The metabolism of glycosaminoglycans is impaired in prion diseases

It is well established that the conversion of PrP(C) to PrP(Sc) is the key event in prion disease biology. In addition, several lines of evidence suggest that glycosaminoglycans (GAGs) and in particular heparan sulfate (HS) may play a role in the PrP(C) to PrP(Sc) conversion process. It has been proposed that PrP(Sc) accumulation in prion diseases may induce aberrant activation of lysosomal activity, which has been shown to result in neurodegeneration in a number of diseases, especially lysosomal storage disorders. Among such diseases, only the ones resulting from defects in GAGs degradation are accompanied by secretion of large amounts of GAG metabolites in urine. In this work, we show that GAGs are secreted in the urine of prion-infected animals and humans, and surprisingly, also in the urine of mice ablated for the PrP gene. We hypothesize that both the presence of PrP(Sc) or the absence of PrP(C) may alter the metabolism of GAGs.     

Neurally-mediated syncope.

"Neurally-mediated (reflex) syncope" refers to a reflex response that, when triggered, gives rise to vasodilation and/or bradycardia; however, the contribution of each of these two factors to systemic hypotension and cerebral hypoperfusion may differ considerably. The initial evaluation may lead to a certain diagnosis in the case of classical vasovagal syncope and of situational syncope. Classical vasovagal syncope is diagnosed if precipitating events such as fear, severe pain, emotional distress, instrumentation or prolonged standing, are associated with typical prodromal symptoms. Situational syncope is diagnosed if syncope occurs during or immediately after urination, defecation, cough or swallowing. In the absence of a certain diagnosis, absence of cardiac disease, long history of syncope, syncope after sudden unexpected unpleasant sight, sound or smell, prolonged standing at attention or crowded, warm places, nausea and vomiting, post-prandial and post-exercise state suggest a neurally-mediated cause which needs to be confirmed by specific tests. Among them, the most useful are carotid sinus massage and tilt testing. In general, education and reassurance are the sufficient initial treatment. Additional treatment may be necessary in high-risk or high-frequency settings. Treatment is not necessary in patients who have sustained a single syncope and are not having syncope in a high-risk setting. It is valuable to assess the relative contribution of cardioinhibition and vasodepression before embarking on treatment as there are different therapeutic strategies for the two aspects. Even if evidence of utility of such an assessment exists only for the carotid sinus massage, it is recommended to extend this assessment also by means of tilt testing or implantable loop recorder. Tilt training and isometric leg and arm counterpressure maneuvers are indicated in patients with recurrent vasovagal syncope. Cardiac pacing is indicated in patients with cardioinhibitory or mixed carotid sinus syndrome and in patients with cardioinhibitory vasovagal syncope with a frequency > 5 attacks per year or severe physical injury or accident and age > 40 years. The evidence fails to support the efficacy of any drug.     

Work-rate affects cardiopulmonary exercise test results in heart failure

AIMS: Cardiopulmonary exercise test (CPET) is used to evaluate patients with chronic heart failure (HF) usually by means of a personalized ramp exercise protocol. Our aim was to evaluate if exercise duration or ramp rate influences the results. METHODS AND RESULTS: Ninety HF patients were studied (peak V (O(2)): >20 ml/min/kg, n=28, 15-20 ml/min/kg, n=39 and <15 ml/min/kg, n=23). Each patient did four CPET studies. The initial study was used to separate the subjects into three groups, according to their exercise capacity. In the remaining studies, work-rate was increased at three different rates designed to have the subjects reach peak exercise in 5, 10 and 15 min from the start of the ramp increase in work-rate, respectively. The order was randomized. The work-rate applied for the total population averaged 22.7+/-8.0, 11.6+/-3.7, 7.5+/-2.9 W/min with effective loaded exercise duration of 5 min and 16 s+/-29 s, 9 min and 43 s+/-49 s and 14 min and 32 s+/-1 min and 12 s for the 5-, 10- and 15-min tests, respectively. Peak V (O(2)) averaged 16.9+/-4.3*, 18.0+/-4.4 and 18.0+/-5.4 ml/min/kg for the 5-, 10- and 15-min tests, (*=p<0.001 vs. 10 min). The shortest test had the lowest peak heart rate and ventilation and highest peak work-rate. Peak V (O(2)) and heart rate were lowest in 5-min tests regardless of HF severity. The DeltaV (O(2))/Deltawork-rate was lowest in 5-min tests and highest in 15-min tests. At all ramp rates, DeltaV (O(2))/Deltawork-rate was lower for the subjects with the lower peak V (O(2)). The V (e)/V (CO(2)) slope and V (O(2)) at anaerobic threshold were not affected by the protocol for any grade of HF. CONCLUSIONS: In chronic HF, exercise protocol has a small effect on peak V (O(2)) and DeltaV (O(2))/Deltawork but does not affect V (O(2)) at anaerobic threshold and V (e)/V (CO(2)) slope.     

