Variation in the Distribution of Large-scale Spatiotemporal Patterns of Activity Across Brain States.

A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

The Jamaican Haemophilia Registry: Describing the burden of disease.

INTRODUCTION: Jamaica has an estimated 200 persons with haemophilia (PWH), who face significant constraints in access to specialized haemophilia care, including access to clotting factor concentrates. AIM: The aim of this paper is to establish the current burden of disease in PWH in Jamaica. METHODS: PWH were enrolled through the University Hospital of the West Indies, Jamaica. The impact of haemophilia was assessed using a comprehensive battery of heath outcome measures that included the following: laboratory, clinical information and validated outcome measures of joint structure and function, activity, and health-related quality of life (HRQoL) to provide a health profile of the Jamaican haemophilia population. RESULTS: In all, 45 PWH were registered (mean age: 29, range: 0.17-69 years), including 13 children (<18 years of age) and 32 adults. In this sample, 41 had haemophilia A (30 severe) and 4 had haemophilia B (3 severe); 10 patients with haemophilia A were inhibitor positive. The results indicate that adults with haemophilia in Jamaica have significant joint damage: mean Haemophilia Joint Health Score (HJHS) = 42.1 (SD = 17.3); moderate activity levels - mean Haemophilia Activities List (HAL) score = 64.8 (SD = 17.8); and low HRQoL scores - mean Haemo-QoL-A score = 62.3 (SD = 19.4). Results for children are also reported but should be interpreted with caution due to the small sample size. CONCLUSIONS: There is a very high burden of disease in PWH in Jamaica. The health profiles reported in this paper are an essential first step in advocating for a multidisciplinary Comprehensive Care Program for assessment and care of PWH in Jamaica.

Evolution of blood donation patterns in a hospital-based blood centre over a seven-year period: implications for donor recruitment and retention.

OBJECTIVE: The aim of this study is to investigate the effect of a public appeal to encourage voluntary blood donation by comparing the pattern of blood donations in 2000 and 2007. METHODS: A retrospective analysis of blood donation records was conducted at the University Hospital of the West Indies (UHWI) Blood Collection Centre from April to December of 2000 and 2007. Data were analysed to identify any significant changes in donation patterns and donor profiles. RESULTS: The total number of blood donor records reviewed was 3194 in 2000 and 2634 in 2007 representing 69.0% and 72.3% of the total blood donations, respectively. Autologous donations accounted for 1% in 2000 and 2.2% in 2007; however, there was no corresponding change in voluntary donations (3.4% in 2000 and 3.2% in 2007). Despite a reduction in the number of first-time donors (1539 in 2000 and 1115 in 2007), the percentage of units discarded for the presence of a marker of transfusion transmission infection (TTI) increased, being 6.5% in 2000 and 7.4% in 2007. Human T-lymphotropic virus (HTLV) was the most common infectious marker in 2000 (3.4% of donors) whereas reactive Venereal Disease Research Laboratory (VDRL) predominated in 2007 (3.6% of donors). CONCLUSION: The per capita donations (0.99% in 2000 and 0.88% in 2007) failed to meet the World Health Organization (WHO) recommendation for an adequate blood supply of 1-3%. Despite a national effort to improve voluntary donations, the positive changes in the pattern of blood donation over a period of seven years were limited to a decrease in the proportion of first-time donors and an increase in blood donors with one to four previous donations.

Effector functions of camelid heavy-chain antibodies in immunity to West Nile virus.

Three classes of IgG have been described for camelids. IgG1 has a conventional four-chain structure, while IgG2 and IgG3 do not incorporate light chains. The structures and antigen-binding affinities of the so-called heavy-chain classes have been studied in detail; however, their regulation and effector functions are largely undefined. The aim of this study was to examine the participation of conventional and heavy-chain IgG antibodies in the camelid immune defense directed against West Nile virus (WNV). We found that natural infection or vaccination with killed WNV induced IgG1 and IgG3. Vaccination also induced IgG1 and IgG3; IgG2 was produced during the anamnestic response to vaccination. When purified IgGs were tested in plaque-reduction neutralization titer (PRNT) tests, IgG3 demonstrated PRNT activities comparable to those of conventional IgG1. In contrast, IgG2 demonstrated only suboptimal activity at the highest concentrations tested. Flow cytometric analysis revealed that macrophages bound IgG1, IgG2, and IgG3. Furthermore, subneutralizing concentrations of all three isotypes enhanced WNV infection of cultured macrophages. Our results document distinctions in regulation and function between camelid heavy-chain isotypes. The reduced size and distinct structure of IgG3 did not negatively impact its capacity to neutralize virus. In contrast, IgG2 appeared to be less efficient in neutralization. This information advances our understanding of these unusual antibodies in ways that can be applied in the development of effective vaccines for camelids.

