Combinatorial effect of two framework mutations (E119V and I222L) in the neuraminidase active site of H3N2 influenza virus on resistance to oseltamivir

Neuraminidase (NA) inhibitors (NIs) are the first line of defense against influenza virus. Reverse genetics experiments allow the study of resistance mechanisms by anticipating the impacts of mutations to the virus. To look at the possibility of an increased effect on the resistance phenotype of a combination of framework mutations, known to confer resistance to oseltamivir or zanamivir, with limited effect on virus fitness, we constructed 4 viruses by reverse genetics in the A/Moscow/10/99 H3N2 background containing double mutations in their neuraminidase genes: E119D+I222L, E119V+I222L, D198N+I222L, and H274Y+I222L (N2 numbering). Among the viruses produced, the E119D+I222L mutant virus was not able to grow without bacterial NA complementation and the D198N+I222L mutant and H274Y+I222L mutant were not stable after passages in MDCK cells. The E119V+I222L mutant was stable after five passages in MDCK cells. This E119V-and-I222L combination had a combinatorial effect on oseltamivir resistance. The total NA activity of the E119V+I222L mutant was low (5% compared to that of the wild-type virus). This drop in NA activity resulted from a decreased NA quantity in the virion in comparison to that of the wild-type virus (1.4% of that of the wild type). In MDCK-SIAT1 cells, the E119V+I222L mutant virus did not present a replicative advantage over the wild-type virus, even in the presence of oseltamivir. Double mutations combining two framework mutations in the NA gene still have to be monitored, as they could induce a high level of resistance to NIs, without impairing the NA affinity. Our study allows a better understanding of the diversity of the mechanisms of resistance to NIs.     

'ome on the Range: altitude adaptation, positive selection, and Himalayan genomics

In 2010, a number of papers were published describing data from genome-wide studies designed to identify genes and genetic variants that contribute (or contributed) to human adaptation to altitude in the Himalaya. The results were exciting, intriguing, and controversial. Several genes, most notably EGLN1 and EPAS1, were identified as strong candidates for a role in evolutionary adaptation to high altitude, and the time course over which this adaptation occurred was calculated by one team to be remarkably brief. Overall, the data suggest that, at least in the ancestors of the modern Tibetans, there was a powerful selective pressure favoring variants in genes central to the molecular response to hypoxia. The most obvious manifestation of this selection seems to be the Tibetan's well known blunted erythropoietic response to hypoxemia. This article briefly reviews recent developments in 'omic' analysis of Tibetan highland natives, with a focus both on the answers found and the questions raised.     

Four-year prospective study of lung function in workers in a high altitude (4000 m) mine

The aim of this study was to determine if work at high altitude is associated with accelerated lung function decline and if smoking could further accelerate this decline. Subjects working at high altitude (3800 to 4500?m) in a gold mine on shift-rotation basis were included, and 7320 spirometry reports were obtained throughout a 4-yr observation period (2005-2009). Out of 3368 selected reports with acceptable quality, for 842 patients aged 38.9?±?8.6 yr we analyzed annual decline in vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume during the first second (FEV(1)). VC was reduced by 46.5?mL, FVC by 67.8?mL, and FEV(1) by 74.5?mL a year, greater than in historical controls. In those having initial FEV(1)/FVC below 70%, yearly VC decline was 59.4?mL, FEV(1) -58.6?mL. In long-term workers with no initial obstruction, FEV(1) declined slower (67.2 vs. 101.3?mL/yr (p?相似文献   

Prolonged succinylcholine action during electroconvulsive therapy (ECT) after cytarabine, vincristine, and rituximab chemotherapy

Succinylcholine is a depolarizing neuromuscular blocker frequently used during electroconvulsive therapy. In most patients, the duration of paralysis is brief, allowing for spontaneous respiration shortly after the therapy. We report a case of delayed return of neuromuscular function after succinylcholine administered during electroconvulsive therapy in a 72-year-old man receiving cytarabine, vincristine, and rituximab chemotherapy for chronic lymphocytic leukemia. We hypothesize that an interaction between succinylcholine and one of the chemotherapeutic agents caused the prolongation of paralysis and believe that this is the first reported case of prolonged duration of succinylcholine following this regimen of chemotherapy. Despite this unexpected prolonged neuromuscular blockade, the patient could be treated uneventfully, with attention paid to his respiratory support and with subsequent succinylcholine dose titration to effect.     

