Longitudinal Cognitive Changes in Genetic Frontotemporal Dementia Within the GENFI Cohort.
Disease-modifying therapeutic trials for genetic frontotemporal dementia (FTD) are underway, but sensitive cognitive outcome measures are lacking. The aim of this study was to identify such cognitive tests in early stage FTD by investigating cognitive decline in a large cohort of genetic FTD pathogenic variant carriers and by investigating whether gene-specific differences are moderated by disease stage (asymptomatic, prodromal, and symptomatic). C9orf72, GRN, and MAPT pathogenic variant carriers as well as controls underwent a yearly neuropsychological assessment covering 8 cognitive domains as part of the Genetic FTD Initiative, a prospective multicenter cohort study. Pathogenic variant carriers were stratified according to disease stage using the global Clinical Dementia Rating (CDR) plus National Alzheimer's Coordinating Center (NACC) FTLD score (0, 0.5, or ≥1). Linear mixed-effects models were used to investigate differences between genetic groups and disease stages as well as the 3-way interaction between time, genetic group, and disease stage. A total of 207 C9orf72, 206 GRN, and 86 MAPT pathogenic variant carriers and 255 controls were included. C9orf72 pathogenic variant carriers performed lower on attention, executive function, and verbal fluency from CDR plus NACC FTLD 0 onwards, with relatively minimal decline over time regardless of the CDR plus NACC FTLD score (i.e., disease progression). The cognitive profile in MAPT pathogenic variant carriers was characterized by lower memory performance at CDR plus NACC FTLD 0.5, with decline over time in language from the CDR plus NACC FTLD 0.5 stage onwards, and executive dysfunction rapidly developing at CDR plus NACC FTLD ≥1. GRN pathogenic variant carriers declined on verbal fluency and visuoconstruction in the CDR plus NACC FTLD 0.5 stage, with progressive decline in other cognitive domains starting at CDR plus NACC FTLD ≥1. We confirmed cognitive decline in the asymptomatic and prodromal stage of genetic FTD. Specifically, tests for attention, executive function, language, and memory showed clear differences between genetic groups and controls at baseline, but the speed of change over time differed depending on genetic group and disease stage. This confirms the value of neuropsychological assessment in tracking clinical onset and progression and could inform clinical trials in selecting sensitive end points for measuring treatment effects as well as characterizing the best time window for starting treatment.


Association of polypharmacy with fall risk among geriatric outpatients.
To investigate the association of fall risk with comorbidities and medications in geriatric outpatients in a cross-sectional design. A total of 262 outpatients (84 men and 178 women, mean age 76.2±6.8years) were evaluated. Physical examination, clinical histories and medication profile were obtained from each patient. History of falls in the past year, 22-item fall risk index, 13-point simple screening test for fall, and time interval of one-leg standing test were examined as markers of fall risk. On univariate analysis, older age, female sex, hypertension, osteoporosis, history of stroke, number of comorbidities, use of antihypertensives, aspirin, bisphosphonates, hypnotics and number of prescribed drugs were significantly associated with either of four indices. On multiple regression analysis, the number of drugs was associated with all of the four indices, independent of other factors associated in the univariate analysis. The association of number of drugs with fall risk indices was stepwise. In geriatric outpatients, polypharmacy rather than number of comorbidities was associated with fall risk. Prospective and intervention studies are needed to clarify the causal relationship between polypharmacy, comorbidities and fall risk.


Laser confocal microscopy analysis of human interphase nuclei by three-dimensional FISH reveals dynamic perinucleolar clustering of telomeres.
Nuclear functions are strongly dependent on the three-dimensional organization of the interphase nucleus. Given the importance of telomeres in the behaviour and stability of chromosomes, we have investigated the architecture of the human nucleus from the telomere perspective by 3D-FISH and laser confocal microscopy. We observed a randomly scattered telomere distribution in all confocal sections of the interphase nuclear volume with various levels of telomere clustering in different cell types. This distribution is independent of H2AX presence or phosphorylation status. We also observed that telomeres usually cluster at the periphery of the nucleolus following its cell cycle dependent dynamic formation but are never present in the interior of the nucleolus. These perinucleolar telomeric clusters contain the telomeres of the short arms of acrocentric chromosomes, explaining the p-arm association of acrocentric chromosomes frequently found in metaphase. Thus, chromosome positioning in metaphase spreads is tightly connected to the three-dimensional architecture of the interphase nucleus.


