Right to die with dignity?

The right to die with dignity is an ill-defined concept, with multiple, often inappropriate, interpretations. The current proposition is that the physician take full responsibility for protecting the patients rights, for ensuring a rational use of resources and for overseeing the decision-making process such that the information is adequate and the steps proportioned. This responsibility extends not only to the health status of the patient situation, to the patients prognosis, and to his/her expectations and wishes, but also to the benefits foreseen and to the cost-benefit ratio. Emphasis is placed on two aspects of this relationship. First, dignity can be interpreted in many ways and sometimes, in the name of dignity, the patient is exposed (or exposes him/herself) to suffering, pain and complications that can be avoided. Second, when no reasonable probability of survival is present and a better quality of life is impossible, efforts are better redirected to offering a better quality of death.     

What to do with HLA-DO?

Antigenic peptide binding to MHC class II molecules in the endocytic pathway occurs via a multifactorial process that requires the support of a specialized lysosomal chaperone called HLA-DM. DM shows both in primary amino acid sequence and quaternary structure a high homology to both MHC class I and class II molecules. Like the peptide presenting class II molecules, DM is expressed in all professional antigen presenting cells. DM catalyzes the dissociation of peptides that do not bind stably to the class II peptide-binding groove, thereby leading to the preferential presentation of stably binding antigenic peptides. The recently discovered HLA-DO molecule is mainly expressed in B cells and associates with DM, thereby markedly affecting DM function. Like DM, the genes encoding the HLA-DO heterodimer lie within the MHC class II region and exhibit strong homology to classical class II molecules. This review evaluates the unique effects of DO on DM-mediated antigen presentation by MHC class II molecules and discusses the possible physiological relevance for the B cell-specific expression of DO and its function.     

How to cope with insect resistance to Bt toxins?

Transgenic Bt crops producing insecticidal crystalline proteins from Bacillus thuringiensis, so-called Cry toxins, have proved useful in controlling insect pests. However, the future of Bt crops is threatened by the evolution of insect resistance. Understanding how Bt toxins work and how insects become resistant will provide the basis for taking measures to counter resistance. Here we review possible mechanisms of resistance and different strategies to cope with resistance, such as expression of several toxins with different modes of action in the same plant, modified Cry toxins active against resistant insects, and the potential use of Cyt toxins or a fragment of cadherin receptor. These approaches should provide the means to assure the successful use of Bt crops for an extended period of time.     

Metformin interacts with AMPK through binding to γ subunit

Metformin acts as an energy regulator by activating 5'-adenosine monophosphate-activated protein kinase (AMPK), which is a key player in the regulation of energy homeostasis, but it is uncertain whether AMPK is its direct target. This study aims to investigate the possible interaction between metformin and AMPK. First, we verified that metformin can promote AMPK activation and induce ACC inactivation in human HepG2 cells using western blot. Then we predicted that metformin may interact with the γ subunit of AMPK by molecular docking analysis. The fluorescence spectrum and ForteBio assays indicated that metformin has a stronger binding ability to the γ subunit of AMPK than to α subunit. In addition, interaction of metformin with γ-AMPK resulted in a decrease in the α-helicity determined by CD spectra, but relatively little change was seen with α-AMPK. These results demonstrate that metformin may interact with AMPK through binding to the γ subunit.     

Should females prefer to mate with low-quality males?

We analyse a model of mate choice when males differ in reproductive quality and provide care for their offspring. Females choose males on the basis of the success they will obtain from breeding with them and a male chooses his care time on the basis of his quality so as to maximise his long-term rate of reproductive success. We use this model to establish whether high-quality males should devote a longer period of care to their broods than low-quality males and whether females obtain greater reproductive success from mating with higher quality males. We give sufficient conditions for optimal care times to decrease with increasing male quality. When care times decrease, this does not necessarily mean that high-quality males are less valuable to the female because quality may more than compensate for the lack of care. We give a necessary and sufficient condition for high-quality males to be less valuable mates, and hence for females to prefer low-quality males. Females can prefer low-quality males if offspring produced and cared for by high-quality males do well even if care is short, and do not significantly benefit from additional care, while offspring produced and cared for by low-quality males do well only if they receive a long period of care.     

