Adaptation of the adult Functional Mobility Assessment (FMA) into a FMA-Family Centred (FMA-FC) paediatric version.

AIM: The aims of this study were to adapt an adult wheeled mobility outcome measure, the Functional Mobility Assessment, for use with children (FMA-Family Centred) and establish the new measure's content validity, test-retest reliability, and internal consistency. BACKGROUND: Although several tools exist to measure a child's ability to operate and move a wheeled mobility device, none focus on the ability of the wheeled mobility device to support children and their families as they perform daily activities. METHODS: After adapting the FMA items with examples relevant to children aged 3-21, parent/caregiver and therapist stakeholder groups recommended adaptations relevant for families with children who cannot respond for themselves. RESULTS: Six of the initial FMA items were retained with child-appropriate examples, and 4 new items were developed. CONCLUSION: The content validity of the FMA-Family Centred was strongly supported, and internal consistency and test-retest reliability met accepted psychometric standards.

Movement Assessment of Children (MAC): validity, reliability, stability and sensitivity to change in typically developing children.

AIM: The purpose of this study was to establish the validity, reliability, stability and sensitivity to change of the family-centred Movement Assessment of Children (MAC) in typically developing infants/toddlers from 2 months (1 month 16 days) to 2 years (24 months 15 days) of age. BACKGROUND: Assessment of infant/toddler motor development is critical so that infants and toddlers who are at-risk for developmental delay or whose functional motor development is delayed can be monitored and receive therapy to improve their developmental outcomes. Infants/toddlers are thought to be more responsive during the MAC assessment because parents and siblings participate and elicit responses. METHODS: Two hundred seventy six children and 405 assessments contributed to the establishment of age-related parameters for typically developing infants and toddlers on the MAC. The MAC assesses three core domains of functional movement (head control, upper extremities and hands, pelvis and lower extremities), and generates a core total score. Four explanatory domains serve to alert examiners to factors that may impact atypical development (general observations, special senses, primitive reflexes/reactions, muscle tone). Construct validity of functional motor development was examined using the relationship between incremental increases in scores and increases in participants' ages. Subsamples were used to establish inter-rater reliability, test-retest reliability, stability and sensitivity to change. RESULTS: Construct validity was established and inter-rater reliability ICCs for the core items and core total ranged from 0.83 to 0.99. Percent agreement for the explanatory items ranged from 0.72 to 0.96. Stability within age grouping was consistent from baseline to 6 months post-baseline, and sensitivity to change from baseline to 6 months was significant for all core items and the total score. CONCLUSION: The MAC has proven to be a well-constructed assessment of infant and toddler functional motor development. It is a family-centred and efficient tool that can be used to assess and follow-up of infants and toddlers from 2 months to 2 years.

Two-year course of cognitive function and instrumental activities of daily living in older adults with bipolar disorder: evidence for neuroprogression?

BACKGROUND: While bipolar disorder (BD) is a leading cause of disability, and an important contributor to disability in BD is cognitive impairment, there is little systematic research on the longitudinal course of cognitive function and instrumental activities of daily living (IADLs) in late-life. In this report, we characterize the 2-year course of cognitive function and IADLs in older adults with BD. Method We recruited non-demented individuals 50 years and older with BD I or BD II (n = 47) from out-patient clinics or treatment studies at the University of Pittsburgh. Comparator subjects ('controls') were 22 individuals of comparable age and education with no psychiatric or neurologic history, but similar levels of cardiovascular disease. We assessed cognitive function and IADLs at baseline, 1- and 2-year time-points. The neuropsychological evaluation comprised 21 well-established and validated tests assessing multiple cognitive domains. We assessed IADLs using a criterion-referenced, performance-based instrument. We employed repeated-measures mixed-effects linear models to examine trajectory of cognitive function. We employed non-parametric tests for analysis of IADLs. RESULTS: The BD group displayed worse cognitive function in all domains and worse IADL performance than the comparator group at baseline and over follow-up. Global cognitive function and IADLs were correlated at all time-points. The BD group did not exhibit accelerated cognitive decline over 2 years. CONCLUSIONS: Over 2 years, cognitive impairment and associated functional disability of older adults with BD appear to be due to long-standing neuroprogressive processes compounded by normal cognitive aging rather than accelerated cognitive loss in old age.

