The pervasive and unyielding impacts of cognitive-communication changes following traumatic brain injury.

BACKGROUND: Cognitive-communication disorders (CCDs) are common in the traumatic brain injury (TBI) population. Despite this, there has been limited research that explores the long-term impacts of reduced cognitive-communication functioning on daily life for this population. AIMS: To identify the long-term impacts of cognitive-communication impairment as reported by adults with TBI and their significant others. METHODS & PROCEDURES: A qualitative descriptive approach grounded in phenomenology was used. Semi-structured, one-on-one interviews were conducted with adults with CCDs following TBI (n = 16) and their significant others (n = 12) to explore their lived experiences. OUTCOMES & RESULTS: Reflexive thematic analysis revealed an overarching theme of 'The pervasive and unyielding impacts of cognitive-communication changes on daily life following TBI'. Within this overarching theme, three subthemes were identified: (1) self-awareness of communication changes; (2) fatigue; and (3) self-identity and life roles. CONCLUSION & IMPLICATIONS: The findings from this study highlight the long-term negative impacts of reduced cognitive-communication functioning on daily life. Health professionals supporting this population should consider ways to reduce the significant impact CCDs have on the lives of adults following TBI and their significant others. In addition, the findings highlight the importance of long-term rehabilitation services following TBI, with further research needed that explores how these services can be optimised. WHAT THIS PAPER ADDS: What is already known on this subject Cognitive-communication disorders (CCDs) affect the majority of adults who experience moderate to severe traumatic brain injury (TBI) and encompass any component of communication that is affected by cognition. The hallmark characteristic of CCDs are breakdowns that affect social communication skills as well as cognitive-linguistic deficits. Combined, these can have dramatic implications for a person's quality of life, their level of independence, employment opportunities and social participation. There has been limited research to date that explores the long-term impacts of CCDs on the lives of adults following TBI. Further research that explores these impacts is needed to improve the support services and rehabilitation models of care available for this population. What this study adds The overarching theme was 'The pervasive and unyielding impacts of communication changes on daily life following TBI' with subthemes including changed communication, self-awareness of communication changes, fatigue and self-identity and life roles. The findings from this study highlight the long-term negative impacts of reduced cognitive-communication functioning on everyday functioning and quality of life as well as the importance of long-term rehabilitation services following TBI. What are the clinical implications of this work? Speech-language therapists and other health professionals working with this clinical population should consider how to address the significant and long-lasting impacts of CCDs. Due to the complex nature of the barriers experienced by this clinical population, an interdisciplinary targeted approach is advised wherever possible when providing rehabilitation services.

Community-based rehabilitation for adults with cognitive-communication disorders following traumatic brain injury: A mixed methods investigation.

OBJECTIVE: To investigate the experiences and perspectives of speech pathologists when delivering cognitive-communication therapy to adults following traumatic brain injury (TBI). METHODS: An explanatory sequential mixed methods design was used to explore the practices of speech pathologists working in community-based rehabilitation (CBR) settings. The first participant group completed an in-depth online survey, whilst the second group participated in an interview to discuss their processes and recommendations when managing adults following TBI. RESULTS: Participants highlighted the need for services to be client-centered and inclusive in their approaches to meet the rehabilitation needs of people following TBI in community-based settings. The key features identified to achieve this included utilizing a flexible service delivery approach, implementation of meaningful therapy, as well as inclusion of significant others. CONCLUSIONS: These findings provide a snapshot of the current practices employed by a range of speech pathology services across Australia and New Zealand. Health professionals and rehabilitation service providers should consider the key factors highlighted by the participants when designing future CBR models of care for this client group.

Systematic Review of Behavioral Interventions Targeting Social Communication Difficulties After Traumatic Brain Injury.

