Acceptability of a Mobile Health Unit for Rural HIV Clinical Trial Enrollment and Participation

Few rural minorities participate in HIV clinical trials. Mobile health units (MHUs) may be one strategy to increase participation. We explored community perceptions of MHU acceptability to increase clinical trial participation for rural minorities living with HIV/AIDS. We conducted 11 focus groups (service providers and community leaders) and 35 interviews (people living with HIV/AIDS). Responses were analyzed using constant comparative and content analysis techniques. Acceptable MHU use included maintaining accessibility and confidentiality while establishing credibility, community ownership and control. Under these conditions, MHUs can service rural locations and overcome geographic barriers to reaching major medical centers for clinical trials.     

Variability in vitamin D assays impairs clinical assessment of vitamin D status

Background: Measuring serum 25(OH)D concentration is common in clinical practice despite the questionable reliability of assays. Aims: The aim of the present study was to examine agreement in 25(OH)D concentrations measured by different assays and laboratories, and consider related clinical implications. Methods: Serum samples from 813 participants in the Australian Multicentre Study of Environment and Immune Function (the Ausimmune Study) were assayed for 25(OH)D concentration. Duplicate samples from subsets of subjects were sent to different laboratories, two using DiaSorin Liaison (Laboratory A and B) and one using Liquid Chromatography‐Tandem Mass Spectrometry (LC‐MS/MS – selected here as the nominal gold standard). Pairwise within‐assay (both within‐laboratory and between‐laboratories) and between‐assay agreement was examined using Deming regression and Bland‐Altman plots. Common 25(OH)D cut‐points for classification of vitamin D deficiency were used to compare the different assays. Results: 25(OH)D concentrations measured using Liaison were substantially lower at Laboratory A than at Laboratory B (mean bias ?11.60 nmol/L, 95% limits of agreement ?46.39, 23.18). Both Liaison assays returned much lower 25(OH)D concentrations than LC‐MS/MS (mean bias up to ?26.05 nmol/L, 95% limits of agreement of ?13.21, 65.31). For Laboratory A participants, 46% (355/765) were classified as vitamin D deficient (25(OH)D <50 nmol/L) using Liaison compared with 17% (128/765) using LC‐MS/MS. For Laboratory B participants, the respective figures were 36% (76/209) and 20% (41/209). Hence, between 1‐in‐5 and 1‐in‐3 participants were misclassified as ‘deficient’. Conclusion: Bias and variability in 25(OH)D measurements sufficient to affect significantly clinical decision‐making were found both between‐laboratories and between‐assays. The adoption of common standards to allow assay calibration is required urgently.     

Lags and leads of accommodation in humans: Fact or fiction?

The focusing response of the human eye — accommodation — exhibits errors known as lags and leads. Lags occur when the stimulus is near and the eye appears to focus farther than the stimulus. Leads occur with far stimuli where the eye appears to focus nearer than the stimulus. We used objective and subjective measures simultaneously to determine where the eye is best focused. The objective measures were made with a wavefront sensor and an autorefractor, both of which analyze light reflected from the retina. These measures exhibited typical accommodative errors, mostly lags. The subjective measure was visual acuity, which of course depends not only on the eye''s optics but also on photoreception and neural processing of the retinal image. The subjective measure revealed much smaller errors. Acuity was maximized at or very close to the distance of the accommodative stimulus. Thus, accommodation is accurate in terms of maximizing visual performance.     

Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome

Background

Idiopathic steroid-resistant nephrotic syndrome (SRNS) has been associated with the presence of a circulating focal sclerosis permeability factor (FSPF) thought to damage the glomerular barrier and increase permeability to albumin. Galactose binds and inactivates FSPF in vitro, but its effect in vivo is uncertain.

Methods

A prospective clinical trial was conducted to investigate the effect of oral galactose on FSPF and proteinuria in children with SRNS. Seven pediatric subjects with idiopathic SRNS and positive FSPF activity (>0.5) were treated with oral galactose (0.2 gm/kg/dose twice daily) for 16 weeks. Post-treatment FSPF and proteinuria were measured.

Results

Focal sclerosis permeability factor activity of the seven subjects decreased from 0.69?±?0.11 to 0.35?±?0.21 (p?=?0.009) in response to galactose. The two subjects with post-transplant recurrence of focal segmental glomerulosclerosis (FSGS) demonstrated the most significant improvement in FSPF (p?=?0.006). Despite this decrease in FSPF, the pre- and post-treatment urine protein:creatinine ratio remained unchanged and no subject achieved remission.

Conclusions

Galactose decreases FSPF in children with SRNS, with the most significant improvement in those with post-transplant FSGS recurrence, but it fails to improve proteinuria. At the present time there is no evidence to support the use of galactose in children with FSGS, either pre- or post-transplant. Future studies to investigate the role of galactose as preemptive therapy to decrease the risk of post-transplant FSGS recurrence may be useful.     

Progressive amnestic dementia, hippocampal sclerosis, and mutation in C9ORF72

The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of “pure” hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer’s disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single “pure” HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.     