Aerosol deposition in neonatal ventilation

Lung deposition of inhaled drugs in ventilated neonates has been studied in models of questionable relevance. With conventional nebulizers, pulmonary deposition has been limited to 1% of the total dose. The objective of this study was to assess lung delivery of aerosols in a model of neonatal ventilation using a conventional and novel electronic micropump nebulizer. Aerosol deposition studies with 99mTc diethylenetriamine pentaacetate (99mTc-DTPA) were performed in four macaques (2.6 kg) that were ventilated through a 3.0-mm endotracheal tube (with neonatal settings (peak inspiratory pressure 12-14 mbar, positive end-expiratory pressure 2 mbar, I/E ratio 1/2, respiratory rate 40/min), comparing a jet-nebulizer MistyNeb (3-mL charge, 4.8 microm), an electronic micropump nebulizer operating continuously [Aeroneb Professional Nebulizer (APN-C); 0.5-mL charge, 4.6 microm], and another synchronized with inspiration [Aeroneb Professional Nebulizer Synchronized (APN-S); 0.5-mL charge, 2.8 microm]. The amount of radioactivity deposited into lungs and connections and remaining in the nebulizer was measured by a gamma counter. Despite similar amounts of 99mTc-DTPA in the respiratory circuit with all nebulizers, both APN-S and APN-C delivered more drug to the lungs than MistyNeb (14.0, 12.6, and 0.5% in terms of percentage of nebulizer charge, respectively; p = 0.006). Duration of delivery was shorter with APN-C than with the two other nebulizers (2 versus 6 and 10 min for the APN-S and the MistyNeb, respectively; p < 0.001). Electronic micropump nebulizers are more efficient to administer aerosols in an animal model of ventilated neonates. Availability of Aerogen's electronic micropump nebulizers offers new opportunities to study clinical efficacy and risks of aerosol therapy in ventilated neonates.     

Pyomyositis: a fatal case in a healthy teenager

Pyomyositis is a common disease in the tropics that is reported with increasing frequency in the United States. We describe an unusually fulminant, fatal case in a previously healthy adolescent male. This case illustrates the clinical progression of pyomyositis from localized muscle infection to disseminated disease, and highlights the importance of considering this rare diagnosis in any stage of occult sepsis.     

Acculturation as a predictor of the onset of sexual intercourse among Hispanic and white teens

