[Treatment of heparin-induced thrombocytopenia with rivaroxaban. Case report]. / Rivaroxaban para el tratamiento de la trombocitopenia inducida por heparina. Caso clínico.

Heparin-induced thrombocytopenia (HIT) is immune-mediated. It occurs more frequently with unfractionated heparin (UFH) than with low molecular weight heparins (LMWH). It is associated with thromboembolic rather than hemorrhagic events, as opposed to thrombocytopenia of other etiologies. The key in therapy is the cessation of heparin and the start of another anticoagulant. We report a 58 years old female with HIT secondary to the use of Enoxaparin who was successfully managed with Rivaroxaban. Our goal is to report a novel therapy and provide the evidence that supports its use.

Evaluation of the new generation dual-lumen catheter for neonatal ECMO.

OBJECTIVES: The purpose of this study was to compare the newly designed dual-lumen venovenous catheter (VR13, OriGen Biomedical, Austin, TX) with the current dual-lumen catheter (VV12, OriGen Biomedical). METHODS: Five newborn lambs, 1 to 5 days old and weighing 4.2 ± 0.5 kg, were cannulated with the VV13 OriGen catheter and placed on extracorporeal membrane oxygenation (ECMO). ECMO flows were increased from 200 to 600 ml/min, with measurements taken after the changes. The experiment was then repeated using the VV12 catheter. RESULTS: Recirculation values were equal for both catheters. The pressure drop at the reinfusion port was equal for both catheters at 200 ml/min, increasing to 275 mmHg at 500 ml/min for the VR13 vs. 240 mmHg for the VV12 catheter. CONCLUSION: These findings indicate that the VR13 catheter resulted in levels of recirculation equal to the VV12. Based on resistance measurements, we do not recommend the use of this new catheter beyond 400 ml/min until minor design changes are made.

Screening over Speech in Unselected Populations for Clinical Trials in AD (PROSPECT-AD): Study Design and Protocol.

BACKGROUND: Speech impairments are an early feature of Alzheimer's disease (AD) and consequently, analysing speech performance is a promising new digital biomarker for AD screening. Future clinical AD trials on disease modifying drugs will require a shift to very early identification of individuals at risk of dementia. Hence, digital markers of language and speech may offer a method for screening of at-risk populations that are at the earliest stages of AD, eventually in combination with advanced machine learning. To this end, we developed a screening battery consisting of speech-based neurocognitive tests. The automated test performs a remote primary screening using a simple telephone. OBJECTIVES: PROSPECT-AD aims to validate speech biomarkers for identification of individuals with early signs of AD and monitor their longitudinal course through access to well-phenotyped cohorts. DESIGN: PROSPECT-AD leverages ongoing cohorts such as EPAD (UK), DESCRIBE and DELCODE (Germany), and BioFINDER Primary Care (Sweden) and Beta-AARC (Spain) by adding a collection of speech data over the telephone to existing longitudinal follow-ups. Participants at risk of dementia are recruited from existing parent cohorts across Europe to form an AD 'probability-spectrum', i.e., individuals with a low risk to high risk of developing AD dementia. The characterization of cognition, biomarker and risk factor (genetic and environmental) status of each research participants over time combined with audio recordings of speech samples will provide a well-phenotyped population for comparing novel speech markers with current gold standard biomarkers and cognitive scores. PARTICIPANTS: N= 1000 participants aged 50 or older will be included in total, with a clinical dementia rating scale (CDR) score of 0 or 0.5. The study protocol is planned to run according to sites between 12 and 18 months. MEASUREMENTS: The speech protocol includes the following neurocognitive tests which will be administered remotely: Word List [Memory Function], Verbal Fluency [Executive Functions] and spontaneous free speech [Psychological and/ or behavioral symptoms]. Speech features on the linguistic and paralinguistic level will be extracted from the recordings and compared to data from CSF and blood biomarkers, neuroimaging, neuropsychological evaluations, genetic profiles, and family history. Primary candidate marker from speech will be a combination of most significant features in comparison to biomarkers as reference measure. Machine learning and computational techniques will be employed to identify the most significant speech biomarkers that could represent an early indicator of AD pathology. Furthermore, based on the analysis of speech performances, models will be trained to predict cognitive decline and disease progression across the AD continuum. CONCLUSION: The outcome of PROSPECT-AD may support AD drug development research as well as primary or tertiary prevention of dementia by providing a validated tool using a remote approach for identifying individuals at risk of dementia and monitoring individuals over time, either in a screening context or in clinical trials.