OBJECTIVE: To determine whether behavioral interventions are beneficial for adults with social communication difficulties after traumatic brain injury (TBI). DATA SOURCES: Electronic databases were searched through October 2013 to find behavioral intervention trials. Keywords used in our search were intervention, therapy, treatment, and program combined with pragmatic disorder, pragmatic impairment, social communication disorder/impairment, conversation disorder/impairment, social disorder/impairment, cognitive-linguistic and cognitive-communication deficit; adult; and traumatic brain injury, head injury, and brain injury. Hand searches of the reference lists of relevant articles were also conducted. STUDY SELECTION: To be selected for detailed review, articles found in the initial search were assessed by 2 reviewers and had to meet the following criteria: (1) population (adults with TBI); (2) intervention (behavioral intervention); and (3) outcomes (changes in social communication). Articles needed to describe interventions that were delivered directly to adults with TBI with or without other people (such as significant others) involved. Of the 2181 articles initially identified, 15 were selected for detailed review. DATA EXTRACTION: Data were independently extracted by members of the research team, then collated and reviewed by the team. DATA SYNTHESIS: Of the 15 publications that met the study criteria, 7 were single-case design studies, 3 were randomized controlled trials, 1 was a nonrandomized controlled trial, and 4 were cohort studies. The methodological qualities of eligible articles were examined using the Physiotherapy Evidence Database and Single-Case Experimental Design rating scales. The interventions described in the studies fell into 2 broad categories: those addressing a specific impairment in social communication, and context-specific interventions with a holistic focus on social communication skills. Studies using context-sensitive approaches had been published more recently and were generally group studies with higher methodological quality. CONCLUSIONS: Overall, interventions addressing social communication skills for people with TBI were found to be beneficial irrespective of treatment approach used. While the evidence base is small and with varying levels of scientific rigor, there is a body of quality evidence that supports the use of context-sensitive approaches. Further research is still required to determine the role of impairment-specific versus context-specific interventions when treating individuals with social communication difficulties after TBI to inform clinical decision-making.

Lumbar intraspinal injection of neural stem cells in patients with amyotrophic lateral sclerosis: results of a phase I trial in 12 patients.

Advances in stem cell biology have generated intense interest in the prospect of transplanting stem cells into the nervous system for the treatment of neurodegenerative diseases. Here, we report the results of an ongoing phase I trial of intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS). This is a first-in-human clinical trial with the goal of assessing the safety and tolerability of the surgical procedure, the introduction of stem cells into the spinal cord, and the use of immunosuppressant drugs in this patient population. Twelve patients received either five unilateral or five bilateral (10 total) injections into the lumbar spinal cord at a dose of 100,000 cells per injection. All patients tolerated the treatment without any long-term complications related to either the surgical procedure or the implantation of stem cells. Clinical assessments ranging from 6 to 18 months after transplantation demonstrated no evidence of acceleration of disease progression due to the intervention. One patient has shown improvement in his clinical status, although these data must be interpreted with caution since this trial was neither designed nor powered to measure treatment efficacy. These results allow us to report success in achieving the phase I goal of demonstrating safety of this therapeutic approach. Based on these positive results, we can now advance this trial by testing intraspinal injections into the cervical spinal cord, with the goal of protecting motor neuron pools affecting respiratory function, which may prolong life for patients with ALS.

Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as a potential prognostic biomarker in amyotrophic lateral sclerosis.

BACKGROUND: The phosphorylated neurofilament heavy subunit (pNF-H), a major structural component of motor axons, is a promising putative biomarker in amyotrophic lateral sclerosis (ALS) but has been studied mainly in CSF. We examined pNF-H concentrations in plasma, serum and CSF as a potential biomarker for disease progression and survival in ALS. METHODOLOGY: We measured pNF-H concentration by monoclonal sandwich ELISA in plasma (n=43), serum and CSF (n=20) in ALS patients collected at the Mayo Clinic Florida and Emory University. We included plasma from an ALS cohort (n=20) from an earlier pilot study in order to evaluate baseline pNF-H levels in relation to disease progression using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), survival and anatomical region of ALS onset. RESULTS: Higher pNF-H levels in plasma, serum and CSF showed evidence of association with faster decline in ALSFRS-R. There was evidence for a relationship of higher serum and plasma pNF-H levels with shorter survival, although evidence was weaker for CSF. pNF-H concentration in plasma (n=62) may be higher in patients with bulbar onset than in patients with spinal onset. CONCLUSIONS: In ALS, increased pNF-H concentration in plasma, serum and CSF appears to be associated with faster disease progression. Factors affecting pNF-H levels or their detection in serum and plasma in relation to disease course may differ from those in CSF. Data raising the possibility that site of ALS onset (bulbar vs spinal) may influence pNF-H levels in peripheral blood seems noteworthy but requires confirmation. These data support further study of pNF-H in CSF, serum and plasma as a potential ALS biomarker.

