In package inactivation of Bacillus atrophaeus spores using high voltage atmospheric cold plasma

Introduction: Hospital acquired infections are of a great concern, considering a large number of infections reported every year. Sterilization is an important step in healthcare industry that is attained by utilizing conventional sterilization approaches. It includes heat treatment, use of chemicals like ethylene oxide, hydrogen peroxide, and gamma radiation. These methods have drawbacks such as material properties of medical devices could be altered or damaged. Therefore, it is necessary to investigate cheap alternative approaches to achieve sterilization without generating toxic residues. Nonthermal atmospheric plasma is a fourth state of matter that consists of charged particles, positive and negative ions and number of reactive species. This plasma mixture has greater microbicidal effects on number of food products and wide range of surfaces. Novel nonthermal plasma technology has number of applications in food and medical industries. Methods: The objective of this study was to investigate the effect of plasma parameters on inactivation of resistant biological forms of Bacillus atrophaeus inside a sealed package. Bacillus atrophaeus spore strip (spore population 6.36 log10/strip) was placed in a petri dish, sealed in a polypropylene container, and was subjected to high voltage atmospheric cold plasma treatment (HVACP). HVACP system was operated at 70 kVRMS and at a frequency of 50 Hz. The two 15-cm diameter aluminum disk electrodes were separated by a rigid polypropylene container which served as a sample holder and as a dielectric barrier. The distance between the two electrodes was equal to the height of the container (22 mm). The top electrode served as a high voltage electrode and bottom electrode was grounded. The discharge was monitored using electrical probes and an Agilent InfiniVision 2000 X-Series Oscilloscope. Influence of different process parameters on spore inactivation including treatment time, mode of exposure (direct/indirect), and working gas types were mainly evaluated. Effect of relative humidity on HVACP inactivation efficacy was also assessed. The inactivation efficacy was determined using standard colony count method. To assess gas composition following HVACP exposure, optical absorption spectroscopy was used. Results: A strong effect of process parameters on inactivation was observed. Direct exposure to plasma was very effective for spore inactivation, achieving ≥6 log cycle reduction of spores in all gas types tested, in only 60 s of treatment time. However, a strong influence of gas type was noted on spore reductions where indirect mode of plasma exposure was utilized. The relative humidity also noted as a critical factor in bacterial spore inactivation by HVACP, where a major role of plasma generated species other than ozone was noted. Conclusion: Overall, a strong influence of process parameters on spore inactivation was noted. Effective in-package bacterial spore inactivation within 30‑60 s demonstrates the promising potential application of HVACP for sterilization of medical devices and heat sensitive materials

A demonstration of an affinity between pyrite and organic matter in a hydrothermal setting

One of the key-principles of the iron-sulphur world theory is to bring organic molecules close enough to interact with each other, using the surface of pyrite as a substrate in a hydrothermal setting. The present paper explores the relationship of pyrite and organic matter in a hydrothermal setting from the geological record; in hydrothermal calcite veins from Carboniferous limestones in central Ireland. Here, the organic matter is accumulated as coatings around, and through, pyrite grains. Most of the pyrite grains are euhedral-subhedral crystals, ranging in size from ca 0.1-0.5 mm in diameter, and they are scattered throughout the matrix of the vein calcite. The organic matter was deposited from a hydrothermal fluid at a temperature of at least 200°C, and gives a Raman signature of disordered carbon. This study points to an example from a hydrothermal setting in the geological record, demonstrating that pyrite can have a high potential for the concentration and accumulation of organic materials

Soluble human Suppression of Tumorigenicity 2 is associated with endoscopic activity in patients with moderate-to-severe ulcerative colitis treated with golimumab

Suppressor of Tumorigenicity 2 (ST2) is an IL33 receptor detected in the mucosa and serum of ulcerative colitis (UC) patients. We evaluated soluble ST2 (sST2) as a surrogate biomarker of disease outcome and therapeutic response, in moderate-to-severe UC patients treated with golimumab.Agência financiadora Merck Sharp and Dohme, Lda, Portugal MK8259-22info:eu-repo/semantics/publishedVersio

Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study

<p>Abstract</p> <p>Background</p> <p>Septic shock is the most feared complication of chemotherapy-induced febrile neutropenia. So far, there are no robust biomarkers that can stratify patients to the risk of sepsis complications. The VEGF-A axis is involved in the control of microvascular permeability and has been involved in the pathogenesis of conditions associated with endothelial barrier disruption such as sepsis. sFlt-1 is a soluble variant of the VEGF-A receptor VEGFR-1 that acts as a decoy receptor down-regulating the effects of VEGF-A. In animal models of sepsis, sFlt-1 was capable to block the barrier-breaking negative effects of VEGF-A and to significantly decrease mortality. In non-neutropenic patients, sFlt-1 has been shown to be a promising biomarker for sepsis severity.</p> <p>Methods</p> <p>We prospectively evaluated concentrations of sFlt-1 and VEGF-A at different time-points during febrile neutropenia, and evaluated the association of these levels with sepsis severity and septic shock development.</p> <p>Results</p> <p>Neutropenic patients that evolved with septic shock (n = 10) presented higher levels of sFlt-1 and VEGF-A measured 48 hours after fever onset than patients with non-complicated sepsis (n = 31) and levels of these biomarkers correlated with sepsis severity scores. Estimation of the diagnostic accuracy of sFlt-1 levels for the discrimination of patients that evolved to septic shock yielded promising results in our study population.</p> <p>Discussion</p> <p>Our data suggest that sFlt-1 and VEGF-A could be useful biomarkers for sepsis severity in patients with febrile neutropenia. In addition, the kinetics of sFlt-1 release in patients that evolve to septic shock suggest that the sFlt-1 could be a salvage compensatory mechanism in patients with septic shock, but that the magnitude of the sFlt-1 release observed in human sepsis is not sufficient to reproduce the beneficial anti-VEGF-A effects observed in animal models of sepsis.</p

Application of molecular cytogenetic techniques to clarify apparently balanced complex chromosomal rearrangements in two patients with an abnormal phenotype: case report

<p>Abstract</p> <p>Background</p> <p>Complex chromosomal rearrangements (CCR) are rare cytogenetic findings that are difficult to karyotype by conventional cytogenetic analysis partially because of the relative low resolution of this technique. High resolution genotyping is necessary in order to identify cryptic imbalances, for instance near the multiple breakpoints, to explain the abnormal phenotype in these patients. We applied several molecular techniques to elucidate the complexity of the CCRs of two adult patients with abnormal phenotypes.</p> <p>Results</p> <p>Multicolour fluorescence in situ hybridization (M-FISH) showed that in patient 1 the chromosomes 1, 10, 15 and 18 were involved in the rearrangement whereas for patient 2 the chromosomes 5, 9, 11 and 13 were involved. A 250 k Nsp1 SNP-array analysis uncovered a deletion in chromosome region 10p13 for patient 1, harbouring 17 genes, while patient 2 showed no pathogenic gains or losses. Additional FISH analysis with locus specific BAC-probes was performed, leading to the identification of cryptic interstitial structural rearrangements in both patients.</p> <p>Conclusion</p> <p>Application of M-FISH and SNP-array analysis to apparently balanced CCRs is useful to delineate the complex chromosomal rearrangement in detail. However, it does not always identify cryptic imbalances as an explanation for the abnormal phenotype in patients with a CCR.</p

Subclinical thyroid dysfunction and cognitive decline in old age

&lt;p&gt;Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).&lt;/p&gt; &lt;p&gt;Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) &#60;0.45 mU/L or &#62;4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.&lt;/p&gt; &lt;p&gt;Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.&lt;/p&gt; &lt;p&gt;Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.&lt;/p&gt

