Functional magnetic resonance imaging (fMRI) is emerging as a powerful tool for studying the process underlying the working of the many regions of the human brain. The standard tool for analyzing fMRI data is some variant of the linear model, which is restrictive in modeling assumptions. In this paper, we develop a semiparametric approach, based on the cubic smoothing splines, to obtain statistically more efficient estimates of the underlying hemodynamic response function (HRF) associated with fMRI experiments. The hypothesis testing of HRF is conducted to identify the brain regions which are activated when a subject performs a particular task. Furthermore, we compare one-level and two-level semiparametric estimates of HRF in significance tests for detecting the activated brain regions. Our simulation studies demonstrate that the one-level estimates combined with a bias-correction procedure perform best in detecting the activated brain regions. We illustrate this method using a real fMRI data set and compare it with popular methods offered by AFNI and FSL.

BACKGROUND

Activity of immunoglobulin (Ig)E-dependent histamine-releasing factor (HRF) is dependent on the IgE molecules bound to the surface of basophils. Sera capable of passively sensitizing basophils to release histamine to HRF were designated IgE+ sera. IgE+ and HRF have been suggested to play a role in late allergic reaction (LAR).

OBJECTIVE

The working hypothesis was tested that IgE+ induces a LAR. Further, activity of HRF produced by mononuclear cells (HRF(mn)) was compared with that of recombinant HRF p23.

METHODS

Atopic patients (n = 82) were bronchially provoked with Dermatophagoides pteronyssinus extract and the change in forced expiratory volume in 1 second was monitored. A LAR was defined as forced expiratory volume in 1 second as percentage of baseline < 80% 4 to 10 hours after allergen challenge. The presence of HRF-responsive IgE in serum was determined using basophils sensitized in vitro by serum.

RESULTS

The presence of HRF(mn)-responsive IgE (IgE(mn+)) in serum was shown not be essential for a LAR: 63% of the patients with a LAR had no IgE(mn+) in their serum. Further, 71% of patients with IgE(mn+) did not have a LAR. HRF(mn) and recombinant HRF p23 were not equivalent in the bioassay: serum of 38 of 82 atopic patients sensitized basophils to release histamine to HRF(mn), whereas this was found with serum of 1 of 82 patients to HRF p23.

CONCLUSIONS

The results do not support the hypothesis that IgE(mn+) induces a LAR, but do not exclude the alternative hypothesis that HRFs are released during a LAR and contribute to asthma severity.

Although fMRI is increasingly used to assess language-related brain activation in patients with aphasia, few studies have examined the hemodynamic response function (HRF) in perilesional, and contralesional areas of the brain. In addition, the relationship between HRF abnormalities and other variables such as lesion size and severity of aphasia has not been explored. The objective of this study was to investigate changes in HRF signal during language-related neural activation in patients with stroke-induced aphasia (SA). We also examined the status of the HRF in patients with aphasia due to nonvascular etiology, namely, primary progressive aphasia (PPA). Five right handed SA patients, three PPA patients, and five healthy individuals participated in the study. Structural damage was quantified with T1-weighted MR images. Functional MR imaging was performed with long trial event-related design and an overt naming task to measure BOLD signal time to peak (TTP) and percent signal change (ΔS). In SA patients, the average HRF TTP was significantly delayed in the left hemisphere regions involved in naming compared to healthy participants and PPA patients. However, ΔS was not different in SA patients compared to the other two groups. Delay in HRF TTP in the left hemisphere naming network of SA patients was correlated with lesion size and showed a negative correlation with global language function. There were no significant differences in the HRF TTP and ΔS in the right hemisphere homologues of the naming network or in the left and the right occipital control regions across the three groups. In PPA patients, HRF had a normal pattern. Our results indicate that abnormal task-related HRF is primarily found in the left hemisphere language network of SA patients and raise the possibility that abnormal physiology superimposed on structural damage may contribute to the clinical deficit. Follow-up investigations in a larger sample of age-matched healthy individuals, SA, and PPA patients will be needed to further confirm and extend our findings.

