Abstract
Background
Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, ...and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown.
Methods
Data from patients who underwent endoscopic TSS for a NFPMA (2009–2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes.
Results
Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (
p
= 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm
3
,
p
= 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm
3
,
p
= 0.004).
Conclusion
Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.
Since their isolation almost 20 years ago, the callipeltosides have been of long standing interest to the synthetic community owing to their unique structural features and inherent biological ...activity. Herein we present our full research effort that has led to the synthesis of these molecules. Key aspects of our final strategy include 1) synthesis of the C1–C9 pyran core (5) using an AuCl3‐catalysed cyclisation; 2) formation of C10–C22 vinyl iodide (55) by sequential bidirectional Stille reactions and 3) diastereoselective union of these advanced fragments by means of an alkenylzinc addition (d.r.=91:9 at C9). The common callipeltoside aglycon (4) was completed in a further five steps. Following this, all three sugar fragments were appended to provide the entire callipeltoside family. In addition to this, D‐configured callipeltose B was synthesised and appended to the callipeltoside aglycon. The 1H NMR spectrum of this molecule was found to be significantly different to the natural isolate, further supporting our assignment of callipeltoside B (2).
Easy as A, B, C: The entire callipeltoside family of natural products have been synthesised in a highly convergent manner. This account details our full research effort and presents further evidence to aid in the stereochemical assignment of the glycosidic linkages present in callipeltosides B and C (see scheme).
Emphysema on CT is common in older smokers. We hypothesised that emphysema on CT predicts acute episodes of care for chronic lower respiratory disease among older smokers.
Participants in a lung ...cancer screening study age ≥ 60 years were recruited into a prospective cohort study in 2001-02. Two radiologists independently visually assessed the severity of emphysema as absent, mild, moderate or severe. Percent emphysema was defined as the proportion of voxels ≤ -910 Hounsfield Units. Participants completed a median of 5 visits over a median of 6 years of follow-up. The primary outcome was hospitalization, emergency room or urgent office visit for chronic lower respiratory disease. Spirometry was performed following ATS/ERS guidelines. Airflow obstruction was defined as FEV1/FVC ratio <0.70 and FEV1<80% predicted.
Of 521 participants, 4% had moderate or severe emphysema, which was associated with acute episodes of care (rate ratio 1.89; 95% CI: 1.01-3.52) adjusting for age, sex and race/ethnicity, as was percent emphysema, with similar associations for hospitalisation. Emphysema on visual assessment also predicted incident airflow obstruction (HR 5.14; 95% CI 2.19-21.1).
Visually assessed emphysema and percent emphysema on CT predicted acute episodes of care for chronic lower respiratory disease, with the former predicting incident airflow obstruction among older smokers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background and aims
Opioid formulations with properties to deter abuse (abuse‐deterrent formulations; ADFs) have been developed as one response to the prescription opioid ‘epidemic’. As for all ...medicines, ADFs undergo evaluation of safety and efficacy prior to registration for marketing. However, reduced extra‐medical use (the primary intended outcome of ADFs and reason for their introduction) can only be established in post‐marketing observational studies, comparing them to opioid formulations without abuse‐deterrent properties. This has implications for various features of study design and analysis. We discuss proposals for the design, conduct, governance and reporting of post‐marketing studies on the effectiveness of pharmaceutical and opioid ADFs.
Methods
A review of current guidance documents, public work‐shops and forums and our own experience with post‐marketing studies of ADFs.
Results and conclusions
Research questions for post‐marketing studies on ADFs of opioids should reasonably be framed around detecting any probable intended or unintended clinical and/or meaningful changes in specific aspects of extra‐medical use (e.g. injection use) and harms. Outcomes reported by prevalence and frequency of occurrence and disaggregated by specific product and route of administration can illustrate the magnitude of ADF impact. We argue that a multi‐faceted approach is required, using data from both general population and sentinel high‐risk cohorts and from primary and secondary data sources. The comparator (historical non‐ADF formulation of that opioid, equivalent current generic or similar opioid product), duration of monitoring and analytical approach require justification and should be sufficient to add weight to conclusions of causality. To maximize transparency, we recommend explicit declarations of funding and conflict of interest, establishment of an advisory committee, publication of study protocol and access to study results.
Ion channels play key roles in almost all facets of cellular physiology and have emerged as key host cell factors for a multitude of viral infections. A catalogue of ion channel-blocking drugs have ...been shown to possess antiviral activity, some of which are in widespread human usage for ion channel-related diseases, highlighting new potential for drug repurposing. The emergence of ion channel-virus interactions has also revealed the intriguing possibility that channelopathies may explain some commonly observed virus induced pathologies. This field is rapidly evolving and an up-to-date summary of new discoveries can inform future perspectives. We herein discuss the role of ion channels during viral lifecycles, describe the recently identified ion channel drugs that can inhibit viral infections, and highlight the potential contribution of ion channels to virus-mediated disease.