Perspectives on care for young adults with type 1 diabetes transitioning from pediatric to adult health systems: A national survey of pediatric endocrinologists.
Healthcare transition from pediatric to adult care for young adults (YA) with type 1 diabetes (T1D) is associated with risk of adverse outcomes. Consensus recommendations exist from US professional societies on transition care for YA with T1D, but it is not known whether they have been widely adopted. We describe experiences, barriers, and provider characteristics associated with transition care in a national sample of pediatric endocrinologists. US pediatric endocrinologists identified through the American Medical Association Physician Masterfile were sent an electronic survey. Response rate was 16% (164/1020) representing 32 states. The majority of pediatric endocrinologists (age 44 ± 10; years in practice 12 ± 11) were female (67%) and worked in academic centers (75%). Main reasons for transfer were age (49%) and glycemic control (18%). Barriers to transition included ending long-therapeutic relationships with patients (74%), lack of transition protocols (46%), and perceived deficiencies in adult care (42%). The majority of pediatric endocrinologists reported lack of transition training (68%); those who received training were less likely to have difficulty ending patient relationships [odds ratio (OR) = 0.39, P = .03], more likely to perform patient record transfer to adult systems (OR=1.27, P = .006), and less likely to report patient returns to pediatric care after transfer (OR=0.49, P = .01), independent of endocrinologist gender, years in practice, or practice type. There is wide variation in transition care for YA with T1D among US pediatric endocrinologists despite consensus recommendations. Dissemination of educational programming on transition care and provision of actionable solutions to overcome local health system and perceived barriers is needed.


Impact of spiking neurons leakages and network recurrences on event-based spatio-temporal pattern recognition.
Spiking neural networks coupled with neuromorphic hardware and event-based sensors are getting increased interest for low-latency and low-power inference at the edge. However, multiple spiking neuron models have been proposed in the literature with different levels of biological plausibility and different computational features and complexities. Consequently, there is a need to define the right level of abstraction from biology in order to get the best performance in accurate, efficient and fast inference in neuromorphic hardware. In this context, we explore the impact of synaptic and membrane leakages in spiking neurons. We confront three neural models with different computational complexities using feedforward and recurrent topologies for event-based visual and auditory pattern recognition. Our results showed that, in terms of accuracy, leakages are important when there are both temporal information in the data and explicit recurrence in the network. Additionally, leakages do not necessarily increase the sparsity of spikes flowing in the network. We also investigated the impact of heterogeneity in the time constant of leakages. The results showed a slight improvement in accuracy when using data with a rich temporal structure, thereby validating similar findings obtained in previous studies. These results advance our understanding of the computational role of the neural leakages and network recurrences, and provide valuable insights for the design of compact and energy-efficient neuromorphic hardware for embedded systems.


Three-dimensional assessment of ultrasound features in women with clomiphene citrate-resistant polycystic ovarian syndrome (PCOS): ovarian stromal volume does not correlate with biochemical indices.
Polycystic ovarian syndrome (PCOS) is a heterogeneous endocrine disorder affecting women of reproductive age. The syndrome is characterized by a combination of polycystic ovarian morphology, clinical features and biochemical indices. The objective of this prospective observational study was to investigate the relationship between the total ovarian volume and the ovarian stromal volume, measured using a three-dimensional (3D) ultrasound scan, with biochemical indices of PCOS. Twenty-three infertile women (mean age +/- SD: 31 +/- 3.1 years; range: 26-37) with clomiphene citrate-resistant PCOS were examined. Early follicular phase (days 2-4) serum FSH, LH and testosterone concentrations were measured following a withdrawal bleed. Total ovarian volume, stromal volume, pre-antral follicle (<10 mm) number and total follicular volume were measured by 3D transvaginal ultrasound. Total ovarian volume, follicular volume and follicle number correlated positively with serum FSH and LH, but not testosterone, concentrations. Ovarian stromal volume correlated strongly with total ovarian volume only, but not with serum FSH, LH or testosterone concentrations. These findings demonstrate an association of the total ovarian volume, pre-antral follicle number and total follicular volume with some of the biochemical indices of PCOS, but no association was observed between ovarian stromal volume and these indices.