OBJECTIVE: To investigate ethnic differences in onset of sexual intercourse among Hispanic/Mexican American and white adolescents based on acculturation. DESIGN/METHODS: Preprogram survey data from 7270 Hispanic or white teens in 7th to 12th grade involved in the Arizona Abstinence-Only Education Program were used to predict the probability of onset of sexual intercourse based on age, sex, family structure, program location, religiosity, free school lunch, grades, rural residence, acculturation, and ethnicity. Specific attention was given to the influence of acculturation among Hispanic teens. The primary language spoken by the respondents (English, Spanish, or both) was used as a proxy measure for acculturation. RESULTS: Hispanic youth were at a greater risk for experiencing onset of intercourse than white youth, while controlling for all other predictors (odds ratio [OR], 1.40 [95% confidence interval (CI), 1.21-1.63]). This risk was amplified for highly acculturated Hispanic teens (OR, 1.69 [95% CI, 1.43-1.99]). However, less acculturated Hispanic youth were actually less likely to have experienced first intercourse than white youth (OR, 0.59 [95% CI, 0.42-0.82]), English-speaking Hispanic youth (OR, 0.35 [95% CI, 0.25-0.49]), or bilingual Hispanic youth (OR, 0.45 [95% CI, 0.31-0.64]). CONCLUSIONS: Low acculturation emerges as a significant protective factor while controlling for other social and cultural factors, in spite of the increased risk of initiating sexual intercourse for Hispanic teens overall. Hispanic Spanish speakers were least likely to have initiated intercourse, while Hispanic English speakers were the most likely.     

Evaluation of a novel method for grading heart murmur intensity

OBJECTIVE: To determine if heart murmur intensity grading performance can be improved using the heart sounds as an internal reference. METHODS: Single-blind controlled trial of 100 medical students, residents, and pediatric attending physicians at a children's hospital. Groups of 1 to 3 participants were alternately assigned to intervention and control groups, reported their method of grading heart murmur intensity, and then graded the intensity of a random sample of 20 recorded murmurs on a 6-point scale. Before rating another random sample of 20 murmurs, the intervention group was taught a system that uses the heart sounds as an internal reference. Primary outcomes were change in accuracy (percentage correct), interrater agreement (kappa), and consistency (kappa). Subgroup analyses were performed by training level and heart murmur grade. RESULTS: Grading accuracy improved more in the intervention group than the control group (Delta improvement, 5%; 95% confidence interval [CI], -0.1%-10.0%]). This was most pronounced among attending physicians (Delta improvement, 11%; 95% CI, 0.4%-22%) and students (Delta improvement, 12%; 95% CI, 3%-20%) and for grade 2 murmurs (Delta improvement, 20%; 95% CI, 10%-31%). Relatively greater improvements in consistency were observed after the intervention for attending physicians (Delta improvement, 0.17; 95% CI, 0.01-0.32) and grades 2 (Delta improvement, 0.22; 95% CI, 0.09-0.36) and 3 murmurs (Delta improvement, 0.16; 95% CI, 0.05-0.28). CONCLUSIONS: A system that uses the heart sounds as an internal reference for grading heart murmur intensity quickly improves accuracy and consistency for some providers and specific murmurs.     

Adoptive transfer of T cells modified with a humanized chimeric receptor gene inhibits growth of Lewis-Y-expressing tumors in mice

In this study, human T cells were provided with a reactivity against the Lewis-Y (Le(Y)) carbohydrate antigen, which is overexpressed on 70% of epithelial-derived tumors, but not normally recognized by T cells. Antitumor reactivity was achieved by transduction of T cells with a gene encoding a cell-surface chimeric receptor composed of single-chain anti-Le(Y) antibody linked to an enhanced cytoplasmic signaling domain made up of CD28 and CD3-zeta. Importantly, the single-chain antibody was humanized to try to reduce potential problems of human anti-mouse antibody responses in patients receiving chimeric receptor-modified T cells in future clinical trials. T cells expressing the chimeric receptor were demonstrated to secrete cytokines and proliferate in response to receptor ligation and lysed Le(Y+) tumors in vitro. Another aspect of this study was the finding that no activity was observed against normal tissue, as represented by autologous neutrophils that express low levels of Le(Y). Significantly, systemic delivery of anti-Le(Y) T cells dramatically inhibited established s.c. human ovarian OVCAR-3 tumors (a recognized difficult model to treat) in mice. Finally, we demonstrated that anti-Le(Y) T cells preferentially expanded or accumulated in the tumor compared with control empty vector T cells, thereby providing mechanistic insight into the specific antitumor response. This study supports the use of humanized gene-modified T cells as a potential therapy for Le(Y+) malignancies.