Subclinical thyroid dysfunction and cognitive decline in old age

&lt;p&gt;Background: Subclinical thyroid dysfunction has been implicated as a risk factor for cognitive decline in old age, but results are inconsistent. We investigated the association between subclinical thyroid dysfunction and cognitive decline in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER).&lt;/p&gt; &lt;p&gt;Methods: Prospective longitudinal study of men and women aged 70–82 years with pre-existing vascular disease or more than one risk factor to develop this condition (N = 5,154). Participants taking antithyroid medications, thyroid hormone supplementation and/or amiodarone were excluded. Thyroid function was measured at baseline: subclinical hyper- and hypothyroidism were defined as thyroid stimulating hormones (TSH) &#60;0.45 mU/L or &#62;4.50 mU/L respectively, with normal levels of free thyroxine (FT4). Cognitive performance was tested at baseline and at four subsequent time points during a mean follow-up of 3 years, using five neuropsychological performance tests.&lt;/p&gt; &lt;p&gt;Results: Subclinical hyperthyroidism and hypothyroidism were found in 65 and 161 participants, respectively. We found no consistent association of subclinical hyper- or hypothyroidism with altered cognitive performance compared to euthyroid participants on the individual cognitive tests. Similarly, there was no association with rate of cognitive decline during follow-up.&lt;/p&gt; &lt;p&gt;Conclusion: We found no consistent evidence that subclinical hyper- or hypothyroidism contribute to cognitive impairment or decline in old age. Although our data are not in support of treatment of subclinical thyroid dysfunction to prevent cognitive dysfunction in later life, only large randomized controlled trials can provide definitive evidence.&lt;/p&gt

Parathyroid adenoma apoplexy as a temporary solution of primary hyperparathyroidism: a case report

<p>Abstract</p> <p>Introduction</p> <p>The natural history of patients with spontaneous parathyroid necrosis is unknown. In this case report we describe the clinical course, laboratory, radiographic, bone densitometry tests, parathyroid ultrasonography and scintigraphy examinations of a patient performed over a period of eight years after she first presented with a sudden episode of spontaneous resolution of primary hyperparathyroidism (PHPT).</p> <p>Case presentation</p> <p>A 24-year-old woman with a clinical history and laboratory and radiographic tests compatible with PHPT suffered a sudden episode of cervical pain and presented with clinical evidence of hypocalcemia. Biopsy of a cervical nodule revealed necrotic material compatible with ischemia of the parathyroid. The follow-up of the patient presented four distinct phases: the first, which lasted two years, was compatible with a period of bone hunger during which it was necessary to introduce calcitriol and calcium carbonate. During this period, the patient showed bone mass gain. The second phase was characterized by normalization of calcium and parathyroid hormone levels and its end was difficult to define. During the third phase there was a recurrence of hypercalcemia associated with elevated parathyroid hormone (PTH) levels and loss of bone mass. The last phase corresponded to the interval after parathyroidectomy, which was characterized by normalization of serum levels of calcium and PTH, as well as bone mass gain.</p> <p>Conclusion</p> <p>This case report indicates that spontaneous resolution of PHPT by adenoma necrosis is potentially temporary. Thus, in cases in which a conservative approach is chosen, clinical and laboratory follow-up is indispensable. Bone mass measurement is a useful tool in the follow-up of these cases. However, this option exposes the patient to a potential roller-coaster ride of bone mass gain and loss, whose long term consequences are still unknown.</p

Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.

FLT3 internal tandem duplication (FLT3ITD) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3ITD AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3ITD AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3ITD and other TK activating mutation-driven leukemias.P.G. is funded by the Wellcome Trust (109967/Z/15/Z) and was previously supported by the Academy of medical Sciences and Lady Tata Memorial Trust. The Huntly lab is funded by European Research Council, MRC, Bloodwise, the Kay Kendall Leukaemia Fund, the Cambridge NIHR Biomedical Research Centre, and core support grants to the Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute. C.F. and A.S.H.C are funded by the Medical Research Council, Core Grant to the Cancer Unit. P.M-P. is supported by a grant from Cancer Research UK (C56179/A21617). D.S. is a Postdoctoral Fellow of the Mildred-Scheel Organisation, German Cancer Aid. This research was supported by the CIMR Flow Cytometry Core Facility. We would like to thank the Welcome Trust Sanger Institute facility for the MiSeq run