Reversible Reprogramming of Circulating Memory T Follicular Helper Cell Function during Chronic HIV Infection.

Despite the overwhelming benefits of antiretroviral therapy (ART) in curtailing viral load in HIV-infected individuals, ART does not fully restore cellular and humoral immunity. HIV-infected individuals under ART show reduced responses to vaccination and infections and are unable to mount an effective antiviral immune response upon ART cessation. Many factors contribute to these defects, including persistent inflammation, especially in lymphoid tissues, where T follicular helper (Tfh) cells instruct and help B cells launch an effective humoral immune response. In this study we investigated the phenotype and function of circulating memory Tfh cells as a surrogate of Tfh cells in lymph nodes and found significant impairment of this cell population in chronically HIV-infected individuals, leading to reduced B cell responses. We further show that these aberrant memory Tfh cells exhibit an IL-2-responsive gene signature and are more polarized toward a Th1 phenotype. Treatment of functional memory Tfh cells with IL-2 was able to recapitulate the detrimental reprogramming. Importantly, this defect was reversible, as interfering with the IL-2 signaling pathway helped reverse the abnormal differentiation and improved Ab responses. Thus, reversible reprogramming of memory Tfh cells in HIV-infected individuals could be used to enhance Ab responses. Altered microenvironmental conditions in lymphoid tissues leading to altered Tfh cell differentiation could provide one explanation for the poor responsiveness of HIV-infected individuals to new Ags. This explanation has important implications for the development of therapeutic interventions to enhance HIV- and vaccine-mediated Ab responses in patients under ART.

Question Waves: A multicast query routing algorithm for social search

This paper describes Question Waves, an algorithm that can be applied to social search protocols, such as Asknext or Sixearch. In this model, the queries are propagated through the social network, with faster propagation through more trustable acquaintances. Question Waves uses local information to make decisions and obtain an answer ranking. With Question Waves, the answers that arrive first are the most likely to be relevant, and we computed the correlation of answer relevance with the order of arrival to demonstrate this result. We obtained correlations equivalent to the heuristics that use global knowledge, such as profile similarity among users or the expertise value of an agent. Because Question Waves is compatible with the social search protocol Asknext, it is possible to stop a search when enough relevant answers have been found; additionally, stopping the search early only introduces a minimal risk of not obtaining the best possible answer. Furthermore, Question Waves does not require a re-ranking algorithm because the results arrive sorted

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology.

BACKGROUND: Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). METHODS: The study consisted of consecutive fine-needle aspiration biopsy (FNAB) cases collected between January 1, 2013 and June 30, 2014 from 5 academic institutions. Demographic information, cytology diagnoses, and surgical pathology follow-up were recorded. The ROM was calculated with and without NI-FVPTC and was presented as a range: all cases (ie, overall risk of malignancy [OROM]) versus those with surgical follow-up only. RESULTS: The FNAB cohort consisted of 6943 thyroid nodules representing 5179 women and 1409 men with an average age of 54 years (range, 9-94 years). The combined average ROM and OROM for the diagnostic categories of TBSRTC were as follows: nondiagnostic, 4.4% to 25.3%; benign, 0.9% to 9.3%; atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS), 12.1% to 31.2%; follicular neoplasm (FN), 21.8% to 33.2%; suspicious for malignancy (SM), 62.1% to 82.6%; and malignant, 75.9% to 99.1%. The impact of reclassifying NI-FVPTC on the ROM and OROM was most pronounced and statistically significant in the 3 indeterminate categories: the AUS/FLUS category had a decrease of 5.2% to 13.6%, the FN category had a decrease of 9.9% to 15.1%, and the SM category had a decrease of 17.6% to 23.4% (P < .05), whereas the benign and malignant categories had decreases of 0.3% to 3.5% and 2.5% to 3.3%, respectfully. The trend of the effect on the ROM and OROM was similar for all 5 institutions. CONCLUSIONS: The results from this multi-institutional cohort indicate that the reclassification of NI-FVPTC will have a significant impact on the ROM for the 3 indeterminate categories of TBSRTC. Cancer Cytopathol 2016;124:181-187. © 2015 American Cancer Society.

