Quality target negotiation in health care: evidence from the English NHS

We examine how public sector third-party purchasers and hospitals negotiate quality targets when a fixed proportion of hospital revenue is required to be linked to quality. We develop a bargaining model linking the number of quality targets to purchaser and hospital characteristics. Using data extracted from 153 contracts for acute hospital services in England in 2010/2011, we find that the number of quality targets is associated with the purchaser’s population health and its budget, the hospital type, whether the purchaser delegated negotiation to an agency, and the quality targets imposed by the supervising regional health authority.     

Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma

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The single-channel properties of human acetylcholine alpha 7 receptors are altered by fusing alpha 7 to the green fluorescent protein

Neuronal nicotinic acetylcholine (AcCho) receptors composed of alpha7-subunits (alpha7-AcChoRs) are involved in many physiological activities. Nevertheless, very little is known about their single-channel characteristics. By using outside-out patch-clamp recordings from Xenopus oocytes expressing wild-type (wt) alpha7-AcChoRs, we identified two classes of channel conductance: a low conductance (gamma(L)) of 72 pS and a high one (gamma(H)) of 87 pS, with mean open-times (tau(op)) of 0.6 ms. The same classes of conductances, but longer tau(op) (3 ms), were seen in experiments with chimeric alpha7 receptors in which the wtalpha7 extracellular C terminus was fused to the green fluorescent protein (wtalpha7-GFP AcChoRs). In contrast, channels with three different conductances were gated by AcCho in oocytes expressing alpha7 receptors carrying a Leu-to-Thr 248 mutation (mutalpha7) or oocytes expressing chimeric mutalpha7-GFP receptors. These conductance levels were significantly smaller, and their mean open-times were larger, than those of wtalpha7-AcChoRs. Interestingly, in the absence of AcCho, these oocytes showed single-channel openings of the same conductances, but shorter tau(op), than those activated by AcCho. Accordingly, human homomeric wtalpha7 receptors open channels of high conductance and brief lifetime, and fusion to GFP lengthens their lifetime. In contrast, mutalpha7 receptors open channels of lower conductance and longer lifetime than those gated by wtalpha7-AcChoRs, and these parameters are not greatly altered by fusing the mutalpha7 to GFP. All this evidence shows that GFP-tagging can alter importantly receptor kinetics, a fact that has to be taken into account whenever tagged proteins are used to study their function.     

Association of RANTES G-403A gene polymorphism with increased risk of coronary arteriosclerosis

Aims Polymorphisms in the RANTES (G-403A), monocyte chemoattractantprotein-1 (MCP-1; A-2518G), stromal cell-derived factor-1ß(SDF-1ß; G801A), and C–C chemokine receptor-5(CCR5; 32) genes have been associated with functional effects.These chemokines have been implicated in leucocyte recruitmentto arterial lesions. In a case-control study, we explored relationsbetween these polymorphisms and coronary artery disease (CAD),with respect to angiographic abnormalities and acute coronarysyndromes (ACS). Methods and Results The LUdwigshafen Risk and Cardiovascularhealth (LURIC) cohort was genotyped by RFLP-PCR. Based on coronaryangiography, individuals were sub-divided into CAD cases and controls . RANTES-403 genotype frequencies were significantly different in cases and controls, as were A allele carrier frequencies (36.01% vs. 30.19%, OR=1.30 [95%-CI=1.06–1.60], ). By multivariate analysis, RANTES A-403 retained significantassociation with CAD . RANTES A-403 was associated with increased ACS prevalence (OR=1.36 [95%-CI=1.08–1.71],). MCP-1 G-2518, SDF-1ß A801, and CCR5 32 were not associated with CAD. Conclusions RANTES A-403 was associated with CAD independentlyfrom conventional risk factors and CRP or fibrinogen as inflammatorybiomarkers. The association was enhanced in smokers and ACS,conditions where platelet activation and inflammation predominate.RANTES A-403 may increase genetic susceptibility to CAD.     

Expression of functional neurotransmitter receptors in Xenopus oocytes after injection of human brain membranes

The Xenopus oocyte is a very powerful tool for studies of the structure and function of membrane proteins, e.g., messenger RNA extracted from the brain and injected into oocytes leads to the synthesis and membrane incorporation of many types of functional receptors and ion channels, and membrane vesicles from Torpedo electroplaques injected into oocytes fuse with the oocyte membrane and cause the appearance of functional Torpedo acetylcholine receptors and Cl(-) channels. This approach was developed further to transplant already assembled neurotransmitter receptors from human brain cells to the plasma membrane of Xenopus oocytes. Membranes isolated from the temporal neocortex of a patient, operated for intractable epilepsy, were injected into oocytes and, within a few hours, the oocyte membrane acquired functional neurotransmitter receptors to gamma-aminobutyric acid, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and glycine. These receptors were also expressed in the plasma membrane of oocytes injected with mRNA extracted from the temporal neocortex of the same patient. All of this makes the Xenopus oocyte a more useful model than it already is for studies of the structure and function of many human membrane proteins and opens the way to novel pathophysiological investigations of some human brain disorders.     

