Noninvasive detection of Alzheimer's disease (AD) with high specificity and sensitivity can greatly facilitate identification of at-risk populations for earlier, more effective intervention. AD ...patients exhibit a myriad of retinal pathologies, including hallmark amyloid β-protein (Aβ) deposits.
Burden, distribution, cellular layer, and structure of retinal Aβ plaques were analyzed in flat mounts and cross sections of definite AD patients and controls (n = 37). In a proof-of-concept retinal imaging trial (n = 16), amyloid probe curcumin formulation was determined and protocol was established for retinal amyloid imaging in live patients.
Histological examination uncovered classical and neuritic-like Aβ deposits with increased retinal Aβ42 plaques (4.7-fold; P = 0.0063) and neuronal loss (P = 0.0023) in AD patients versus matched controls. Retinal Aβ plaque mirrored brain pathology, especially in the primary visual cortex (P = 0.0097 to P = 0.0018; Pearson's r = 0.84-0.91). Retinal deposits often associated with blood vessels and occurred in hot spot peripheral regions of the superior quadrant and innermost retinal layers. Transmission electron microscopy revealed retinal Aβ assembled into protofibrils and fibrils. Moreover, the ability to image retinal amyloid deposits with solid-lipid curcumin and a modified scanning laser ophthalmoscope was demonstrated in live patients. A fully automated calculation of the retinal amyloid index (RAI), a quantitative measure of increased curcumin fluorescence, was constructed. Analysis of RAI scores showed a 2.1-fold increase in AD patients versus controls (P = 0.0031).
The geometric distribution and increased burden of retinal amyloid pathology in AD, together with the feasibility to noninvasively detect discrete retinal amyloid deposits in living patients, may lead to a practical approach for large-scale AD diagnosis and monitoring.
National Institute on Aging award (AG044897) and The Saban and The Marciano Family Foundations.
This paper investigates the order-batching problem both as a theoretical problem, including its special variants, and as a practical problem, with possible heuristic solution procedures. It shows ...that certain special cases or variants of the order batching problem are solvable, while other cases of the problem are NP-hard. It also develops a new Mixed-Integer Programming (MIP) model to obtain near-exact solutions to the problem. The MIP provides good lower and upper bounds to the problem, which prove useful in the investigation of the heuristic solution procedures. The paper identifies and modifies slightly the order batching heuristic, which shows the strongest results in the numerical experiments. Although good solutions are obtained with this particular heuristic, the results indicate that it is computationally intensive. Furthermore, solutions obtained through the MIP model suggest there is still room to obtain even better solutions to the problem via heuristic procedures, although the challenge is to do so without further increasing the computational burden.
The suppressors of cytokine signaling (SOCS) family of proteins act as intracellular inhibitors of several cytokine signal transduction pathways. Their expression is induced by cytokine activation of ...the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and they act as a negative feedback loop by subsequently inhibiting the JAK/STAT pathway either by direct interaction with activated JAKs or with the receptors. These interactions are mediated at least in part by the SH2 domain of SOCS proteins but these proteins also contain a highly conserved C-terminal homology domain termed the SOCS box. Here we show that the SOCS box mediates interactions with elongins B and C, which in turn may couple SOCS proteins and their substrates to the proteasomal protein degradation pathway. Analogous to the family of F-box-containing proteins, it appears that the SOCS proteins may act as adaptor molecules that target activated cell signaling proteins to the protein degradation pathway.
Background. In 2003, human monkeypox was first identified in the United States. The outbreak was associated with exposure to infected prairie dogs, but the potential for person-to-person transmission ...was a concern. This study examines health care worker (HCW) exposure to 3 patients with confirmed monkeypox. Methods. Exposed HCWs, defined as HCWs who entered a 2-m radius surrounding case patients with confirmed monkeypox, were identified by infection-control practitioners. A self-administered questionnaire and analysis of paired serum specimens determined exposure status, immune response, and postexposure signs and symptoms of monkeypox. Results. Of 81 exposed HCWs, 57 (70%) participated in the study. Among 57 participants, 40 (70%) had ⩾1 unprotected exposure; none reported signs or symptoms consistent with monkeypox illness. One exposed HCW (2%), who had been vaccinated for smallpox within the past year, had serological evidence of recent orthopoxvirus infection; acute- and convalescent-phase serum specimens tested positive for anti-orthopoxvirus IgM. No exposed HCWs had signs and symptoms consistent with monkeypox. Conclusion. More than three-quarters of exposed HCWs reported at least 1 unprotected encounter with a patient who had monkeypox. One asymptomatic HCW showed laboratory evidence of recent orthopoxvirus infection, which was possibly attributable to either recent infection or smallpox vaccination. Transmission of monkeypox likely is a rare event in the health care setting.
