Caring for an individual with mild cognitive impairment: a qualitative perspective of health-related quality of life from caregivers.

OBJECTIVES: Little is known regarding the effect that caring for an individual with Mild Cognitive Impairment (MCI) has on health-related quality of life (HRQOL). We sought to identify the most important aspects of HRQOL related to caring for an individual with MCI. METHODS: Six focus groups were conducted with caregivers of individuals with MCI (n = 32). Qualitative frequency analysis was used to analyze the data. RESULTS: Findings indicated that caregivers most frequently discussed social health, including changes in social roles and an increased need for social support (51.2% of the total discussion). This was followed by mental health concerns (37.9%) centering on anger/frustration, and a need for patience in the caregiving role, as well as caregiver-specific anxiety. Other topics included physical health (10.0%; including the impact that stress and burden have on medical heath), and caregivers' cognitive health (0.9%; including memory problems in relation to caregiver strain, sleep disruption, and cognitive fatigue). CONCLUSIONS: Findings illustrate the multiple domains of HRQOL that are affected in individuals providing care for someone with MCI. Moreover, the findings highlight the need for extending support services to MCI caregivers, a group that is typically not offered support services due to the 'less severe' nature of an MCI diagnosis.

The effect of by-product inclusion level on milk production, nutrient digestibility and excretion, and rumen fermentation parameters in lactating dairy cows offered a pasture-based diet.

The objective of this study was to investigate the effects of replacing barley and soybean meal with increasing levels of by-products on production, digestive, and metabolic parameters in early-mid lactation dairy cows offered perennial ryegrass-based pasture. Forty-eight (32 multiparous and 16 primiparous) dairy cows that were 64 ± 24 d in milk were assigned to 1 of 4 pasture-based dietary treatments (n = 12) in a randomized block design experiment that ran for 70 d. Treatments consisted of a perennial ryegrass-based pasture and 1 of 4 supplementary concentrates: BP35, BP55, BP75, and BP95 containing 35, 55, 75, and 95% by-products, respectively, in the concentrate on a dry matter basis. The by-products used were soyhulls, dried distillers grains, and palm kernel extract in equal proportions. Barley and soybean meal were replaced as by-product inclusion level increased. In this study, intakes of pasture dry matter (15.7 kg) and total dry matter (21.1 kg) were not affected by treatment. Similarly, milk production parameters (milk yield, milk composition, somatic cell count, and urea) were not different between treatments. Unsaturated fatty acids were lower in the milk of cows offered BP35 and BP55 compared with those offered BP75 and BP95. Concentrations of ß-hydroxybutyrate, nonesterified fatty acids, and other blood metabolites were within normal range and did not differ between treatments, and cow body condition score and body weight were also not different. Equally, N was unaffected by diet. Blood urea N was lower in the BP75 group compared with BP35. This study demonstrated that barley and soybean meal can be replaced with soyhulls, dried distillers grains, and palm kernel extract without affecting milk production, digestive, or metabolic parameters in dairy cows offered a pasture-based diet.

The impact of water use fees on dispatching and water requirements for water-cooled power plants in Texas.

We utilize a unit commitment and dispatch model to estimate how water use fees on power generators would affect dispatching and water requirements by the power sector in the Electric Reliability Council of Texas' (ERCOT) electric grid. Fees ranging from 10 to 1000 USD per acre-foot were separately applied to water withdrawals and consumption. Fees were chosen to be comparable in cost to a range of water supply projects proposed in the Texas Water Development Board's State Water Plan to meet demand through 2050. We found that these fees can reduce water withdrawals and consumption for cooling thermoelectric power plants in ERCOT by as much as 75% and 23%, respectively. To achieve these water savings, wholesale electricity generation costs might increase as much as 120% based on 2011 fuel costs and generation characteristics. We estimate that water saved through these fees is not as cost-effective as conventional long-term water supply projects. However, the electric grid offers short-term flexibility that conventional water supply projects do not. Furthermore, this manuscript discusses conditions under which the grid could be effective at "supplying" water, particularly during emergency drought conditions, by changing its operational conditions.

Predicted genetic burden and frequency of phenotype-associated variants in the horse.

Disease-causing variants have been identified for less than 20% of suspected equine genetic diseases. Whole genome sequencing (WGS) allows rapid identification of rare disease causal variants. However, interpreting the clinical variant consequence is confounded by the number of predicted deleterious variants that healthy individuals carry (predicted genetic burden). Estimation of the predicted genetic burden and baseline frequencies of known deleterious or phenotype associated variants within and across the major horse breeds have not been performed. We used WGS of 605 horses across 48 breeds to identify 32,818,945 variants, demonstrate a high predicted genetic burden (median 730 variants/horse, interquartile range: 613-829), show breed differences in predicted genetic burden across 12 target breeds, and estimate the high frequencies of some previously reported disease variants. This large-scale variant catalog for a major and highly athletic domestic animal species will enhance its ability to serve as a model for human phenotypes and improves our ability to discover the bases for important equine phenotypes.

