Accessible Compartment Research Articles

Differential diagnosis to malignant neoplasia: Nasopharyngeal mass in a cat with nasal cryptococcosis in Germany

A 2-year-old Norwegian Forest cat was presented for evaluation of bilateral purulent nasal discharge and stertorous breathing. A computed tomography (CT) scan of the head revealed an intranasal mass of the left nasal cavity extending behind the tube openings and completely obstructing the nasopharynx. Rhinoscopy confirmed a pinkish, shiny mass. CT scan showed both compartments of the right middle ear filled with abnormal soft tissue attenuating material. There was no change in the bony outline of the middle ear. In the endoscopic examination, after endoscopically assisted tympanocentesis, this material in the accessible dorsolateral compartment proved to be classic polypous tissue in addition to highly viscous glue-like secretions. A secondary otitis media due to a drainage disorder was suspected.Using an endoscopic-interventional approach through the nostril, the nasopharyngeal mass was removed for histopathological examination, in order to restore the nasal airway, and to allow tube drainage. In contrast to cats with classical malignant nasal cavity masses, the cat showed several attachment points of the mass and multiple undulating elevations bilaterally in the nasopharyngeal mucosa.Cytological and histopathological examination identified the mass as a fungal granuloma in the context of a cryptococcus infection only rarely observed in Germany. Molecular genetic analysis confirmed an infection with Cryptococcus neoformans var. grubii.A single intranasal and nasopharyngeal endoscopic debridement resulted in a significant improvement of the clinical signs and a complete healing of the right middle ear (including the tympanic membrane) within 14 days, but not in a complete cure of the disease. The cat was therefore treated with oral itraconazole solution for several weeks.The case report shows that nasal cryptococcosis can also affect cats in Germany. Rhinoscopy reveals a nasopharyngeal mass with multiple attachment points, which is unusual for a neoplasia. In addition to the recommended removal of the mass, oral administration of systemic antimycotics is strongly advised.

Hyperglycemia Suppresses Lactate Clearance During Exercise in Type 1 Diabetes.

Circulating lactate concentration is an important determinant of exercise tolerance. This work aimed to determine the role of hyperglycemia on lactate metabolism during exercise in individuals with type 1 diabetes (T1D). The protocol at the University of Virginia compared 7 T1D participants and 7 participants without diabetes (ND) at euglycemia (5.5 mM) or hyperglycemia (9.2 mM) in random order in T1D and at euglycemia in ND. Intervention included [1-13C] lactate infusion, exercise at 65% maximal oxygen uptake (VO2max), euglycemia, and hyperglycemia visits. The main outcome measure was lactate turnover before, during, and after 60 minutes of exercise at 65% VO2max. A 2-compartment model with loss only from the peripheral compartment described lactate kinetics. Volume of distribution of the accessible compartment was similar between T1D and ND individuals (P = .76) and concordant with plasma volume (∼40 mL/kg). Circulating lactate concentrations were higher (P < .001) in T1D participants during exercise at hyperglycemia than euglycemia. Exercise-induced lactate appearance did not differ (P = .13) between hyperglycemia and euglycemia. However, lactate clearance (CL) was lower (P = .03) during hyperglycemia than euglycemia in T1D participants. There were no differences in any of the aforementioned parameters between T1D and ND participants during euglycemia. Hyperglycemia modulates lactate metabolism during exercise by lowering CL, leading to higher circulating lactate concentrations in T1D individuals. This novel observation implies that exercise during hyperglycemia can lead to higher circulating lactate concentrations thus increasing the likelihood of reaching the lactate threshold sooner in T1D, and has high translational relevance both for providers and recreationally active people with T1D.