The CORCOBIA study: Cut-off points of Alzheimer's disease CSF biomarkers in a clinical cohort.

INTRODUCTION: The analysis of the core biomarkers of Alzheimer's Disease (AD) in the cerebrospinal fluid (CSF) is recommended in the clinical units where it is available. Because of the absence of universal validated values, the determination of specific cut-off points for each center and its population is recommended. The main objective of the CORCOBIA study was to determine the cut-off points of core AD CSF biomarkers for several centers (Parc de Salut Mar, Barcelona and Hospital General de Granollers), which work with the same reference laboratory (Laboratori de Referència de Catalunya). METHODS: Prospective study including cognitively unimpaired individuals (CU, n = 42), subjects with amnestic mild cognitive impairment (aMCI, n = 35) and patients with dementia due to Alzheimer's Disease (AD, n = 48), in whom clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture to analyse amyloid beta peptides (Aß42, Aß40), total tau (tTau) and phosphorylated Tau (pTau181) using the Lumipulse G600II (Fujirebio) was performed. The values of sensitivity (SE), specificity (SP), predictive values and area under the curve (AUC) were calculated, determining the cut-off point according to the Youden index by comparing the CU and AD groups. RESULTS: The resulting cut-offs and their AUC were the following: Aß42 750 pg/mL (AUC 0.809); Aß42/Aß40 0.062 (AUC 0.78); pTau181 69.85 pg/mL (AUC 0.81); tTau 522.0 pg/mL (AUC 0.79); Aß42/tTau 1.76 (AUC 0.86); Aß42/pTau181 10.25 (AUC 0.86). CONCLUSIONS: The determination of cut-off points of core AD CSF biomarkers for the participating centers allows a better diagnostic accuracy. The ratio CSF Aß42/pTau181 shows the highest AUC and better balance between sensitivity and specificity.

Comparative Analysis of Different Definitions of Amyloid-ß Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer.

Amyloid-ß (Aß) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aß pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer's continuum is critical. Here, we compare different Aß classification approaches and we show their performance in detecting pathophysiological changes downstream Aß pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer's continuum. Participants underwent Aß PET and CSF biomarkers assessment. We classified participants as Aß -positive using five approaches: (1) CSF Aß42 < 1098 pg/ml; (2) CSF Aß42/40 < 0.071; (3) Aß PET Centiloid > 12; (4) Aß PET Centiloid > 30 or (5) Aß PET Positive visual read. We assessed the correlations between Aß biomarkers and compared the prevalence of Aß positivity. We determined which approach significantly detected associations between Aß pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aß-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aß-positive but PET Aß-negative than CSF Aß-negative but PET Aß-positive. The CSF Aß 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aß-positive group. Altogether, we highlight the need for sensitive Aß -classifications to study the preclinical Alzheimer's continuum. Approaches that define Aß positivity based on optimal discrimination of symptomatic Alzheimer's disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.

Color Regression and Maintenance Effect of Intracoronal Whitening on the Quality of Life: RCT-A One-year Follow-up Study.

OBJECTIVE:: This randomized clinical study evaluated two parameters: 1) the clinical color rebound of whitening patients' tooth discoloration using the walking bleaching technique and 2) the impact on psychological and aesthetic self-perception at the one-year follow-up of patients who underwent bleaching of nonvital teeth. METHODS AND MATERIALS:: Fifty study participants with nonvital tooth discoloration were recruited. Teeth were assigned randomly into one of two groups: 1) 35% hydrogen peroxide (n=25) and 2) 37% carbamide peroxide (n=25). Intracoronal bleaching was carried out over the course of four sessions using the walking bleach technique. Tooth color was evaluated after each session in order to measure the total color variation (ΔE). The guide was arranged from highest (B1) to lowest values (C4) for evaluating color, and color changes using Vita Classical Shade (ΔSGUs) units were calculated. Subjective and objective assessments were compared with the counterpart of the tooth. Aesthetic perception and psychosocial factors were evaluated before and after treatment by the Oral Health Impact Profile (OHIP) and Psychological Impact of Dental Impact Questionnaire (PIDAQ) surveys. RESULTS:: Color changes (ΔE) were 15.48 ± 5.17 and 14.02 ± 4.85 for carbamide and hydrogen peroxide groups, respectively. There were no significant differences ( p>0.05) between these two groups at the one-year follow-up. There was a decrease in the PIDAQ scores after treatment compared to baseline values ( p<0.05). The majority of OHIP values regressed to baseline values. CONCLUSION:: The technique of walking bleaching was highly effective and showed minimal color rebound in nonvital teeth and had a positive effect on patients' psychological impact at the one-year follow-up.