Functional near-infrared spectroscopy (fNIRS) is a neuroimaging technique that measures changes in oxy-hemoglobin (ΔHbO) and deoxy-hemoglobin (ΔHbR) concentration associated with brain activity. The signal acquired with fNIRS is naturally affected by disturbances engendering from ongoing physiological activity (e.g., cardiac, respiratory, Mayer wave) and random measurement noise. Despite its several drawbacks, the so-called conventional averaging (CA) is still widely used to estimate the hemodynamic response function (HRF) from noisy signal. One such drawback is related to the number of trials necessary to derive stable HRF functions adopting the CA approach, which must be substantial (N>>) 50). In this work, a pre-processing procedure to remove artifacts followed by the application of a non-parametric Bayesian approach is proposed that capitalizes on a priori available knowledge about HRF and noise. Results with the proposed Bayesian approach were compared with CA and with a straightforward band-pass filtering approach. On simulated data, a five times lower estimation error on HRF was obtained with respect to that obtained by CA, and 2.5 times lower than that obtained by band pass filtering. On real data, the improvement achieved by the present method was attested by an increase in the contrast to noise ratio (CNR) and by a reduced variability in single trial estimation. An application of the present Bayesian approach is illustrated that was optimized to monitor changes in hemodynamic activity reflecting variations in visual short-term memory load in humans, which are notoriously hard to detect using functional magnetic resonance imaging (fMRI). In particular, statistical analyses of HRFs recorded during a memory task established with high reliability the crucial role of the intraparietal sulcus and the intra-occipital sulcus in posterior areas of the human brain in visual short-term memory maintenance.

Identifying brain hemodynamics in event-related functional MRI (fMRI) data is a crucial issue to disentangle the vascular response from the neuronal activity in the BOLD signal. This question is usually addressed by estimating the so-called hemodynamic response function (HRF). Voxelwise or region-/parcelwise inference schemes have been proposed to achieve this goal but so far all known contributions commit to pre-specified spatial supports for the hemodynamic territories by defining these supports either as individual voxels or a priori fixed brain parcels. In this paper, we introduce a joint parcellation-detection-estimation (JPDE) procedure that incorporates an adaptive parcel identification step based upon local hemodynamic properties. Efficient inference of both evoked activity, HRF shapes and supports is then achieved using variational approximations. Validation on synthetic and real fMRI data demonstrate the JPDE performance over standard detection estimation schemes and suggest it as a new brain exploration tool.

OBJECTIVE

Recent Medicare health maintenance organization (HMO) disenrollees use a high level of medical services. This study examined admissions for total hip arthroplasty (THA) and osteoarthritis-related knee replacements (OKR) among Medicare HMO disenrollees and continuously enrolled fee-for-service (FFS) beneficiaries to determine whether Medicare beneficiaries are returning to the FFS system to receive quality-of-life enhancing elective care.

METHODS

Retrospective analysis of Medicare inpatient claims for elderly Medicare beneficiaries residing in South Florida between 1990 and 1993.

METHODS

Inpatient admission rates for THA, OKR, and for 2 acute conditions--total hip replacements related to fracture of the hip (HRF) and acute myocardial infarction (AMI)--were estimated for Medicare HMO disenrollees over the 3-month period immediately following their disenrollment. These rates were compared with standardized rates for Medicare FFS enrollees.

RESULTS

The annualized adjusted rates of both THA and OKR were 3.5 to 4 times higher among Medicare HMO disenrollees than among FFS beneficiaries (P < or = .0001 for both procedures); substantially smaller differences were noted for HRF (P < or = .05), and no difference was present for AMI. HMO disenrollees and FFS enrollees did not differ in their levels of comorbidity at the time of admission.

CONCLUSIONS

These data provide indirect evidence that Medicare HMOs in South Florida are rationing THA and OKR and that beneficiaries respond by returning to the FFS system to seek care. This apparent rationing has important implications regarding for the management of serious, but nonemergent, medical conditions within the evolving Medicare system.