585-P: Lactate Kinetics in Type 1 Diabetes—A 1-13C Lactate Study

Lactate kinetics in individuals with type 1 diabetes (T1D) has not been assessed quantitatively. Defining lactate kinetics in T1D under steady state condition is vital for estimating non-steady state lactate turnover. We studied 5 T1D and 7 nondiabetic (ND) anthropometrically matched participants during [1-13C]-sodium-lactate bolus injection in the resting, overnight fasted state. A two-compartment model with loss only from the peripheral compartment reliably described [1-13C]-lactate kinetics. Volume of distribution of the accessible compartment, V1, was similar between T1D and ND groups (40.32±21.08 vs. 47.64±33.32 mL/kg, p=0.76) thus concordant to plasma volume (~40 ml/kg). The irreversible loss from the peripheral compartment was impaired in T1D vs ND (0.08±0.03 vs. 0.13±0.03 min−1, p=0.03); rate of lactate appearance (12.4±5.2 vs. 18.5±9.6 µmol/kg/min, p=0.34), disappearance (12.7±5.2 vs. 18.8±9.7 µmol/kg/min, p=0.34) and lactate clearance (15.9±4.7 vs. 21.9±7.8 mL/kg/min, p=0.20) were numerically but not statistically lower in T1D vs. ND individuals. To conclude, we have defined lactate kinetics under resting, overnight fasted state in T1D and ND subjects. While the volume of distribution was similar in both groups, irreversible loss from the peripheral compartment was lower in T1D subjects. Further studies are needed to better define lactate kinetics during exercise in individuals with and without T1D. Disclosure D.Romeres: None. F.Ruchi: None. Y.Yadav: None. C.Cobelli: None. A.Basu: None. R.Basu: Consultant; Sparrow Pharmaceuticals Inc, Research Support; Abbott Diabetes, AstraZeneca. Funding National Institutes of Health (DK29953 to R.B.), (DK85516 to A.B.)

Exploring associations between postpartum depression and oxytocin levels in cerebrospinal fluid, plasma and saliva

BackgroundPostpartum depression (PPD) is a serious mental health concern affecting approximately 17.22 % of new mothers worldwide. In addition to its obstetric effects, oxytocin (OXT) has also been considered to play a role in PPD. However, most previous studies exploring associations between PPD and OXT levels focus on easier accessible compartments such as blood or saliva. Study aimTo explore the possible association between PPD and OXT levels, and to assess the interaction between peripheral secretion and central release of OXT. MethodsIn this study, we prospectively measured OXT concentrations in cerebrospinal fluid (CSF), plasma and saliva of 94 women with elective cesarean section by enzyme-linked immunosorbent assay (ELISA) kits. The participants were divided into the PPD group if the score of Edinburgh Postpartum Depression Scale (EPDS) ≥ 10 at 3 months postpartum, otherwise into the non-PPD (nPPD) group. ResultsThe incidence of PPD was 30.85 %. OXT concentrations in CSF (r = −0.518, p < 0.001), plasma (r = −0.240, p = 0.020) and saliva (r = −0.263, p = 0.010) were negatively correlated with EPDS score, and were valuable for the prediction of PPD, with AUC and 95%CI of 0.890 (0.809–0.945), 0.683 (0.579–0.775) and 0.699 (0.596–0.790), respectively. Moreover, OXT concentrations in plasma (r = 0.407, p < 0.001) and saliva (r = 0.624, p < 0.001) were positively correlated with CSF OXT concentrations. LimitationsOnly full-term pregnant women undergoing elective cesarean section were included in this study, which may affect study generalizability. ConclusionsThe central and peripheral release of OXT is coordinated, and OXT level measured prenatally in CSF, plasma, or saliva is valuable for the prediction of PPD.