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. PNI is characterized by nerve degeneration distal to the site of nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generate a mouse model in which NANOG, a pluripotency-associated transcription factor is expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulates the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression leads to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation. Further, NANOG mice demonstrate extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice show greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. The onset of PNI is characterized by nerve degeneration distal to the nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generated a mouse model in which NANOG, a pluripotency-associated transcription factor can be expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulated the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression led to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation, and downregulation of key muscle atrophy genes. Further, NANOG mice demonstrated extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice showed greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming the muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

Impact of untreated portal vein thrombosis on pre and post liver transplant outcomes in cirrhosis.

BACKGROUND AND AIMS: Most portal vein thromboses (PVT) in cirrhotics are discovered incidentally. While case series demonstrate improved portal vein patency with anti-coagulation, there is little information on impact of PVT on morbidity and mortality. This study aimed to compare morbidity and mortality in cirrhotics with untreated PVT with those without PVT. MATERIAL AND METHODS: Cirrhotics evaluated for orthotopic liver transplant in a single large transplant center were prospectively followed. Subjects had contrast CT or MRI at initial evaluation and serial imaging every 6 months until transplantation, removal from the list or death. Univariate and multivariate Cox regression analysis were used to assess associations between new PVT and factors of interest. RESULTS: Of the 290 prospectively followed cirrhotics who met inclusion criteria, PVT was detected in 70 (24.1%)-47 had PVT at the time of initial evaluation and 23 developed one during the pre-transplant study period. A third of the patients with PVT had re-canalization or spontaneous resolution of thrombus while awaiting transplantation. There was no difference in the pre or posttransplant mortality between cirrhotics with and without PVT. CONCLUSION: Cirrhotics with untreated PVT fared equally well as those without PVT before and after transplantation. Further studies with larger numbers of patients are needed to determine if anticoagulation therapy truly improves outcomes in cirrhotics with portal vein thrombosis.

Energy return on investment for algal biofuel production coupled with wastewater treatment.

This study presents a second-order energy return on investment analysis to evaluate the mutual benefits of combining an advanced wastewater treatment plant (WWTP) (with biological nutrient removal) with algal biofuel production. With conventional, independently operated systems, algae production requires significant material inputs, which require energy directly and indirectly, and the WWTP requires significant energy inputs for treatment of the waste streams. The second-order energy return on investment values for independent operation of the WWTP and the algal biofuels production facility were determined to be 0.37 and 0.42, respectively. By combining the two, energy inputs can be reduced significantly. Consequently, the integrated system can outperform the isolated system, yielding a second-order energy return on investment of 1.44. Combining these systems transforms two energy sinks to a collective (second-order) energy source. However, these results do not include capital, labor, and other required expenses, suggesting that profitable deployment will be challenging.

Pineal Gland from the Cell Culture to Animal Models: A Review.

This review demonstrates current literature on pineal gland physiology, pathology, and animal model experiments to concisely explore future needs in research development with respect to pineal gland function and neuro-regenerative properties. The pineal gland plays an integral role in sleep and recovery by promoting physiologic circadian rhythms via production and release of melatonin. Yet, the current literature shows that the pineal gland has neuroprotective effects that modulate both peripheral and central nerve injuries through several direct and indirect mechanisms, such as angiogenesis and induction of growth factors and anti-inflammatory mediators. Animal models have also shown correlations between pineal gland function and metabolic homeostasis. Studies have shown that a functional pineal gland is essential in preventing and slowing the progression of certain diseases such as diabetes, osteoporosis, vertebral osteoarthritis, and neurodegenerative processes. Lastly, the array of cell culturing methods and animal models that can be used to further develop the study of pineal gland function and nervous system injury were reviewed.

Genetic Variation and the Distribution of Variant Types in the Horse.

