Background
Video-assisted thoracoscopic surgery (VATS) approaches are increasingly used in lung cancer surgery, but little is known about their impact on patients’ health-related quality of life ...(HRQL). This prospective study measured recovery and HRQL in the year after VATS for non-small cell lung cancer (NSCLC) and explored the feasibility of HRQL data collection in patients undergoing VATS or open lung resection.
Patients and Methods
Consecutive patients referred for surgical assessment (VATS or open surgery) for proven/suspected NSCLC completed HRQL and fatigue assessments before and 1, 3, 6 and 12 months post-surgery. Mean HRQL scores were calculated for patients who underwent VATS (segmental, wedge or lobectomy resection). Paired
t
-tests compared mean HRQL between baseline and expected worst (1 month), early (3 months) and longer-term (12 months) recovery time points.
Results
A total of 92 patients received VATS, and 18 open surgery. Questionnaire response rates were high (pre-surgery 96–100%; follow-up 67–85%). Pre-surgery, VATS patients reported mostly high (good) functional health scores (European Organisation for Research and Treatment of Cancer) EORTC function scores > 80 and low (mild) symptom scores (EORTC symptom scores < 20). One-month post-surgery, patients reported clinically and statistically significant deterioration in overall health and physical, role and social function (19–36 points), and increased fatigue, pain, dyspnoea, appetite loss and constipation EORTC 12–26; multidimensional fatigue inventory (MFI-20) 3–5. HRQL had not fully recovered 12 months post-surgery, with reduced physical, role and social function (10–14) and persistent fatigue and dyspnoea (EORTC 12–22; MFI-20 2.7–3.2).
Conclusions
Lung resection has a considerable detrimental impact on patients’ HRQL that is not fully resolved 12 months post-surgery, despite a VATS approach.
Graphic Abstract
Penicillin binding proteins (PBPs) are responsible for synthesizing and modifying the bacterial cell wall, and in Escherichia coli the loss of several nonessential low-molecular-weight PBPs gives ...rise to abnormalities in cell shape and division. To determine whether these proteins help connect the flagellar basal body to the peptidoglycan wall, we surveyed a set of PBP mutants and found that motility in an agar migration assay was compromised by the simultaneous absence of four enzymes: PBP4, PBP5, PBP7, and AmpH. A wild-type copy of any one of these restored migration, and complementation depended on the integrity of the PBP active-site serine. However, the migration defect was caused by the absence of flagella instead of improper flagellar assembly. Migration was restored if the flhDC genes were overexpressed or if the rcsB or cpxR genes were deleted. Thus, migration was inhibited because the Rcs and Cpx stress response systems were induced in the absence of these four specific PBPs. Furthermore, in this situation Rcs induction depended on the presence of CpxR. The results imply that small changes in peptidoglycan structure are sufficient to activate these stress responses, suggesting that a specific cell wall fragment may be the signal being sensed. The fact that four PBPs must be inactivated may explain why large perturbations to the envelope are required to induce stress responses.
Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the ...neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.
The High Seas are increasingly the subject of exploitation. Although Marine Protected Areas (MPAs) are seen as a useful tool in the sustainable management of the oceans, progress in the ...implementation of MPA networks in areas beyond national jurisdiction has been limited. Specifically, the criteria of "representativeness" has received little consideration. This study uses the systematic conservation planning software Marxan coupled with a biologically meaningful biophysical habitat map to investigate representative MPA network scenarios and to assess the efficiency and representativeness of the existing High Seas MPA network in the Northeast Atlantic. Habitat maps were created based on the layers of water mass structure and seabed topography resulting in 30 different habitats, in six distinct regions. Conservation targets were set at 10 and 30% representation of each habitat within the final network. Two portfolios were created. The first portfolio (P1) ignored the presence of the existing MPA network within the study area allowing a non-biased selection of planning units (PUs) or sites to be chosen. The second (P2) enforced the selection of areas within the existing MPA network. Efficiency was measured as the difference in the percentage area contained within the "best scenario" MPAs from the un-bias run (P1) compared with (P2). Representativety of the existing network was assessed through the investigation of the properties of PUs included within MPAs in the "best scenario" Marxan output of P2. The results suggest that the current MPA network is neither efficient nor representative. There were clear differences in the spatial distribution of PUs selected in P1 compared with P2. The area required to be protected to achieve that the representation of 10 and 30% of each habitat was 8-10 and 1-4% higher, respectively, in P2 compared with P1. Abyssal areas in all regions are underrepresented within the current MPA network.