Combining sequential extraction and 3D fluorescence to investigate the behavior of antibiotic and polycyclic aromatic hydrocarbons during solar drying of sewage sludge

Solar drying and liming are commonly used for sludge treatment, but little is known about their efficiency on antibiotics and Polycyclic Aromatic Hydrocarbons (PAHs) removal. This study aimed to investigate the removal of antibiotics and PAHs during solar drying of Limed Sludge (LS) and Non-Limed Sludge (NLS). Thus, organic matter fractionation and 3D fluorescence were used to assess the accessibility and the complexity of organic matter. 2 experiments have been conducted using LS and NLS for 45 days of drying in a pilot scale tunnel. Physicochemical results indicated significant decrease of water content (90%) for both sludge samples within 15 days of drying. For both treatments, the removal of total organic carbon and total nitrogen was low and similar for both treatments. Through this study, it has been confirmed that liming and drying contributed to a strong modification of the organic matter quality with an increase of its accessibility. On the other hand, drying alone increased the less accessible compartments, while the presence of lime affected the interconnexion between the organic matter pools. 3D fluorescence confirmed the obtained results and indicated that LS leads to obtaining more simple molecules in the most accessible compartments, while NLS leads to obtaining more complex molecules in the less accessible compartments. In addition, solar radiations and leaching may contribute to the significant removal (p < 0.01) of roxithromycin, benzo(a)anthracene, chrysene, benzo[k]fluoranthene, benzo[a]pyrene, and benzo(g, h, i) perylene in the presence of lime. Furthermore, the evolution of organic matter pools in terms of accessibility and complexity may drive the bioavailability of these pollutants, leading to their significant removal.

Virtual diabetic patient with physical activity dynamics

Background and objectiveDiabetes is a disease of impaired blood glucose regulation due to the absence or insufficient secretion of insulin hormone or insulin resistance induced in the human body. In literature, the impact of exercise is considered in few models based on the minimal representation of glucose dynamics along with the assumption that no endogenous insulin is produced in the body. Hence these models are not capable of describing diabetic behavior which is independent of exogenous insulin. This type of diabetes, known as type-2, affects almost 90% of the total diabetes population. In this article, a constraint-based comprehensive physiological model of blood glucose dynamics is aimed to build for filling up the gap in the literature. MethodsFor physiological comprehensiveness, the model is considered to consist of several compartments separately connected with a common compartment named ‘plasma’. Plasma is the only accessible compartment and contains the state variables. Plasma variables are the integrated result of the net change in rates of metabolic processes and basal rates are influenced between two saturation constraints for an operating range of each plasma variable. The influence of a plasma variable on a metabolic rate is represented using a form of the hyperbolic tangent function. Validation is done by fitting the model with clinical experiments and continuous glucose monitoring data of a free-living environment. ResultsThe proposed model generates an average correlation coefficient of 0.85 ± 0.13 on all simulated responses with the target in the fitting experiments. Besides this, the model can produce a spectrum of metabolic effects of plasma variables for showing more insight into glucose metabolism. ConclusionsA constraint-based comprehensive glucose regulation with exercise dynamics for modeling diabetes is pursued. The model doesn't consider age, gender, physical, and mental condition of the human body but can be applied in operation research by mathematical programming.

Dysphagia in amyotrophic lateral sclerosis: Quantification of bulbar motor dysfunction.

Dysphagia as a sequel and possible early sign of amyotrophic lateral sclerosis (ALS) is caused by progressive impaired bulbar motor function. To evaluate bulbar motor dysfunction in patients suffering from ALS compared to a healthy reference group. A clinical study and prospective group comparison was designed. Patients and healthy volunteers were examined in the outpatient clinic of our university medical center. Ten patients with ALS and 20 healthy volunteers were included. All participants underwent a flexible endoscopic evaluation of swallowing (FEES) and a manometric measurement of the maximal sub-palatal atmospheric pressure generated by suction as well as of the prevalent pressure during swallowing. Additionally, the Sydney Swallow Questionnaire (SSQ) was completed by all participants to score the self-rated extent of dysphagia. Comparing maximal suction pressures, the group of patients showed significantly lower values (p<.001). There was a significant correlation between reduced pressures and the degree of dysphagia (SSQ score) (r=-0.73). As the oral cavity is an easily accessible compartment of the upper digestive tract, manometric measurements might serve as a simple instrument in order to detect or to monitor bulbar motor dysfunction. Oral manometry may facilitate early detection and monitoring of dysphagia in ALS. Larger studies are required to confirm our findings.