Oscillations of Hes7 caused by negative autoregulation and ubiquitination.

Loss of Hes7 function leads to irregular somite formation demonstrating that Hes7 is a crucial component of the segmentation clock during somitogenesis. Experiments revealed that not only the repressor functionality but also the half-life of the protein is crucial for oscillatory expression of Hes7 and regular somite formation. Numerical integration of a delay equation system supported this finding. However, in a recent paper it was shown that the number of binding sites is also decisive for damped or undamped oscillations. It was shown that for more than one binding site the Hill coefficient increases. This leads to a completely different behavior. The oscillations are undamped and thus the mathematical model can no longer explain the results observed in the experiments. In this paper we propose a more sophisticated model for the Hes7 oscillator. Since Hes7 is degraded by the ubiquitin-proteasome pathway we include Michaelis-Menten kinetics for the ubiquitination of Hes7. We identify the Michaelis-Menten constant as an additional model parameter for oscillatory behavior. By increasing the Michaelis-Menten constant we found damped oscillations even if the Hill coefficient is increased.

Simplified superovulatory treatments in Corriedale ewes.

Two experiments were designed to evaluate the possibility of simplifying superovulatory treatments in Corriedale ewes with use of ovine FSH (oFSH). Ewes received intravaginal progestogen sponges for 14 days. In Experiment 1, several simplified schedules were tested. Ewes were treated with 176 NIH-FSH-S1 units' oFSH given as a single injection in saline, along with 500 IU eCG 48 h before sponge removal (Group A1), in four equal doses (B1), or given as a single injection in a polyvinylpyrrolidone vehicle (C1) 24 h before sponge removal. In Experiment 2, the simplified protocol that exhibited the most desirable results in Experiment 1 (A2) was compared with the same protocol, but using less oFSH (132 units) (B2) and with the most conventional protocol (176 units of oFSH in eight decreasing doses; C2). Estrus was detected and ewes were naturally mated. The ovarian response and embryo production were assessed on Day 6 after estrus. LH was measured at 6h intervals from pessary withdrawal. The onset of estrus and the pre-ovulatory LH surge were advanced (P<0.05) in ewes treated with FSH and eCG. In Experiment 1, protocol A1 produced a greater percentage of superovulated ewes compared to C1 (100.0 compared with 58.3%; P<0.05), increased ovulation rate (13.8 corpora lutea compared with 6.2 and 4.7 for B1 and C1, respectively; P<0.05), and tended to increase the number of transferable embryos compared to B1 (P=0.08). In Experiment 2, percentages of superovulated ewes and ovulation rates were similar among groups; however, Group A2 tended to have more large follicles (P=0.07) than C2. The number of transferable embryos was similar among the three treatments. In conclusion, the reduced-dose oFSH given once along with eCG is the most appropriate superovulatory treatment because it combines simplicity and a lesser dose of gonadotropin, which also implies a reduction in cost, without reducing embryo production.

Influence of central hemodynamics on VV ECMO oxygen delivery in neonatal animal model.

BACKGROUND: Recirculation of oxygenated blood in venovenous extracorporeal membrane oxygenation (VV ECMO) can decrease the oxygen delivery provided by the ECMO support. This study investigated the influence of central hemodynamics and catheter position on the amount of recirculation and oxygen delivery during VV ECMO. METHODS: Recirculation was measured in seven newborn lambs (mean weight 4.7 kg) during VV ECMO using the ELSA Monitor (Transonic Systems, Inc., Ithaca, NY) and using the central venous line (CVL) method. The ECMO pump was set at the prescribed flow of 110-120 mL/kg/min for a targeted oxygen delivery rate of 6cc/kg/min without recirculation. Hemodynamic status before and during ECMO was also measured by the COstatus Monitor (Transonic Systems, Inc.,Ithaca, NY). RESULTS: Lambs with a higher cardiac index (>160 ml/min/kg), had a tendency to have higher percent oxygen delivery (65-94%, at prescribed flow) while lambs with lower cardiac index (<150 ml/min/kg), tended to have lower percent oxygen delivery (39-62%, at prescribed flow). ELSA recirculation measurements had a squared correlation coefficient R2 = 0.8 with the CVL method. CONCLUSIONS: The ELSA monitor provides an easy to use, non-invasive method to measure recirculation in VV ECMO. The data suggests that cardiac function may play an important prognostic role in achieving effective VV ECMO support.