Anti-IL6 treatment of serious COVID-19 disease: A monocentric retrospective experience

COVID-19 is causing a high influx of patients suffering from serious respiratory complications leading the necessity to find effective therapies. These patients seem to present with cytokine perturbation and high levels of IL6. Tocilizumab and sarilumab could be effective in this condition.We retrospectively collected data about 112 consecutive hospitalized in a single center.Fifty (IL6 group) treated with tocilizumab (8 mg/kg intravenously [IV], 2 infusions 12 hours apart) or sarilumab 400 mg IV once and 62 treated with the standard of care but not anti-cytokine drugs (CONTROL group).To determine whether anti-IL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality in COVID-19 pneumonia.To date 84% (42/50) of IL6 group patients have already been discharged and only 2/50 are still recovered and intubated in intensive care. Six/fifty patients (12%) died: 5/6 due to severe respiratory failure within a framework of severe acute respiratory distress syndrome (ARDS), 1 suffered an acute myocardial infarction, and 1 died of massive pulmonary thromboembolism. There were no adverse treatment events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate (12% versus 43%), for the same number of complications and days of hospitalization.Anti-IL6 drugs seem to be effective in the treatment of medium to severe forms of COVID-19 pneumonia reducing the risk of mortality due to multi-organ failure, acting at the systemic level and reducing inflammation levels and therefore microvascular complications. However, it is essential to identify the best time for treatment, which, if delayed, is rendered useless as well as counterproductive. Further studies and ongoing clinical trials will help us to better define patients eligible as candidates for more aggressive intervention.     

Special FX: Harnessing the Farnesoid-X-Receptor to Control Bile Acid Synthesis

Digestive Diseases and Sciences -     

Primary lymphoma of the heart: three-dimensional reconstruction

Primary cardiac lymphoma is defined as a lymphoma of the heart and pericardium with little or no extracardiac or local involvement such as mediastinal lymph nodes or pleural effusion. Most cases are diagnosed only post mortem (1). If this disease could be diagnosed earlier, therapy with chlorpropamide, doxorubicin, vincristine and prednisone (CHOP) could bring about a remission (2,3,4). Transoesophageal echocardiography with three-dimensional acquisition is a new technique which can allow earlier diagnosis, and facilitate guided transvenous biopsy (5,6). We here report an example of the pre-mortem diagnosis of cardiac lymphoma by these techniques.     

Leukotrienes stimulate pepsinogen secretion from guinea pig gastric chief cells by a nitric oxide-dependent pathway

Leukotrienes (LTs) are involved in many inflammatory conditions including gastric damage induced by nonsteroidal anti-inflammatory drugs. Although LTs stimulate acid secretion, the effect they exert on pepsinogen secretion is unknown. The aim of this study was to investigate whether LTs stimulate pepsinogen secretion by isolated chief cells and to identify the intracellular messengers that mediate this action. Isolated chief cells were incubated with concentrations of LTB₄, LTC₄, LTD₄, or LTE₄ ranging from 0.1 pmol/L to 10 μmol/L, and pepsinogen release, intracellular calcium and inositol(1,4,5)-trisphosphate (IP₃) concentrations were measured. Nitric oxide generation was determined by the amount of citrulline generated during incubation. All four LTs caused a concentration-dependent stimulation of pepsinogen secretion with 50% effective concentration of 0.05-0.1 nmol/L and a dose-dependent increase in cytoplasmic free calcium and IP₃ concentration. The LTB₄ and LTD₄ antagonists caused selective, concentration-dependent inhibition of LTB₄- and LTD₄-induced pepsinogen secretion, calcium mobilization, and IP₃ generation. All four LTs increased NO generation, and the effect was inhibited by LTB₄ and LTD₄ antagonists and an NO synthase inhibitor N^G-monomethyl-l-arginine and reversed by l-arginine. N^G-monomethyl-l-arginine caused a 50%–60% reduction of LT-induced pepsinogen release. Each of the four LTs caused a fivefold increase in 5′-cyclic guanosine monophosphate. LTs are powerful stimulators of pepsinogen secretion in isolated chief cells and act via occupancy of specific cell-surface receptors.