Gestational potential space hypothesis: Evolutionary explanation of human females body fat redistribution.

Homo sapiens, as well as other primates, developed the evolutionary advantage of storing excess energy as body fat, primarily in the readily accessible visceral fat compartment when food is plentiful for use during scarcity. However, uniquely to female humans, a second transient dimorphic phenotypic change begins at menarche and is reversed by menopause. It is the diversion of visceral fat stores from the abdominal cavity to the gluteofemoral region. The evolutionary purpose for this remains unclear. The author proposes the gestational potential space hypothesis: that such fat diversion is for the reproductive purpose of increasing the potential abdominal space available for gestation and reducing the intra-abdominal pressure. This hypothesis is supported by the basic laws of physics and increased rates of maternal and fetal complications experienced by those with visceral adiposity.

Stem cell-directed therapies for osteoarthritis: The promise and the practice.

Osteoarthritis (OA) is a disease of an entire synovial joint characterized by clinical symptoms and distortion of joint tissues, including cartilage, muscles, ligaments, and bone. Although OA is a disease of all joint tissues, it is a defined accessible compartment and is thus amenable to topical surgical and regenerative therapies, including stem cells. All tissues arise from stem progenitor cells, and the relative capacity of different cellular compartments, and different individuals, to renew tissues into adulthood may be important in the onset of many different degenerative diseases. OA is driven by both mechanical and inflammatory factors, but how these factors affect the proliferation and differentiation of cells into cartilage in vivo is largely unknown. Indeed, our very basic understanding of the physiological cellular kinetics and biology of the stem-progenitor cell unit of the articular cartilage, and how this is influenced by mechano-inflammatory injury, is largely unknown. OA seems, rather deceptively, to be the low-hanging fruit for stem cell therapy. Without the basic understanding of the stem cell and progenitor unit that generate and maintain articular cartilage in vivo, we will continue to waste opportunities to both prevent and manage this disease. In this review, we discuss the biology of chondrogenesis, the stem cell populations that support articular cartilage in health and disease, and future opportunities afforded through the translation of basic articular chondrocyte stem cell biology into new clinical therapies.

Enhanced Delivery of Rituximab Into Brain and Lymph Nodes Using Timed-Release Nanocapsules in Non-Human Primates.

Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments.

Weak correlations between serum and cerebrospinal fluid levels of estradiol, progesterone and testosterone in males

BackgroundNeuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and diseases. Yet, the correlation and association between steroids in the periphery, e.g. blood, and the central compartments, e.g. cerebrospinal fluid (CSF), have not yet been comprehensively assessed. As the brain is not directly accessible, and the collection of human CSF usually requires invasive procedures, easier accessible compartments, such as blood, have always attracted attention. However, studies in humans are scarce. In the present study we determined estradiol, progesterone and testosterone levels in CSF and serum of 22 males without cerebral disorders or diseases.ResultsSamples were taken under conditions corresponding closest to basal conditions with patients expecting only spinal anesthesia and minor surgery. All samples per patient were collected concomitantly. Total estradiol, progesterone and testosterone concentrations were measured by electro-chemiluminescence immunoassay. The strength of correlation was assessed by Spearman’s rank correlation coefficient. Correlation analysis revealed merely weak to very weak correlations for estradiol, progesterone and testosterone respectively between the CSF and serum compartments.ConclusionsTotal steroid levels of estradiol, progesterone and testosterone in CSF and serum of males without neurological disorders were determined. Weak to very weak correlations between CSF and serum were found thus suggesting that concentrations in the periphery do not parallel concentrations in the central compartments. Further research is needed to clarify to what extent and under which conditions serum levels of estradiol, progesterone and testosterone may possibly serve as a biomarker reflecting the respective concentrations in the CSF or in the brain.