Fight or learn to live with the consequences?

Individuals can fight their infectious diseases by reducing the growth of a pathogen (resistance), but they can also ameliorate the disease it causes (tolerance). A recent paper shows that there is variation between mouse strains in tolerance to a rodent malaria and that this was negatively correlated with resistance. This is important, because tolerance has major implications for the epidemiology and coevolution of host-parasite interactions, but has been neglected in the animal literature.     

TNFα cooperates with IFN-γ to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis

Background

TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis.

Methodology/Principal Findings

The efficacy and underlying molecular mechanism of cooperation between TNFα and IFN-γ in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFα- and IFN-γ-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFα or IFN-γ alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFα and IFN-γ cooperate to repress Bcl-xL expression, whereas TNFα represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFα and IFN-γ also synergistically enhanced TRAIL-induced caspase-8 activation. TNFα and IFN-γ was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor-infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFα/IFN-γ-producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo.

Conclusions/Significance

TNFα and IFN-γ cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer.     

Do aphids infected with entomopathogenic fungi continue to produce and respond to alarm pheromone?

The response of pea aphids, Acyrthosiphon pisum, to aphid alarm pheromone was not modified by infection with Beauveria bassiana. Approximately 50% of uninfected and infected aphids responded to synthetic alarm pheromone. The simulated attack of aphids infected with B. bassiana did not elicit a response in uninfected aphids. Preliminary air entrainment experiments of both uninfected aphids and aphids at different stages of B. bassiana (generalist pathogen) or P. neoaphidis (obligate pathogen of aphids) demonstrated that B. bassiana infected aphids produced less alarm pheromone than uninfected aphids and, conversely, P. neoaphidis infected aphids produced more alarm pheromone than uninfected aphids. These results are discussed with particular emphasis on the different life history strategies of these two pathogens. We hypothesise that the obligate, specialist pathogen, P. neoaphidis, is under greater selection pressure to increase pathogen transmission and survival resulting in modified host behaviour, than the generalist pathogen, B. bassiana.     

Two brothers with non-classical 21-hydroxylase deficiency: to treat or not to treat?

Variations in phenotype in 21-hydroxylase deficiency (21OHD) have cautioned against initiating treatment in the absence of abnormal clinical features. We report 2 Caucasian brothers with compound heterozygous mutations of the CYP21 gene and mild clinical and biochemical features of late-presenting 21OHD. The index case presented aged 8.5 years with mild genital virilization and bone age advanced by 5 years. Elevated basal and synacthen-stimulated 17-hydroxyprogesterone (17OHP; 22.4 and 246 nmol/l) and androstenedione (10.9 and 19.9 nmol/l) levels confirmed 21OHD. His younger brother was investigated at age 7.3 years, and although examination showed normal pre-pubertal genitalia, basal and synacthen-stimulated 17OHP (32.4 and 281 nmol/l) and androstenedione (6.2 and 9.0 nmol/l) were abnormal, and bone age was advanced by 1.5 years. Because of actual or incipient virilization, both patients were treated with glucocorticoid replacement 8-12 mg/m(2)/day. This decision is discussed in the context of published guidelines for the management of 21OHD.     

Can Italian Healthcare Administrative Databases Be Used to Compare Regions with Respect to Compliance with Standards of Care for Chronic Diseases?

Background

Italy has a population of 60 million and a universal coverage single-payer healthcare system, which mandates collection of healthcare administrative data in a uniform fashion throughout the country. On the other hand, organization of the health system takes place at the regional level, and local initiatives generate natural experiments. This is happening in particular in primary care, due to the need to face the growing burden of chronic diseases. Health services research can compare and evaluate local initiatives on the basis of the common healthcare administrative data.However reliability of such data in this context needs to be assessed, especially when comparing different regions of the country. In this paper we investigated the validity of healthcare administrative databases to compute indicators of compliance with standards of care for diabetes, ischaemic heart disease (IHD) and heart failure (HF).