Exposure of fish to wastewater treatment works (WwTWs) effluents can result in reproductive anomalies consistent with exposure to estrogenic compounds. However, UK WwTWs effluents also contain ...compounds with androgen receptor activities which may contribute to reproductive dysfunction in fish. A toxicity identification and evaluation (TIE) approach was used to profile (anti)androgenic compounds in bile of fish exposed to two WwTWs effluents. Extracts of bile from exposed fish and effluent were fractionated by liquid chromatography and tested for (anti)androgenic activity using a yeast androgen receptor transcription screen (YAS). A number of bile fractions contained (anti)androgenic activity unique to the effluent-exposed fish. Some of these fractions contained di(chloromethyl)anthracene or dichlorophene, and these contaminants showed antagonistic activity in the YAS when tested as pure compounds. No androgenic activity was detected in the effluents, but TIE analysis of bile revealed a number of androgenic fractions which contained testosterone metabolites that were unique to effluent-exposed fish. This is the first work reported on the nature of some of the (anti)androgenic compounds that bioaccumulate in fish from WwTWs effluents and indicates that other contaminants, besides estrogenic substances, need to be considered for their potential to contribute to the disruption of reproductive system of fish in UK waters.
Mounting evidence suggests there is a reduced mobilization of stored fat in obese compared to lean women. It has been suggested that this decreased lipid mobilization may lead to, or perpetuate, the ...obese state; however, there may be a beneficial effect of reduced lipolysis, either by allowing for a sink of excess fatty acids, or by limiting a potentially harmful rise in interstitial and circulating fatty acid concentration. Nitric oxide (NO) may be responsible for a portion of the reduced in vivo rates of lipolysis in obese women because NO reduces adipose tissue lipolysis and adipose tissue nitric oxide synthase (NOS) mRNA is higher in obese than lean individuals. The purpose of this study was to determine if the inhibition of NOS by l‐Ng‐monomethyl‐l‐arginine (l‐NMMA) in the absence and presence of lipolytic stimulation would result in a larger increase in lipolytic rate in obese (OB) than lean (LN) women. Microdialysis probes were inserted into the subcutaneous abdominal adipose tissue of seven obese and six lean women to monitor lipolysis. Dialysate glycerol concentration increased in response to l‐NMMA in OB (basal 125 ± 26 µmol/l; l‐NMMA 225 ± 35 µmol/l) to a greater extent than in LN (basal 70 ± 18 µmol/l; l‐NMMA 84 ± 20 µmol/l) women (P < 0.05). Dialysate glycerol increased to a similar extent in OB and LN in response to adrenergic stimulation by isoprenaline or norepinephrine in the presence of l‐NMMA. The differential glycerol responses to l‐NMMA between obese and lean could not be explained by differential blood flow responses. It can be concluded that NO suppresses basal lipolysis in obese women to a greater extent than in lean women.
Abstract Cytochrome P450 2E1 (CYP2E1) is a microsomal enzyme that generates reactive oxygen species during its catalytic cycle. We previously found an important role for calcium in CYP2E1-potentiated ...injury in HepG2 cells. The possibility that CYP2E1 may oxidatively damage and inactivate the microsomal Ca2+ -ATPase in intact liver cells was evaluated, in order to explain why calcium is elevated during CYP2E1 toxicity. Microsomes were isolated by differential centrifugation from two liver cell line: E47 cells (HepG2 cells transfected with the pCI neo expression vector containing the human CYP2E1 cDNA, which overexpress active microsomal CYP2E1), and control C34 cells (HepG2 cells transfected with the pCI neo expression vector alone, which do not express significantly any cytochrome P450). The Ca2+ -dependent ATPase activity was determined by measuring the accumulation of inorganic phosphate from ATP hydrolysis. CYP2E1 overexpression produced a 45% decrease in Ca2+ -dependent ATPase activity (8.6 nmol Pi/min/mg protein in C34 microsomes versus 4.7 nmol Pi/min/mg protein in microsomes). Saturation curves with Ca2+ or ATP showed that CYP2E1 overexpression produced a decrease in Vmax but did not affect the Km for either Ca2+ or ATP. The decrease in activity was not associated with a decrease in SERCA protein levels. The ATP-dependent microsomal calcium uptake was evaluated by fluorimetry using fluo-3 as the fluorogenic probe. Calcium uptake rate in E47 microsomes was 28% lower than in C34 microsomes. Treatment of E47 cells with 2 mM N-acetylcysteine prevented the decrease in microsomal Ca2+ -ATPase found in E47 cells. These results suggest that CYP2E1 overexpression produces a decrease in microsomal Ca2+ -ATPase activity in HepG2 cells mediated by reactive oxygen species. This may contribute to elevated cytosolic calcium and to CYP2E1-potentiated injury.
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