Diagnostic Approaches in Sepsis - Part 1: General Diagnostic Principles, Focus Identification and Source Control

Sepsis and septic shock represent medical emergencies with persistently high mortality rates. According to the lately revised Surviving Sepsis Campaign (SSC) guidelines, focus identification/pathogen detection and the initial administration of broad-spectrum antibiotics are to be secluded within one hour after recognition of the symptoms of sepsis. However, there is dispute concerning the so called hour-1 bundle. Being a core aspect of focus identification, imaging modalities mainly depend on the suspected site of infection and the individual patient. Contrast agent-enhanced computed tomography (CT) is the modality usually used in critically ill patients. The microbiological pathogen detection still largely remains culture-based. This emphasizes the significance of microbiological specimen obtained from easily accessible body compartments and at least 2 blood culture sets. If possible, blood cultures should be drawn prior to antibiotic administration. Intraoperatively obtained swabs of otherwise sterile body compartments are of utmost importance with regard to microbiological pathogen detection. Catheters and implanted medical devices (i.e. cardiac pacemakers or defibrillators) suspicious of infection should be explanted and sent in for microbiological workup as soon as possible. All necessary source control measures should be realized as soon as medically possible but at least within 6 - (12) hours after the onset of symptoms. There is no specific biomarker for sepsis so far. Procalcitonin (PCT) and C-reactive protein (CRP) are crucial biomarkers in terms of infectious disease management and guidance of antimicrobial therapy in the ICU. Positive clinical trials showed that biomarkers like the midregional pro-adrenomedullin (MR-proADM) or presepsin might be promising candidates in the diagnosis of sepsis in the future. As an important marker of microcirculatory failure and disrupted cell metabolism, lactate serum concentrations (and lactate-clearance, respectively) are of prognostic value in septic patients.

Use of Stable Isotopes to Evaluate Bioefficacy of Provitamin A Carotenoids, Vitamin A Status, and Bioavailability of Iron and Zinc.

The ability of nutrition scientists to measure the status, bioavailability, and bioefficacy of micronutrients is affected by lack of access to the parts of the body through which a nutrient may travel before appearing in accessible body compartments (typically blood or urine). Stable isotope–labeled tracers function as safe, nonradioactive tools to follow micronutrients in a quantitative manner because the absorption, distribution, metabolism, and excretion of the tracer are assumed to be similar to the unlabeled vitamin or mineral. The International Atomic Energy Agency (IAEA) supports research on the safe use of stable isotopes in global health and nutrition. This review focuses on IAEA's contributions to vitamin A, iron, and zinc research. These micronutrients are specifically targeted by the WHO because of their importance in health and worldwide prevalence of deficiency. These 3 micronutrients are included in food fortification and biofortification efforts in low- and middle-income regions of the world. Vitamin A isotopic techniques can be used to evaluate the efficacy and effectiveness of interventions. For example, total body retinol stores were estimated by using 13C2-retinol isotope dilution before and after feeding Zambian children maize biofortified with β-carotene to determine if vitamin A reserves were improved by the intervention. Stable isotopes of iron and zinc have been used to determine mineral bioavailability. In Thailand, ferrous sulfate was better absorbed from fish sauce than was ferrous lactate or ferric ammonium citrate, determined with the use of different iron isotopes in each compound. Comparisons of one zinc isotope injected intravenously with another isotope taken orally from a micronutrient powder proved that the powder increased total absorbed zinc from a meal in Pakistani infants. Capacity building by the IAEA with appropriate collaborations in low- and middle-income countries to use stable isotopes has resulted in many advancements in human nutrition.

Oxytocin levels in saliva correlate better than plasma levels with concentrations in the cerebrospinal fluid of patients in neurocritical care.