The seasonal evolution of high vertical–mode internal waves in a deep reservoir

The causal mechanism and seasonal evolution of the internal wave field in a deep, warm, monomictic reservoirare examined through the analysis of field observations and numerical techniques. The study period extends fromthe onset of thermal stratification in the spring until midsummer in 2005. During this time, wind forcing wasperiodic, with a period of 24 h (typical of land–sea breezes), and the thermal structure in the lake wascharacterized by the presence of a shallow surface layer overlying a thick metalimnion, typical of small to mediumsized reservoirs with deep outtakes. Basin-scale internal seiches of high vertical mode (ranging from mode V3 toV5) were observed in the metalimnion. The structure of the dominant modes of oscillation changed asstratification evolved on seasonal timescales, but in all cases, their periods were close to that of the local windforcing (i.e., 24 h), suggesting a resonant response. Nonresonant oscillatory modes of type V1 and V2 becamedominant after large frontal events, which disrupted the diurnal periodicity of the wind forcing

Palaeolithic Populations and Waves of Advance

The wave-of-advance model has been previously applied to Neolithic human range expansions, yielding good agreement to the speeds inferred from archaeological data. Here, we apply it for the first time to Palaeolithic human expansions by using reproduction and mobility parameters appropriate to hunter-gatherers (instead of the corresponding values for preindustrial farmers). The order of magnitude of the predicted speed is in agreement with that implied by the AMS radiocarbon dating of the lateglacial human recolonization of northern Europe (14.2–12.5 kyr BP). We argue that this makes it implausible for climate change to have limited the speed of the recolonization front. It is pointed out that a similar value for the speed can be tentatively inferred from the archaeological data on the expansion of modern humans into the Levant and Europe (42–36 kyr BP)

Dispersion of Hybrid Electromagnetic-Spin Waves in the Slotline

The presented thesis is devoted to investigation of wave processes in hybrid ferrite / ferroelectric structures. Spin wave devices based on ferrite films have such disadvantages, as huge size of the magnetic systems, low tuning velocity, considerable power inputs for parameters control that limits possible device applications. The considered layered structures allow to overcome the disadvantages mentioned and to promote the development of novel class of tunable microwave devices. The proposed theoretical analysis is intended to construct a model of hybrid electromagnetic-spin waves. Based on the theoretical analysis the experimental investigations were carried out. The experimental resonance characteristics of ferrite / ferroelectric resonator were obtained and their tunability by means of magnetic and electric field was demonstrated.

Evaluation of follicular lymphoid depletion in the Bursa of Fabricius: an alternative methodology using digital image analysis and artificial neural networks

Fifty Bursa of Fabricius (BF) were examined by conventional optical microscopy and digital images were acquired and processed using Matlab® 6.5 software. The Artificial Neuronal Network (ANN) was generated using Neuroshell® Classifier software and the optical and digital data were compared. The ANN was able to make a comparable classification of digital and optical scores. The use of ANN was able to classify correctly the majority of the follicles, reaching sensibility and specificity of 89% and 96%, respectively. When the follicles were scored and grouped in a binary fashion the sensibility increased to 90% and obtained the maximum value for the specificity of 92%. These results demonstrate that the use of digital image analysis and ANN is a useful tool for the pathological classification of the BF lymphoid depletion. In addition it provides objective results that allow measuring the dimension of the error in the diagnosis and classification therefore making comparison between databases feasible.

Effect of medroxy-progesterone acetate on follicular growth and endometrial cycloxygenase-2 (COX-2) expression during the bovine estrous cycle

The objective of this study was to evaluate the effect of medroxy-progesterone acetate (MAP) with or without estradiol benzoate (EB) on follicular growth during the estrous cycle in cattle. In the first experiment, Hereford cows were synchronized with a synthetic analogue of PGF2 alpha and were treated with two different doses of MAP (250 or 500 mg) with or without EB for 7 days starting on day 8 of the estrous cycle. Follicular growth was inhibited (P<0.05) in all cows except controls and those receiving 250mg MAP without EB. Seventy-five percent of the animals (15/20) showed estrus on days 21 and 22 of the cycle rather than at MAP withdrawal, demonstrating that these treatments did not induce estrus. To determine whether the EB treatment altered endometrial sensitivity to oxytocin and thus the luteolytic cascade, multiparous pre-synchronized cows received 5 mg of EB followed 6 hours later with 50 IU of oxytocin (OT; n=9). Eight hours after EB injection, endometrial fragments were collected from the cows on days 4, 13 and 17 of the estrous cycle and COX-2 gene expression was measured by PCR. EB increased COX-2 mRNA levels only on day 17 of the estrous cycle (P<0.05). In conclusion, MAP alone or associated with EB is able to suppress bovine follicular growth. However, EB in the presence of MAP is not efficient to induce luteolysis in cows when injected on day 8 of the estrous cycle.