Nucleotide excision repair deficiency is intrinsic in sporadic stage I breast cancer.

The molecular etiology of breast cancer has proven to be remarkably complex. Most individual oncogenes are disregulated in only approximately 30% of breast tumors, indicating that either very few molecular alterations are common to the majority of breast cancers, or that they have not yet been identified. In striking contrast, we now show that 19 of 19 stage I breast tumors tested with the functional unscheduled DNA synthesis assay exhibited a significant deficiency of DNA nucleotide excision repair (NER) capacity relative to normal epithelial tissue from disease-free controls (n = 23). Loss of DNA repair capacity, including the complex, damage-comprehensive NER pathway, results in genomic instability, a hallmark of carcinogenesis. By microarray analysis, mRNA expression levels for 20 canonical NER genes were reduced in representative tumor samples versus normal. Significant reductions were observed in 19 of these genes analyzed by the more sensitive method of RNase protection. These results were confirmed at the protein level for five NER gene products. Taken together, these data suggest that NER deficiency may play an important role in the etiology of sporadic breast cancer, and that early-stage breast cancer may be intrinsically susceptible to genotoxic chemotherapeutic agents, such as cis-platinum, whose damage is remediated by NER. In addition, reduced NER capacity, or reduced expression of NER genes, could provide a basis for the development of biomarkers for the identification of tumorigenic breast epithelium.

Speech pathologists' perspectives when managing adults following traumatic brain injury in community-based rehabilitation settings: A qualitative investigation.

Purpose: Across Australia and New Zealand, speech-language pathologists (SLPs) routinely assess and treat adults with cognitive-communication disorders following traumatic brain injury (TBI). Despite their regular involvement, little is known about how clinicians provide management to this client group, particularly in community-based contexts. Therefore the aim of this study is to explore the clinical practices of SLPs who have experience working in community-based rehabilitation services with adults with cognitive-communication disorders following TBI.Method: A qualitative descriptive study using one-on-one semi-structured interviews was conducted as part of an explanatory sequential mixed-methods design. Fourteen SLPs with experience working with individuals with TBI completed an interview with content analysis used to explore the data.Result: The overarching theme identified was that a "Client-centred and inclusive approach to community-based rehabilitation services" is required. The three subthemes to emerge from the data included the importance of utilising a (1) "flexible service delivery approach", with (2) "meaningful therapy focus", and (3) "collaboration" with multidisciplinary team members and significant others when managing this client group.Conclusion: SLPs play a crucial role in client-centred inclusive rehabilitation for community-dwelling adults with cognitive-communication disorders following TBI. The complexity of working with this population requires current and future models of care to incorporate an interdisciplinary approach that is flexible in its delivery and meaningful in focus.

A systematic review of group intervention for acquired dysarthria in adults.