Genetic variation is a key contributor to health and disease. Understanding the link between an individual's genotype and the corresponding phenotype is a major goal of medical genetics. Whole genome sequencing (WGS) within and across populations enables highly efficient variant discovery and elucidation of the molecular nature of virtually all genetic variation. Here, we report the largest catalog of genetic variation for the horse, a species of importance as a model for human athletic and performance related traits, using WGS of 534 horses. We show the extent of agreement between two commonly used variant callers. In data from ten target breeds that represent major breed clusters in the domestic horse, we demonstrate the distribution of variants, their allele frequencies across breeds, and identify variants that are unique to a single breed. We investigate variants with no homozygotes that may be potential embryonic lethal variants, as well as variants present in all individuals that likely represent regions of the genome with errors, poor annotation or where the reference genome carries a variant. Finally, we show regions of the genome that have higher or lower levels of genetic variation compared to the genome average. This catalog can be used for variant prioritization for important equine diseases and traits, and to provide key information about regions of the genome where the assembly and/or annotation need to be improved.

So Close and Yet So Irritating: Negative Relations and Implications for Well-being by Age and Closeness.

OBJECTIVES: Negative social relationships are associated with poor health, chronic illness, and mortality. Yet, we know little about the dynamics of negative aspects of relationships within individual's closest relationships over time, how those experiences vary by age, and the implications of those relationships for well-being. METHOD: A total of 592 participants (ages 25-97; M = 57.5; 63.3% women) from the Social Relations Study completed monthly web surveys for up to 12 months. Each month they reported negative relationship quality with their three closest network members and multiple dimensions of well-being (positive affect, negative affect, self-rated health, and sleep quality). RESULTS: Multilevel models revealed older individuals reported less negativity in their relationships than younger people, but fewer age differences in the closest tie. Greater negative relationship quality predicted poor well-being (i.e., greater negative affect, sleep problems). Links between negative relations and well-being were less strong among older individuals; especially in the closest ties. DISCUSSION: Results were partially consistent with the strength and vulnerability integration (SAVI) model, which proposes fewer age-related improvements in emotion regulation when individuals are unable to avoid tensions. Despite feeling just as negative as younger individuals, older individuals may be more resilient to tensions in their closest relationships.

Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons.

N-methyl-d-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation.

Defining the limitations of transcutaneous bilirubin measurement in late preterm newborns.

OBJECTIVE: The objective of this study is to determine the impact of postnatal age on the bias between transcutaneous (TcB) and total serum bilirubin (TSB), and evaluate a TcB screening protocol. STUDY DESIGN: Preterm and term infants had paired TcB and TSB performed on days 1 to 3 of life; a subset of preterm infants had measurements on days 4 to 7. Sensitivity and specificity of TcB (plotted on an age-specific TSB nomogram) for prediction of high-intermediate (HIR) or high-risk TSB were calculated. RESULTS: Median TcB bias was 2.6 and 2.5 mg dl-1 for term and preterm infants in the first 3 days of life, respectively. However, median bias was 2.2 mg dl-1 for preterm infants at 4 to 7 days of life. TcB in preterm infants predicted HIR or high-risk TSB with 94% sensitivity and 56% specificity. CONCLUSION: TcB screening protocols developed for term infants can be used for late preterm infants in the first 3 days of life.

Local anesthetic effect of intrathecal normal saline.

The effects of intrathecally administered normal saline have been studied in patients undergoing graduated spinal anesthesia. The injection of 5 or 10 ml volumes resulted in segmental hypesthesia to pin-scratch and cold stimuli extending from the lower thoracic to the sacral dermatomes. There was also partial sympathetic block evidenced by a diminished psychogalvanic skin reflex. The sites and possible mechanisms of action of saline are discussed; its use as placebo in graduated spinal anesthesia is questioned. It is concluded that normal saline acts as a weak local anesthetic when injected intrathecally.

Dicesium N-succinimidyl 3-(undecahydro-closo-dodecaboranyldithio)propionate, a novel heterobifunctional boronating agent.

The synthesis of a novel heterobifunctional agent, dicesium N-succinimidyl 3-(undecahydro-closo-dodecaboranyldithio)propionate, is described. This structure contains an active ester component known to react rapidly under very mild conditions with amino groups of proteins, resulting in covalent linkage. With use of this boronating agent, approximately 480 boron atoms have been incorporated per molecule of a polyclonal antibody directed against human thymocytes and 1300 boron atoms per molecule were incorporated into a monoclonal antibody, 17-1A, directed against human colorectal carcinoma cells. Binding of the boronated antibodies to the corresponding target cells was demonstrated by means of membrane immunofluorescence. There was some loss in reactivity, as determined by fluorescent end point titers, but specificity remained unchanged. The data suggest that boronated antibodies potentially could be used to selectively deliver boron-10 to tumor cells in order to achieve their destruction by neutron capture.

Neurologic complications of liver transplantation.