In the converging fields of neuroendocrinology and behavioural neuroscience, the interaction between peripheral secretion and central release of oxytocin in humans has not yet been comprehensively assessed. As the human brain is not directly accessible and as the collection of human cerebrospinal fluid (CSF) usually requires invasive procedures, easier accessible compartments such as blood or saliva attract increasing attention. In this study, we prospectively determined oxytocin concentrations in the three compartments plasma, CSF and saliva of fifty critically ill patients with neurological and neurosurgical diseases. All samples per patient were collected concomitantly. Oxytocin was measured by a highly sensitive and specific radioimmunoassay. Strength of correlation was assessed by the Spearman rank correlation coefficient. Correlation analyses revealed modest to strong correlations for oxytocin between the saliva and CSF compartments while predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments. In conclusion, we demonstrated modest to strong correlations between the saliva and CSF compartment suggesting that saliva oxytocin may help to assess CSF oxytocin levels. In contrast, plasma oxytocin failed to correspond well with CSF oxytocin levels as predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments which are unlikely to have a biological relevance. Further research is needed to clarify to what extent saliva oxytocin may serve as a biomarker reflecting brain oxytocin activity. This article is protected by copyright. All rights reserved.

Untargeted mass spectrometry discloses plasma solute levels poorly controlled by hemodialysis.

Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated.

Neuropilin-1 Associated Molecules in the Blood Distinguish Poor Prognosis Breast Cancer: A Cross-Sectional Study

Circulating plasma and peripheral blood mononuclear (PBMCs) cells provide an informative snapshot of the systemic physiological state. Moreover, they provide a non-invasively accessible compartment to identify biomarkers for personalized medicine in advanced breast cancer. The role of Neuropilin-1 (NRP-1) and its interacting molecules in breast tumor tissue was correlated with cancer progression; however, the clinical impact of their systemic levels was not extensively evaluated. In this cross-sectional study, we found that circulating and tumor tissue expression of NRP-1 and circulating placental growth factor (PlGF) increase in advanced nodal and metastatic breast cancer compared with locally advanced disease. Tumor tissue expression of NRP-1 and PlGF is also upregulated in triple negative breast cancer (TNBC) compared to other subtypes. Conversely, in PBMCs, NRP-1 and its interacting molecules SEMA4A and SNAI1 are significantly downregulated in breast cancer patients compared to healthy controls, indicating a protective role. Moreover, we report differential PBMC expression profiles that correlate inversely with disease stage (SEMA4A, SNAI1, PLXNA1 and VEGFR3) and can differentiate between the TNBC and non-TNBC tumor subtypes (VEGFR3 and PLXNA1). This work supports the importance of NRP-1-associated molecules in circulation to characterize poor prognosis breast cancer and emphasizes on their role as favorable drug targets.

Can research at the end of life be a useful tool to advance HIV cure?

