“It’s like a problem that doesn’t exist”: The emotional well-being of mothers caring for a child with brain injury.

Background: Although research has shown that significant burden and adverse psychological impact are associated with caring for a child with brain injury, limited knowledge exists concerning the qualitative experience and impact of this burden.
Objective: To provide an account of the experiences of mothers who care for a childhood survivor of brain injury.
Research design: Postal survey.
Methods and procedures: A self-report questionnaire was sent to a consecutive sample of mothers (n=86) of children (aged 8-28) with acquired brain injury, registered with a UK children’s brain injury charity. Five essay style questions enabled mothers to reflect on and describe at length their caring experiences, with particular emphasis placed on the perceived impact on emotional well-being.
Main outcomes and results: Thematic analysis identified five key themes: Perpetually Anxious, The Guilty Carer, The Labour of Caring, A Self-Conscious Apologist and Perpetually Grieving. Collectively, these themes highlight two core processes shaping mothers’ caring experiences and concomitant mental well-being. Firstly, the collective and enduring nature of caregiver burden over time. Second, the crucial role played by socio-cultural values in perpetuating caregiver burden.
Conclusions: Societal norms, particularly those relating to the nature and outcome of brain injury and motherhood, serve to marginalise mothers and increase feelings of isolation. Findings suggest the value of peer support programs as an effective means of providing appropriate social support.

Assessing the consequences of traumatic brain injury

Research concerned with assessing the rehabilitation outcome for the survivor of traumatic brain injury has suffered from both conceptual and procedural difficulties. The purpose of this paper is twofold: to assess the psychometric features in instruments used in assessing outcome; and to describe a test development framework based on the principles of construct validity. A construct validation approach is viewed as a means of avoiding common measurement difficulties, as well as integrating perspectives important to this population. Emphasis has been given to the cognitive/social dimensions of recovery, as it is this area which has the greatest impact for rehabilitation success.

Transpupillary thermotherapy for choroidal melanoma:Tumor control and visual results in 100 consecutive cases

Objective: The authors evaluated the results of primary transpupillary thermotherapy for choroidal melanoma in 100 cases. Design: Prospective nonrandomized analysis of treatment method. Participants: One hundred patients with choroidal melanoma were studied. Main Outcome Measures: Tumor response, ocular side effects, and visual results. Results: Of 100 consecutive patients with choroidal melanoma treated with transpupillary thermotherapy, the mean tumor basal diameter was 7.1 mm and tumor thickness was 2.8 mm. The tumor margin touched the optic disc in 34 eyes (34%) and was beneath the fovea in 42 eyes (42%). Documented growth was present in 64 eyes (64%), and known clinical risks for growth were present in all of the remaining 36 eyes (36%), with an average of 4 of 5 statistical risk factors for growth per tumor. After a mean of three treatment sessions and 14 months of follow-up, the mean tumor thickness was reduced to 1.4 mm. Treatment was successful in 94 eyes (94%) and failed in 6 eyes (6%). Three patients with amelanotic tumors showed no initial response to thermotherapy, but subsequent intravenous indocyanine green administration during thermotherapy resulted in improved heat absorption and tumor regression to a flat scar. The six eyes classified as treatment failures included four eyes with tumors that showed partial or no response to thermotherapy, thus requiring plaque radiotherapy or enucleation, and two eyes with recurrence, subsequently controlled with additional thermotherapy. After treatment, the visual acuity was the same (within 1 line) or better than the pretreatment visual acuity in 58 eyes (58%) and worse in 42 eyes (42%). The main reasons for poorer vision included treatment through the foveola for subfoveal tumor (25 eyes), retinal traction (10 eyes), retinal vascular obstruction (5 eyes), optic disc edema (1 eye), and unrelated ocular ischemia (1 eye). Temporal location (versus nasal and superior, P = 0.02) and greater distance from the optic disc (P = 0.04) were risks for retinal traction. Conclusions: Transpupillary thermotherapy may be an effective treatment for small posterior choroidal melanoma, especially those near the optic disc and fovea. Despite satisfactory local tumor control, ocular side effects can result in decreased vision. Longer follow- up will be necessary to assess the impact of thermotherapy on ultimate local tumor control and metastatic disease.

