Proteostasis impairment in ALS.

In physiological conditions the maintenance of the cellular proteome is a prerequisite for optimal cell functioning and cell survival. Additionally, cells need to constantly sense and adapt to their changing environment and associated stressors. Cells achieve this via a set of molecular chaperones, protein clearance pathways as well as stress-associated signaling networks which work together to prevent protein misfolding, its aggregation and accumulation in subcellular compartments. These processes together form the proteostasis network which helps in maintaining cellular proteostasis. Imbalance or impairment in this processes is directly linked to ageing associated disorders such as diabetes, cancer, stroke, metabolic disorders, pulmonary fibrosis, inflammation and neurodegenerative diseases. In this review, we provide insights into the proteostasis process and how its failure governs neurodegenerative disorders with a special focus on Amyotrophic lateral sclerosis (ALS).

Tooth loss, chewing efficiency and cognitive impairment in geriatric patients.

BACKGROUND Patients with dementia have poorer oral health and fewer teeth than their peers without cognitive impairment. OBJECTIVE The hypothesis of this study is that the number of natural teeth and the chewing efficiency are associated with cognitive functioning. METHODS This cross-sectional study included 29 patients diagnosed with dementia aged 75 years or older and 22 controls who were either cognitively normal (n = 19) or with mild cognitive impairment (n = 3). Neuropsychological, nutritional and dental assessments were performed. The chewing efficiency was evaluated with a two-colour mixing test. RESULTS Demented patients and controls presented with a mean of 4.9 and 6.5 teeth, respectively (n.s.). The number of natural teeth was not associated with dementia (p = 0.553). Same results were found for age (p = 0.746) and sex (p = 0.901). The chewing efficiency by visual inspection proved worse in participants with dementia than in the controls (p < 0.011) and explained 9.3% of the variance in the diagnosis of dementia. Neither dental state nor chewing efficiency was related to the nutritional state. CONCLUSION Chewing efficiency seems stronger associated with cognitive impairment than the number of teeth. Hence, in a more holistic approach for the geriatric assessment, the dental examination may be complemented by a chewing efficiency test.

Driving and emergency braking may be impaired after tibiotalar joint arthrodesis: conclusions after a case series.

PURPOSE To assess whether reaction time (RT) and movement time (MT), as the two components of the total brake response time (TBRT) and brake force (BF) are different in patients with a foot joint arthrodesis in comparison to controls. METHODS The study was a comparative case series in a driving simulator under realistic driving conditions. Mobile patients without a walker, ≥6 months after surgery who were driving a car and had no neurological co-morbidity, knee or hip joint prosthesis were included in the study. The selection criteria resulted in 12 patients with right tibiotalar joint arthrodesis (TTJA) and 12 patients with another right foot joint arthrodesis (OFJA), who were compared to 17 individuals without any ankle-joint pathology. For TBRT, an empirical safe driving threshold of 700 ms was used. The outcome measures were RT, MT, TBRT, BF and McGuire score. RESULTS MT (p = 0.034) and TBRT (p = 0.026) were longer in TTJA patients in comparison with the controls. Also, more patients with TTJA than patients with OFJA and controls exceeded the safe driving threshold (p = 0.028). The outcomes in OFJA patients and in controls were comparable. The McGuire score was similar between the TTJA and OFJA patients (p = 0.26). CONCLUSIONS Significantly slower MT and TBRT, and significantly more patients exceeding the safe driving threshold, were observed after a tibiotalar-joint arthrodesis in comparison to the controls. Patients with OFJAs were not significantly different from the controls. Driving and emergency braking may be impaired after tibiotalar-joint arthrodesis.

History of Maltreatment and Psychiatric Impairment in Children in Outpatient Psychiatric Treatment

There is increasing evidence that childhood victimization and attachment disruptions impact a child’s development. In this study, children and adolescents from an outpatient psychiatric clinic were assessed, measuring history of trauma, history of out-of-home placement, initial diagnoses, and CBCL internalizing and externalizing problem scores. Multiple regression analyses showed that both violent abuse trauma (physical/sexual abuse) and victim trauma (physical abuse/sexual abuse/witnessing domestic violence/witnessing community violence) are prevalent among patients with externalizing severity problems; concluding that diagnosis alone may not account for a history of victimization, but externalizing problem severity does. Overall, the study is consistent with past literature that it is important to acknowledge a child’s history of maltreatment and out-of-home placement when understanding their psychiatric development and diagnosis.