PURPOSE: This review aimed to evaluate the evidence for group therapy in improving speech production in adults with acquired dysarthria. Secondary outcomes included communication effectiveness and/or wellbeing. MATERIALS AND METHODS: A review protocol was prospectively published on PROSPERO. Fourteen electronic databases were searched to identify experimental studies investigating adults with acquired dysarthria participating in group intervention with outcomes related to communication and/or wellbeing. The quality of included studies was assessed using the Mixed Methods Appraisal Tool (MMAT) or the McMaster University's Critical Review Form, and the TIDieR template for intervention description and replication. RESULTS: 21 studies were identified involving 330 individuals with dysarthria, from mostly Parkinson's disease (PD) (97%; n = 321). Treatment approaches included singing therapy (n = 10), loudness therapy (n = 5) and multi-components therapy (including a combination of impairment and/or compensatory approaches) (n = 4). Studies varied in intensity and outcome measures used. Statistically significant improvements to speech production and/or wellbeing were reported following most approaches. CONCLUSION: There is some preliminary moderate-quality evidence to suggest that group therapy may improve speech production and in some cases communication effectiveness or wellbeing in people with dysarthria following PD, with more consistent improvements being found for loudness approaches. Singing approaches were frequently studied in PD with some improvements to intelligibility evident. Further well-designed controlled studies including individuals with non-progressive aetiologies is warranted to establish the effectiveness of group treatment.IMPLICATIONS FOR REHABILITATIONGroup therapy may be an effective means of improving speech production and/or wellbeing in individuals with dysarthria following Parkinson's disease.Studies' employing loudness-based group therapy for PD demonstrated more consistent improvements to intensity measures.Some controlled studies utilising singing group therapy resulted in improved intelligibility in PD.PROSPERO registration number: CRD42015029374.

A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling.

In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.

The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex.

Specificity protein 1 (SP1) is an essential transcription factor implicated in the regulation of genes that control multiple cellular processes, including cell cycle, apoptosis, and DNA damage. Very few nontranscriptional roles for SP1 have been reported thus far. Using confocal microscopy and centrosome fractionation, we identified SP1 as a centrosomal protein. Sp1-deficient mouse embryonic fibroblasts and cells depleted of SP1 by RNAi have increased centrosome number associated with centriole splitting, decreased microtubule nucleation, chromosome misalignment, formation of multipolar mitotic spindles and micronuclei, and increased incidence of aneuploidy. Using mass spectrometry, we identified P70S6K, an effector of the mTOR/raptor (mTORC1) kinase complex, as a novel interacting protein of SP1. We found that SP1-deficient cells have increased phosphorylation of the P70S6K effector ribosomal protein S6, suggesting that SP1 participates in the regulation of the mTORC1/P70S6K/S6 signaling pathway. We previously reported that aberrant mTORC1 activation leads to supernumerary centrosomes, a phenotype rescued by the mTORC1 inhibitor rapamycin. Similarly, treatment with rapamycin rescued the multiple centrosome phenotype of SP1-deficient cells. Taken together, these data strongly support the hypothesis that SP1 is involved in the control of centrosome number via regulation of the mTORC1 pathway, and predict that loss of SP1 function can lead to aberrant centriole splitting, deregulated mTORC1 signaling, and aneuploidy, thereby contributing to malignant transformation.

Implications of Antipsychotic Use: Antipsychotic-Induced Movement Disorders, with a Focus on Tardive Dyskinesia.

Antipsychotics can be life changing, but like all medications, they can also have unwanted effects, including drug-induced movement disorders such as tardive dyskinesia (TD). More patients are receiving antipsychotic treatment from non-psychiatry health care providers, including primary care and general practitioners. Despite misconceptions to the contrary, recent analyses suggest that the risk of drug-induced movement disorders such as TD has not been eliminated. Nurses across all care settings will increasingly encounter patients treated with antipsychotics. Nurses are critical for ensuring that patients exposed to antipsychotics receive screening and monitoring, care, and education.

Metastatic neuroendocrine carcinoma presenting as multifocal liver lesions with elevated alpha-fetoprotein.

Significant elevations in alpha-fetoprotein should raise suspicion for hepatocellular carcinoma as malignancies with metastasis to the liver can elevate the alpha-fetoprotein level but typically <300 ng/mL. Diagnosis should be confirmed with typical characteristics of hepatocellular carcinoma on imaging and or liver biopsy to confirm diagnosis.

Waldenström's macroglobulinemia masquerading as ovarian cancer with peritoneal carcinomatosis, ascites, and elevated CA-125.