Characterization of DNA excreted from phytohemagglutinin-stimulated lymphocytes.

The DNA released into the culture medium after phytohemagglutinin (PHA) stimulation of human peripheral blood lymphocytes has been purified and characterized. It is double stranded, sediments at 7-8S in alkaline sucrose, and has a Tm determined optically and by thermal elution from hydroxyapatite that is substantially lower than that found for lymphocyte cell DNA. Media DNA contains a major component reassociating with an average Cot-1/2 of 87 mol X s/liter, compared to a Cot-1/2 of 770 mol X s/liter for the unique fraction of cell DNA as measured by reassociation in 0.6 M Na+. This component of media DNA consists of unique sequence elements which are largely shared in media DNA preparations from cultures derived from different cell donors. The marked difference between media DNA and cell DNA indicates that media DNA is not derived from cell death and lysis, rather than some unique portion of lymphocyte DNA is apparently excreted from the cells during PHA-stimulated growth.

Integral membrane protein sorting to vacuoles in plant cells: evidence for two pathways.

Plant cells may contain two functionally distinct vacuolar compartments. Membranes of protein storage vacuoles (PSV) are marked by the presence of alpha-tonoplast intrinsic protein (TIP), whereas lytic vacuoles (LV) are marked by the presence of gamma-TIP. Mechanisms for sorting integral membrane proteins to the different vacuoles have not been elucidated. Here we study a chimeric integral membrane reporter protein expressed in tobacco suspension culture protoplasts whose traffic was assessed biochemically by following acquisition of complex Asn-linked glycan modifications and proteolytic processing, and whose intracellular localization was determined with confocal immunofluorescence. We show that the transmembrane domain of the plant vacuolar sorting receptor BP-80 directs the reporter protein via the Golgi to the LV prevacuolar compartment, and attaching the cytoplasmic tail (CT) of gamma-TIP did not alter this traffic. In contrast, the alpha-TIP CT prevented traffic of the reporter protein through the Golgi and caused it to be localized in organelles separate from ER and from Golgi and LV prevacuolar compartment markers. These organelles had a buoyant density consistent with vacuoles, and alpha-TIP protein colocalized in them with the alpha-TIP CT reporter protein when the two were expressed together in protoplasts. These results are consistent with two separate pathways to vacuoles for membrane proteins: a direct ER to PSV pathway, and a separate pathway via the Golgi to the LV.

Biogenesis of the protein storage vacuole crystalloid.

We identify new organelles associated with the vacuolar system in plant cells. These organelles are defined biochemically by their internal content of three integral membrane proteins: a chimeric reporter protein that moves there directly from the ER; a specific tonoplast intrinsic protein; and a novel receptor-like RING-H2 protein that traffics through the Golgi apparatus. Highly conserved homologues of the latter are expressed in animal cells. In a developmentally regulated manner, the organelles are taken up into vacuoles where, in seed protein storage vacuoles, they form a membrane-containing crystalloid. The uptake and preservation of the contents of these organelles in vacuoles represents a unique mechanism for compartmentalization of protein and lipid for storage.

The protein storage vacuole: a unique compound organelle.

Storage proteins are deposited into protein storage vacuoles (PSVs) during plant seed development and maturation and stably accumulate to high levels; subsequently, during germination the storage proteins are rapidly degraded to provide nutrients for use by the embryo. Here, we show that a PSV has within it a membrane-bound compartment containing crystals of phytic acid and proteins that are characteristic of a lytic vacuole. This compound organization, a vacuole within a vacuole whereby storage functions are separated from lytic functions, has not been described previously for organelles within the secretory pathway of eukaryotic cells. The partitioning of storage and lytic functions within the same vacuole may reflect the need to keep the functions separate during seed development and maturation and yet provide a ready source of digestive enzymes to initiate degradative processes early in germination.

Prostaglandins in the preparation of blood components.

Prostaglandin E(1) significantly improved the separation of blood components in blood bags. The recovery in vivo and the life-span values of the platelets were not altered. The hemostatic effectiveness of platelets treated with prostaglandin was shown to be normal in man.