Chronic myeloid leukaemia at the University Hospital of the West Indies: a 17-year review.

OBJECTIVE: To determine the presenting features and evolution of patients diagnosed with chronic myeloid leukaemia between 1983 and 1999 at the University Hospital of the West Indies. METHODS: Forty-one records were retrospectively analyzed for the patients' demographics, reasons for referral, clinical features, laboratory investigations and the time to blast transformation and death. RESULTS: Seventy-one per cent were males and 29% were females. The male to female ratio was 2.4:1. The median age at presentation was 37 years (range 14-81 years). Seventy-eight per cent of the patients presented in the chronic phase. Weight loss and splenomegaly were the most frequent presenting features being seen in 54 and 83 per cent respectively. The median survival was 36 months. CONCLUSION: In this study, the clinical features and evolution were comparable to existing data. Improved accrual and routine Philadelphia chromosome testing would provide a more accurate reflection of the status of CML in our population.

Arf family GTPases: roles in membrane traffic and microtubule dynamics.

Database mining and phylogenetic analysis of the Arf (ADP-ribosylation factor) superfamily revealed the presence in mammals of at least 22 members, including the six Arfs, two Sars and 14 Arl (Arf-like) proteins. At least six Arf family members were found in very early eukaryotes, including orthologues of Arf, Sar, Arl2, Arl3, Arl6 and Arl8. While roles for Arfs in membrane traffic are well known, those for most of the Arls remain unknown. Depletion in cells of the most closely related human Arf proteins, Arf1-Arf5, reveals specificities among their cellular roles and suggests that they may function in pairs at different steps in endocytic and secretory membrane traffic. In addition, recent results from a number of laboratories suggest that several of the Arl proteins may be involved in different aspects of microtubule-dependent functions. Thus, a second major role for Arf family GTPases, that of regulating microtubules, is emerging. Because membrane traffic is often dependent upon movement of vesicles along microtubules this raises the possibility that these two fundamental functions of Arf family members, regulation of vesicle traffic and microtubule dynamics, diverged from one function of Arfs in the earliest cells that has continued to branch and allow additional levels of regulation.

Application of monoclonal antibodies in functional and comparative investigations of heavy-chain immunoglobulins in new world camelids.

Of the three immunoglobulin G (IgG) isotypes described to occur in camelids, IgG2 and IgG3 are distinct in that they do not incorporate light chains. These heavy-chain antibodies (HCAbs) constitute approximately 50% of the IgG in llama serum and as much as 75% of the IgG in camel serum. We have produced isotype-specific mouse monoclonal antibodies (MAbs) in order to investigate the roles of HCAbs in camelid immunity. Seventeen stable hybridomas were cloned, and three MAbs that were specific for epitopes on the gamma chains of llama IgG1, IgG2, or IgG3 were characterized in detail. Affinity chromatography revealed that each MAb bound its isotype in solution in llama serum. The antibodies bound to the corresponding alpaca IgGs, to guanaco IgG1 and IgG2, and to camel IgG1. Interestingly, anti-IgG2 MAbs bound three heavy-chain species in llama serum, confirming the presence of three IgG2 subisotypes. Two IgG2 subisotypes were detected in alpaca and guanaco sera. The MAbs detected llama serum IgGs when they were bound to antigen in enzyme-linked immunosorbent assays and were used to discern among isotypes induced during infection with a parasitic nematode. Diseased animals, infected with Parelaphostrongylus tenuis, did not produce antigen-specific HCAbs; rather, they produced the conventional isotype, IgG1, exclusively. Our data document the utility of these MAbs in functional and physiologic investigations of the immune systems of New World camelids.

Relations among joint attention, amount of intervention and language gain in autism.

The purpose of the present study was to investigate the unconditional and conditional relations between amount of intervention and language development in children with autism. Joint attention skills were proposed as child characteristics that might moderate this relation. The results replicated previous findings that better joint attention skills were associated with greater language development. The results further indicated that the relation between amount of intervention and gain in language age was conditional; it depended upon the child's ability to respond to bids for joint attention from others and initial language skills. The current study demonstrated the utility of employing characteristics of children as moderators of relations between interventions and developmental outcomes.

The role of a clinical outcome research evaluator. A graduate nursing student's experience.