Dealing With Patient Death on International Health Electives: A Qualitative Study of Residents' Experiences.
International health electives (IHEs) provide numerous educational benefits; potential harms are less well understood. One potential harm is trainee distress associated with increased patient death during IHEs. The purpose of this study was to explore residents' and fellows' IHE experiences with patient death. The authors used applied thematic analysis to explore residents' and fellows' IHE experiences with patient death. The Mayo International Health Program supports IHEs from all specialties across three Mayo Clinic sites. Data were collected and analyzed in two steps. First the authors collected, coded, and analyzed narrative reflections from 43 postrotation reports gathered in 2001-2017 and identified themes relating to experiences with patient death. Second, in 2016-2017 the authors conducted semistructured interviews with six previous participants to refine thematic analysis. Participants described impacts of experiencing increased patient death and identified themes in two domains: difficult experiences with patient death and potential interventions to help residents process their experiences. They identified four themes illustrating why these experiences were difficult: lack of preparation for increased exposure to death, lack of closure, consequences of limited resources, and differences in cultural beliefs regarding death. While pretrip preparation for dealing with death was viewed as important, trainees identified support during and debriefing after IHEs as additional important interventions. Given the popularity of IHEs, residency programs should consider the effect on trainees of increased exposure to patient death. Study findings can inform IHE preparation, support, and debriefing to minimize distress associated with witnessing patient deaths on IHEs.


A randomized, controlled trial to increase discussion of breast cancer in primary care.
Assessment and discussion of individual risk for breast cancer within the primary care setting are crucial to discussion of risk reduction and timely referral. We conducted a randomized controlled trial of a multiethnic, multilingual sample of women ages 40 to 74 years from two primary care practices (one academic, one safety net) to test a breast cancer risk assessment and education intervention. Patients were randomly assigned to control or intervention group. All patients completed a baseline telephone survey and risk assessment (via telephone for controls, via tablet computer in clinic waiting room before visit for intervention). Intervention (BreastCARE) patients and their physicians received an individualized risk report to discuss during the visit. One-week follow-up telephone surveys with all patients assessed patient-physician discussion of family cancer history, personal breast cancer risk, high-risk clinics, and genetic counseling/testing. A total of 655 control and 580 intervention women completed the risk assessment and follow-up interview; 25% were high-risk by family history, Gail, or Breast Cancer Surveillance Consortium risk models. BreastCARE increased discussions of family cancer history [OR, 1.54; 95% confidence interval (CI), 1.25-1.91], personal breast cancer risk (OR, 4.15; 95% CI, 3.02-5.70), high-risk clinics (OR, 3.84; 95% CI, 2.13-6.95), and genetic counseling/testing (OR, 2.22; 95% CI, 1.34-3.68). Among high-risk women, all intervention effects were stronger. An intervention combining an easy-to-use, quick risk assessment tool with patient-centered risk reports at the point of care can successfully promote discussion of breast cancer risk reduction between patients and primary care physicians, particularly for high-risk women. Next steps include scaling and dissemination of BreastCARE with integration into electronic medical record systems.