Voltage sensor-trapping: enhanced activation of sodium channels by beta-scorpion toxin bound to the S3-S4 loop in domain II.

Polypeptide neurotoxins alter ion channel gating by binding to extracellular receptor sites, even though the voltage sensors are in their S4 transmembrane segments. By analysis of sodium channel chimeras, a beta-scorpion toxin is shown here to negatively shift voltage dependence of activation and enhance closed state inactivation by binding to a receptor site that requires glycine 845 (Gly-845) in the S3-S4 loop at the extracellular end of the S4 segment in domain II of the alpha subunit. Toxin action requires prior depolarization to drive the S4 voltage sensors outward, but these effects are lost in the mutant G845N. The results reveal a voltage sensor-trapping model of toxin action in which the IIS4 voltage sensor is trapped in its outward, activated position by toxin binding.

Selective release of excreted DNA sequences from phytohemagglutinin-stimulated human peripheral blood lymphocytes. Effects of trypsin and divalent cations.

We studied the synthesis of excreted DNA sequences and their release from phytohemagglutinin-stimulated human peripheral blood lymphocytes under conditions permitting optimal cell growth. Cells were labeled by constant exposure to low specific activity [3H]thymidine. Excreted DNA sequences were synthesized during the period of logarithmic cell growth and moved slowly from the high molecular weight chromosomal DNA fraction into the low molecular weight cell DNA fraction (Hirt supernate) from which they could be specifically released by treating the cells briefly with small amounts of various proteases; 1 microgram/ml trypsin for 5 min was optimal. On day 5 of culture, 13.3 +/- 6.9% of the total cellular acid-precipitable [3H]thymidine was released by this treatment. Trypsin-induced release was partially and reversibly inhibited by incubating the cells for 16 h with 5 mM dibutyryl-cyclic AMP. Cells incubated in the absence of divalent cations spontaneously released this Hirt supernatant DNA; after maximal release had occurred under these circumstances, additional trypsin treatment caused no further release of DNA. Trypsin-induced DNA release could be completely and reversibly inhibited by incubating the cells in the presence of 10 mM calcium. Trypsin-released DNA was isolated and analyzed by reassociation kinetics. A major component, representing 54% of the DNA, reassociated with a C0t1/2 of 68 mol.s/liter (the value at which DNA association is 50% complete). The reassociation of this DNA was studied in the presence of an excess of DNA isolated from stimulated lymphocytes on day 3 in culture, and in the presence of an excess of resting lymphocyte DNA. The high molecular weight fraction of day-3 cell DNA contained three times more copies of the trypsin-released DNA major component as compared to resting lymphocyte DNA. Hirt supernatant DNA isolated from day-5 stimulated lymphocytes reassociated in an intermediate component representing 34% of the DNA with a Cot1/2 of mol.s/liter; after cells were treated with trypsin, this component could no longer be identified in the Hirt supernatant fraction, presumably because it had been released into the incubation medium. These data describe a quantitatively reproducible system with which synthesis and release of excreted DNA sequences can be studied.

In Vitro Processing of Aleurain, a Barley Vacuolar Thiol Protease.

Aleurain, originally described from its cDNA as a thiol protease [Rogers, J.C., Dean, D., and Heck, G.R. (1985). Proc. Natl. Acad. Sci. USA 82, 6512-6516], is characterized here as a glycoprotein that is targeted to a distinct vacuolar compartment in aleurone cells. Monospecific antibodies to a bacterial trpE-aleurain fusion protein were used to show that aleurain is made as a 42-kilodalton (kD) proenzyme (proaleurain) that is proteolytically processed in a post-Golgi compartment in two steps to form a 32-kD protein. The first processing step is the discrete loss of 9 kD from proaleurain to yield a 33-kD intermediate that is further processed by the gradual loss of 1 kD resulting in mature 32-kD aleurain. Using proaleurain secreted from Xenopus oocytes as a substrate, we established an in vitro system using aleurone cell extracts that correctly processes proaleurain to a stable protein that is indistinguishable from native barley aleurain as judged by partial digestion with staphylococcal V8 protease. Proaleurain is not capable of self-cleavage in the absence of aleurone cell extracts and mature aleurain appears not to participate in processing in vitro.