Outcome evaluation research is a relatively new paradigm that allows those in nursing to explain the impact of an intervention. The term efficacy is used when an intervention is evaluated as part of a controlled research study, while effectiveness denotes outcome evaluation of uncontrolled interventions in diverse settings. This article describes a graduate nursing student's supervised research experience that contributed to evaluating the efficacy of an intervention consisting of counseling caregivers of elders with dementia via telecommunications. The student's preparation for the role of research evaluator included acquisition of conceptual knowledge about evaluation research, interviewing techniques, and analytical skills to interpret evaluation data. Conceptual knowledge focused on the application of the Donabedian Structure. Process, Outcome Model and issues such as stakeholder, vested interest, and confidentiality. Data collection interviews involved the use of open-ended questions (qualitative) and administration of a structured questionnaire (quantitative). Analysis of qualitative data required identification of positive and negative themes; item responses on the structured questionnaire were compiled as percentages. Findings from the evaluation were used to improve the design of an ongoing intervention study.

Audit of pressure area care and documentation.

Intensive care patients are at particular risk of pressure damage. Documentation does not always fully reflect practice. Pressure sore identification remains a subjective issue. Nurses do not always complete patient documentation.

Synthesis and antitumor activity of new glycosides of epipodophyllotoxin, analogues of etoposide, and NK 611.

A series of 3-amino- and 3-alkylamino-2-deoxy-beta-D-ribo- and beta-D-arabino-glycosides of 4'-demethylepipodophyllotoxin have been synthesized by means of an improved trimethylsilyliodide procedure for the podophyllotoxin-4'-demethylepipodophyllotoxin conversion, an efficient and high yielding synthesis of silyl glycoside donors of 3-azido-2,3-dideoxy-beta-D-ribo- and beta-D-arabino-hexopyranosides and stereoselective glycosylations. In vitro evaluation of cytotoxic effects against murine L1210 leukemia critically demonstrates the essential role played by a 4,6-acetal for biological activity. Among the most cytotoxic compounds, 3-amino-2,3-dideoxy- and 3-N, N-(dimethylamino)-2,3-dideoxy etoposide analogues, 17 and 27-29 are at least as potent as etoposide on the in vivo P388 (iv/ip) murine leukemia models. However, surprisingly enough, none of these compounds inhibits the human DNA topoisomerases I or II or binds to tubulin to prevent its polymerization and microtubule assembly. Therefore, their mechanism of action remains to be cleared up.

Diagnosis of pedal osteomyelitis with Tc-99m HMPAO labeled leukocytes.

The diagnosis of pedal osteomyelitis is often complicated by the presence of pre-existing bony abnormalities. In this study, the utility of radiolabeled white blood cell imaging for the detection of complicated pedal osteomyelitis was evaluated. Twenty-seven men and women were prospectively enrolled and underwent plain film radiography, three-phase bone scan, and Tc-99m hexamethylpropylamine oxine white blood cell scintigraphy of their feet. The presence or absence of osteomyelitis was confirmed in all subjects by microbiologic and histopatholigic analysis of resected bone tissue. The results indicated that white blood cell imaging was more sensitive (90%) and specific (86%) for infection than either bone scan (75% sensitive, 29% specific) or plain film radiography (55% sensitive, 57% specific). This preliminary study suggests that Tc-99m hexamethylpropylamine oxine-labeled white blood cell scintigraphy is a simple, accurate test for the detection of pedal osteomyelitis.

Effects of bile salt structure on chiral separations with mixed micelles of bile salts and polyoxyethylene ethers using micellar electrokinetic capillary chromatography.

The chiral resolving abilities of micellar solutions of four different bile salts alone and in mixtures with polyoxyethylene-4-dodecyl ether (C12E4) and methanol were investigated using MECC. The four bile salts investigated were the unconjugated sodium salts of cholic, deoxycholic, chenodeoxycholic and ursodeoxycholic acids. The test solutes included verapamil, norverapamil, gallopamil, bi-2-naphthol, atenolol and BAYK8644. The relative hydrophobicities of the micellar aggregates formed in solutions of binary mixtures of each bile salt with C12E4 were investigated by fluorescence spectroscopy using pyrene as a probe molecule. The observed enantiomeric resolution for the test compounds using these binary mixtures as MECC pseudo-stationary phases was determined. Correlations between micellar hydrophobicity for these solutions and chiral resolution of these test solutes are presented. The addition of C12E4 with or without methanol to solutions of sodium cholate and sodium deoxycholate enhanced the chiral resolution observed for compounds containing a longer hydrocarbon chain separating some of the major functional groups from the chiral center. The pure bile salt solutions generally provided better chiral resolution for the compounds where the major functional groups, such as aromatic rings, were closer to the chiral center.

