A man with hypophosphataemia

Case report; A section on BMJ, 2011, v. 342, p. 715published_or_final_versio

Plasma EGFR Mutation Detection Associated With Survival Outcomes in Advanced-Stage Lung Cancer

published_or_final_versio

Recurrent pneumothorax in pregnancy: What should we do after placing an intercostal drain

Recurrent pneumothorax is rare during pregnancy. We describe a Chinese woman, with a history of spontaneous pneumothorax managed with an intercostal drain, who developed a recurrent pneumothorax during her 32nd week of pregnancy. There is no consensus on management in this situation. We review the literature and discuss different management approaches. Thirty-six cases of antepartum pneumothorax have been reported in 31 case reports. An intercostal drain only (n=11) or surgeries (thoracotomy, n=9; or video-assisted thoracoscopy, n=2) were common treatment options with no surgical complications reported. Twenty-two (61%) patients progressed to a normal vaginal delivery, while the rest required forceps delivery (22%) or Caesarean section (14%). No single treatment option outweighed the others. There were no maternal or foetal complications reported in those who underwent antepartum surgical intervention. Surgical management of recurrent pneumothorax during pregnancy is well tolerated.published_or_final_versio

Optimized CRISPR-mediated gene knockin reveals FOXP3-independent maintenance of human Treg identity

Regulatory T cell (Treg) therapy is a promising curative approach for a variety of immune-mediated conditions. CRISPR-based genome editing allows precise insertion of transgenes through homology-directed repair, but its use in human Tregs has been limited. We report an optimized protocol for CRISPR-mediated gene knockin in human Tregs with high-yield expansion. To establish a benchmark of human Treg dysfunction, we target the master transcription factor FOXP3 in naive and memory Tregs. Although FOXP3-ablated Tregs upregulate cytokine expression, effects on suppressive capacity in vitro manifest slowly and primarily in memory Tregs. Moreover, FOXP3-ablated Tregs retain their characteristic protein, transcriptional, and DNA methylation profile. Instead, FOXP3 maintains DNA methylation at regions enriched for AP-1 binding sites. Thus, although FOXP3 is important for human Treg development, it has a limited role in maintaining mature Treg identity. Optimized gene knockin with human Tregs will enable mechanistic studies and the development of tailored, next-generation Treg cell therapies

Metabonomics and Intensive Care

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2016. Other selected articles can be found online at http://www.biomedcentral.com/collections/annualupdate2016. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901

Age-Specific Associations of Usual Blood Pressure Variability With Cardiovascular Disease and Mortality: 10-Year Diabetes Mellitus Cohort Study

BACKGROUND: The detrimental effects of increased variability in systolic blood pressure (SBP) on cardiovascular disease (CVD) and mortality risk in patients with diabetes mellitus remains unclear. This study evaluated age‐specific association of usual SBP visit‐to‐visit variability with CVD and mortality in patients with type 2 diabetes mellitus. METHODS AND RESULTS: A retrospective cohort study investigated 155 982 patients with diabetes mellitus aged 45 to 84 years without CVD at baseline (2008–2010). Usual SBP variability was estimated using SBP SD obtained from a mixed‐effects model. Age‐specific associations (45–54, 55–64, 65–74, 75–84 years) between usual SBP variability, CVD, and mortality risk were assessed by Cox regression adjusted for patient characteristics. After a median follow‐up of 9.7 years, 49 816 events (including 34 039 CVD events and 29 211 mortalities) were identified. Elevated SBP variability was independently, positively, and log‐linearly associated with higher CVD and mortality risk among all age groups, with no evidence of any threshold effects. The excess CVD and mortality risk per 5 mm Hg increase in SBP variability within the 45 to 54 age group is >3 times higher than the 70 to 79 age group (hazard ratio, 1.66; 95% CI, 1.49–1.85 versus hazard ratio, 1.19; 95% CI, 1.15–1.23). The significant associations remained consistent among all subgroups. Patients with younger age had a higher association of SBP variability with event outcomes. CONCLUSIONS: The findings suggest that SBP visit‐to‐visit variability was strongly associated with CVD and mortality with no evidence of a threshold effect in a population with diabetes mellitus. As well as controlling overall blood pressure levels, SBP visit‐to‐visit variability should be monitored and evaluated in routine practice, in particular for younger patients

Oral Delivery of Photopolymerizable Nanogels Loaded with Gemcitabine for Pancreatic Cancer Therapy: Formulation Design, and in vitro and in vivo Evaluations