The Texas driver responsibility program: A preliminary analysis of the impact on impaired driving and trauma system funding

Objective. In 2003, the State of Texas instituted the Driver Responsibility Program (TDRP), a program consisting of a driving infraction point system coupled with a series of graded fines and annual surcharges for specific traffic violations such as driving while intoxicated (DWI). Approximately half of the revenues generated are earmarked to be disbursed to the state's trauma system to cover uncompensated trauma care costs. This study examined initial program implementation, the impact of trauma system funding, and initial impact on impaired driving knowledge, attitudes and behaviors. A model for targeted media campaigns to improve the program's deterrence effects was developed. ^ Methods. Data from two independent driver survey samples (conducted in 1999 and 2005), department of public safety records, state health department data and a state auditor's report were used to evaluate the program's initial implementation, impact and outcome with respect to drivers' impaired driving knowledge, attitudes and behavior (based on constructs of social cognitive theory) and hospital uncompensated trauma care funding. Survey results were used to develop a regression model of high risk drivers who should be targeted to improve program outcome with respect to deterring impaired driving. ^ Results. Low driver compliance with fee payment (28%) and program implementation problems were associated with lower surcharge revenues in the first two years ($59.5 million versus $525 million predicted). Program revenue distribution to trauma hospitals was associated with a 16% increase in designated trauma centers. Survey data demonstrated that only 28% of drivers are aware of the TDRP and that there has been no initial impact on impaired driving behavior. Logistical regression modeling suggested that target media campaigns highlighting the likelihood of DWI detection by law enforcement and the increased surcharges associated with the TDRP are required to deter impaired driving. ^ Conclusions. Although the TDRP raised nearly $60 million in surcharge revenue for the Texas trauma system over the first two years, this study did not find evidence of a change in impaired driving knowledge, attitudes or behaviors from 1999 to 2005. Further research is required to measure whether the program is associated with decreased alcohol-related traffic fatalities. ^

The impact of functional impairment on the survival of patients with Alzheimer's disease

Alzheimer's disease (AD), the most common form of dementia, is the fifth leading cause of death among U.S. adults aged 65 or older. Most AD patients have shorter life expectancy compared with older people without dementia. This disease has become an enormous challenge in the aging society and is also a global problem. Not only do families of patients with Alzheimer's disease need to pay attention to this problem, but also the healthcare system and society as a whole have to confront. In dementia, functional impairment is associated with basic activities of daily living (ADL) and instrumental activities of daily living (IADL). For patients with Alzheimer's disease, problems typically appear in performing IADL and progress to the inability of managing less complex ADL functions of personal care. Thus, assessment of ADLs can be used for early accurate diagnosis of Alzheimer's disease. It should be useful for patients, caregivers, clinicians, and policy planners to estimate the survival of patients with Alzheimer's disease. However, it is unclear that when making predictions of patient outcome according to their histories, time-dependent covariates will provide us with important information on how changes in a patient's status can effect the survival. In this study, we examined the effect of impaired basic ADL as measured by the Physical Self-Maintenance Scale (PSMS) and utilized a multistate survival analysis approach to estimate the probability of death in the first few years of initial visit for AD patients taking into consideration the possibility of impaired basic ADL. The dataset used in this study was obtained from the Baylor Alzheimer's Disease and Memory Disorders Center (ADMDC). No impaired basic ADL and older age at onset of impaired basic ADL were associated with longer survival. These findings suggest that the occurrence of impaired basic ADL and age at impaired basic ADL could be predictors of survival among patients with Alzheimer's disease. ^

Folate pathway polymorphisms and neuropsychological impairment after leukemia therapy

Neuropsychological impairment occurs in 20%-40% of childhood acute lymphoblastic leukemia (ALL) survivors, possibly mediated by folate depletion following methotrexate chemotherapy. We evaluated the relationship between two folate pathway polymorphisms and neuropsychological impairment after childhood ALL chemotherapy. Eighty-six childhood ALL survivors were recruited between 2004-2007 at Texas Children's Hospital after exclusion for central nervous system leukemia, cranial irradiation, and age<1 year at diagnosis. Neuropsychological evaluation at a median of 5.3 years off therapy included a parental questionnaire and the following child performance measures: Trail Making Tests A and B, Grooved Pegboard Test Dominant-Hand and Nondominant-Hand, and Digit Span subtest. We performed genotyping for polymorphisms in two folate pathway genes: reduced folate carrier (RFC1 80G>A, rs1051266) and dihydrofolate reductase (DHFR Intron-1 19bp deletion). Fisher exact test, logistic regression, Student's t-test, and ANOVA were used to compare neuropsychological test scores by genotype, using a dominant model to group genotypes. In univariate analysis, survivors with cumulative methotrexate exposure ≥9000 mg/m2 had an increased risk of attention disorder (OR=6.2, 95% CI 1.2 – 31.3), compared to survivors with methotrexate exposure <9000 mg/m2. On average, female survivors scored 8.5 points higher than males on the Digit Span subtest, a test of working memory (p=0.02). The RFC1 80G>A and DHFR Intron-1 deletion polymorphisms were not related to attention disorder or impairment on tests of attention, processing speed, fine motor speed, or memory. These data imply a strong relationship between methotrexate dose intensity and impairment in attention after childhood ALL therapy. We did not find an association between the RFC1 80G>A or DHFR Intron-1 deletion polymorphisms and long-term neuropsychological impairment in childhood ALL survivors.^