Resolution of severe suicidality with a single electroconvulsive therapy

Electroconvulsive therapy is a rapid and effective treatment of severe depression that has been shown to quickly decrease or eliminate suicidal thoughts and behaviors. We describe the case of an 88-year-old man hospitalized for a carefully premeditated suicide attempt with highly lethal means. He was treated with a single electroconvulsive therapy (ECT) and improved markedly. His suicidal ideation remitted, and the patient was still free of suicidal ideation at 5 months of follow-up. We discuss the effect of ECT on suicidal ideation, the benefit of minimizing the number of total ECT treatments, and the possible biological markers of change after a single treatment in an ECT-naive patient.     

Coagulation activation and fibrinolysis impairment are reduced in patients with anxiety and depression when medicated with serotonergic antidepressants

Aims: Anxiety disorders have been shown to be correlated with an activation of coagulation and impairment of fibrinolysis. The aim of the study was to assess whether medication with a serotonergic antidepressant, which has been associated with abnormal bleeding, may modify this effect. Methods: Thirty‐one anxiety patients, mostly with comorbid depression, and 31 healthy controls were included in the study. Group differences between anxiety patients medicated with a serotonergic antidepressant, patients without serotonergic antidepressant and controls were assessed for activated partial thromboplastin time, fibrinogen, factor VII, factor VIII, von Willebrand factor, von Willebrand ristocetin cofactor activity, prothrombin fragment 1 + 2, thrombin‐antithrombin complex, d ‐dimer, α2‐antiplasmin, plasmin‐α2‐antiplasmin complex (PAP), tissue plasminogen activator and plasminogen activator inhibitor. Intervening variables, such as age, sex, body mass index and smoking, were accounted for. Results: We found lower coagulation measures for fibrinogen (P = 0.03) and plasminogen activator inhibitor (P = 0.01), and higher levels of PAP (P = 0.046) in patients with serotonergic antidepressant than in patients without serotonergic antidepressant. When controlling for smoking and body mass index, differences between the two groups were significant for PAP (P = 0.02), von Willebrand ristocetin cofactor activity (P = 0.02) and activated partial thromboplastin time (P = 0.046). Coagulation scores were similar in patients with serotonergic antidepressant to those of healthy controls. Conclusions: Serotonergic antidepressants may counteract a procoagulant effect of anxiety and/or depression in anxiety patients.     

Accuracy of a P300 speller for people with motor impairments: a comparison

A Brain-Computer Interface (BCI) provides a completely new output pathway that can provide an additional option for a person to express himself/herself if he/she suffers a disorder like amyotrophic lateral sclerosis (ALS), brainstem stroke, brain or spinal cord injury or other diseases which impair the function of the common output pathways which are responsible for the control of muscles. For a P300 based BCI a matrix of randomly flashing characters is presented to the participant. To spell a character the person has to attend to it and to count how many times the character flashes. Although most BCIs are designed to help people with disabilities, they are mainly tested on healthy, young subjects who may achieve better results than people with impairments. In this study we compare measurements, performed on people suffering motor impairments, such as stroke or ALS, to measurements performed on healthy people. The overall accuracy of the persons with motor impairments reached 70.1% in comparison to 91% obtained for the group of healthy subjects. When looking at single subjects, one interesting example shows that under certain circumstances, when it is difficult for a patient to concentrate on one character for a longer period of time, the accuracy is higher when fewer flashes (i.e., stimuli) are presented. Furthermore, the influence of several tuning parameters is discussed as it shows that for some participants adaptations for achieving valuable spelling results are required. Finally, exclusion criteria for people who are not able to use the device are defined.