Waldenström's macroglobulinemia is a rare hematology malignancy which often presents with "B symptoms," anemia, and thrombocytopenia. A 46-year-old woman presented with 2 months of abdominal distension accompanied by an unintentional 20-lb weight loss. Her abdominal CT scan demonstrated diffuse carcinomatosis with bilateral ovarian lesions and screening labs revealed a markedly elevated CA-125, suggesting a diagnosis of ovarian cancer. Upon admission for workup, patient was found to have a significant protein gap, later attributed to a markedly elevated IgM. Omental and bone marrow biopsy confirmed the diagnosis of Waldenström's macroglobulinemia, with elevation in CA-125 thought to be secondary to peritoneal irritation. This patient has since been successfully treated with six cycles of bendamusine and rituximab with no evidence of disease on staging scans and normalization of both CA-125 and IgM. To our knowledge, this is the first documented case of Waldenström's macroglobulinemia presenting with symptoms classically associated with ovarian cancer and demonstrates the importance of maintaining a broad differential when evaluating patients with abdominal carcinomatosis.

Phosphorylation of Sp1 in response to DNA damage by ataxia telangiectasia-mutated kinase.

Sp1, a transcription factor that regulates expression of a wide array of essential genes, contains two SQ/TQ cluster domains, which are characteristic of ATM kinase substrates. ATM substrates are transducers and effectors of the DNA damage response, which involves sensing damage, checkpoint activation, DNA repair, and/or apoptosis. A role for Sp1 in the DNA damage response is supported by our findings: Activation of ATM induces Sp1 phosphorylation with kinetics similar to H2AX; inhibition of ATM activity blocks Sp1 phosphorylation; depletion of Sp1 sensitizes cells to DNA damage and increases the frequency of double strand breaks. We have identified serine 101 as a critical site phosphorylated by ATM; Sp1 with serine 101 mutated to alanine (S101A) is not significantly phosphorylated in response to damage and cannot restore increased sensitivity to DNA damage of cells depleted of Sp1. Together, these data show that Sp1 is a novel ATM substrate that plays a role in the cellular response to DNA damage.

Unscheduled DNA synthesis: a functional assay for global genomic nucleotide excision repair.

The unscheduled DNA synthesis (UDS) assay measures a cell's ability to perform global genomic nucleotide excision repair (NER). This chapter provides instructions for the application of this technique in living cells by creating 6-4 photoproducts and pyrimidine dimers using UVC irradiation, then allowing for their repair. Repair is quantified by the amount of radioactive thymidine incorporated after this insult, and the length of time allowed for this incorporation is specific for repair of particular lesions. Radioactivity is evaluated by grain counting after autoradiography. The results are used to diagnosis repair-deficient disorders clinically and provide a basis for investigation of repair deficiency in human tissues or tumors. At the present time, no other functional assay is available that directly measures the capacity to perform NER on the entire genome without the use of specific antibodies. Since live cells are required for this assay, explant culture techniques must be previously established. Host cell reactivation, as discussed in Chapter 28, is not an equivalent technique, as it specifically measures transcription-coupled repair at active genes, a subset of total NER.

Unscheduled DNA synthesis: the clinical and functional assay for global genomic DNA nucleotide excision repair.

The unscheduled DNA synthesis (UDS) assay measures the ability of a cell to perform global genomic nucleotide excision repair (NER). This chapter provides instructions for the application of this technique by creating 6-4 photoproducts and pyrimidine dimers using UV-C irradiation. This procedure is designed specifically for quantification of the 6-4 photoproducts. Repair is quantified by the amount of radioactive thymidine incorporated during repair synthesis after this insult, and radioactivity is evaluated by grain counting after autoradiography. The results are used to clinically diagnose human DNA repair deficiency disorders and provide a basis for investigation of repair deficiency in human tissues or tumors. No other functional assay is available that directly measures the capacity to perform NER on the entire genome without the use of specific antibodies. Since live cells are required for this assay, explant culture techniques must be previously established. Host cell reactivation (HCR), as discussed in Chapter 37, is not an equivalent technique, as it measures only transcription-coupled repair (TCR) at active genes, a small subset of total NER.