Immunologic mechanisms contributing to diisocyanate-induced occupational asthma (OA) are poorly defined. There is a relatively low incidence of diisocyanate-specific IgE antibody responses. The frequent occurrence of delayed onset asthmatic responses in workers with diisocyanate asthma suggests a role for cellular immune mechanisms. We have shown in vitro production of antigen-specific mononuclear cell-derived histamine releasing factors (HRF) by peripheral blood mononuclear cells (PBMCs) of workers with OA. Monocyte chemoattractant protein-1 (MCP-1) and RANTES (acronym for "regulated on activation normal T expressed and secreted") are chemokines found in PBMC supernatants that express HRF activity. Diisocyanate-exposed workers were tested for diisocyanate antigen-stimulated enhancement of HRF, MCP-1, and RANTES production in supernatants of PBMCs and for serum specific IgE and IgG antibody levels to diisocyanate antigens bound to human serum albumin (HSA). PBMCs of workers with diisocyanate OA showed significantly increased production of antigen-specific HRF activity and MCP-1 (>> 300 ng/ml) compared to diisocyanate-exposed asymptomatic workers (P < 0.05). Antigen-stimulated enhancement of MCP-1 mRNA was demonstrated by reverse-transcription PCR. RANTES mRNA and chemokine secretion ( < 1 ng/ml) was also demonstrated in PBMCs, but did not show antigen enhancement in OA workers. Hapten specificity for the diisocyanate chemical to which a patient had been exposed was demonstrated for HRF enhancement and for IgG antibody reactions, but not for IgE reactions. HRF production was demonstrated in PBMC subpopulations, including lymphocytes and purified T cells. OA subjects showed increased CD8+ cells by immunofluorescence (mean CD4+: CD8+ = 1.2 +/- 0.2). The results suggest that diisocyanate antigen enhancement of HRF and MCP-1 production are stimulated by hapten-specific T cell reactions. Since a weak association has been found between IgE antibody synthesis and induction of diisocyanate OA, the role of T cell cytokines and chemokines in the pathogenesis of OA requires further investigation.

Introduction: Histopathological features in retinoblastoma are considered high-risk factors (HRF) for tumor progression and metastasis, thus their presence becomes an indication for adjuvant chemotherapy. Present study was undertaken to evaluate the incidence of HRF in retinoblastoma and to correlate them with p53 expression. Materials and Methods: This was a retrospective study where 17 diagnosed cases of retinoblastoma were included. Cases were re-evaluated for various histomorphological parameters. Immuno-histochemical analysis was done with p53 antibody by Streptavidin biotin method. Results: The patients were in the age range of 1.5-50 years. Common histological features included necrosis (70.5%), calcification (64.7%), and retinal detachment (58.8%). Incidence of various morphological parameters was anterior chamber seeding (47.2%), ciliary body involvement (29.4%), iris involvement (29.4%), choroid involvement (58.8%), scleral invasion (29.4%), extrascleral invasion (11.8%), and optic nerve infiltration (23.5%). p53 expression was present in four cases out of 13 cases (30.7%) and showed a significant association with choroid invasion (P = 0.02). Discussion: The presence of HRF should alert the physician for a possible metastasis, and such patients should be kept on regular follow-up to detect an early recurrence. p53 expression, a known poor prognostic indicator, showed significant association with choroid invasion, however, no association was seen with other HRF. Conclusion: Histopathological HRF have significant therapeutic and prognostic implications. The incidence of HRF is higher in developing countries as patients present with a more advanced stage of disease. p53 expression is significantly associated with choroid invasion out of all HRF.

OBJECTIVE

The aim of the study was to examine the influence of a medium-impact aquaerobic program on the health-related quality of life (HRQoL) and health-related fitness (HRF) level of middle-aged healthy female subjects.

