also promotes sleep in other species, and what the underlying mechanisms are, has yet to be explored. In the current study, C57BL/6J mice equipped with EEG and EMG electrodes were rocked laterally during their main sleep period, i.e., the 12-h light phase. We observed that rocking affected sleep in mice with a faster optimal rate than in humans (1.0 versus 0.25 Hz). Specifically, rocking mice at 1.0 Hz increased time spent in NREM sleep through the shortening of wake episodes and accelerated sleep onset. Although rocking did not increase EEG activity in the slow-wave and spindle-frequency ranges in mice, EEG theta activity (6-10 Hz) during active wakefulness shifted toward slower frequencies. To test the hypothesis that the rocking effects are mediated through the vestibular system, we used the otoconia-deficient tilted (tlt) mouse, which cannot encode linear acceleration. Mice homozygous for the tlt mutation were insensitive to rocking at 1.0 Hz, while the sleep and EEG response of their heterozygous and wild-type littermates resembled those of C57BL/6J mice. Our findings demonstrate that rocking also promotes sleep in the mouse and that this effect requires input from functional otolithic organs of the vestibule. Our observations also demonstrate that the maximum linear acceleration applied, and not the rocking rate per se, is key in mediating the effects of rocking on sleep