Neurocognitive impairment in relation to glutathione S-transferase enzyme polymorphisms among medulloblastoma patients

Background. Medulloblastoma is a type of brain cancer that accounts for approximately 7-8% of all intracranial tumors and 20-30% of pediatric brain tumors. It is the most common type of malignant brain tumor in childhood. It was reported that majority of survivors with medulloblastoma have social problems, endocrine deficits, and neurological complications. Furthermore, all had significant deficits in neurocognitive functioning. Glutathione S-transferases belong to a family of isoenzymes that catalyze the glutathione conjugation of a variety of electrophilic compounds. ^ Objective. We aimed to determine whether the development of neurocognitive impairment is associated with GST polymorphisms among children and adolescents diagnosed with medulloblastoma (MB) after radiation therapy. ^ Methods. A pilot study composing of 16 children and adolescents diagnosed with MB at Texas Children's Cancer Center was conducted. The t-test was used to determine if the GST polymorphisms were related to neurocognitive impairment and logistic regression was performed to explore association between GST polymorphisms and gender, age at diagnosis, race/ethnicity, and risk group. ^ Results. An association was observed between GSTT1 polymorphism and cognitive impairment one year after radiation and GSTM1 polymorphism two years after radiation. It was observed that patients with GSTT1 null genotype have lower performance IQ (p=0.03) and full scale IQ (p=0.02) one year after radiation and patients with GSTM1 null genotype have lower verbal IQ (p=0.02) two years after radiation. Patients under age 8 have a statistically non-significant higher risk of having not null genotypes compared to those older than age 8 (OR= 7.5, 95%CI: 0.62-90.65 and OR= 2.63, 95%CI: 0.30-23.00 for GSTT1 and GSTM1 respectively). ^ Conclusion. There was a significant association between GSTT1 polymorphism and cognitive impairment one year after radiation and between GSTM1 polymorphism and cognitive impairment two years after radiation. Further large scale studies may be needed to confirm this finding and to examine the underlying mechanism of neurocognitive impairments after treatment of medulloblastoma patients.^

The feasibility of self-report advance directives among elderly patients with cognitive impairment

The central objective of this dissertation was to determine the feasibility of self-completed advance directives (AD) in older persons suffering from mild and moderate stages of dementia. This was accomplished by identifying differences in ability to complete AD among elderly subjects with increasing degrees of dementia and cognitive incompetence. Secondary objectives were to describe and compare advance directives completed by elders and identified proxy decision makers. Secondary objectives were accomplished by measuring the agreement between advance directives completed by proxy and elder, and comparing that agreement across groups defined by the elder's cognitive status. This cross-sectional study employed a structured interview to elicit AD, followed by a similar interview with a proxy decision maker identified by the elder. A stratified sampling scheme recruited elders with normal cognition, mild, and moderate forms of dementia using the Mini Mental-State Exam (MMSE). The Hopkins Competency Assessment Test (HCAT) was used for evaluation of competency to make medical decisions. Analysis was conducted on "between group" (non-demented $\leftrightarrow$ mild dementia $\leftrightarrow$ moderate dementia, and competent $\leftrightarrow$ incompetent) and "within group" (elder $\leftrightarrow$ family member) variation.^ The 118 elderly subjects interviewed were generally male, Caucasian, and of low socioeconomic status. Mean age was 77. Overall, elders preferred a "trial of therapy" regarding AD rather than to "always receive the therapy". No intervention was refused outright more often than it was accepted. A test-retest of elders' AD revealed stable responses. Eleven logic checks measured appropriateness of AD responses independent of preference. No difference was found in logic error rates between elders grouped by MMSE or HCAT. Agreement between proxy and elder responses showed significant dissimilarity, indicating that proxies were not making the same medical decisions as the elders.^ Conclusions based on these data are: (1) Self reporting AD is feasible among elders showing signs of cognitive impairment and they should be given all opportunities to complete advance directives, (2) variation in preferences for advance directives in cognitively impaired elders should not be assumed to be the effects of their impairment alone, (3) proxies do not appear to forego life-prolonging interventions in the face of increasing impairment in their ward, however, their advance directives choices are frequently not those of the elder they represent. ^