METHODS

Twenty apparently healthy women (mean age: 43.1 [standard deviation: 9.7] years) participated in the study. Criteria for inclusion were absence of diagnosed illnesses, as well and signs and symptoms of disease as evaluated by the Physical Activity Readiness Questionnaire. Participants carried out a medium-impact aquaerobic exercise program consisting of 2 weekly sessions of 60 min during 8 months. Before and after the exercise program, HRQoL was assessed by the 36-item short form health survey (SF-36) questionnaire, and HRF was measured using a simplified version of the AFISAL-INEFC HRF test battery.

RESULTS

Following the exercise program, an increase in all domains of HRQoL, except general health and role-emotional, was observed. Total body mass and body fat percentage decreased, and estimated aerobic power increased.

CONCLUSIONS

Completion of a medium-impact aquaerobic program (2 weekly sessions of 60 min during 8 months) improves HRQoL in most domains, particularly bodily pain and vitality, and shows to be among the most effective programs for improving perceived quality of life. Moreover, this exercise program proved to have a positive influence on the body composition and functional capacity of the subjects, being effective in reducing fat body mass and improving cardiorespiratory function.

The light effect on photoheterotrophic processes in Prochlorococcus, and primary and bacterial productivity in the oligotrophic North Pacific Subtropical Gyre was investigated using (14)C-bicarbonate and (3)H-leucine. Light and dark incubation experiments were conducted in situ throughout the euphotic zone (0-175 m) on nine expeditions to Station ALOHA over a 3-year period. Photosynthetrons were also used to elucidate rate responses in leucine and inorganic carbon assimilation as a function of light intensity. Taxonomic group and cell-specific rates were assessed using flow cytometric sorting. The light:dark assimilation rate ratios of leucine in the top 150 m were ∼7:1 for Prochlorococcus, whereas the light:dark ratios for the non-pigmented bacteria (NPB) were not significant different from 1:1. Prochlorococcus assimilated leucine in the dark at per cell rates similar to the NPB, with a contribution to the total community bacterial production, integrated over the euphotic zone, of approximately 20% in the dark and 60% in the light. Depth-resolved primary productivity and leucine incorporation showed that the ratio of Prochlorococcus leucine:primary production peaked at 100 m then declined steeply below the deep chlorophyll maximum (DCM). The photosynthetron experiments revealed that, for Prochlorococcus at the DCM, the saturating irradiance (E k) for leucine incorporation was reached at approximately half the light intensity required for light saturation of (14)C-bicarbonate assimilation. Additionally, high and low red fluorescing Prochlorococcus populations (HRF and LRF), co-occurring at the DCM, had similar E k values for their respective substrates, however, maximum assimilation rates, for both leucine and inorganic carbon, were two times greater for HRF cells. Our results show that Prochlorococcus contributes significantly to bacterial production estimates using (3)H-leucine, whether or not the incubations are conducted in the dark or light, and this should be considered when making assessments of bacterial production in marine environments where Prochlorococcus is present. Furthermore, Prochlorococcus primary productivity showed rate to light-flux patterns that were different from its light enhanced leucine incorporation. This decoupling from autotrophic growth may indicate a separate light stimulated mechanism for leucine acquisition.

The gray matter of human cortex is characterized by depth-dependent differences in neuronal activity and connections (Shipp, 2007) as well as in the associated vasculature (Duvernoy et al., 1981). The resolution limit of functional magnetic resonance imaging (fMRI) measurements is now below a millimeter, promising the non-invasive measurement of these properties in awake and behaving humans (Muckli et al., 2015; Olman et al., 2012; Ress et al., 2007). To advance this endeavor, we present a detailed spatiotemporal hemodynamic response function (HRF) reconstructed through the use of high-resolution, submillimeter fMRI. We decomposed the HRF into directions tangential and perpendicular to the cortical surface and found that key spatial properties of the HRF change significantly with depth from the cortical surface. Notably, we found that the spatial spread of the HRF increases linearly from 4.8mm at the gray/white matter boundary to 6.6mm near the cortical surface. Using a hemodynamic model, we posit that this effect can be explained by the depth profile of the cortical vasculature, and as such, must be taken into account to properly estimate the underlying neuronal responses at different cortical depths.