Porcine follicular fluid concentration of free insulin-like growth factor-I collected from different diameter ovarian follicles

The study aimed to quantify the concentrations of free IGF-I in serum and fluid of ovarian follicles in pre-pubertal gilts and describe the ovarian morphology by measuring the size of the ovaries and counting the number of surface follicles. Ovaries (n=1,000) from pre-pubertal gilts were obtained immediately after slaughter. A total of 10 samplings were performed, with ovaries obtained from 50 females for each collection. The follicles situated on the surface of each ovary were classified as small (SFs, 2 to 5mm in diameter) or large (LFs 6 to 10mm in diameter) and the follicular fluid was obtained by follicle aspiration. The collection of serum samples was performed after the gilts exsanguination using sterile tubes. From the pool of serum and follicular fluid obtained from 50 females, the concentration of free IGF-I was determined in each sample using an enzyme immunoassay kit (ELISA). The description of ovarian morphometry was performed in 100 ovaries from randomly selected gilts. The larger and smaller lengths of ovaries were measured, and the total number of SFs and LFs present on the surface of each ovary were also counted. The IGF-I concentration was greater (P<0.05) in LFs (170.92±88.29 ng/mL) compared with SFs (67.39±49.90ng/mL) and serum (73.48±34.63ng/mL). The largest and smallest length of the ovaries was 26.0±3.0 and 19.0mm ±2.0mm, respectively. The number of SFs (70.86±25.76) was greater (P<0.01) than LFs (6.54±5.26). The study concluded that LFs present greater levels of IGF-I when compared with SFs and blood, which is related to increased activity of the LFs and its differentiation to ovulation. In addition, ovaries of pre-pubertal gilts have a higher number of SFs compared to LFs. Therefore, our study demonstrated unique data regarding the physiological concentration of free IGF-I in ovarian follicles, that can be used in future research to evaluate the addition of this hormone in the in vitro production media of porcine embryos with the goal to improve the technique efficiency.

Cytoskeletal proteins in the follicular wall of normal andcystic ovaries of sows

The expression of cytoskeletal proteins was evaluated immunohistochemically in 36 normal ovaries sampled from 18 sows and 44 cystic ovaries sampled from of 22 sows, was evaluated. All sows had history of reproductive problems, such as infertility or subfertility. The immunohistochemically stained area (IHCSA) was quantified through image analysis to evaluate the expression of these proteins in the follicular wall of secondary, tertiary, and cystic follicles. Cytokeratins (CK) immunoreactivity was strong in the granulosa cell layer (GC) and mild in the theca interna (TI) and externa (TE) of the normal follicles. There was severe reduction of the reaction to CK in the GC in the cystic follicles, mainly in the luteinized cysts. The immunoreactivity for vimentin was higher in the GC from normal and cystic follicles in contrast with the other follicular structures. In the luteinized cysts, the IHCSA for vimentin was significantly higher in TI and in both observed cysts, the labeling was more accentuated in TE. Immunohistochemical detection of desmin and α-SMA was restricted to the TE, without differences between the normal and cystic follicles. The results of the current study show that the development of ovarian cysts in sows is associated to changes in the expression of the cytoskeletal proteins CK and vimentin.

Effect of wave frequency on the nonlinear interaction between Görtler vortices and three-dimensional Tollmien-Schlichting waves

The nonlinear interaction between Görtler vortices (GV) and three-dimensional Tollmien-Schlichting (TS) waves nonlinear interaction is studied with a spatial, nonparallel model based on the Parabolized Stability Equations (PSE). In this investigation the effect of TS wave frequency on the nonlinear interaction is studied. As verified in previous investigations using the same numerical model, the relative amplitudes and growth rates are the dominant parameters in GV/TS wave interaction. In this sense, the wave frequency influence is important in defining the streamwise distance traveled by the disturbances in the unstable region of the stability diagram and in defining the amplification rates that they go through.

A survey of the generation of ocean waves in a test basin

At present stage the analytical design of wave tolerance for floating structures and vessels is still imperfect due to the mutually complex and nonlinear phenomena between structures and waves. Wave tolerance design is usually carried out through iterative evaluations of results from model tests in a wave basin, and this is done in order to reach a final structural design. The wave generation has then become an important technology in the field of the coastal and ocean engineering. This paper summarizes the facilities of a test basin and a wave maker in Japan and also surveys the methodology of the generation of ocean waves in a test basin.

Electrical status epilepticus during sleep. Continuous spikes and waves during sleep

