Three-dimensional structure of human serum albumin

The binding locations to human serum albumin (HSA) of several drug molecules were determined at low resolution using crystallographic methods. The principal binding sites are located within subdomains IIA and IIIA. Preliminary studies suggest that an approach to increasing the in vivo efficacy of drugs which are rendered less effective or ineffective by virtue of their interaction with HSA, would be the use of competitive displacement in drug therapies and/or the development of a general inhibitor to the site within subdomain IIIA. These findings also suggest that the facilitated transfer of various ligands across organ/circulatory interfaces such as liver, kidney, and brain may be associated with binding to the IIIA subdomain

Linear Growth through 12 Years is Weakly but Consistently Associated with Language and Math Achievement Scores at Age 12 Years in 4 Low- or Middle-Income Countries.

BackgroundWhether linear growth through age 12 y is associated with language and math achievement at age 12 y remains unclear.ObjectiveOur objective was to investigate associations of linear growth through age 12 y with reading skill, receptive vocabulary, and mathematics performance at age 12 y in 4 low- or middle-income countries (LMICs).MethodsWe analyzed data from the Young Lives Younger Cohort study in Ethiopia (n = 1275), India (n = 1350), Peru (n = 1402), and Vietnam (n = 1594). Age 1, 5, 8, and 12 y height-for-age z scores (HAZ) were calculated. Language and math achievement at age 12 y was assessed with the use of country-specific adaptations of the Peabody Picture Vocabulary Test, the Early Grades Reading Assessment, and a mathematics test; all test scores were standardized by age within country. We used path analysis to examine associations of HAZ with achievement scores. Twelve models were examined at each age (3 tests across 4 countries).ResultsMean HAZ in each country was <-1.00 at all ages. Overall, linear growth through age 12 y was associated with 0.4-3.4% of the variance in achievement scores. HAZ at 1 y was positively and significantly associated with the test score in 11 of the 12 models. This association was significantly mediated through HAZ at 5, 8, and 12 y in 9 of the models. HAZ at 5, 8, and 12 y was positively and significantly associated with test scores in 8, 8, and 6 models, respectively. These associations were mediated through HAZ at older ages in 6 of the HAZ at 5-y models and in 6 of the HAZ at 8-y models.ConclusionChild relative linear growth between ages 1 and 12 y was weakly but consistently associated with language and math achievement at age 12 y in 4 LMICs

Mitochondrial myopathy and comorbid major depressive disorder. effectiveness of dTMS on gait and mood symptoms

Background: Mitochondrial myopathies (MMs) often present with leukoencephalopathy and psychiatric symptoms, which do not respond to or worsen with psychiatric drugs. Case report: A 67-year-old woman with a 10-year history of probable chronic progressive external ophthalmoplegia, an MM, had drug-resistant, anxious-depressive symptoms. Since she had never had seizures, we proposed 20 sessions of deep transcranial magnetic stimulation (dTMS) for her depression. Surprisingly, besides the expected improvement of depression, we observed marked improvement of movement disorder that lasted as long as the patient was undergoing dTMS. She also improved her performance on neuropsychological tests of executive function and cognitive speed. Depressive symptom improvement was persistent, while anxiety symptoms recurred after the end of the sessions. Conclusions: dTMSmay be an alternative antidepressant strategy in patients withMMs, provided that they are free from seizures. The mechanism of improvement of motor disturbance may relate to dorsolateral prefrontal cortex stimulation and improved executive function and needs further investigation

Post-modern ‘languagers’: the effects of texting by university students on three South African languages

The present post-modern society has witnessed a growth spurt in technology, and with the development of Information and Communication Technologies (ICTs), mobile text messaging (texting) is now seen as the norm among the youth. For these late-modern languagers (Lytra and Jørgensen 2008: 5), it has become a common if not almost natural process to send and receive an SMS (Short Message Service) in different languages. Although some studies have examined the transformation and modification of the English language by mobile communication, hardly any, apart from Deumert and Masinyana (2008), have looked at how local South African languages are being reshaped and modified through this medium. Drawing on texting data from university undergraduate students, this paper examines the ways in which three South African languages – Afrikaans, isiXhosa and Setswana – are used, transformed and modified through this medium of communication. It is argued here that the intense creativity displayed by these young cell phone users as they play with the multilingual resources at their disposal may lead to some form of language revitalisation for these languages

Transitions between care settings after enrolment in a palliative care service in Italy: a retrospective analysis

This study was a retrospective analysis of prospectively collected data that aimed to map patients' care transitions following admission to a specialist palliative care service in Italy called Antea Centre. Patients' data was extracted from the Antea local database from 2007 to 2011. External transitions were defined as a change in the setting of care, with the patient no longer being cared for by Antea staff. Internal transitions were defined as a change in the setting of care, with the care still being provided by Antea staff. A total of 1123 patients out of 5313 admitted to the palliative service (21%) experienced transitions. Patients who experienced no transitions after their admission to the palliative care service were more likely to have a Karnofsky Performance Scale Index <30, to have been referred by a hospital physician, to have a shorter survival time, and to have home as their place of death (P<0.001). Although the patients with no transitions had worse clinical conditions, organisations should pay attention to reducing the possible negative effects of transitions, such as discontinuity of care and poor coordination