Threat-related stimuli consistently activate the posterior cingulate cortex in normal subjects and have exaggerated effects on memory in patients with panic disorder. We hypothesized that panic ...patients would show increased response to threat-related stimuli in the posterior cingulate cortex. While undergoing fMRI, six panic patients and eight healthy volunteers made valence judgements of threat-related and neutral words. Both groups showed threat-related activation in the left posterior cingulate and left middle frontal cortices, but the activation was significantly greater in panic patients. Panic patients also had more right>left asymmetry of activation in the mid-parahippocampal region. The increased responsivity observed in the posterior cingulate and dorsolateral prefrontal cortices is consistent with the hypothesis that panic disorder patients engage in more extensive memory processing of threat-related stimuli.
The disposition index, calculated by multiplying measures of insulin secretion and insulin sensitivity, is widely applied as a sensitivity-adjusted measure of insulin secretion. We have recently ...shown that linearizing the underlying relationship uniquely permits identification of terms relating to maximal insulin secretion capacity and the secretion-coupling relationship, with both terms separately contributing to differences in the secretion-sensitivity relationship across gradations of glycemia. Here, we demonstrate the application of this linearized equation to the evaluation of treatment-induced changes in the insulin secretion-sensitivity relationship. We applied a combination of repeated-measures multivariate linear regression (evaluating treatment-induced changes in the joint relationship of insulin sensitivity and secretion) plus mixed-model repeated measures (evaluating treatment effects on maximal secretion capacity and on the secretion-sensitivity coupling slope) and compared against a usual application of the disposition index calculated from the same measurements. This novel approach allows a more informative description of treatment-induced changes compared with the usual disposition index, including isolating the source of change within the mutually adjusted relationship and identifying treatment-induced changes in the secretion-sensitivity coupling slope and in maximal insulin secretion. Application of this linearized approach provides an expanded understanding of treatment-induced changes in the insulin sensitivity-secretion relationship.
The linearized insulin secretion-sensitivity relationship allows separate evaluation of the secretion-sensitivity slope and of maximal insulin secretion. Here, we demonstrate the application of this methodology to the evaluation of clinical trial data, showing that it provides an expanded understanding of treatment-induced changes compared with the disposition index.
Highlights • During 2006–2010 in Vietnam, influenza viruses co-circulated most years and often peaked multiple times each year. • 22% of patients with ILI enrolled in the National Influenza ...Surveillance System (NISS) in Vietnam were influenza positive. • 9.3% of ILI patients in NISS in Vietnam were reported as subsequently hospitalized, of which 19% were influenza positive. • NISS suggests influenza is an important cause of ILI and reported subsequent hospitalization among outpatients in Vietnam.
After an outbreak of West Nile virus (WNV) infections in Slidell, Louisiana, in 2002, we detected neutralizing antibodies to WNV in 13 of 120 mammals, representing five of six species sampled. ...Seroprevalence was measured in opossum, Didelphis virginiana (75%, n = 8), raccoons, Procyon lotor (60%, n = 5), black rats, Rattus rattus (6%, n = 36), hispid cotton rats, Sigmodon hispidus (4%, n = 24), and eastern gray squirrels, Sciurus carolinensis (2%, n = 43).
A higher dose of GnRH is required to stimulate release of FSH than of LH, both in vivo and in vitro. Therefore, we tested the hypothesis that secretion of FSH may be mediated via a second messenger ...pathway different from the one that modulates secretion of LH. Pituitary cells from intact ewes were cultured in suspension in DMEM plus 10% wether serum. After 18 h, cell were washed and challenged for 2 h with agents capable of activating protein kinase A (dibutyryl cAMP), protein kinase C (phorbol 12-myristate 13-acetate; PMA), or increasing intracellular calcium (the calcium ionophore A23187). GnRH (0.01-10 nM) and PMA (0.2-20 nM) stimulated dose-dependent increases in secretion of LH. FSH secretion also was stimulated by GnRH and PMA; however, the percentage of total cellular FSH released was lower (p 0.05) than the percentage of total cellular LH released. Dibutyryl cAMP (10 nM) induced a modest release (p 0.05) of both LH and FSH. A23187 (1-10 micromolar) stimulated secretion of LH in a dose-dependent manner but did not influence secretion of FSH; however, GnRH- and PMA-induced secretion of FSH required the presence of intracellular calcium. On the basis of the results of this study, we suggest that secretion of FSH is less than secretion of LH following direct activation of these second messenger systems. Furthermore, we suggest that in contrast to the situation for LH, increased intracellular calcium is not the primary stimulus for inducing secretion of FSH
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