Miracle-dz/UniFAR-FTUs huggingface dataset:
HIV cure strategists: ignore the central nervous system at your patients' peril.

Early in the AIDS epidemic, numerous investigators determined that central nervous system (CNS) disorders including dementia were common among persons infected with HIV. Moreover, it has been established that infected persons without clearly identified dementia can have mild HIV associated neurological disorders [1]. HIV can be identified within cerebrospinal fluid (CSF) of almost all HIV-infected persons not receiving antiretroviral therapy (ART) and post-mortem brain tissues have readily detectable viral expression primarily within resident microglial cells and macrophages [2,3]. Furthermore, in patients with undetectable viral load in both plasma and CSF, HIV DNA was detectable in all subjects in brain autopsy tissue [4]. Further, experimental animal models in which CD4þ T cells are depleted or absent emphasize the importance of the macrophage reservoir [5,6]. Thus, it is somewhat surprising that the CNS as an important reservoir in persons receiving treatment remains hotly debated.
Relevance of Human Parechovirus Detection in Cerebrospinal Fluid Samples From Young Infants With Sepsis‐Like Illness

The human parechoviruses (HPeVs) were recently recognized as important viral pathogens involved in various illnesses in young children. However, routine detection is not performed in most clinical laboratories. Therefore, in this study, we aim to assess the relevance of HPeV detection in cerebrospinal fluid (CSF) of infants, according to clinical presentation.
Stereotactic Radiosurgery in the Treatment of Metastatic Disease to the Brain

We review 190 consecutive patients with 434 metastatic tumors treated by gamma knife stereotactic radiosurgery, from August 1994 to February 1999. Median actuarial survival for all patients was 34 weeks. Factors correlated with significantly improved survival included controlled systemic disease and nonmelanoma histology. We found that no significant survival benefit could be discerned from adjuvant whole brain radiotherapy in this patient group. Survival was not statistically different for patients initially presenting with 1–4 metastases at initial treatment.
Lidocaine for lumbar punctures. A help not a hindrance.

OBJECTIVE To determine whether premedication for lumbar puncture (LP) with lidocaine hinders collection of cerebrospinal fluid (CSF) through either increased number of attempts or increased incidence of traumatic punctures. DESIGN A randomized controlled trial. SETTING The pediatric emergency department of an innercity teaching hospital. PATIENTS A convenience sample of 100 children, younger than 3 years, who required an LP as part of their diagnostic workup. INTERVENTION Patients were randomized to receive either lidocaine or no local anesthetic before undergoing an LP. MAIN OUTCOME MEASURES Comparison of the number of attempts needed to obtain CSF and the number of traumatic LPs between the lidocaine-treated and no local anesthetic groups. RESULTS The 51 patients randomized to receive lidocaine did not differ markedly in age from the 49 patients randomized to receive no local anesthetic. Ease of obtaining CSF, as measured by number of attempts, did not differ with 59% of the patients in each group requiring 1 attempt. Defining a traumatic LP as more than 1000 x 10(6)/L red blood cells in the CSF showed notably more traumatic LPs in the lidocaine-treated group. Defining a traumatic LP as one with more than 10,000 x 10(6)/L red blood cells in the CSF showed no significant difference in the number of traumatic LPs whether or not the patient was premedicated with lidocaine. The level of experience of the physician performing the LP did not affect the outcome. CONCLUSIONS Premedication with lidocaine for an LP does not binder the ease of obtaining CSF. The clinical relevance of a greater number of traumatic LPs in the lidocaine-treated group is questionable because this finding is negated when traumatic is defined as more than 10,000 x 10(6)/L CSF red blood cells. Based on these results, we advocate premedication with a local anesthetic when an LP is performed in the pediatric emergency department.
Purification of Alginate for Tissue Engineering