Functional neuroimaging studies have demonstrated that mental rotation paradigms activate a network of spatially distributed cortical areas rather than a discrete brain region. Although the neuro-anatomical nodes of the rotation network are well established, their specific functional role is less well identified. It was the aim of the present study to dissociate network components involved in the visual perception of 3D cubic objects from regions involved in their mental spatial transformation. This was achieved by desynchronizing the time course of the perceptional process (i.e., stimulus duration) from the duration of the cognitive process (i.e., reaction times) and by comparing these with the temporal characteristics of the hemodynamic response functions (HRFs) in regions of interest. To minimize intersubject variability, an all-female subject group was chosen for this investigation. Time-resolved fMRI analysis revealed a significant increase in the full width at half maximum (FWHM) of the HRF with reaction times in the supplementary motor area (pre-SMA), in the bilateral premotor cortex (PMd-proper), and in the left parietal lobe (PP). The FWHM in visual system components such as the bilateral lateral occipital complex (LOC) and dorsal extrastriate visual areas (DE) was constant across trials and roughly equal to the stimulus duration. These findings suggest that visual system activation during mental rotation reflects visual perception and can be dissociated from other network components whose response characteristics indicates an involvement in the mental spatial transformation itself.

BACKGROUND

IgE-dependent histamine-releasing factor (HRF) can distinguish between IgE+ and IgE-. In contrast to IgE-, IgE+ sensitizes basophils to release histamine in response to HRF. But we do not know what particular feature distinguishes IgE+ from IgE-. The objective was to investigate the hypothesis that IgE+ is polymeric IgE.

METHODS

IgE+ plasma was separated by size-exclusion chromatography. The basophil-sensitizing capacity of the fractions was analyzed in response to HRF produced by mononuclear cells.

RESULTS

We showed that monomeric IgE sensitized basophils to release histamine in response to HRF and to house-dust mite, whereas no enhanced reactivity was found in the fractions containing polymeric IgE.

CONCLUSIONS

HRF reacts with monomeric IgE, and not (exclusively) with polymeric IgE.

The aim of our work was to investigate the effect of histamine releasing factor (HRF), produced in vitro by lymphocytes obtained from atopic and non-atopic asthmatics, on mast cells of various species (mouse - peritoneal mast cells, hamster and rat - peritoneal and pleural mast cells, guinea-pig - mesenteric and pulmonary mast cells). We found that human HRF is able to release histamine from the examined mast cell populations in a dose-dependent fashion. Mast cells from various species differed in their susceptibility to the action of HRF; rat pleural and guinea-pig mesenteric and pulmonary mast cells were the most susceptible, while mouse and hamster peritoneal mast cells - the least susceptible. The presence of 50% D2O in the medium significantly increased HRF-induced histamine release from rat mast cells, while the addition of phosphatidylserine did not change it. HRF-induced histamine release from guinea-pig mesenteric mast cells was not related to sensitization of these cells. We also compared histamine release from guinea-pig pulmonary and mesenteric mast cells induced by human HRF produced in vitro by lymphocytes obtained from atopic and non-atopic asthmatics. We have found that supernatant from atopic asthmatics lymphocyte cultures released significantly more histamine than supernatant from non-atopic asthmatics lymphocyte cultures. Our studies give evidence that human HRF acts across the species barrier and induces histamine release from mast cells of various species. The mechanism of HRF action on mast cells seems to be different from that of allergen.