Adi Yugatama,1,2,&ast; Ya-Lin Huang,1,&ast; Ming-Jen Hsu,3 Jia-Pei Lin,1 Fang-Ching Chao,4 Jenny KW Lam,5 Chien-Ming Hsieh1,5,6 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan; 2Department of Pharmacy, Sebelas Maret University, Surakarta, 57126, Indonesia; 3Department of Pharmacology, Taipei Medical University, Taipei, 11031, Taiwan; 4CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay, 91400, France; 5Department of Pharmaceutics, School of Pharmacy, University College, London, WC1N 1AX, UK; 6Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jenny KW Lam, Department of Pharmaceutics, School of Pharmacy, University College London, 29– 39 Brunswick Square, London, WC1N 1AX, UK, Email [email protected] Chien-Ming Hsieh, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan, Email [email protected]: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients.Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug.Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91± 7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07± 19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM’s AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p< 0.01), highlighting NGs’ efficacy in impeding rapid drug metabolism and enhancing retention.Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.Keywords: oral delivery, nanogel, gemcitabine, pancreatic cance

Mastitis diagnostics and performance monitoring: a practical approach

In this paper a review is given of frequently used mastitis diagnostic methods in modern dairy practice. Methods used at the quarter, cow, herd and regional or national level are discussed, including their usability for performance monitoring in udder health. Future developments, such as systems in which milk-derived parameters are combined with modern analytical techniques, are discussed. It is concluded that, although much knowledge is available and science is still developing and much knowledge is available, it is not always fully exploited in practice

Abundance measurements of H₂O and carbon-bearing species in the atmosphere of WASP-127b confirm its super-solar metallicity

The chemical abundances of exoplanet atmospheres may provide valuable information about the bulk compositions, formation pathways, and evolutionary histories of planets. Exoplanets with large, relatively cloud-free atmospheres, and which orbit bright stars provide the best opportunities for accurate abundance measurements. For this reason, we measured the transmission spectrum of the bright (V∼10.2), large (1.37 RJ), sub-Saturn mass (0.19 MJ) exoplanet WASP-127b across the near-UV to near-infrared wavelength range (0.3–5 μm), using the Hubble and Spitzer Space Telescopes. Our results show a feature-rich transmission spectrum, with absorption from Na, H2O, and CO2, and wavelength-dependent scattering from small-particle condensates. We ran two types of atmospheric retrieval models: one enforcing chemical equilibrium, and the other which fit the abundances freely. Our retrieved abundances at chemical equilibrium for Na, O and C are all super-solar, with abundances relative to solar values of 9+15−6⁠, 16+7−5⁠, and 26+12−9 respectively. Despite giving conflicting C/O ratios, both retrievals gave super-solar CO2 volume mixing ratios, which adds to the likelihood that WASP-127b’s bulk metallicity is super-solar, since CO2 abundance is highly sensitive to atmospheric metallicity. We detect water at a significance of 13.7 σ. Our detection of Na is in agreement with previous ground-based detections, though we find a much lower abundance, and we also do not find evidence for Li or K despite increased sensitivity. In the future, spectroscopy with JWST will be able to constrain WASP-127b’s C/O ratio, and may reveal the formation history of this metal-enriched, highly observable exoplanet

Etoricoxib-induced life-threatening hyperkalemia and acute kidney dysfunction against the background of telmisartan and a low sodium diet

Drug-induced hyperkalemia is not uncommon and may be life-threatening when presenting acutely in the emergency department. We present a case of severe hyperkalemia precipitated acutely by etoricoxib in a patient who was on telmisartan and a low sodium (potassium chloride-rich) diet. A 75-year-old male with a past medical history of well-controlled diabetes and hypertension was prescribed etoricoxib (90 mg daily) for 3 days for musculoskeletal backache. He had been taking his routine medications including telmisartan and a potassium-rich salt substitute for many years, without any recent change in dosage or quantity. There was evidence of microalbuminurea; however, the renal functions and electrolytes prior to starting etoricoxib were normal. He presented to the emergency department with signs and symptoms of life-threatening hyperkalemia (serum potassium 7.7 mEq/dl), accelerated hypertension, congestive heart failure, pulmonary edema and acute renal failure. Acute medical management and withholding all drugs that could cause hyperkalemia improved his serum potassium levels over 24 h and renal parameters within 5 days. All the other drugs except etoricoxib were restarted under observation over 8 weeks with no recurrence of the acute episode. Non-steroidal analgesics and other COX-2 inhibitors (rofecoxib and celecoxib) have been known to precipitate renal failure and hyperkalemia specially in patients at risk for the same; although not unexpected, this may be the first reported case of life-threatening hyperkalemia precipitated by etoricoxib in a previously stable patient having increased risk of renal failure and hyperkalemia