Alginate, as a natural polymer, has been widely used in fields of medical delivery and tissue engineering. However, the commercial alginate contains a large number of impurities to be responsible for side effects on humans. So purification is crucial for alginate application in biomedicine fields. In this work, a study about a method which used chloroform/butanol and activated charcoal to purify commercial alginate was presented. The results showed that the purification procedure described here is simple and effective to reduce proteins and polyphenols to a very low level. The proteins content in the purified sample was low to 3.36% compared with 8.54% in the raw material. And the polyphenols content was only 0.4% of the initial content. Compared with other methods had been published, the method introduced here was more efficient in the reduction of contamination. MTT assay also indicated that the biocompatibility of purified alginate sample was better than the unpurified one.
Inhibiting Heat Shock Protein 90 Protects Nucleus Pulposus-Derived Stem/Progenitor Cells From Compression-Induced Necroptosis and Apoptosis

Nucleus pulposus-derived stem/progenitor cells (NPSCs) provide novel prospects for the regeneration of degenerated intervertebral disc (IVD). Nevertheless, with aging and degeneration of IVD, the frequency of NPSCs markedly decreases. Excessive cell death could be the main reason for declined frequency of NPSCs, however, the exact mechanisms remain elusive. Thus, the present study was undertaken to explore the mechanisms of compression-induced NPSCs death, and the effects of heat shock protein 90 (HSP90) on NPSCs survival. Here, we found that compression could trigger receptor-interacting protein kinase 1 (RIPK1)/receptor-interacting protein kinase 3 (RIPK3)/mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis of NPSCs. Furthermore, we found that elevated expression of HSP90 was involved in compression-induced NPSCs death, and inhibiting HSP90 could dramatically attenuate compression-induced necroptosis of NPSCs via regulating the expression and activity of RIPK1/RIPK3/MLKL, and alleviating the mitochondrial dysfunction (mitochondrial membrane potential loss and ATP depletion) and oxidative stress [production of mitochondrial reactive oxygen species (ROS), cellular total ROS and malondialdehyde, and downregulation of superoxide dismutase 2]. Besides necroptosis, compression-induced apoptosis of NPSCs was also attenuated by HSP90 inhibition. In addition, we found that enhanced expression of HSP70 contributed to the cytoprotective effects of inhibiting HSP90. More encouragingly, our results demonstrated that inhibiting HSP90 could also mitigate the exhaustion of NPSCs in vivo. In conclusion, RIPK1/RIPK3/MLKL-mediated necroptosis participates in compression-induced NPSCs death. Furthermore, targeting HSP90 to simultaneously inhibit necroptosis and apoptosis of NPSCs might be an efficient strategy for preventing the death of NPSCs, thus rescuing the endogenous repair capacity of NP tissue.
Neuroimmune Mechanisms in Signaling of Pain During Acute Kidney Injury (AKI)

Acute kidney injury (AKI) is a significant global health concern. The primary causes of AKI include ischemia, sepsis and nephrotoxicity. The unraveled interface between nervous system and immune response with specific focus on pain pathways is generating a huge interest in reference to AKI. The nervous system though static executes functions by nerve fibers throughout the body. Neuronal peptides released by nerves effect the immune response to mediate the hemodynamic system critical to the functioning of kidney. Pain is the outcome of cellular cross talk between nervous and immune systems. The widespread release of neuropeptides, neurotransmitters and immune cells contribute to bidirectional neuroimmune cross talks for pain manifestation. Recently, we have reported pain pathway genes that may pave the way to better understand such processes during AKI. An auxiliary understanding of the functions and communications in these systems will lead to novel approaches in pain management and treatment through the pathological state, specifically during acute kidney injury.
Laminar- and Target-Specific Amygdalar Inputs in Rat Primary Gustatory Cortex