Gastrointestinal lymphoproliferative disorders

Malignant lymphomas can be first detected in some patients in endoscopic biopsies of the gastrointestinal (GI) tract. However, their recognition and accurate classification often pose problems for the pathologist for several reasons. First, the small sampling size limits pattern recognition and the number of ancillary studies which can be performed. Second, the immune system of the GI tract is capable of intense hyperplastic responses which may mimic lymphoma. Third, in a fashion similar to cutaneous lesions, those in the alimentary tract may be visualized and biopsied at a very early phase in their development when differentiation into neoplasia may be incomplete. Some forms of immune response actually pass through a poorly defined transition into lymphoma. Examples of such 'dysplasia' of the gut immune system include Helicobacter gastritis, coeliac disease and multicentric lymphoid hyperplasia associated with underlying immunodeficiency. With ever increasing endoscopic scrutiny of the gut by gastroenterologists, it is not surprising that the frequency of these indeterminate cases seems to be growing. In combination with careful clinical correlation and conventional microscopic analysis, selective immunohistochemical studies currently constitute the most powerful ancillary method in the pathologist's effort to recognize and classify GI lymphomas accurately.     

Lower serum DHEAS levels are associated with a higher degree of physical disability and depressive symptoms in middle-aged to older African American women

BACKGROUND: Changes in androgen levels and associations with chronic disease, physical and neuropsychological function and disability in women over the middle to later years of life are not well understood and have not been extensively studied in African American women. AIMS: The present cross-sectional analysis reports such levels and associations in community dwelling, African American women aged 49-65 years from St. Louis, Missouri. METHODS: A home-based physical examination and a health status questionnaire were administered to randomly sampled women. Body composition (DEXA), lower limb and hand-grip muscle strength, physical and neuropsychological function and disability levels were assessed. Blood was drawn and assayed for total testosterone (T), sex hormone-binding globulin (SHBG), dehydroepiandrosterone-sulfate (DHEAS), oestradiol (E2), adiponectin, leptin, triglycerides, glucose, C-reactive protein (CRP) and cytokine receptors (sIL2r, sIL6r, sTNFr1 and sTNFr2). Multiple linear regression modelling was used to identify the best predictors of testosterone, DHEAS and free androgen index (T/SHBG). RESULTS: Seventy-four percent of women were menopausal and a quarter of these were taking oestrogen therapy. DHEAS and E2 declined between the ages of 49 and 65 years, whereas total T, SHBG and FAI remained stable. Total T and DHEAS levels were strongly correlated. In this population sample there were no independent associations of either total T or FAI with indicators of functional limitations, disability or clinically relevant depressive symptoms. Unlike total T and FAI, lower DHEAS levels were independently associated with both higher IADL scores (indicating a higher degree of physical disability) and higher CESD scores (indicating a higher degree of clinically relevant depressive symptoms). CONCLUSION: There is an age-related decline in serum DHEAS in African American women. Lower DHEAS levels appear to be associated with a higher degree of physical disability and depressive symptoms in this population.     

A Bayesian model of the disambiguation of gravitoinertial force by visual cues

The otoliths are stimulated in the same fashion by gravitational and inertial forces, so otolith signals are ambiguous indicators of self-orientation. The ambiguity can be resolved with added visual information indicating orientation and acceleration with respect to the earth. Here we present a Bayesian model of the statistically optimal combination of noisy vestibular and visual signals. Likelihoods associated with sensory measurements are represented in an orientation/acceleration space. The likelihood function associated with the otolith signal illustrates the ambiguity; there is no unique solution for self-orientation or acceleration. Likelihood functions associated with other sensory signals can resolve this ambiguity. In addition, we propose two priors, each acting on a dimension in the orientation/acceleration space: the idiotropic prior and the no-acceleration prior. We conducted experiments using a motion platform and attached visual display to examine the influence of visual signals on the interpretation of the otolith signal. Subjects made pitch and acceleration judgments as the vestibular and visual signals were manipulated independently. Predictions of the model were confirmed: (1) visual signals affected the interpretation of the otolith signal, (2) less variable signals had more influence on perceived orientation and acceleration than more variable ones, and (3) combined estimates were more precise than single-cue estimates. We also show that the model can explain some well-known phenomena including the perception of upright in zero gravity, the Aubert effect, and the somatogravic illusion.     

Ionophore and Biometal Modulation of P-glycoprotein Expression and Function in Human Brain Microvascular Endothelial Cells

Purpose

Biometals such as zinc and copper have been shown to affect tight junction expression and subsequently blood-brain barrier (BBB) integrity. Whether these biometals also influence the expression and function of BBB transporters such as P-glycoprotein (P-gp) however is currently unknown.

Methods

Using the immortalised human cerebral microvascular endothelial (hCMEC/D3) cell line, an in-cell western assay (alongside western blotting) assessed relative P-gp expression after treatment with the metal ionophore clioquinol and biometals zinc and copper. The fluorescent P-gp substrate rhodamine-123 was employed to observe functional modulation, and inductively coupled plasma mass spectrometry (ICP-MS) provided information on biometal trafficking.

Results

A 24-h treatment with clioquinol, zinc and copper (0.5, 0.5 and 0.1 μM) induced a significant upregulation of P-gp (1.7-fold) assessed by in-cell western and this was confirmed with western blotting (1.8-fold increase). This same treatment resulted in a 23% decrease in rhodamine-123 accumulation over a 1 h incubation. ICP-MS demonstrated that while t8his combination treatment had no effect on intracellular zinc concentrations, the treatment significantly enhanced bioavailable copper (4.6-fold).

Conclusions

Enhanced delivery of copper to human brain microvascular endothelial cells is associated with enhanced expression and function of the important efflux pump P-gp, which may provide therapeutic opportunities for P-gp modulation.