OPINION Can research at the end of life be a useful tool to advance HIV cure? Sara Gianella a , Jeff Taylor b , Timothy R. Brown c , Andy Kaytes b , Cristian L. Achim a , David J. Moore a , Susan J. Little a , Ronald J. Ellis a and Davey M. Smith a,d AIDS 2017, 31:1–4 Keywords: end of life, eradication, HIV cure, last gift, legacy, peri-mortem research model, research Modern antiretroviral therapy (ART) has saved millions of years of life [1], but it cannot eradicate latently infected cells [2,3]. The replication-competent provirus that remains during ART represents the major barrier to curing HIV [4]. Most of this latent reservoir resides in solid tissues and not in circulating blood, and we have yet to fully define the sanctuary sites of HIV persistence [5]. Timothy Ray Brown (known by many as the ‘Berlin Patient’) may be the closest to an HIV cure after being treated with an allogeneic hematopoietic stem cell transplant from a donor who was homozygous for the CCR5D32 deletion [6]. Unfortunately, this remarkable success has not been reproduced, and robust viral replication resumes almost universally following treat- ment interruption [7–9]. Even if strategies currently in development succeed in purging HIV from circulating CD4 þ T cells, residual virus can remain in the central nervous system (CNS), gut-associated lymphoid tissue (GALT), genital tract, adipose tissue, and others [9–12]. Thus, cure efforts must tackle the eradication of HIV reservoirs in anatomic compartments and sanctuaries throughout the body. The earliest stages of HIV infection are characterized by high levels of viral replication and little immune response [13,14]. This window of uncontrolled replication allows the virus to seed reservoirs throughout the body, as early as within 2 weeks of HIV infection [15], and to persist indefinitely throughout the lifespan of HIV-infected individuals [10]. These proviral reservoirs continue to expand and diversify until viral replication is successfully suppressed with ART. Despite extensive investigations, we still do not fully understand the dynamics of the total body HIV reservoir and how sub-reservoirs in various compart- ments relate to one another. For example, it remains unclear what factors govern the size and the activity of replication-competent HIV DNA in the CNS compared to the genital tract and blood. Most studies that have explored nonblood reservoirs among persons living with HIV infection have been limited to small samples of cerebrospinal fluid (CSF), genital secretion, gut, and shallow lymph nodes [10,16]. Studies using macaque models with simian immunodeficiency viruses (SIVs) have been enlightening for reservoirs in different tissues [17–23], but while SIV shares a high degree of structural and sequence identity to HIV, studies of SIV will not suffice to test eradication strategies for humans. For example, the Merck adenovirus type 5 (Ad5) trivalent HIV-1 vaccine trial (STEP trial) did not show efficacy in preventing HIV infection or slowing disease progression [24], despite promising results in various macaques’ trials [25–27]. As the field tackles the ambitious goal of eradicating HIV from the human body, we will need to test the effectiveness of cure interventions in living persons. a University of California, San Diego, La Jolla, b Community Advisory Board (CAB) AntiViral Research Center (AVRC), c Las Vegas, Nevada, and d Veterans Affairs San Diego Healthcare System, San Diego, California, USA. Correspondence to Sara Gianella, University of California San Diego, 9500 Gilman Drive, MC 0679, La Jolla, CA 92093-0679, USA. Tel: +1 858 642 1620; fax: +1 858 552 7445; e-mail: gianella@ucsd.edu Received: 18 August 2016; revised: 23 September 2016; accepted: 27 September 2016. DOI:10.1097/QAD.0000000000001300 ISSN 0269-9370 Copyright Q 2016 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Concentration of circulating miRNA-containing particles in serum enhances miRNA detection and reflects CRC tissue-related deregulations

The emerging potential of miRNAs as biomarkers for cancer detection demands parallel evaluation of strategies for reliable identification of disease-related signatures from easily accessible and pertinent body compartments. Here, we addressed whether efficient concentration of circulating miRNA-carrying particles is a rationale for miRNA biomarker discovery. We systematically compared miRNA signatures in 93 RNA preparations from three serum entities (whole serum, particle-concentrated, and particle-depleted fractions) and corresponding tissue samples from patients with colorectal cancer (CRC) as a model disease. Significant differences between whole sera and particle-concentrated serum fractions of CRC patients emerged for 45 of 742 tested miRNAs. Twenty-eight of these 45 miRNAs were differentially expressed between particle-concentrated serum fractions of metastatic CRC- and healthy individuals. Over half of these candidates (15 of 28) showed deregulations only in concentrated serum fractions, but not in whole sera, compared to the respective controls.Our results also provided evidence of a consistent downregulation of miR-486 and miR-92a, and further showed a possible “strand-specific” deregulation of extracellular miRNAs in CRC. More importantly, most of the identified miRNAs in the enriched sera reflected the patterns of the corresponding tumor tissues and showed links to cancer-related inflammation. Further investigation of seven serum pools revealed a subset of potential extracellular miRNA candidates to be implicated in both neoplastic and inflammatory bowel disease.Our findings demonstrate that enrichment and sensitive detection of miRNA carriers is a promising approach to detect CRC-related pathological changes in liquid biopsies, and has potential for clinical diagnostics.

Six-SOMAmer Index Relating to Immune, Protease and Angiogenic Functions Predicts Progression in IPF.