Comparative study of human mitochondrial proteome reveals extensive protein subcellular relocalization after gene duplications.
Gene and genome duplication is the principle creative force in evolution. Recently, protein subcellular relocalization, or neolocalization was proposed as one of the mechanisms responsible for the retention of duplicated genes. This hypothesis received support from the analysis of yeast genomes, but has not been tested thoroughly on animal genomes. In order to evaluate the importance of subcellular relocalizations for retention of duplicated genes in animal genomes, we systematically analyzed nuclear encoded mitochondrial proteins in the human genome by reconstructing phylogenies of mitochondrial multigene families. The 456 human mitochondrial proteins selected for this study were clustered into 305 gene families including 92 multigene families. Among the multigene families, 59 (64%) consisted of both mitochondrial and cytosolic (non-mitochondrial) proteins (mt-cy families) while the remaining 33 (36%) were composed of mitochondrial proteins (mt-mt families). Phylogenetic analyses of mt-cy families revealed three different scenarios of their neolocalization following gene duplication: 1) relocalization from mitochondria to cytosol, 2) from cytosol to mitochondria and 3) multiple subcellular relocalizations. The neolocalizations were most commonly enabled by the gain or loss of N-terminal mitochondrial targeting signals. The majority of detected subcellular relocalization events occurred early in animal evolution, preceding the evolution of tetrapods. Mt-mt protein families showed a somewhat different pattern, where gene duplication occurred more evenly in time. However, for both types of protein families, most duplication events appear to roughly coincide with two rounds of genome duplications early in vertebrate evolution. Finally, we evaluated the effects of inaccurate and incomplete annotation of mitochondrial proteins and found that our conclusion of the importance of subcellular relocalization after gene duplication on the genomic scale was robust to potential gene misannotation. Our results suggest that protein subcellular relocalization is an important mechanism for the retention and gain of function of duplicated genes in animal genome evolution.


Approaching the Ocean Color problem using fuzzy rules.
In this paper, we propose a fuzzy logic-based approach which exploits remotely sensed multispectral measurements of the reflected sunlight to estimate the concentration of optically active constituents of the sea water. The relation between the concentrations of interest and the subsurface reflectances is modeled by a set of fuzzy rules extracted automatically from the data through a two-step procedure. First, a compact initial rule base is generated by projecting onto the input variables the clusters produced by a fuzzy clustering algorithm. Then, a genetic algorithm is applied to optimize the rules. Appropriate constraints maintain the semantic properties of the initial model during the genetic evolution. Results of the application of the fuzzy model obtained from data simulated with an ocean color model over the channels of the Medium Resolution Imaging Spectrometer are shown and discussed.


Calcium-channel blockers and advanced cardiac life support.
Calcium channel-blocking drugs have potent antiarrhythmic and antianginal effects and in addition may reduce the extent of cellular injury after anoxia/ischemia. Verapamil is the treatment of choice (90% effective) for uncomplicated episodes of paroxysmal supraventricular tachycardia. All three calcium-channel blockers available, diltiazem, nifedipine, and verapamil, can reduce the frequency of angina occurring both at rest and with exertion. Calcium may mediate several cytotoxic events during the reperfusion period after prolonged ischemia that lead to irreversible cell injury. There is experimental evidence that calcium-channel blockers may reduce the cellular influx of calcium after ischemia and reperfusion, and thereby attenuate cerebral and myocardial injury, although most studies have failed to show benefit of treatment unless the drug is administered before the onset of ischemia. Most trials using calcium-channel blockers in the setting of acute myocardial infarction have failed to show a benefit of treatment. The safety and efficacy of calcium-channel blockers have yet to be shown in controlled studies of human resuscitation, although the potential for such treatment, if it is effective in attenuating myocardial cerebral cellular injury, could be enormous.


[Photocoagulation in diabetic rubeosis iridis and neovascular glaucoma].
This retrospective study was performed to examine the effect of retinal coagulation on the course of iris neovascularization and neovascular glaucoma in patients with diabetic retinopathy. Sixty-four eyes in 42 patients were examined. Following retinal coagulation iris neovascularization regressed in 47 eyes (73%), while 17 eyes (27%) showed no improvement. In eyes with neovascular glaucoma, a drop in intraocular pressure was noted. Visual acuity decreased in 60% of the treated eyes. Regression of iris neovascularization was related to the number of burns applied.


Distinct mechanisms for the upconversion of NaYF4:Yb3+,Er3+ nanoparticles revealed by stimulated emission depletion.
Upconversion nanoparticles (UCNPs) have attracted enormous interest over the past few years because of their unique optical properties and potential for use in various applications such as bioimaging probes, biosensors, and light-harvesting materials for photovoltaics. The improvement of imaging resolution is one of the most important goals for UCNPs used in biological applications. Super-resolution imaging techniques that overcome the fundamental diffraction limit of light rely on the photochemistry of organic dyes or fluorescent proteins. Here we report our progress toward super-resolution microscopy with UCNPs. We found that the red emission (655 nm) of core/shell UCNPs with the structure NaYF4:Yb3+,Er3+/NaYF4 could be modulated by emission depletion (ED) of the intermediate state that interacts resonantly with an infrared beam (1540 nm). In contrast, the green emission bands (525 and 545 nm) of the UCNPs were less affected by irradiation with the infrared beam. The origin of such distinct behaviors between the green and red emissions was attributed to their different photophysical pathways.