Phosphorylation of S1505 in the cardiac Na+ channel inactivation gate is required for modulation by protein kinase C.

Inactivation of both brain and cardiac Na+ channels is modulated by activation of protein kinase C (PKC) but in different ways. Previous experiments had shown that phosphorylation of serine 1506 in the highly conserved loop connecting homologous domains III and IV (LIII/IV) of the brain Na+ channel alpha subunit is necessary for all effects of PKC. Here we examine the importance of the analogous serine for the different modulation of the rH1 cardiac Na+ channel. Serine 1505 of rH1 was mutated to alanine to prevent its phosphorylation, and the resulting mutant channel was expressed in 1610 cells. Electrophysiological properties of these mutant channels were indistinguishable from those of wild-type (WT) rH1 channels. Activation of PKC with 1-oleoyl-2-acetyl-sn-glycerol (OAG) reduced WT Na+ current by 49.3 +/- 4.2% (P < 0.01) but S1505A mutant current was reduced by only 8.5 +/- 5.4% (P = 0.29) when the holding potential was -94 mV. PKC activation also caused a -17-mV shift in the voltage dependence of steady-state inactivation of the WT channel which was abolished in the mutant. Thus, phosphorylation of serine 1505 is required for both the negative shift in the inactivation curve and the reduction in Na+ current by PKC. Phosphorylation of S1505/1506 has common and divergent effects in brain and cardiac Na+ channels. In both brain and cardiac Na+ channels, phosphorylation of this site by PKC is required for reduction of peak Na+ current. However, phosphorylation of S1506 in brain Na+ channels slows and destabilizes inactivation of the open channel. Phosphorylation of S1505 in cardiac, but not S1506 in brain, Na+ channels causes a negative shift in the inactivation curve, indicating that it stabilizes inactivation from closed states. Since LIII/IV containing S1505/S1506 is completely conserved, interaction of the phosphorylated serine with other regions of the channel must differ in the two channel types.

Processes and outcomes of care for patients with community-acquired pneumonia: results from the Pneumonia Patient Outcomes Research Team (PORT) cohort study.

BACKGROUND: Although understanding the processes of care and medical outcomes for patients with community-acquired pneumonia is instrumental to improving the quality and cost-effectiveness of care for this illness, limited information is available on how physicians manage patients with this illness or on medical outcomes other than short-term mortality. OBJECTIVES: To describe the processes of care and to assess a broad range of medical outcomes for ambulatory and hospitalized patients with community-acquired pneumonia. METHODS: This prospective, observational study was conducted at 4 hospitals and 1 health maintenance organization in Pittsburgh, Pa, Boston, Mass, and Halifax, Nova Scotia. Data were collected via patient interviews and reviews of medical records for 944 outpatients and 1343 inpatients with clinical and radiographic evidence of community-acquired pneumonia. Processes of care and medical outcomes were assessed 30 days after presentation. RESULTS: Only 29.7% of outpatients had 1 or more microbiologic tests performed, and only 5.7% had an assigned microbiologic cause. Although 95.7% of inpatients had 1 or more microbiologic tests performed, a cause was established in only 29.6%. Six outpatients (0.6%) died, and 3 of these deaths were pneumonia related. Of surviving outpatients, 8.0% had 1 or more medical complications. At 30 days, 88.9% (nonemployed) to 95.6% (employed) of the surviving outpatients had returned to usual activities, yet 76.0% of outpatients had 1 or more persisting pneumonia-related symptoms. Overall, 107 inpatients (8.0%) died, and 81 of these deaths were pneumonia related. Most surviving inpatients (69.0%) had 1 or more medical complications. At 30 days, 57.3% (non-employed) to 82.0% (employed) of surviving inpatients had returned to usual activities, and 86.1% had 1 or more persisting pneumonia-related symptoms. CONCLUSIONS: In this study, conducted primarily at hospital sites with affiliated medical education training programs, virtually all outpatients and most inpatients had pneumonia of unknown cause. Although outpatients had an excellent prognosis, pneumonia-related symptoms often persisted at 30 days. Inpatients had substantial mortality, morbidity, and pneumonia-related symptoms at 30 days.