Lymphocyte from 12 intrinsic asthmatic patients and 10 healthy controls were studied for their capability to produce histamine releasing factor (HRF) in vitro. Spontaneous HRF production was measured by culturing the lymphocytes alone for 20 h. In another set of experiments lymphocytes were first preincubated separately with phytohaemagglutinin, antigens of Haemophilus influenzae, Streptococcus viridans, Staphylococcus sp. and Neisseria catarrhalis for 4 h then carefully washed three times and cultured alone for an additional 16 h. Cell-free supernatant was assayed for histamine releasing activity using basophils from healthy donors. It was observed that lymphocytes from intrinsic asthmatic patients spontaneously produced HRF. The production of this lymphokine was enhanced following preincubation of lymphocytes with phytohaemagglutinin or bacterial antigens. Results of skin test with bacterial antigens did not correlate with the magnitude of the production of HRF by lymphocytes. At gel chromatography over Sephadex G-75 bacterial antigen-stimulated lymphocyte supernatant revealed two peaks of HRF activity in the molecular weight ranges 35,000-50,000 and 3,000-7,000.

Histamine H1-antagonists inhibit the weal-and-flare responses to the intradermal injection of platelet activating factor (PAF) in humans, and PAF response is reduced in histamine-depleted skin sites. This indicates that mast cell histamine release is likely to be the mechanism of this response. We have therefore studied the interaction of PAF with cutaneous mast cells by observing whether it releases histamine directly from human dispersed foreskin mast cells, potentiates the activity of known mast cell stimulants or liberates histamine releasing factors (HRFs) from human platelets and leucocytes to release mast cell histamine by an indirect mechanism. At a concentration of 100 microM both PAF C18 and PAF C16 caused near maximal release (83.5 +/- 4.3% and 88.2 +/- 4.5% respectively) of the total histamine content of the cell. This release was not inhibited in the absence of extracellular Ca2+, by the lack of metabolic energy or in the presence of the PAF antagonists WEB 2086 (100 nM-3 microM) or BN 52021 (100 nM-10 microM). These results indicate a cytotoxic mechanism of histamine release by PAF 100 microM. PAF (10 nM-1 microM) failed to potentiate the mast cell-stimulating activity of anti-IgE, calcium ionophore A23187 or substance P and it did not induce the release of HRFs for skin mast cells when incubated with platelets and leucocytes in concentrations up to 1 microM.

Basophil responsiveness to histamine-releasing factors (HRF) is limited to cells from atopic donors; this response can be transferred passively to non-reactive basophils by IgE molecules from the sera of donors who are intrinsically responsive to HRF. Deuterium oxide (D2O) also causes mediator release from the basophils of atopic asthmatic subjects. To assess whether basophil responsiveness is IgE dependent, and, if so, whether this release revealed IgE heterogeneity, we tested the ability of sera from HRF responders (IgE+) and non-responders (IgE-) to sensitize basophils to D2O. Both purified IgE+ and unpurified sera from an HRF responder were passively used to sensitize basophils whose IgE had been removed by lactic acid treatment. As a control, an IgE- myeloma-containing serum was used for passive sensitization. In five experiments, histamine release in the presence of 44% D2O was 9 +/- 2% and 46 +/- 4% using control IgE- and IgE+ sensitized cells, respectively. The non-responder serum, even at higher IgE levels, did not sensitize the cells for D2O release. If the IgE receptors on lactic-acid treated cells were first exposed to serum from an IgE- donor, sensitization to D2O by IgE+ was blocked. The percentage histamine release to D2O was directly related to both the amount of IgE+ used for passive sensitization and the concentration of D2O used for release. These experiments further support the concept of IgE heterogeneity and suggest that the occupancy of IgE receptors on the basophil surface 'activate' the cell to make it more responsive to various stimuli.

OBJECTIVE

Using the cold pressor test the authors investigated the change in retinal and neuroretinal capillary perfusion in vasospastic patients suffering from capsular glaucoma (CG) and in vasospastic control subjects.