Clonal expansion of hypermutated measles virus in a SSPE brain

Nucleotide sequence analysis was carried out to study genes encoding the matrix (M) protein of measles virus (MV) from several regions of the brain of a case of subacute sclerosing panencephalitis. This analysis revealed the presence of MV with 'wild-type' sequences as well as variants which had undergone at least five biased hypermutation events (U to C and A to G in the positive strand sequences). Despite the presence of MV variants with genes encoding the intact matrix protein open reading frame, M protein could not be detected in any of the brain regions. The distribution of virus variants was studied by cDNA cloning and sequence analysis and by in situ hybridization. The hypermutated viruses appeared to expand clonally throughout the brain of patient B.

MicroRNA-34c inversely couples the biological functions of the runt-related transcription factor RUNX2 and the tumor suppressor p53 in osteosarcoma

Osteosarcoma (OS) is a primary bone tumor that is most prevalent during adolescence. RUNX2, which stimulates differentiation and suppresses proliferation of osteoblasts, is deregulated in OS. Here, we define pathological roles of RUNX2 in the etiology of OS and mechanisms by which RUNX2 expression is stimulated. RUNX2 is often highly expressed in human OS biopsies and cell lines. Small interference RNA (siRNA)-mediated depletion of RUNX2 inhibits growth of U2OS OS cells. RUNX2 levels are inversely linked to loss of p53 (which predisposes to OS) in distinct OS cell lines and osteoblasts. RUNX2 protein levels decrease upon stabilization of p53 with the MDM2 inhibitor Nutlin-3. Elevated RUNX2 protein expression is post-transcriptionally regulated and directly linked to diminished expression of several validated RUNX2 targeting microRNAs (miRNAs) in human OS cells compared to mesenchymal progenitor cells. The p53-dependent miR-34c is the most significantly down-regulated RUNX2 targeting miRNA in OS. Exogenous supplementation of miR-34c markedly decreases RUNX2 protein levels, while 3UTR reporter assays establish RUNX2 as a direct target of miR-34c in OS cells. Importantly, Nutlin-3 mediated stabilization of p53 increases expression of miR-34c and decreases RUNX2. Thus, a novel RUNX2-p53-miR34 network controls cell growth of osseous cells and is compromised in OS.

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin's influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites.

Prolyl isomerase Pin1 downregulates tumor suppressor RUNX3 in breast cancer

Emerging evidence demonstrates that RUNX3 is a tumor suppressor in breast cancer. Inactivation of RUNX3 in mice results in spontaneous mammary gland tumors, and decreased or silenced expression of RUNX3 is frequently found in breast cancer cell lines and human breast cancer samples. However, the underlying mechanism for initiating RUNX3 inactivation in breast cancer remains elusive. Here, we identify prolyl isomerase Pin1, which is often overexpressed in breast cancer, as a key regulator of RUNX3 inactivation. In human breast cancer cell lines and breast cancer samples, expression of Pin1 inversely correlates with the expression of RUNX3. In addition, Pin1 recognizes four phosphorylated Ser/Thr-Pro motifs in RUNX3 via its WW domain. Binding of Pin1 to RUNX3 suppresses the transcriptional activity of RUNX3. Furthermore, Pin1 reduces the cellular levels of RUNX3 in an isomerase activity-dependent manner by inducing the ubiquitination and proteasomal degradation of RUNX3. Knocking down Pin1 enhances the cellular levels and transcriptional activity of RUNX3 by inhibiting the ubiquitination and degradation of RUNX3. Our results identify Pin1 as a new regulator of RUNX3 inactivation in breast cancer.