Direct assessment of activities of daily living in Alzheimer's disease. A controlled study.

The relationship between severity of dementia and performance in four experimental tasks was studied in nine patients with Alzheimer's disease and nine age-matched controls. The experimental tasks were developed in order to establish a direct measure of functional performance in common activities of daily living. In the Alzheimer's patients, significant but moderate positive associations were found between the Clinical Dementia Rating Scale (CDR), a comprehensive rating tool designed specifically for Alzheimer's disease, and performance on the experimental tasks. A significant correlation was also found between the results of the Short Portable Mental Status Questionnaire (SPMSQ), a less specific dementia assessment instrument, and the CDR but not between the SPMSQ and the performance measure. When compared to nine normal subjects matched for gender, age, and education, the cognitively impaired subjects required more assistance and time (P less than .01) in completing the tasks. The findings support the conclusion that severity of dementia and performance on activities of daily living tasks are related but distinct concepts and should be measured separately.

Improving morning care routines of nursing home residents with dementia.

OBJECTIVES: This study examined the effectiveness of a behavioral rehabilitation intervention for improving the performance of morning care activities of daily living (ADL) of nursing home residents with dementia. DESIGN: Participants and their caregivers were observed for 5 days each under conditions of Usual Care (naturalistic) and Skill Elicitation (intervention), and for 15 days under Habit Training (intervention follow-up). Observations involved the ADL categories of DRESSING, OTHER ADL, and NO ADL. A 3 x 3 design (condition x ADL category) was used. SETTING: Observations occurred in five proprietary nursing homes in Pittsburgh, Pennsylvania. PARTICIPANTS: The participants were 58 women and 26 men, mean age 82 years (range = 64-97, SD = 6.3), with Probable Alzheimer 's disease (AD) (n = 19) and Possible AD (n = 65), with a mean MMSE score of 6.07. INTERVENTION: Condition 1, Usual Care, was the naturalistic caregiving condition. Condition 2, Skill Elicitation, consisted of an individualized behavioral rehabilitation intervention designed to identify and elicit retained ADL skills. Under Condition 3, Habit Training, the behavioral rehabilitation intervention was continued to reinforce and solidify retained skills and to facilitate further functional gains. MEASUREMENTS: A computer-assisted data collection system was used to document in real-time the assists used by caregivers, the participants' ADL performance, and the participants' responses to caregiving, including disruptive behavior. RESULTS: Compared with Usual Care, during Skill Elicitation participants increased the proportion of time engaged in nonassisted and assisted dressing significantly and increased their overall participation in ADL, with a concomitant significant decrease in disruptive behavior. These functional gains were demonstrated within 5 days of initiating the behavioral rehabilitation intervention and were maintained for 3 weeks during Habit Training. Physical assists were provided for significantly smaller proportions of a morning care session during Skill Elicitation and Habit Training compared with Usual Care. CONCLUSIONS: Even very severely cognitively impaired and functionally disabled nursing home residents can respond to a systematically implemented behavioral rehabilitation intervention. Their rapid response to this intervention suggests that it is alleviating excess disabilities brought on by care patterns rather than retraining ADL task performance. Residents with dementia benefit from behavioral rehabilitation by becoming more appropriately involved in their care and being less disruptive. However, behavioral rehabilitative care takes considerably more time than usual care.

Predictors of functional disability in patients with rheumatoid arthritis.

OBJECTIVE: Using the World Health Organization's classification system of the consequences of disease, this study sought to examine the impact of physical and psychological impairment variables, beyond that contributed by social, demographic, and disease variables, on the functional disability of a rheumatoid arthritis (RA) sample. Data collected during an acute episode were used to predict concurrent and future disability status. METHOD: A secondary data analysis of 85 adults hospitalized for exacerbations in arthritis was undertaken. Disability was assessed with the Health Assessment Questionnaire. Physical impairment was measured with the Keitel Function Test and Pain Analog Scales, and psychological impairment was measured with the Center for Epidemiologic Studies Depression Scale and the Perceived Self-Efficacy Scale for People with Arthritis. RESULTS: Our findings indicated that physical impairment, demographic, and disease variables accounted for 64% of the explained variance in disability during the concurrent episode. Psychological impairment as well as demographic and disease variables accounted for 49% of the explained variance in future disability status. CONCLUSION: The combined influence of demographic characteristics and the consequences of the pathology of RA experienced as physical and psychological impairments contributed differentially to disability during concurrent and future time periods.