Methods

We compared indicators estimated from healthcare administrative data collected by Local Health Authorities in five Italian regions with corresponding estimates from clinical data collected by General Practitioners (GPs). Four indicators of diagnostic follow-up (two for diabetes, one for IHD and one for HF) and four indicators of appropriate therapy (two each for IHD and HF) were considered.

Results

Agreement between the two data sources was very good, except for indicators of laboratory diagnostic follow-up in one region and for the indicator of bioimaging diagnostic follow-up in all regions, where measurement with administrative data underestimated quality.

Conclusion

According to evidence presented in this study, estimating compliance with standards of care for diabetes, ischaemic heart disease and heart failure from healthcare databases is likely to produce reliable results, even though completeness of data on diagnostic procedures should be assessed first. Performing studies comparing regions using such indicators as outcomes is a promising development with potential to improve quality governance in the Italian healthcare system.     

Failure to respond to interferon-α 2a therapy is associated with increased hepatic iron levels in patients with chronic hepatitis C

Recent reports suggest the hepatic iron concentration (HIC) may influence the activity of hepatitis and the response to interferon (IFN) therapy in patients with chronic hepatitis C (CH-C). We have evaluated iron status in 28 patients with CH-C and determined if pretreatment iron status can predict the response to IFN-α therapy in these patients. Increased serum iron, transferrin saturation, and ferritin levels were observed in 3 (11%), 11 (39%), and 5 (18%) patients, respectively. Hepatic iron deposits were histologically detected in 17 (61%) patients, and 14 of them had stainable hepatocytic iron. However, all HIC values were within the normal range (203–1279 μg/g). Seven of 17 patients treated with IFN-α for 6 mo had normalization of serum transaminases and disappearance of serum HCV-RNA (responders). Nonresponders had a significantly higher median HIC compared with responders (710 vs 343 μg/g, respectively;p < 0.05). There was no significant difference in other pretreatment iron parameters, serum HCV-RNA level, or HCV-genotype between responders and nonresponders. In conclusion, mild hepatic iron accumulation occurs in patients with CH-C. Increased hepatic iron stores are associated with poor response to IFN therapy. Pretreatment HIC may be an additional host-specific parameter with a predictive value for responsiveness to IFN therapy, in addition to well-known predictive viral factors.     

Dopamine quinones interact with α-synuclein to form unstructured adducts

α-Synuclein (αsyn) fibril formation is considered a central event in the pathogenesis of Parkinson’s disease (PD). In recent years, it has been proposed that prefibrillar annular oligomeric β-sheet-rich species, called protofibrils, rather than fibrils themselves, may be the neurotoxic species. The oxidation products of dopamine (DAQ) can inhibit αsyn fibril formation supporting the idea that DAQ might stabilize αsyn protofibrils.In the present work, through different biochemical and biophysical techniques, we isolated and structurally characterized αsyn/DAQ adducts. Contrary to protofibrils, we demonstrated that αsyn/DAQ adducts retain an unfolded conformation. We then investigated the nature of the modifications induced on αsyn by DAQ. Our results indicate that only a small fraction of αsyn interacts with DAQ in a covalent way, so that non-covalent interaction appears to be the major modification induced by DAQ on αsyn.     

What Are You Going to Conquer with the Spear？

Almost everyone in China knows this story, even elementary school pupils： Once upon a time, there was a weapon salesman claiming with confidence to one crowd that all his spears were capable of piercing every shield that existed in the world, then he turned around and told the other crowd mysteriously that all his shields were not penetrable. A bystander who heard both claims asked him, “How about stabbing your shields with your spears？” It was indeed an unexpected question that made the eloquent salesman mute right on the spot. Since then,