METHODS

Changes in retinal and optic nerve head capillary perfusion induced by the cold pressor test (one hand immersed in 4 degrees C water for 30 seconds, then in 30 degrees C water for 2 minutes) was measured using the Heidelberg Retina Flowmeter in 4 patients with CG and in 5 healthy control subjects. Previously all subjects showed a reduction of cutaneous capillary flow higher than 70% in the cold pressor test (vasospastic reaction). One eye per subject was investigated. Two images were obtained for each phase (baseline, cold phase and warm phase), and the better quality image from each phase was selected for the measurements. One location on the temporal neuroretinal rim and one location on the temporal retina outside the peripapillary area were selected for the HRF measurements.

RESULTS

In the CG group neuroretinal rim "Volume" decreased by 26.05%, "Flow" by 25.82% and "Velocity" by 23.91% (p<0.05), retinal "Volume" decreased by 12.30% (p=0.051), and retinal "Flow" by 22.36% (p=0.01) in the cold phase. All these parameters returned to the corresponding baseline values in the warm phase. In the control group a significant decrease was observed in retinal "Volume" (15.96%), "Flow" (17.81%), and "Velocity" (16.11%) in the cold phase (p<0.05), which diminished in the warm phase but remained still significant for "Flow" and "Velocity".

CONCLUSIONS

Cutaneous cold provocation can induce an immediate decrease in retinal and optic nerve head capillary perfusion at least in a part of the vasospastic subjects with or without capsular glaucoma. This decrease diminishes or disappears quickly when the hand is immersed in warm water. To evaluate the potential role of cold-induced retinal and optic nerve head vasoconstriction in the pathogenesis of capsular glaucoma further investigations are necessary since this reaction was also present in the vasospastic control subjects.

Future priorities for the management of hypoxemic respiratory failure (HRF) and pulmonary hypertension include primary prevention of neonatal lung diseases, 'precision medicine' and translating promising clinical and preclinical research into novel therapies. Promising areas of investigation include noninvasive ventilation strategies, emerging pulmonary vasodilators (for example, cinaciguat, intravenous bosentan, rho-kinase inhibitors, peroxisome proliferator-activated receptor-γ agonists) and hemodynamic support (arginine vasopressin). Research challenges include the optimal timing for primary prevention interventions and development of validated biomarkers that predict later disease or serve as surrogates for long-term respiratory outcomes. Differentiating respiratory disease endotypes using biomarkers and experimental therapies tailored to the underlying pathobiology are central to the concept of 'precision medicine' (that is, prevention and treatment strategies that take individual variability into account). The ideal biomarker should be expressed early in the neonatal course to offer an opportunity for effective and targeted interventions to modify outcomes. The feasibility of this approach will depend on the identification and validation of accurate, rapid and affordable point-of-care biomarker tests. Trials targeting patient-specific pathobiology may involve less risk than traditional randomized controlled trials that enroll all at-risk neonates. Such approaches would reduce trial costs, potentially with fewer negative trials and improved health outcomes. Initiatives such as the Prematurity and Respiratory Outcomes Program, supported by the National Heart, Lung, and Blood Institute, provide a framework to develop refined outcome measures and early biomarkers that will enhance our understanding of novel, mechanistic therapeutic targets that can be tested in clinical trials in neonates with HRF.

The hrf-1 gene from Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV) prevents translation arrest and promotes Autographa californica multiple nucleopolyhedrovirus (AcMNPV) replication in IPLB-Ld652Y cells (Ld652Y), a non-permissive L. dispar cell line. There are no motifs in the predicted protein sequence to suggest how it might function and the only homolog identified is encoded by another baculovirus, Orgyia pseudotsugata multiple nucleopolyhedrovirus (OpMNPV). In this study, we report a functional analysis of the hrf-1 protein. AcMNPV bearing carboxy- or amino-terminally truncation hrf-1, and hrf-1 mutated by two-amino acid insertions did not replicate Ld652Y cells. Neither OpMNPV hrf-1 nor an OpMNPV/LdMNPV chimeric hrf-1 supported AcMNPV replication. Mutations in a highly acidic domain of hrf-1, in which aspartic acid residues were replaced with alanine, had varied effects on hrf-1 function. They had no effect, abolished hrf-1 function completely, or partially supported protein synthesis in infected Ld652Y cells. A slight increase in protein synthesis was achieved by increasing the expression of hrf-1 acidic domain mutant proteins. Together, these results indicate a critical role for hrf-1 structure and suggest a functional role for the acidic domain.