Can first-year students master clinical skills?

Performances on a clinical skills OSCE of first- and second-year students were compared to measure the success of a new interviewing and physical examination component of the first-year curriculum.

Inhibitory activity of cigarette-smoke condensate on the mutagenicity of heterocyclic amines.

Cigarette-smoke condensate (CSC) is a complex mixture containing over 3800 identified chemicals including nicotine, water, mutagens, antimutagens, cytotoxins and inert chemicals. Although CSC is mutagenic in the Ames test, its effect on the activity of other mutagens has not been characterized. Using the Ames Salmonella bacterial mutagenesis assay, we found CSC exerts a significant inhibitory effect on mutagens requiring bioactivation. Those studied included heterocyclic amines (Glu-P-1, Glu-P-2, IQ, MeIQ, Trp-P-1 and Trp-P-2), benzo[a]pyrene (B[a]P) and aflatoxin B1. However, CSC had no effect on the activity of direct-acting mutagens (2-nitrofluorene, sodium azide, 4-nitro-1,2-phenylenediamine, 4-nitroquinoline N-oxide and methyl methanesulfonate). With indirect-acting mutagens, the reduced number of revertants observed in the presence of CSC was not attributable to cytotoxicity. CSC exhibited a potent inhibitory effect on the cytochrome P-450 dependent monooxygenases, ethoxyresorufin O-deethylase and B[a]P hydroxylase. This suggests inhibition of the cytochrome P-450 isozymes as one possible mechanism for the antimutagenicity of CSC. Fractionation studies of CSC revealed that the neutral, weakly acidic (phenolic) and basic fractions are all effective as antimutagens against Glu-P-1, a representative heterocyclic amine. This indicates that several classes of chemicals contribute to the inhibitory effect of CSC on the mutagenicity of the heterocyclic amines.

Sinoatrial and atrioventricular dysfunction associated with the use of guanabenz acetate.

Guanabenz acetate is an antihypertensive drug that is closely related to clonidine hydrochloride. Clonidine is well known to potentiate atrioventricular (AV) node conduction disturbances, but to date that effect has not been attributed to guanabenz. A case of electrocardiographic and electrophysiologic studies in a patient with both sinus and AV node conduction disturbances associated with the use of guanabenz acetate is reported. The sinus cycle length was increased by 50% after guanabenz and the sinus node recovery time was prolonged by 42%. AV block occurred proximal to the His bundle and His-ventricular prolongation of 42% also occurred. This drug should be used cautiously in patients with evidence of sinus or AV node dysfunction.

Chemical and biological studies of a new cigarette that primarily heats tobacco. Part 1. Chemical composition of mainstream smoke.

A new-technology cigarette has been developed. While the new cigarette burns some tobacco, it does not use tobacco as the fuel to sustain combustion and provide heat to the cigarette. Rather, the new cigarette primarily heats tobacco thereby reducing products of smoke formation mechanisms such as tobacco combustion, tobacco pyrolysis and pyrosynthesis. The mainstream smoke composition from a cigarette based on the new design (TOB-HT) has been characterized in comparative chemical testing with two reference cigarettes using the FTC puffing regimen. Thermal properties, UV absorption characteristics, elemental composition and materials balance studies all suggest a simplified smoke aerosol. Twenty-five smoke constituents ("target compounds") identified by the scientific community as compounds that may contribute to the diseases statistically associated with smoking have also been measured. Mainstream smoke concentrations of most target compounds are significantly lower with the TOB-HT cigarette when compared with reference cigarettes in the ultra-light "tar" and light "tar" categories. Taken together, chemical analysis results suggest simplified TOB-HT smoke chemistry with marked reductions in specific chemicals reported to be biologically active.