Impaired ovarian response to exogenous gonadotropins in female rat offspring born to mothers perinatally exposed to Bisphenol A.

The ovary is sensitive to disruption by the environmental estrogen Bisphenol A (BPA). Our aim was to investigate whether perinatal exposure to BPA (50µg/kgday), orally administered, affects ovarian response to exogenous gonadotrophins (PMSG or PMSG+hCG) in prepubertal female offspring. An altered response to gonadotrophins was observed in BPA-exposed rats. Increased proportion of antral follicles, altered levels of ovarian steroidogenic enzymes, gonadotropin receptors, AR and ERß were observed in PMSG group. Besides that, in response to PMSG+hCG, a persistent high Fshr mRNA expression and a decreased number of follicles with high expression of PR before ovulation were observed. After ovulation, there was an increase in antral atretic follicles, reduced Lhcgr mRNA expression and high serum levels of E2. Therefore, an early exposure to a low dose of BPA during perinatal period induces ovarian changes leading to an altered response to exogenous gonadotropin treatment later in life.

Extended gamma-ray sources around pulsars constrain the origin of the positron flux at Earth.

The unexpectedly high flux of cosmic-ray positrons detected at Earth may originate from nearby astrophysical sources, dark matter, or unknown processes of cosmic-ray secondary production. We report the detection, using the High-Altitude Water Cherenkov Observatory (HAWC), of extended tera-electron volt gamma-ray emission coincident with the locations of two nearby middle-aged pulsars (Geminga and PSR B0656+14). The HAWC observations demonstrate that these pulsars are indeed local sources of accelerated leptons, but the measured tera-electron volt emission profile constrains the diffusion of particles away from these sources to be much slower than previously assumed. We demonstrate that the leptons emitted by these objects are therefore unlikely to be the origin of the excess positrons, which may have a more exotic origin.

Validation of a noninvasive neonatal optical cerebral oximeter in veno-venous ECMO patients with a cephalad catheter.

INTRODUCTION: Cerebral Oximetry is an optical technique that allows for noninvasive and continuous monitoring of brain oxygenation by determining tissue oxygen saturation (SctO2). In conjunction with pulse oximetry, cerebral oximetry offers a promising method to estimate cerebral venous oxygen saturation (SvO2). OBJECTIVE: The aim of this study was to validate the cerebral oximetry measurements with the cerebral oxygen saturation measured from blood drawn in neonates on veno-venous ECMO with existing cephalad catheter with a prototype neonatal cerebral oximeter developed by CAS Medical Systems (Branford, CT, USA). STUDY DESIGN: After obtaining informed consent, neonates undergoing VV-ECMO with cephalad catheterization were monitored by the CAS cerebral oximeter. Cephalad blood samples were periodically obtained to validate the monitor's accuracy. RESULTS: Seventeen neonates were studied with 1718 h of cerebral oximetry data collected. Compared to the reference values, the bias+/-precision for cerebral oximetry SctO2 was 0.4+/-5.1% and derived SvO2 was 0.6+/-7.3%. CONCLUSION: We recommend the use of this noninvasive method as an alternative to blood draws for cerebral venous saturation measurements in neonates requiring extracorporeal life support.

Use of the rebreathing method in the differential diagnosis of congenital heart disease and persistent fetal circulation.

The differential diagnosis of congenital heart disease from persistent fetal circulation is clinically difficult and cardiac catheterization is often needed. The development of a safe, new technique for use of the rebreathing method has allowed the determination of effective pulmonary blood flow, lung tissue volume, lung diffusion capacity and functional residual capacity in 7 critically ill, ventilator-dependent infants at the bedside. Analysis of the data revealed highly significant differences for lung tissue volume and diffusion capacity, a minimally significant difference for effective pulmonary blood flow and no difference for functional residual capacity between the groups. Use of this method allows not only attainment of clinically useful information but also permits better insight into the pathophysiology of the disease state.

Herbaceous vegetation in the Chilean matorral : Dynamics of growth and evaluation of allelopathic effects of some dominant shrubs.

The phenology, growth, and productivity of 7 species of the understory vegetation of the matorral zone of Central Chile were studied. The activity of the herb strata lasts about 6 months, starting soon after the first rain of the season: most of their vegetative growth occurs between early June and mid-September. Experimental plots designed in the field with leaf litter of some dominant shrubs showed no indication of the presence of allelopathic compounds that inhibit either germination or growth of the annual species in the matorral.