The purpose of this study was to examine the following: (a) the relationships among the latent constructs of fundamental motor skills (FMS), health-related physical fitness (HRF), and observed body fatness in South Korean adolescents with mental retardation (MR); (b) the indirect effect of fundamental motor skills on body fatness when mediated by health-related fitness; and (c) whether the degree of MR and gender affects these relationships. Students ages 13 to 18 years (287 boys and 134 girls) were recruited for the study. Separate structural equation models were estimated based on gender and the level of disability: mild or moderate MR. Group differences in the model structure were not found, so the data were combined and a single model estimated. The results showed that FMS significantly contributed to HRF (standardized effects beta = .53), p < .01 and indirectly contributed to decreased body fatness mediated by HRF (-.27), p < .01. HRF directly contributed to decreased fatness (-.50), p < .01. The results from this study support the importance of both increased FMS and increased HRF in relation to decreased body fatness.

Understanding how changes in the cardiovascular system contribute to cerebral blood flow (CBF) and volume (CBV) increases is critical for interpreting hemodynamic signals. Here we investigated how systemic cardiovascular changes affect the cortical hemodynamic response during voluntary locomotion. In the mouse, voluntary locomotion drives an increase in cortical CBF and arterial CBV that is localized to the forelimb/hindlimb representation in the somatosensory cortex, as well as a diffuse venous CBV increase. To determine if the heart rate increases that accompany locomotion contribute to locomotion-induced CBV and CBF increases, we occluded heart rate increases with the muscarinic cholinergic receptor antagonist glycopyrrolate, and reduced heart rate with the β1-adrenergic receptor antagonist atenolol. We quantified the effects of these cardiovascular manipulations on CBV and CBF dynamics by comparing the hemodynamic response functions (HRF) to locomotion across these conditions. Neither the CBF HRF nor the arterial component of the CBV HRF was significantly affected by pharmacological disruption of the heart rate. In contrast, the amplitude and spatial extent of the venous component of the CBV HRF were decreased by atenolol. These results suggest that the increase in venous CBV during locomotion was partially driven by peripheral cardiovascular changes, whereas CBF and arterial CBV increases associated with locomotion reflect central processes.

OBJECTIVE

Altered energy metabolism plays an important role in the development and progression of cancer. The objective of this study was to elucidate the role of mitochondrial oxidative phosphorylation complexes and their prognostic significance in retinoblastoma (Rb).

METHODS

Immunohistochemistry was performed on 109 primary enucleated retinoblastoma tissues for mitochondrial OXPHOS complexes and their expression was confirmed by western blotting.

RESULTS

Histopathological high risk factors (HRFs) were identified in 42.2% cases. Mitochondrial OXPHOS complexes III, IV and V were expressed in more than 50% of primary retinoblastoma cases each whereas mitochondrial complex I was expressed in only 29/109 (26.60%) cases by immunohistochemistry. Loss of mitochondrial complex I correlated well with poor tumor differentiation and tumor invasion (p < 0.05) whereas expression of mitochondrial complexes III, IV and V was associated with better survival (Kaplan-Meier method).

CONCLUSIONS

This was the first study predicting a relevant role of mitochondrial OXPHOS complexes and highlights the prognostic significance with patient outcome in retinoblastoma. Loss of mitochondrial complex I immunoexpression could prove to be a useful independent prognostic biomarker to identify high risk retinoblastoma patients. Differential expression of these mitochondrial complexes is a novel finding and may be used as an attractive future anticancer target in primary retinoblastoma tumors.

BACKGROUND

The author(s) have no proprietary or commercial interest in any materials discussed in this article.