Nineteen adult patients underwent 21 orthotopic liver transplants at the Cleveland Clinic between November 1984, and August 1986. Eight of 19 (42%) patients developed seizures. One patient suffered a single seizure, and seven patients had multiple, generalized seizures. Two of these seven patients became comatose after several days of seizure activity. Over several weeks, both of these patients regained consciousness--however, they exhibited a cerebellar-type syndrome, manifested as severe ataxia, weakness, and dysarthria. Both patients have improved, but remain neurologically impaired. Laboratory evaluation included serum electrolytes, magnesium, osmolality, and cyclosporine levels. Neurologic testing consisted of cerebrospinal fluid (CSF) analysis, computed tomographic (CT) scanning, and electroencephalography (EEG). Although the CSF protein was mildly elevated in two patients, all cultures remained sterile. None of the CT scans demonstrated any abnormalities. In five patients, the EEG showed generalized slowing consistent with diffuse encephalopathy. Other factors associated with seizures in transplant patients were analyzed, including fluid retention, hypertension, high-dose steroids, hypomagnesemia, graft dysfunction, and demyelinization. Many of our patients had the first three of these factors, since all but one developed their seizures within the first ten postoperative days. Only one patient had mild hypomagnesemia. Trough cyclosporine levels (whole blood, HPLC) were not in the toxic range (greater than 500 ng/mL). The serum osmolality was elevated in all four patients in whom it was measured, ranging from 309 to 341 mOsm/kg. Only three patients exhibited graft dysfunction--two moderate and one severe. The cause of neurologic toxicity following transplantation is unclear. Although many factors have been implicated, no common denominator has emerged. Several reports have linked cyclosporine with seizures and other neurologic problems, such as the cerebellar-type syndrome exhibited in two of our patients. Future studies should include magnetic resonance (MR) imaging of the head and measuring osmolality and cyclosporine levels in the blood and CSF.

The prevalence of coronary artery disease in liver transplant candidates over age 50.

The prevalence of angiographically proven coronary artery disease (CAD) in adults with end-stage liver disease who undergo evaluation for liver transplantation is unknown; also it is unclear if cholestatic liver disease represents an independent risk factor. Patients with end-stage liver disease over age 50 having liver transplantation were studied using coronary angiography. Arterial stenosis was graded as normal, mild (< 30%), moderate (30 to 70%), or severe (> 70%). Risk factors for CAD were also assessed (male sex, smoking, hypertension, diabetes, family history of premature heart disease). Complications related to the angiography and decision making based on the findings were recorded. Thirty seven patients (23 females) with a median age of 61 years (range 50 to 71) underwent angiography. Thirteen patients (35.1%) had cholestatic liver disease. Thirty patients had no history of heart disease. The overall prevalence of severe coronary artery disease was 16.2% (95% confidence interval [CI] = 6.2% to 32.0%). No association was detected between CAD and cholestatic liver disease (P = 0.72). After eliminating seven patients with a prior history of angina (n = 1), myocardial infarction (n = 1), or coronary revascularization (n = 5), the frequency of moderate or severe CAD was 13.3% (95% CI = 3.8% to 30.7%). No association was detected between unsuspected CAD and cholestatic liver disease (P = 0.61). Diabetes was the most important risk factor for moderate or severe disease (P = 0.01). Patients without risk factors had significantly less CAD than the group as a whole regardless of the liver disease type (P = 0.02). Two patients experienced transient renal insufficiency after the angiography. Three patients with severe CAD were denied transplantation. We conclude that CAD represents a significant problem in patients over age 50 undergoing liver transplant evaluation. Cholestatic liver disease was not associated with a significantly higher prevalence of moderate or severe CAD in our population. Diabetes was the most predictive risk factor, and those without risk factors do not require extensive preoperative cardiac evaluation.

Revision of the Infant Temperament Questionnaire.

The Infant Temperament Questionnaire, originally published in 1970, has been revised to improve its psychometric characteristics. The number of items was increased from 70 to 95, rating options were increased from three to six, more items have high-low reversals, and they are randomized as to content area. The new form was standardized on 203 4- to 8-month-old infants. Good test-retest reliability was maintained and internal consistency of the nine categories was raised to a higher level, thereby assuring a greater reliability of the instrument. These improvements should enhance the questionnaire's use in clinical and research applications.

Temperament as a factor in early school adjustment.

Infant temperament profiles of "difficult," "intermediate," and "easy" in a randomly selected group of 51 children were shown to correlate with impulsivity and school adjustment at ages 5 1/2 to 7 years. However, the nonlinear relationship makes this a finding of uncertain significance. On the other hand, contemporaneous temperament determinations using the Behavioral Style Questionnaire completed by the children's mothers showed a significant correlation between the adaptability subscale and teacher judgments of school adjustment. This latter finding adds support to the view that temperament is a significant factor in school adjustment and that it can be measured by a clinical instrument appropriate for pediatric use.