RationaleBiomarkers in easily accessible compartments like peripheral blood that can predict disease progression in idiopathic pulmonary fibrosis (IPF) would be clinically useful regarding clinical trial participation or treatment decisions for patients. In this study, we used unbiased proteomics to identify relevant disease progression biomarkers in IPF.MethodsPlasma from IPF patients was measured using an 1129 analyte slow off-rate modified aptamer (SOMAmer) array, and patient outcomes were followed over the next 80 weeks. Receiver operating characteristic (ROC) curves evaluated sensitivity and specificity for levels of each biomarker and estimated area under the curve (AUC) when prognostic biomarker thresholds were used to predict disease progression. Both logistic and Cox regression models advised biomarker selection for a composite disease progression index; index biomarkers were weighted via expected progression-free days lost during follow-up with a biomarker on the unfavorable side of the threshold.ResultsA six-analyte index, scaled 0 to 11, composed of markers of immune function, proteolysis and angiogenesis [high levels of ficolin-2 (FCN2), cathepsin-S (Cath-S), legumain (LGMN) and soluble vascular endothelial growth factor receptor 2 (VEGFsR2), but low levels of inducible T cell costimulator (ICOS) or trypsin 3 (TRY3)] predicted better progression-free survival in IPF with a ROC AUC of 0.91. An index score ≥ 3 (group ≥ 2) was strongly associated with IPF progression after adjustment for age, gender, smoking status, immunomodulation, forced vital capacity % predicted and diffusing capacity for carbon monoxide % predicted (HR 16.8, 95% CI 2.2–126.7, P = 0.006).ConclusionThis index, derived from the largest proteomic analysis of IPF plasma samples to date, could be useful for clinical decision making in IPF, and the identified analytes suggest biological processes that may promote disease progression.

Characterization of the serum metabolome following radiation treatment in patients with high-grade gliomas.

BackgroundGlioblastomas progress rapidly making response evaluation using MRI insufficient since treatment effects are not detectable until months after initiation of treatment. Thus, there is a strong need for supplementary biomarkers that could provide reliable and early assessment of treatment efficacy. Analysis of alterations in the metabolome may be a source for identification of new biomarker patterns harboring predictive information. Ideally, the biomarkers should be found within an easily accessible compartment such as the blood.MethodUsing gas-chromatographic- time-of-flight-mass spectroscopy we have analyzed serum samples from 11 patients with glioblastoma during the initial phase of radiotherapy. Fasting serum samples were collected at admittance, on the same day as, but before first treatment and in the morning after the second and fifth dose of radiation. The acquired data was analyzed and evaluated by chemometrics based bioinformatics methods. Our findings were compared and discussed in relation to previous data from microdialysis in tumor tissue, i.e. the extracellular compartment, from the same patients.ResultsWe found a significant change in metabolite pattern in serum comparing samples taken before radiotherapy to samples taken during early radiotherapy. In all, 68 metabolites were lowered in concentration following treatment while 16 metabolites were elevated in concentration. All detected and identified amino acids and fatty acids together with myo-inositol, creatinine, and urea were among the metabolites that decreased in concentration during treatment, while citric acid was among the metabolites that increased in concentration. Furthermore, when comparing results from the serum analysis with findings in tumor extracellular fluid we found a common change in metabolite patterns in both compartments on an individual patient level. On an individual metabolite level similar changes in ornithine, tyrosine and urea were detected. However, in serum, glutamine and glutamate were lowered after treatment while being elevated in the tumor extracellular fluid.ConclusionCross-validated multivariate statistical models verified that the serum metabolome was significantly changed in relation to radiation in a similar pattern to earlier findings in tumor tissue. However, all individual changes in tissue did not translate into changes in serum. Our study indicates that serum metabolomics could be of value to investigate as a potential marker for assessing early response to radiotherapy in malignant glioma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-016-0626-6) contains supplementary material, which is available to authorized users.