Social, psychological and existential well-being in patients with glioma and their caregivers: a qualitative study

Background:

Cerebral glioma has a devastating impact on cognitive, physical, social, psychological and spiritual well-being. We sought to understand the multidimensional experience of patients with this form of cancer as they progressed from receiving a diagnosis to the terminal phase of the disease.

Methods:

We recruited patients with a suspected brain tumour from a tertiary referral centre in the United Kingdom. We interviewed patients and their caregivers at key stages of the illness: before receiving a formal diagnosis, at the start of initial treatment, after initial treatment was completed and at six months’ follow-up; caregivers were also interviewed postbereavement. We interviewed the patients’ general practitioners once, after treatment had been completed. We transcribed the interviews and analyzed them thematically using the constant comparative method of a grounded theory approach.

Results:

We conducted in-depth interviews with 26 patients, 23 of their relatives and 19 general practitioners. We saw evidence of physical, social, psychological and existential distress even before a diagnosis was confirmed. Social decline followed a similar trajectory to that of physical decline, whereas psychological and existential distress were typically acute around diagnosis and again after initial treatment. Each patient’s individual course varied according to other factors including the availability of support and individual and family resources (e.g., personal resilience and emotional support).

Interpretation:

There are practical ways that clinicians can care for patients with glioma and their caregivers, starting from before a diagnosis is confirmed. Understanding the trajectories of physical, social, psychological and existential well-being for these patients allows health care professionals to predict their patients’ likely needs so they can provide appropriate support and sensitive and effective communication.Cerebral glioma (hereafter glioma) is a rare but devastating cancer.¹ Despite increased treatment options, average survival for the most aggressive form, glioblastoma multiforme, is less than one year.² In addition to physical decline and increasing social isolation,³ patients may undergo a shattering of preconscious assumptions about their life and its meaning,⁴ causing existential anxiety.^5–7 Fear around death and dying are not always verbalized, but may be expressed in other ways, such as concern for relatives or a desire to get one’s affairs in order.⁸ Anxiety related to shock, anger, fear and uncertainty may, with time, be replaced by acceptance.⁸ However, little is known about how these issues interact and vary dynamically as the tumour progresses.We sought to explore qualitatively whether patients with glioma follow archetypal trajectories of physical, social, psychological and existential well-being as their illness progresses. We investigated how people experience and deal with a diagnosis of glioma and the associated transition toward death in an effort to understand the issues patients and caregivers face and the support they need.     

Broadening the genetic base of European maize heterotic pools with US Cornbelt germplasm using field and molecular marker data

Maize (Zea mays L.) breeders are concerned about the narrowing of the genetic base of elite germplasm. To reverse this trend, elite germplasm from other geographic regions can be introgressed, but due to lack of adaptation it is difficult to assess their breeding potential in the targeted environment. The objectives of this study were to (1) investigate the relationship between European and US maize germplasm, (2) examine the suitability of different mega-environments and measures of performance to assess the breeding potential of exotics, and (3) study the relationship of genetic distance with mid-parent heterosis (MPH). Eight European inbreds from the Dent and Flint heterotic groups, 11 US inbreds belonging to Stiff Stalk (SS), non-Stiff Stalk (NSS), and CIMMYT Pool 41, and their 88 factorial crosses in F₁ and F₂ generations were evaluated for grain yield and dry matter concentration. The experiments were conducted in three mega-environments: Central Europe (target mega-environment), US Cornbelt (mega-environment where donor lines were developed), and Southeast Europe (an intermediate mega-environment). The inbreds were also fingerprinted with 266 SSR markers. Suitable criteria to identify promising exotic germplasm were F₁ hybrid performance in the targeted mega-environment and F₁ and parental performance in the intermediate mega-environment. Marker-based genetic distances reflected relatedness among the inbreds, but showed no association with MPH. Based on genetic distance, MPH, and F₁ performance, we suggest to introgress SS germplasm into European Dents and NSS into European Flints, in order to exploit the specific adaptation of European flint germplasm and the excellent combining ability of US germplasm in European maize breeding programs.     

Lithium Selectively Inhibits Muscarinic Receptor-Stimulated Inositol Tetrakisphosphate Accumulation in Mouse Cerebral Cortex Slices

The in vitro effects of Li on agonist- and depolarization-stimulated accumulation of inositol phosphates were determined in mouse cerebral cortex slices. Of the agents examined, only the cholinergic agonist carbachol produced a significant accumulation of inositol tetrakisphosphate (InsP4) in the absence of Li. Lithium at 5 mM enhanced the accumulation of inositol monophosphate (InsP1) and inositol bisphosphate (InsP2) due to all the stimuli used and potentiated inositol trisphosphate (InsP3) accumulation due to histamine and noradrenaline, although at lower Li concentrations, carbachol-stimulated InsP3 accumulation was reduced. Li also enhanced InsP4 accumulation in the presence of noradrenaline, histamine, and elevated KCl level but, in marked contrast, reduced carbachol-stimulated InsP4 accumulation with an IC50 of 100 microM. There was a significant time delay between the initiation of carbachol stimulation and the beginning of the InsP4 inhibition due to Li. The phorbol ester 4 beta-phorbol 12 beta-myristate 13 alpha-acetate did not mimic the effects of Li. The results suggest that muscarinic receptor-mediated InsP4 production might be one of the targets for the therapeutic action of Li.     