Effect of nitric oxide and high-frequency oscillatory ventilation in meconium aspiration syndrome.

OBJECTIVE: To test the hypothesis that inhaled nitric oxide, when combined with high-frequency oscillatory ventilation, is an effective therapeutic agent in meconium aspiration syndrome. DESIGN: Prospective, interventional study. SETTING: The animal research laboratory at The Children's National Medical Center. SUBJECTS: Five newborn piglets, 1-2 wks old, weighing 3.6 +/- 0.2 kg. INTERVENTION: Animals were anesthetized, paralyzed, intubated, and ventilated. Catheters were placed in the femoral vein and artery and the pulmonary artery. After 1 hr of recovery, 10 mL/kg of 20% meconium in normal saline solution was insufflated into the lungs. Animals were ventilated with a SensorMedics oscillator to maintain arterial blood gases in a normal range (pH, 7.35-7.45; Paco2, 40-45 mm Hg [5.3-6.0 kPa]; Pao2, 70-90 mm Hg [9.3-12.0 kPa]). Ventilator settings were increased as needed until maximum settings as follows: Fio2, 1.00; proximal oscillatory pressure amplitude, 36 cm H2O; mean airway pressure, 25 cm H2O; frequency, 10 Hz. After a short period of stabilization, inhaled nitric oxide was administered. Concentrations of 40, 20, and 10 ppm were given and measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. To assure that there was no additive effect of inhaled nitric oxide, each dose was given for 20 mins followed by a 15-min normalization period at 0 ppm. MEASUREMENTS AND MAIN RESULTS: Physiologic measurements, ventilatory settings, arterial blood gases, and methemoglobin were recorded at each study period. Measurements were taken after each exposure to inhaled nitric oxide and after its discontinuation. Arterial saturation and partial pressure of arterial oxygen (Pao2) were significantly lower after meconium aspiration when compared with baseline. Administration of inhaled nitric oxide improved oxygenation without a significant decrease in pulmonary artery pressure. CONCLUSION: In this model of meconium aspiration syndrome, short-term exposure to inhaled nitric oxide when combined with high-frequency oscillatory ventilation improved oxygenation secondary to better distribution of inhaled nitric oxide. The increase in oxygenation may be secondary to improved ventilation perfusion mismatch, as the primary etiology of hypoxia in this model may be a combination of parenchymal lung disease and pulmonary hypertension.

Acute hydrocephalus after subarachnoid hemorrhage.

BACKGROUND: Acute hydrocephalus as a consequence of subarachnoid hemorrhage is a relatively frequent problem. It is associated with more neurologic impairment and mortality than subarachnoid hemorrhage without hydrocephalus. A review of the literature was done to determine its frequency of presentation, the associated causes of morbidity and mortality, its clinical presentation, and treatment options. METHODS: A search was done through the Med-Line system to obtain pertinent literature of the last 10 years. Articles before this date were obtained from references from the original search. RESULTS: Acute hydrocephalus is present in 20% of patients with subarachnoid hemorrhage. One third of them may be asymptomatic on admission; 50% of those who have clinical hydrocephalus recover spontaneously within the first 24 h. The presence of acute hydrocephalus after subarachnoid hemorrhage is associated with additional morbidity and higher mortality secondary to rebleeding, to cerebral infarction or to shunt infection. Once hydrocephalus develops, ventricular size is not related to the clinical status of the patient, nor to the associated complications. CONCLUSIONS: If a patient presents with subarachnoid hemorrhage accompanied by acute hydrocephalus and preserved level of consciousness, he/she should be carefully observed for the first 24 h. If deterioration of consciousness ensues and is not attributable to rebleeding or metabolic causes, ventriculostomy should be performed. If a patient presents with subarachnoid hemorrhage accompanied by acute hydrocephalus and depressed level of consciousness ventriculostomy should be immediately placed. After ventriculostomy, intracranial pressure should be maintained above 15 mm Hg to prevent rebleeding. Prophylactic antibiotics and long subcutaneous catheters should be used to avoid shunt infections.

Zinc protection against cadmium effect on estrual cycle of Wistar rat.

A single dose of cadmium chloride (2.2 mg/kg of body wt) increased the estrual cycle period about two times. This effect could be prevented by means of simultaneous administration of zinc at the same dose.