The primary gustatory cortex (GC) receives projections from the basolateral nucleus of the amygdala (BLA). Behavioral and electrophysiological studies demonstrated that this projection is involved in encoding the hedonic value of taste and is a source of anticipatory activity in GC. Anatomically, this projection is largest in the agranular portion of GC; however, its synaptic targets and synaptic properties are currently unknown. In vivo electrophysiological recordings report conflicting evidence about BLA afferents either selectively activating excitatory neurons or driving a compound response consistent with the activation of inhibitory circuits. Here we demonstrate that BLA afferents directly activate excitatory neurons and two distinct populations of inhibitory neurons in both superficial and deep layers of rat GC. BLA afferents recruit different proportions of excitatory and inhibitory neurons and show distinct patterns of circuit activation in the superficial and deep layers of GC. These results provide the first circuit-level analysis of BLA inputs to a sensory area. Laminar- and target-specific differences of BLA inputs likely explain the complexity of amygdalocortical interactions during sensory processing. SIGNIFICANCE STATEMENT Projections from the basolateral nucleus of the amygdala (BLA) to the cortex convey information about the emotional value and the expectation of a sensory stimulus. Although much work has been done to establish the behavioral role of BLA inputs to sensory cortices, very little is known about the circuit organization of BLA projections. Here we provide the first in-depth analysis of connectivity and synaptic properties of the BLA input to the gustatory cortex. We show that BLA afferents activate excitatory and inhibitory circuits in a layer-specific and pattern-specific manner. Our results provide important new information about how neural circuits establishing the hedonic value of sensory stimuli and driving anticipatory behaviors are organized at the synaptic level.
No deterioration in insulin sensitivity, but impairment of both pancreatic β‐cell function and glucose sensitivity, in Japanese women with former gestational diabetes mellitus

To identify the primary pathogenic factors involved in the development of Type 2 diabetes mellitus (DM), we studied Japanese women with former gestational diabetes mellitus (GDM) who are at risk for the later development of Type 2 DM. We used the minimal model analysis derived from frequently sampled intravenous glucose tolerance test (FSIGT). The subjects consisted of eight non‐obese women with a history of GDM and eight non‐obese normal women as control subjects. The 75 g oral glucose tolerance test (75 g OGTT) performed within 6 months of delivery confirmed that all the subjects with former GDM had a normal glucose tolerance. Insulin sensitivity (SI) derived from the minimal model analysis was not different between the two groups. Glucose effectiveness at zero insulin (GEZI), reflecting tissue glucose sensitivity, was significantly lower in former GDM patients than in control subjects (1.18 ± 0.34 vs 2.26 ± 0.29 × 10−2 min−1, p < 0.05). The early phase insulin secretion found in FSIGT was markedly reduced to 56 % of that observed in control subjects (1250 ± 187.4 vs 2223 ± 304.3 pmol l−1 min, p < 0.01). Our results indicate that in former GDM patients, who are Japanese and non‐obese, impairment of the acute insulin response to glucose and a decrease in tissue glucose sensitivity rather than insulin sensitivity are the primary pathogenic factors involved. Copyright © 1998 John Wiley & Sons, Ltd.
Omission of systematic transrectal ultrasound guided biopsy from the MRI targeted approach in men with previous negative prostate biopsy might still be premature.

In the emerging field of MRI in prostate cancer (PCa) diagnosis, it has become clear that targeted biopsy with MRI guidance has additional value over systematic transrectal ultrasound-guided biopsies (TRUS-GB) alone. The MRI targeted biopsy approach increased the diagnostic yield of high-grade PCa, while concomitantly reducing the number of biopsy cores and the detection of low-grade PCa (1,2). Consequently, the question arises if in current clinical practice the TRUS-GB could be reduced or even omitted from the MRI targeted diagnostic process.
Isolation and characterization of a monoclonal antibody, K1, reactive with ovarian cancers and normal mesothelium