C(8)-substituted 1-azabicyclo[3.3.1]non-3-enes: a novel scaffold for muscarinic receptor ligands

The [3.3.1]-bicyclic amine, exo-8-benzyloxymethyl-3-ethoxycarbonyl-4-hydroxy-1-azabicyclo[3.3.1]non-3-ene (1), has been shown to be a potent competitive antagonist against the hM(1)-hM(5) muscarinic receptors. This heterocyclic system has not been extensively evaluated despite the notable activities reported for other bicyclic amines. Synthetic strategies permitted the selective alteration of five structural sites in 1. Pharmacological evaluation demonstrated that modification of either the C(3) alkoxycarbonyl or the C(4) enol units in 1 gave compounds with high affinity for the hM(1)-hM(5) muscarinic receptors with selectivity for the hM(2) receptor.     

Surface engineering of living myoblasts via selective periodate oxidation

Cell surface molecules are vital for normal cell activity. To study the functions of these molecules or manipulate cell behavior, the ability to decorate cell surfaces with bioactive molecules of our choosing is a potentially powerful technique. Here, we describe the molecular engineering of living L6 myoblast monolayers via selective periodate oxidation of sialic acid residues and the application of this surface modification in the artificial aggregation of cells. The aldehyde groups generated by this reaction were used to selectively ligate a model molecule, biotin hydrazide, to the cell surfaces. Flow cytometry analysis after staining with fluorescently conjugated avidin revealed a concentration-dependent increase in fluorescence compared to untreated cells with a maximal shift of 345.1 +/- 27.4-fold and an EC(50) of 17.4 +/- 1.1 microM. This mild oxidation reaction did not affect cell number, viability, or morphology. We then compared this chemical technique with the metabolic incorporation of reactive cell surface ketone groups using N-levulinoylmannosamine (ManLev). In this cell line, only a 22.3-fold fluorescence shift was observed compared to untreated cells when myoblasts were incubated with a high concentration of ManLev for 48 hours. Periodate oxidation was then used to modify myoblast surfaces to induce cell aggregation. Crosslinking biotinylated myoblasts, which do not spontaneously aggregate in culture, with avidin resulted in the rapid formation of millimeter-sized, multicellular structures. These data indicate that sodium periodate treatment is an effective, noncytotoxic method for the in vitro molecular engineering of living cell surfaces with the potential for cell biology and tissue engineering applications.     

Purification of plasmid DNA by an integrated operation comprising tangential flow filtration and nitrocellulose adsorption

There is an increasing interest in the development of scaleable and reproducible plasmid DNA purification protocols for vaccine and gene therapy. The use of an integrated unit operation, comprising tangential flow microfiltration coupled with the adsorption of contaminants onto nitrocellulose membranes as a single processing step was examined in this work. Experiments were performed using a custom-built tangential flow microfiltration rig (membrane area=12.5 cm(2)). Tangential flow filtration-adsorption of E. coli lysates containing a plasmid product removed most solids (>75%) and decreased chromosomal DNA contamination by 75% w/w. Total plasmid DNA concentration and supercoiled content of the permeate were virtually identical to those of the feed, indicating a recovery yield of 100% (transmission equal to 1). Results were similar for E. coli lysates containing either a 6.9 kb or a 20 kb plasmid. Significant reductions in RNA, endotoxin, and protein levels were also observed. The reproducibility and potential for scale up of this integrated filtration-adsorption operation makes it at attractive option for intermediate- to large-scale pharmaceutical-grade plasmid processing.     

Apoaequorin monitors degradation of endoplasmic reticulum (ER) proteins initiated by loss of ER Ca(2+)

Apoaequorin was targeted to the cytosol, nucleus, and endoplasmic reticulum of HeLa cells in order to determine the effect of Ca(2+) release from the ER on protein degradation. In resting cells apoaequorin had a rapid half-life (ca. 20-30 min) in the cytosol or nucleus, but was relatively stable for up to 24 h in the ER (t(1/2) > 24 h). However, release of Ca(2+) from the ER, initiated by the addition of inhibitors of the ER Ca(2+)/Mg(2+) ATPase such as 2 microM thapsigargin or 1 microM ionomycin, initiated rapid loss of apoaequorin in the ER, but had no detectable effect on apoaequorin turnover in the cytosol nor the nucleus. This loss of apoprotein was not the result of secretion into the external fluid, and could not be inhibited by inhibitors of protein degradation by proteosomes. Proteolysis of apoaequorin in cell extracts (t(1/2) < 20 min) was completely inhibited in the presence of 1 mM Ca(2+), and this effect was independent of the ER retention signal KDEL at the C-terminus. Proteolysis was unaffected by the presence of selected serine protease inhibitors, or 10 microM Zn(2+), a known caspase-3 inhibitor. The results show that apoaequorin can monitor proteolysis of ER proteins activated by loss of ER Ca(2+). Several Ca(2+)-binding proteins exist in the ER, acting as the Ca(2+) store and chaperones. Our results have important implications both for the role of ER Ca(2+) in cell activation and stress and when using aequorin for monitoring free ER Ca(2+) over long time periods.