In vivo imaging of the interior of Tradescantia zebrina leaves by optical cross-correlation interferometry.

Using optical correlation interferometry, a novel method for plant sciences, we in imaged in vivo the z-direction, perpendicular to the leaf surface, through Tradescantia zebrina leaves. Non-invasively we determined number of major cell layers, followed the time sequence of decrease in cell z-axis after exposure of tissues to high salt, and observed disruption of cells caused by freezing and thawing.

Regulation of inorganic sulfate activation in filamentous fungi. Allosteric inhibition of ATP sulfurylase by 3'-phosphoadenosine-5'-phosphosulfate.

ATP sulfurylases from Penicillium chrysogenum, Penicillium duponti, Aspergillus nidulans, and Neurospora crassa are strongly inhibited by 3'-phosphoadenosine-5'-phosphosulfate (PAPS), the product of the second (adenosine-5'-phosphosulfate kinase-catalyzed) reaction in the two-step activation of inorganic sulfate. The v versus [PAPS] plots are sigmoidal. At physiological concentrations of MgATP (0.17-3 mM) and SO4(2-) (0.4-10 mM), the [I]0.5 for PAPS inhibition of the P. chrysogenum enzyme is 35-200 microM; [I]0.9 is 68-310 microM. In the presence of PAPS, the [S]0.5 values for both substrates are increased and the v versus [MgATP] and v versus [SO4(2-)] or [MoO4(2-)] plots are sigmoidal. Fluorosulfonate (FSO3-) and thiosulfate (S2O3(2-] (non-reactive sulfate analogs) inhibit the enzyme at subsaturating substrate concentrations in the absence of PAPS, but low concentrations of the analogs activate the enzyme when PAPS is present. Thus, PAPS behaves as an allosteric inhibitor of ATP sulfurylase. In contrast, adenosine-5'-phosphosulfate (APS = product Q), the immediate product of the SO4(2-)-dependent reaction, is a linear inhibitor of the P. chrysogenum enzyme, competitive with both MgATP and MoO4(2-) (Kiq = 36-73 nM). FSO3- or S2O3(2-) does not activate the enzyme in the presence of APS. The effect of PAPS on fungal ATP sulfurylase is very similar to that observed when a single highly reactive cysteinyl SH group/subunit (SH-1) is covalently modified (Renosto, F., Martin, R. L., and Segel, I. H. (1987) J. Biol. Chem. 262, 16279-16288). The results suggest that in vitro SH-1 modification induces a conformational change in the enzyme that mimics the change induced in vivo by the reversible binding of PAPS. No evidence was obtained to suggest that PAPS covalently modifies SH-1. ATP sulfurylases from rat liver (Yu, M., Martin, R. L., Jain, S., Chen, L. T., and Segel, I. H. (1989) Arch. Biochem. Biophys. 269, 156-174), spinach leaf, cabbage leaf, and Saccharomyces cerevisiae are not strongly inhibited by PAPS, do not display sigmoidal initial velocity plots in the presence of PAPS, and do not contain a highly reactive cysteinyl residue whose modification induces increased [S]0.5 values and sigmoidal velocity curves. The allosteric effect of PAPS on the fungal ATP sulfurylase may be part of a sequential feedback process unique to a group of organisms that use PAPS for two diverging pathways, reductive assimilation and sulfate ester formation.

Regional myocardial blood flow with a reperfusion catheter and an autoperfusion balloon catheter during total coronary occlusion.

We investigated the ability of two new coronary perfusion catheters to maintain regional myocardial blood flow throughout a 90-minute period of occlusion. In 21 dogs (group I = total occlusion control; group II = reperfusion catheter; group III = autoperfusion balloon catheter) we studied regional blood flow, distal coronary perfusion pressure, infarct size, and red blood cell hemolysis after placement of either catheter into the left anterior descending coronary artery. Regional (microsphere) blood flow showed a reduction in transmural blood flow during occlusion in comparison to baseline values (1.07 +/- 0.12 to 0.81 +/- 0.11 and 1.01 +/- 0.16 to 0.73 +/- 0.08 ml/min subendocardial perfusion for groups II and III, respectively). Comparable changes in blood flow were observed in the subepicardial and midmyocardial regions. Distal coronary perfusion pressures were reduced by 26% and 28% for groups II and III, respectively. Both catheters prevented significant infarction and maintained adequate regional myocardial blood flow throughout the 90-minute period of occlusion without significant complications of clotting or destruction of erythrocytes.