We have isolated a new monoclonal antibody (MAb), K1, that reacts with an epitope on the surface of human ovarian carcinoma cells. This antibody was generated by immunization of mice with periodate‐treated human ovarian carcinoma (OVCAR‐3) cells. These mice had been previously made tolerant with normal human kidney membranes. Spleen lymphocytes from these mice were selected prior to fusion using a panning purification method on living OVCAR‐3 cells. Initial screening of surface‐reactive clones was performed in a single day using immunofluorescence on living OVCAR‐3 cells, and secondary screening was performed using immunoperoxidase histochemistry on cryostat sections of normal human tissues and human tumors. The K1 clone was subcloned and identified as an IgM isotype, but was subsequently isotype‐switched to lgGIK using a panning selection method. When evaluated by immunohistochemistry, the antigen reactive with K1 was found in many ovarian non‐mucinous tumors, as well as in squamous tumors of the esophagus, and cervical cancer. The only normal adult human tissues showing uniform reactivity with K1 were the mesothelia of the peritoneal, pleural and pericardial cavities. There was also limited reactivity with epithelia of the trachea, tonsil and Fallopian tube. A similar tissue reactivity for K1 was found in tissues from cynomolgus monkeys. K1 reacted with many of the same tissues and tumors as the previously identified antibody OC125, but several lines of evidence indicate that K1 reacts with a different epitope and probably a different molecule, when compared to OC125. This evidence included assays employing immunofluorescence competition, double‐ label immunofluorescence, and solid‐phase and live‐cell radioim‐ munoassays. Since our data indicate that the antigen reactive with the K1 antibody is a new molecular species, we have named the antigen CAKI. Unlike the shed antigen CA125, CAKI was only cell‐associated and was not found in the supernatant of cultured OVCAR‐3 cells or in the blood of ovarian cancer patients. The K1 antibody may be useful as a targeting agent for therapy and in the diagnosis of ovarian carcinoma, as well as some other human cancers.
Biochemical and Structural Characterization of Selective Allosteric Inhibitors of the Plasmodium falciparum Drug Target, Prolyl-tRNA-synthetase

Plasmodium falciparum (Pf) prolyl-tRNA synthetase (ProRS) is one of the few chemical-genetically validated drug targets for malaria, yet highly selective inhibitors have not been described. In this paper, approximately 40,000 compounds were screened to identify compounds that selectively inhibit PfProRS enzyme activity versus Homo sapiens (Hs) ProRS. X-ray crystallography structures were solved for apo, as well as substrate- and inhibitor-bound forms of PfProRS. We identified two new inhibitors of PfProRS that bind outside the active site. These two allosteric inhibitors showed >100 times specificity for PfProRS compared to HsProRS, demonstrating this class of compounds could overcome the toxicity related to HsProRS inhibition by halofuginone and its analogues. Initial medicinal chemistry was performed on one of the two compounds, guided by the cocrystallography of the compound with PfProRS, and the results can instruct future medicinal chemistry work to optimize these promising new leads for drug development against malaria.
A survey of older peoples' attitudes towards advance care planning.

BACKGROUND advance care planning (ACP) is a process to establish an individual's preference for care in the future; few UK studies have been conducted to ascertain public attitudes towards ACP. OBJECTIVE the aim of this study was to assess the attitudes of older people in East Midlands through the development and administration of a survey. DESIGN the survey questionnaire was developed on the basis of a literature review, exploratory focus groups with older adults and expert advisor input. The final questions were then re-tested with lay volunteers. SETTING thirteen general practices were enrolled to send out surveys to potential participants aged 65 or older. There were no additional inclusion or exclusion criteria for participants. METHODS simple descriptive statistics were used to describe the responses and regression analyses were used to evaluate which items predicted responses to key outcomes. RESULTS of the 5,375 (34%) community-dwelling older peoples, 1,823 returned questionnaires. Seventeen per cent of respondents had prepared an ACP document; of whom, 4% had completed an Advance Decision to Refuse Treatment (ADRT). Five per cent of respondents stated that they had been offered an opportunity to talk about ACP. Predictors of completing an ACP document included: being offered the opportunity to discuss ACP, older age, better physical function and male gender. Levels of trust were higher for families than for professionals. One-third of the respondents would be interested in talking about ACP if sessions were available. CONCLUSION although a third of the respondents were in favour of discussing ACP if the opportunity was available with their GP, only a relative minority (17%) had actively engaged. Preferences were for informal discussions with family rather than professionals.
A probabilistic model for secondary structure prediction from protein chemical shifts