OBJECTIVE—Macrophage proinflammatory responses induced by modified low-density lipoproteins (modLDL) contribute to atherosclerotic progression. How modLDL causes macrophages to become proinflammatory ...is still enigmatic. Macrophage foam cell formation induced by modLDL requires glycerolipid synthesis. Lipin-1, a key enzyme in the glycerolipid synthesis pathway, contributes to modLDL-elicited macrophage proinflammatory responses in vitro. The objective of this study was to determine whether macrophage-associated lipin-1 contributes to atherogenesis and to assess its role in modLDL-mediated signaling in macrophages.
APPROACH AND RESULTS—We developed mice lacking lipin-1 in myeloid-derived cells and used adeno-associated viral vector 8 expressing the gain-of-function mutation of mouse proprotein convertase subtilisin/kexin type 9 (adeno-associated viral vector 8-proprotein convertase subtilisin/kexin type 9) to induce hypercholesterolemia and plaque formation. Mice lacking myeloid-associated lipin-1 had reduced atherosclerotic burden compared with control mice despite similar plasma lipid levels. Stimulation of bone marrow–derived macrophages with modLDL activated a persistent protein kinase Cα/βII–extracellular receptor kinase1/2–jun proto-oncogene signaling cascade that contributed to macrophage proinflammatory responses that was dependent on lipin-1 enzymatic activity.
CONCLUSIONS—Our data demonstrate that macrophage-associated lipin-1 is atherogenic, likely through persistent activation of a protein kinase Cα/βII–extracellular receptor kinase1/2–jun proto-oncogene signaling cascade that contributes to foam cell proinflammatory responses. Taken together, these results suggest that modLDL-induced foam cell formation and modLDL-induced macrophage proinflammatory responses are not independent consequences of modLDL stimulation but rather are both directly influenced by enhanced lipid synthesis.
The Herschel ATLAS Eales, S.; Dunne, L.; Clements, D. ...
Publications of the Astronomical Society of the Pacific,
05/2010, Letnik:
122, Številka:
891
Journal Article
Recenzirano
Odprti dostop
The Herschel ATLAS is the largest open-time key project that will be carried out on theHerschel Space Observatory. It will survey 570deg2
de
g
2
of the extragalactic sky, 4 times larger than all the ...other Herschel extragalactic surveys combined, in five far-infrared and submillimeter bands. We describe the survey, the complementary multiwavelength data sets that will be combined with the Herschel data, and the six major science programs we are undertaking. Using new models based on a previous submillimeter survey of galaxies, we present predictions of the properties of the ATLAS sources in other wave bands.
Background
This study provides an integrative review of existing risk factors and models for bulimia nervosa (BN) in young girls. We offer a new model for BN that describes two pathways of risk that ...may lead to the initial impulsive act of binge eating and purging in children and adolescents.
Scope
We conducted a selective literature review, focusing on existing and new risk processes for BN in this select population.
Findings
We identify two ways in which girls increase their risk to begin engaging in the impulsive behavior of binge eating and purging. The first is state‐based: the experience of negative mood, in girls attempting to restrain eating, leads to the depletion of self‐control and thus increased risk for loss of control eating. The second is personality‐based: elevations on the trait of negative urgency, or the tendency to act rashly when distressed, increase risk, particularly in conjunction with high‐risk psychosocial learning. We then briefly discuss how these behaviors are reinforced, putting girls at further risk for developing BN.
Conclusions
We highlight several areas in which further inquiry is necessary, and we discuss the clinical implications of the new risk model we described.
Pseudomonas putida KT2440 has long been studied for its diverse and robust metabolisms, yet many genes and proteins imparting these growth capacities remain uncharacterized. Using pooled mutant ...fitness assays, we identified genes and proteins involved in the assimilation of 52 different nitrogen containing compounds. To assay amino acid biosynthesis, 19 amino acid drop-out conditions were also tested. From these 71 conditions, significant fitness phenotypes were elicited in 672 different genes including 100 transcriptional regulators and 112 transport-related proteins. We divide these conditions into 6 classes, and propose assimilatory pathways for the compounds based on this wealth of genetic data. To complement these data, we characterize the substrate range of three promiscuous aminotransferases relevant to metabolic engineering efforts
. Furthermore, we examine the specificity of five transcriptional regulators, explaining some fitness data results and exploring their potential to be developed into useful synthetic biology tools. In addition, we use manifold learning to create an interactive visualization tool for interpreting our BarSeq data, which will improve the accessibility and utility of this work to other researchers.
Understanding the genetic basis of P. putida's diverse metabolism is imperative for us to reach its full potential as a host for metabolic engineering. Many target molecules of the bioeconomy and their precursors contain nitrogen. This study provides functional evidence linking hundreds of genes to their roles in the metabolism of nitrogenous compounds, and provides an interactive tool for visualizing these data. We further characterize several aminotransferases, lactamases, and regulators, which are of particular interest for metabolic engineering.
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