ABSTRACT Maria Peltola Electrical status epilepticus during sleep – Continuous spikes and waves during sleep Department of Clinical Neurophysiology, University of Turku Department of Clinical Neurophysiology and Department of Pediatric Neurology, Children’s Hospital, Helsinki University Central Hospital Annales Universitatis Turkuensis, Medica-Odontologica, Turku, Finland, 2014 Background: Electrical status epilepticus during sleep (ESES) is an EEG phenomenon of frequent spikes and waves occurring in slow sleep. ESES relates to cognitive deterioration in heterogeneous childhood epilepsies. Validated methods to quantitate ESES are missing. The clinical syndrome, called epileptic encephalopathy with continuous spikes and waves during sleep (CSWS) is pharmacoresistant in half of the patients. Limited data exists on surgical treatment of CSWS. Aims and methods: The effects of surgical treatment were studied by investigating electroclinical outcomes in 13 operated patients (nine callosotomies, four resections) with pharmacoresistant CSWS and cognitive decline. Secondly, an objective paradigm was searched for assessing ESES by the semiautomatic quantification of spike index (SI) and measuring spike strength from EEG. Results: Postoperatively, cognitive deterioration was stopped in 12 (92%) patients. Three out of four patients became seizure-free after resective surgery. Callosotomy resulted in greater than 90% reduction of atypical absences in six out of eight patients. The preoperative propagation of ESES from one hemisphere to the other was associated with a good response. Semiautomatic quantification of SI was a robust method when the maximal interspike interval of three seconds was used to determine the “continuous” discharge in ten EEGs. SI of the first hour of sleep appeared representative of the whole night SI. Furthermore, the spikes’ root mean square was found to be a stable measure of spike strength when spatially integrated over multiple electrodes during steady NREM sleep. Conclusions: Patients with pharmacoresistant CSWS, based on structural etiology, may benefit from resective surgery or corpus callosotomy regarding both seizure outcome and cognitive prognosis. The semiautomated SI quantification, with proper userdefined settings and the new spatially integrated measure of spike strength, are robust and promising tools for quantifying ESES. Keywords: Electrical status epilepticus during sleep, ESES, continuous spikes and waves during sleep, CSWS, epilepsy surgery, spike index, spike strength, RMS TIIVISTELMÄ Maria Peltola Unenaikainen sähköinen status epilepticus Kliininen neurofysiologia, Turun yliopisto Kliininen neurofysiologia ja lastenneurologia, Lasten ja nuorten sairaala, Helsingin yliopistollinen keskussairaala Annales Universitatis Turkuensis, Medica-Odontologica, Turku, Suomi, 2014 Tausta: Sähköinen status epilepticus unessa (ESES) on aivosähkökäyrä (EEG)-ilmiö, jossa hidasaaltounen aikana esiintyy tiheä piikkihidasaaltopurkaus. ESES:n kvantifioimiseen ei ole olemassa validoituja menetelmiä. ESES on liitetty kognitiivisen tason laskuun ja tällöin puhutaan CSWS (continuous spikes and waves during sleep) - oireyhtymästä. CSWS ei vastaa lääkehoitoon puolella potilaista ja sen epilepsiakirurgisesta hoidosta on olemassa vain vähän tietoa. Tavoitteet ja menetelmät: Selvitimme retrospektiivisesti epilepsiakirurgian vaikusta elektrokliinisiin löydöksiin 13:lla lääkeresistenttiä CSWS-oireyhtymää sairastavalla lapsella, joilla oli rakenteellinen aivojen poikkeavuus. Toinen tavoite oli löytää objektiivinen puoliautomaattinen tapa mitata purkauksen määrää ja piikkien voimakkuutta EEG:stä. Tulokset: Kognitiivisen tason jatkuva heikentyminen loppui 12 (92 %) potilaalla leikkauksen jälkeen. Kolme neljästä resektiopotilaasta tuli kohtauksettomaksi. Kallosotomian jälkeen kuudella kahdeksasta potilaasta päivittäiset kohtaukset vähenivät yli 90 %:lla. Purkauksen leviäminen leikkausta edeltävästi vain yhdestä hemisfääristä toiseen liittyi hyvään leikkaushoitovasteeseen. Piikki-indeksi, jossa käytetään jatkuvan purkauksen määritelmänä maksimissaan kolmea sekuntia piikkien välillä, osoittautui luotettavaksi menetelmäksi ESES:n kvantifioimiseen. Useammasta elektrodista integroitu piikkien neliöllinen keskiarvo oli piikin voimakkuuden vakaa mitta häiriintymättömässä NREM-unessa. Päätelmät: Lääkehoidolle vastaamatonta CSWS:ää sairastavat potilaat, joilla on rakenteellinen aivopoikkeavuus ja yhdensuuntainen purkauksen leviämismalli, näyttävät kohtausten vähenemisen lisäksi hyötyvän epilepsiakirurgiasta kognitiivisesti. Puoliautomaattinen piikki-indeksin kvantifiointi sopivilla käyttäjäasetuksilla ja uusi spatiaalisesti integroitu piikin voimakkuuden mittari ovat stabiileja ja lupaavia ESES:n kvantitatiivisia mittareita. Avainsanat: Unenaikainen sähköinen status epilepticus, ESES, CSWS, epilepsiakirurgia, piikki-indeksi, piikin voimakkuus, neliöllinen keskiarvo