Protein chemical shifts encode detailed structural information that is difficult and computationally costly to describe at a fundamental level. Statistical and machine learning approaches have been used to infer correlations between chemical shifts and secondary structure from experimental chemical shifts. These methods range from simple statistics such as the chemical shift index to complex methods using neural networks. Notwithstanding their higher accuracy, more complex approaches tend to obscure the relationship between secondary structure and chemical shift and often involve many parameters that need to be trained. We present hidden Markov models (HMMs) with Gaussian emission probabilities to model the dependence between protein chemical shifts and secondary structure. The continuous emission probabilities are modeled as conditional probabilities for a given amino acid and secondary structure type. Using these distributions as outputs of first‐ and second‐order HMMs, we achieve a prediction accuracy of 82.3%, which is competitive with existing methods for predicting secondary structure from protein chemical shifts. Incorporation of sequence‐based secondary structure prediction into our HMM improves the prediction accuracy to 84.0%. Our findings suggest that an HMM with correlated Gaussian distributions conditioned on the secondary structure provides an adequate generative model of chemical shifts. Proteins 2013; © 2012 Wiley Periodicals, Inc.
An Augmented Reality Architecture for the Creation of Hardware-in-the-Loop & Hybrid Simulation Test Scenarios for Unmanned Underwater Vehicles

System evaluation and testing of unmanned underwater vehicles (UUVs) in their destined environment can be tedious, error prone, time consuming and consequently, expensive. However, pre-real world testing facilities, such as Hard- ware-in-the-loop (HIL), are not always available. This is due to the time and expense required to create a specific test environment for the vehicle. Thus the system is not as fault tolerant as it could be since problems can remain undetected until the real- world testing phase. Debugging and fixing errors in the real- world testing phase is much more time consuming and expensive due to the nature of the harsh underwater environment. This paper introduces a novel framework for the rapid construction of virtual environment testing scenarios for remote platforms with embedded systems such as AUVs. The framework provides testing facilities across all stages of the reality continuum providing capabilities for pure simulation, HIL, Hybrid Simulation (HS) and Real world testing. The framework architecture is both very generic and flexible and allows mixing of real and simulated components. The framework is supported by a distributed communications protocol to provide location transparency of systems which is key to providing mixed reality testing facilities.
Cost effectiveness of adalimumab for the treatment of ankylosing spondylitis in the United Kingdom.

OBJECTIVES This study evaluated the cost effectiveness of adalimumab vs conventional therapy in patients with active ankylosing spondylitis (AS). METHODS The analysis was based on pooled data from two Phase III studies of adalimumab in active AS. Patients with an inadequate response to >/=1 NSAID received adalimumab 40 mg every other week (n = 246) or placebo (n = 151) for 24 weeks. A microsimulation model was developed with patients being treated with adalimumab according to the International ASAS Consensus Statement and BSR guidelines. The pooled adalimumab data, as well as data from the Outcome Assessment in AS International Study (OASIS) database and the literature, were used to model patients' BASDAI and BASFI scores and costs and health-related quality of life associated with various degrees of disease activity. Costs (in 2004 British pound) of AS, drug, administration, monitoring, hospitalization and AEs were calculated from the perspective of the UK NHS. Discounting was applied at 3.5% per year for costs and benefits as per the NICE reference case for economic evaluations. Uncertainty was addressed via sensitivity analyses. RESULTS The incremental cost-effectiveness ratio (ICER) of adalimumab vs conventional therapy was estimated to improve with longer time horizons (48 weeks to 5 and 30 yrs). The central estimate was that, over 30 yrs, adalimumab therapy yielded 1.03 more quality-adjusted life-years (QALYs) per patient initiating therapy. Some AS treatment-related costs were estimated to be offset by adalimumab (at 10,750 pounds/patient), leaving a total incremental cost (adalimumab vs conventional therapy) at 23,857 pounds per patient. The 30-yr ICER of adalimumab vs conventional therapy was estimated at 23 pounds 097/QALY. Sensitivity analyses demonstrated robustness of results. When indirect costs were also included (analysis from societal perspective), ICER improved to 5093 pounds/QALY. CONCLUSIONS This analysis indicates that adalimumab, when used according to UK treatment guidelines, is cost-effective vs conventional therapy for treating AS patients.