RUNX3 acts as a tumor suppressor in breast cancer by targeting estrogen receptor α

Transcription factor RUNX3 is inactivated in a number of malignancies, including breast cancer, and is suggested to function as a tumor suppressor. How RUNX3 functions as a tumor suppressor in breast cancer remains undefined. Here, we show that about 20% of female Runx3(+/-) mice spontaneously developed ductal carcinoma at an average age of 14.5 months. Additionally, RUNX3 inhibits the estrogen-dependent proliferation and transformation potential of ERa-positive MCF-7 breast cancer cells in liquid culture and in soft agar and suppresses the tumorigenicity of MCF-7 cells in severe combined immunodeficiency mice. Furthermore, RUNX3 inhibits ERa-dependent transactivation by reducing the stability of ERa. Consistent with its ability to regulate the levels of ERa, expression of RUNX3 inversely correlates with the expression of ERa in breast cancer cell lines, human breast cancer tissues and Runx3(+/-) mouse mammary tumors. By destabilizing ERa, RUNX3 acts as a novel tumor suppressor in breast cancer.

Identification of RBCK1 as a novel regulator of FKBPL: implications for tumor growth and response to tamoxifen

FKBPL has been implicated in processes associated with cancer, including regulation of tumor growth and angiogenesis with high levels of FKBPL prognosticating for improved patient survival. Understanding how FKBPL levels are controlled within the cell is therefore critical. We have identifed a novel role for RBCK1 as an FKBPL-interacting protein, which regulates FKBPL stability at the post-translational level via ubiquitination. Both RBCK1 and FKBPL are upregulated by 17-b-estradiol and interact within heat shock protein 90 chaperone complexes, together with estrogen receptor-a (ERa). Furthermore, FKBPL and RBCK1 associate with ERa at the promoter of the estrogen responsive gene, pS2, and regulate pS2 levels. MCF-7 clones stably overexpressing RBCK1 were shown to have reduced proliferation and increased levels of FKBPL and p21. Furthermore, these clones were resistant to tamoxifen therapy, suggesting that RBCK1 could be a predictive marker of response to endocrine therapy. RBCK1 knockdown using targeted small interfering RNA resulted in increased proliferation and increased sensitivity to tamoxifen treatment. Moreover, in support of our in vitro data, analysis of mRNA microarray data sets demonstrated that high levels of FKBPL and RBCK1 correlated with increased patient survival, whereas high RBCK1 predicted for a poor response to tamoxifen. Our findings support a role for RBCK1 in the regulation of FKBPL with important implications for estrogen receptor signaling, cell proliferation and response to endocrine therapy.

An exploration of seniors’ motivation to use mobile brain-exercise software

This article reports on the development of an iPhone-based brain-exercise tool for seniors involving a series of focus groups (FGs) and field trials (FTs). Four FGs with 34 participants were conducted aimed at understanding the underlying motivational and de-motivational factors influencing seniors’ engagement with mobile brain-exercise software. As part of the FGs, participants had approximately 40 minutes hands-on experience with commercially available brain-exercise software. A content analysis was conducted on the data resulting in a ranking of 19 motivational factors, of which the top three were challenge, usefulness and familiarity and 15 de-motivational factors, of which the top-three were usability issues, poor communication and games that were too fast. Findings were used to inform the design of three prototype brain-exercise games for the iPhone contained within one overall application, named Brain jog. Subsequently, two FTs were conducted using Brain jog to investigate the part that time exposure has to play in shaping the factors influencing engagement. New factors arose with respect to the initial FGs including the motivational factor feedback and the de-motivational factor boring. The results of this research provide valuable guidelines for the design and evaluation of mobile brain-exercise software for seniors.

Parallels between machine and brain decoding

We report some existing work, inspired by analogies between human thought and machine computation, showing that the informational state of a digital computer can be decoded in a similar way to brain decoding. We then discuss some proposed work that would leverage this analogy to shed light on the amount of information that may be missed by the technical limitations of current neuroimaging technologies. © 2012 Springer-Verlag.