Psychiatric emergencies in a Nigerian general hospital.
Subjects attending the emergency services of the Ibadan teaching hospital for psychological problems in a 14-month period were studied, with a view to highlighting the pattern of psychiatric emergencies in a large general hospital. Three hundred and twenty-six subjects made 335 emergency visits. The 181 new cases seen at the Casualty constituted 2% of the newly registered patients attending that unit of the hospital. About 7% of the subjects attended for deliberate self-harm, while 45.7% and 20.9% of the visits were for functional psychotic and non-psychotic illnesses respectively. Cases with acute undifferentiated psychosis of suspected organic aetiology constituted 13.7% of the visits. About 5% of the visits were for substance abuse problems, 6.3% for extrapyramidal reaction to anti-psychotic drugs, while 5.7% were cases of other forms of organic psychotic conditions. In only 19.5% of the visits requiring admission could the subjects be admitted because of scarcity of in-patient beds.


Baseline and Dynamic Expression of Activating NK Cell Receptors in the Control of Chronic Viral Infections: The Paradigm of HIV-1 and HCV.
Natural killer (NK) cell function is regulated by a balance between the triggering of activating and inhibitory receptors expressed on their surface. A relevant effort has been focused so far on the study of KIR carriage/expression setting the basis for NK cell education and self-tolerance. Focus on the evolution and regulation of activating NK receptors has lagged behind so far. Our understanding of activating receptor expression and regulation has recently improved by evidences derived from in vitro and in vivo studies. Virus infection - either acute or chronic - determines preferential expansion of NK cells with specific phenotype, activating receptors, and with recall-like functional activity. Studies on patients with viral infection (HIV and HCV) and specific diverging clinical courses confirm that inter-individual differences may exist in baseline expression of natural cytotoxicity receptors (NKp46 and NKp30). The findings that patients with divergent clinical courses have different kinetics of activating receptor density expression upon NK cell activation in vitro provide an additional, time-dependent, functional parameter. Kinetic changes in receptor expression thus represent an additional parameter to basal receptor density expression. Different expression and inducibilities of activating receptors on NK cells contribute to the high diversity of NK cell populations and may help our understanding of the inter-individual differences in innate responses that underlie divergent disease courses.


Inhibition of hepatic deoxyribonucleic acid-dependent ribonucleic acid polymerases by the exotoxin of Bacillus thuringiensis in comparison with the effects of -amanitin and cordycepin.
The action of Bacillus thuringiensis exotoxin, a structural analogue of ATP, on mouse liver DNA-dependent RNA polymerases was studied and its effects were compared with those of alpha-amanitin and cordycepin. (1) Administration of exotoxin in vivo caused a marked decrease in RNA polymerase activity of isolated nuclei at various concentrations of Mg(2+), Mn(2+) and (NH(4))(2)SO(4). A similar action was recorded after addition of exotoxin to isolated nuclei from control or exotoxin-treated mice. (2) Chromatographic separation of nuclear RNA polymerases from mice treated in vivo with exotoxin showed a drastic decrease of the peak of nucleoplasmic RNA polymerase, whereas the peak of nucleolar RNA polymerase remained unaltered. The same effect was observed after administration of alpha-amanitin in vivo, but cordycepin did not alter the relative amounts of the two main RNA polymerase peaks. (3) Administration of exotoxin in vivo did not alter the template activity of isolated DNA or chromatin tested with different fractions of RNA polymerase from control or exotoxin-treated mice. (4) Addition of exotoxin to isolated liver RNA polymerases inhibited both enzyme fractions. However, the alpha-amanitin-sensitive RNA polymerase was also 50-100-fold more sensitive to exotoxin inhibition than was the alpha-amanitin-insensitive RNA polymerase. Kinetic analysis indicated the exotoxin produces a competitive inhibition with ATP on the nucleolar enzyme, but a mixed type of inhibition with nucleoplasmic enzyme. The results obtained indicate that the B. thuringiensis exotoxin inhibits liver RNA synthesis by affecting nuclear RNA polymerases, showing a preferential inhibition of the nucleoplasmic alpha-amanitin-sensitive RNA polymerase.