Vocational guidance in people with special educational needs as the result of visual impairment during the transition stage from high school to advanced education

This work proposes to seek for the factors related to the choices that people with special educational needs make as the result of the visual impairment, during the transition stage from high school to advanced education. Therefore, we have taken into consideration that Vocational Guidance and the transition towards adulthood get specific characteristics in case of visually impaired young people, particularly in what's related to continue with advanced education. The focus of this work is to be able to clarify the existence of factors that make this transition stage easier or harder, through the observation of visually impaired and blind people who complete high school. This matter has aroused interest and concern about the strategies to follow to ensure the successful entrance and remaining in the selected advanced education. However, if we don?t know the factors involved in the described fact, it's difficult to design an appropriate intervention strategy. Then, in order to take acknowledge about the specific issues of visually impaired young people who complete high school, we chose a special school for this disability and some students who will join this project

Vocational guidance in people with special educational needs as the result of visual impairment during the transition stage from high school to advanced education

This work proposes to seek for the factors related to the choices that people with special educational needs make as the result of the visual impairment, during the transition stage from high school to advanced education. Therefore, we have taken into consideration that Vocational Guidance and the transition towards adulthood get specific characteristics in case of visually impaired young people, particularly in what's related to continue with advanced education. The focus of this work is to be able to clarify the existence of factors that make this transition stage easier or harder, through the observation of visually impaired and blind people who complete high school. This matter has aroused interest and concern about the strategies to follow to ensure the successful entrance and remaining in the selected advanced education. However, if we don?t know the factors involved in the described fact, it's difficult to design an appropriate intervention strategy. Then, in order to take acknowledge about the specific issues of visually impaired young people who complete high school, we chose a special school for this disability and some students who will join this project

Vocational guidance in people with special educational needs as the result of visual impairment during the transition stage from high school to advanced education

This work proposes to seek for the factors related to the choices that people with special educational needs make as the result of the visual impairment, during the transition stage from high school to advanced education. Therefore, we have taken into consideration that Vocational Guidance and the transition towards adulthood get specific characteristics in case of visually impaired young people, particularly in what's related to continue with advanced education. The focus of this work is to be able to clarify the existence of factors that make this transition stage easier or harder, through the observation of visually impaired and blind people who complete high school. This matter has aroused interest and concern about the strategies to follow to ensure the successful entrance and remaining in the selected advanced education. However, if we don?t know the factors involved in the described fact, it's difficult to design an appropriate intervention strategy. Then, in order to take acknowledge about the specific issues of visually impaired young people who complete high school, we chose a special school for this disability and some students who will join this project

Seawater carbonate chemistry and survival, impairment of three phytoplankton species in a laboratory experiment

Sodium hypochlorite (NaOCl) is widely used to disinfect seawater in power plant cooling systems in order to reduce biofouling, and in ballast water treatment systems to prevent transport of exotic marine species. While the toxicity of NaOCl is expected to increase by ongoing ocean acidification, and many experimental studies have shown how algal calcification, photosynthesis and growth respond to ocean acidification, no studies have investigated the relationship between NaOCl toxicity and increased CO2. Therefore, we investigated whether the impacts of NaOCl on survival, chlorophyll a (Chl-a), and effective quantum yield in three marine phytoplankton belonging to different taxonomic classes are increased under high CO2 levels. Our results show that all biological parameters of the three species decreased under increasing NaOCl concentration, but increasing CO2 concentration alone (from 450 to 715 µatm) had no effect on any of these parameters in the organisms. However, due to the synergistic effects between NaOCl and CO2, the survival and Chl-a content in two of the species, Thalassiosira eccentrica and Heterosigma akashiwo, were significantly reduced under high CO2 when NaOCl was also elevated. The results show that combined exposure to high CO2 and NaOCl results in increasing toxicity of NaOCl in some marine phytoplankton. Consequently, greater caution with use of NaOCl will be required, as its use is widespread in coastal waters.