Prognosis and epidemiology of amyotrophic lateral sclerosis: Analysis of a clinic population, 1997-2011.

Amyotrophic lateral sclerosis is a disease with highly variable clinical features and prognosis. We analyzed the prognostic indicators of age, sex, bulbar or spinal onset, body mass index (BMI), and forced vital capacity (FVC) for 728 deceased patients from the Emory ALS Clinic. The median overall survival was 29.8 months from symptom onset, 15.8 months from diagnosis, and 14.3 months from the initial clinic visit. While univariate analyses revealed that each of the identified clinical features was strongly associated with patient survival, in multivariable analyses only age, BMI, and FVC measured at the first clinic visit were independent prognostic indicators; bulbar onset and sex were not significantly associated with survival prognosis after adjustment for the other clinical features.

Behavior matters--cognitive predictors of survival in amyotrophic lateral sclerosis.

BACKGROUND: It is difficult to longitudinally characterize cognitive impairment in amyotrophic lateral sclerosis (ALS) due to motor deficits, and existing instruments aren't comparable with assessments in other dementias. METHODS: The ALS Brief Cognitive Assessment (ALS-BCA) was validated in 70 subjects (37 with ALS) who also underwent detailed neuropsychological analysis. Cognitive predictors for poor survival were then analyzed in a longitudinal cohort of 171 ALS patients. RESULTS: The ALS-BCA was highly sensitive (90%) and specific (85%) for ALS-dementia (ALS-D). ALS-D patients had shorter overall survival, primarily due to the poor survival among ALS-D patients with disinhibited or apathetic behaviors after adjusting for demographic variables, ALS site of onset, medications, and supportive measures. ALS-D without behavioral changes was not a predictor of poor survival. CONCLUSION: ALS-D can present with or without prominent behavioral changes. Cognitive screening in ALS patients should focus on behavioral changes for prognosis, while non-behavioral cognitive impairments may impact quality of life without impacting survival.

Exome sequencing to identify de novo mutations in sporadic ALS trios.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease whose causes are still poorly understood. To identify additional genetic risk factors, we assessed the role of de novo mutations in ALS by sequencing the exomes of 47 ALS patients and both of their unaffected parents (n = 141 exomes). We found that amino acid-altering de novo mutations were enriched in genes encoding chromatin regulators, including the neuronal chromatin remodeling complex (nBAF) component SS18L1 (also known as CREST). CREST mutations inhibited activity-dependent neurite outgrowth in primary neurons, and CREST associated with the ALS protein FUS. These findings expand our understanding of the ALS genetic landscape and provide a resource for future studies into the pathogenic mechanisms contributing to sporadic ALS.

Sp1 facilitates DNA double-strand break repair through a nontranscriptional mechanism.

Sp1 is a ubiquitously expressed transcription factor that is phosphorylated by ataxia telangiectasia mutated kinase (ATM) in response to ionizing radiation and H(2)O(2). Here, we show by indirect immunofluorescence that Sp1 phosphorylated on serine 101 (pSp1) localizes to ionizing radiation-induced foci with phosphorylated histone variant γH2Ax and members of the MRN (Mre11, Rad50, and Nbs1) complex. More precise analysis of occupancy of DNA double-strand breaks (DSBs) by chromatin immunoprecipitation (ChIP) shows that Sp1, like Nbs1, resides within 200 bp of DSBs. Using laser microirradiation of cells, we demonstrate that pSp1 is present at DNA DSBs by 7.5 min after induction of damage and remains at the break site for at least 8 h. Depletion of Sp1 inhibits repair of site-specific DNA breaks, and the N-terminal 182-amino-acid peptide, which contains targets of ATM kinase but lacks the zinc finger DNA binding domain, is phosphorylated, localizes to DSBs, and rescues the repair defect resulting from Sp1 depletion. Together, these data demonstrate that Sp1 is rapidly recruited to the region immediately adjacent to sites of DNA DSBs and is required for DSB repair, through a mechanism independent of its sequence-directed transcriptional effects.