Adding hydroxyurea in combination with ruxolitinib improves clinical responses in hyperproliferative forms of myelofibrosis

Ruxolitinib, an orally bioavailable and selective inhibitor of Janus kinase 1 (JAK1) and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea might improve hematological response. This observational multi-center study enrolled 20 adult patients with intermediate- or high-risk primary MF, post- polycythemia vera MF, or postessential thrombocythemia MF with hyperproliferative manifestations of the disease and WBC and/or platelet counts not controlled by ruxolitinib therapy. The patients received treatment with a combination of ruxolitinib and hydroxyurea. A clinical response of any type was obtained in 8 patients (40%) during ruxolitinib monotherapy and in 17 patients (85%) during ruxolitinib-hydroxyurea combination (P = 0.003). After a median duration of 12.4 months of combination therapy, 16/20 patients had a hematological response; 14/17 patients who had started combination therapy to control WBC count and 2/3 who started in order to reduce platelets count. The number of patients requiring ruxolitinib dosage reduction or discontinuations was lower during combination therapy and, at the end of follow-up the median ruxolitinib dose was increased in 50% of patients. In conclusion, the combination of hydroxyurea with ruxolitinib yielded a high clinical response rate and increased ruxolitinib exposure in patients with hyperproliferative forms of MF

The cellular and synaptic architecture of the mechanosensory dorsal horn

The deep dorsal horn is a poorly characterized spinal cord region implicated in processing low-threshold mechanoreceptor (LTMR) information. We report an array of mouse genetic tools for defining neuronal components and functions of the dorsal horn LTMR-recipient zone (LTMR-RZ), a role for LTMR-RZ processing in tactile perception, and the basic logic of LTMR-RZ organization. We found an unexpectedly high degree of neuronal diversity in the LTMR-RZ: seven excitatory and four inhibitory subtypes of interneurons exhibiting unique morphological, physiological, and synaptic properties. Remarkably, LTMRs form synapses on between four and 11 LTMR-RZ interneuron subtypes, while each LTMR-RZ interneuron subtype samples inputs from at least one to three LTMR classes, as well as spinal cord interneurons and corticospinal neurons. Thus, the LTMR-RZ is a somatosensory processing region endowed with a neuronal complexity that rivals the retina and functions to pattern the activity of ascending touch pathways that underlie tactile perception

First national intercomparison of solar ultraviolet radiometers in Italy

A blind intercomparison of ground-based ultraviolet (UV) instruments has been organized for the first time in Italy. The campaign was coordinated by the Environmental Protection Agency of Aosta Valley (ARPA Valle d'Aosta) and took place in Saint-Christophe (45.8 degrees N, 7.4 degrees E, 570 m a.s.l.), in the Alpine region, from 8 to 23 June 2010. It involved 8 institutions, 10 broadband radiometers, 2 filter radiometers and 2 spectroradiometers. Synchronized measurements of downward global solar UV irradiance at the ground were collected and the raw series were then individually processed by the respective operators on the base of their own procedures and calibration data. A radiative transfer model was successfully applied as an interpretative tool. The input parameters and output results are described in detail. The comparison was performed in terms of global solar UV Index and integrated UV-A irradiance against a well-calibrated double monochromator spectroradiometer as reference. An improved algorithm for comparing broadband data and spectra has been developed and is discussed in detail. For some instruments, we found average deviations ranging from -16% up to 20% relative to the reference and diurnal variations as large as 15% even in clear days. Remarkable deviations were found for the instruments calibrated in the manufacturers' facilities and never involved in field intercomparison. Finally, some recommendations to the UV operators based on the campaign results are proposed

Portuguese validation of the Bergen Facebook Addiction Scale: an Empirical Study

Previous research on Social Networking Sites (SNSs) addiction have suggest the need to improve assessment of this behavioral addiction. The present study aimed at validating a Portuguese version of the Bergen Facebook Addiction Scale (BFAS), a widely used instrument to assess addiction to Facebook. A study was conducted in a sample of 509 Portuguese adolescent using an online survey. The psychometric properties (construct validity, criterion validity, and reliability) of the Portuguese BFAS was scrutinized. The results from the psychometric analyses suggested that the new validated instrument had excellent psychometric properties. The CFA confirmed the original one-factor solution of the BFAS and criterion validity was warranted. The reliability of the BFAS was supported by satisfactory levels of internal consistency as measured by the Cronbach’s alpha (α = .83), composite reliability (CR = .82), and factor determinacy (FD = .91). Overall, the results provided empirical support for the validity and reliability of the Portuguese BFAS. Moreover, the results were highly comparable with the findings of the original development study of the BFAS and cross-cultural support for the scale was obtained

Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits

Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.American Heart Association (12PRE10410000)American Heart Association (CIRMTG2-01152)National Institutes of Health (U.S.) (NIHNS089076