Aerosolized endothelin-1, but not its C-terminal hexapeptide, causes airway narrowing in the rat.
We investigated the effects of aerosolized endothelin-1 (ET-1) and of its C-terminal hexapeptide, ET-(16-21), on the pulmonary mechanics of anaesthetized spontaneously-breathing rats. ET-1 inhalation caused a concentration-dependent increase in pulmonary resistance (RL) and decrease in dynamic lung compliance (Cdyn). In control conditions RL and Cdyn were 0.17 +/- 0.04 cmH2O.ml-1.s (mean +/- SE; n = 6) and 6.25 +/- 0.66 ml.cmH2O.1. respectively. After ET-1 4 x 10(-5) M RL and Cdyn averaged 1.45 +/- 0.28 cmH2O.ml-1.s (p less than 0.05) and 1.12 +/- 0.36 ml.cmH2O-1 (p less than 0.05), respectively. The pulmonary responses to ET-1 lasted up to 60 min. By contrast, ET-(16-21) inhaled up to a concentration of 10(-3) M did not affect pulmonary mechanics. These results indicate that the bronchoconstrictor activity of aerosolized endothelin-1 in the rat is not dependent on its C-terminal sequence, and suggests a role for endothelin-1 in the regulation of airway calibre.


Compensatory Changes in Parenchymal Mass and Function after Radical Nephrectomy.
Loss of renal function remains a major limitation of radical nephrectomy. The extent of renal functional compensation by the preserved kidney after radical nephrectomy has not been adequately studied in this elderly population with comorbidities. A total of 273 patients treated with radical nephrectomy without end stage renal disease with available preoperative nuclear renal scans were included in the analysis. Renal functional compensation was defined as percent change in estimated glomerular filtration rate of the preserved kidney after radical nephrectomy. Estimated glomerular filtration rate was calculated by the Chronic Kidney Disease-Epidemiology Collaboration formula up to 5 years postoperatively. Preoperative/postoperative parenchymal volumes of the preserved kidney were measured from cross-sectional imaging. Multiple regression was used to identify predictive factors for renal functional compensation. Median age was 67 years and 67% of the patients were male. Overall 70% had hypertension, 26% diabetes and 37% preexisting chronic kidney disease. Locally advanced (T3a or greater) tumors were found in 53% of cases. Renal functional compensation was observed at 2 weeks (median 10%) and increased during the first 3 months (median 26%) after radical nephrectomy. Functional stability was then observed to 5 years. Renal parenchymal volume increased a median of 10% at 3 to 12 months but in addition, the functional efficiency per unit of parenchymal volume also increased 8% (estimated glomerular filtration rate units/cm3 of parenchyma was 0.236 postoperatively vs 0.208 preoperatively, p=0.004). Age (-0.85, p <0.01), global preoperative estimated glomerular filtration rate (-0.28, p <0.01) and split renal function of the removed kidney (0.61, p <0.01) were independent predictors of renal functional compensation. Percent renal functional compensation after radical nephrectomy is greater in younger patients, when preoperative estimated glomerular filtration rate is lower and when the removed kidney has more robust function. Increases in measurable parenchymal mass and functional efficiency contribute substantially to renal functional compensation.


Difference between the Right and Left Phrenic Nerve Conduction Times, Latency, and Amplitude.
We studied phrenic nerve conduction times in 90 phrenic nerves of 45 normal subjects. The phrenic nerve was stimulated at the posterior border of the sternomastoid muscle in the supraclavicular fossa, just above the clavicle, with bipolar surface electrodes. For recording, positive and negative electrodes were placed on the xiphoid process and at the eighth intercostal bone-cartilage transition, respectively. We studied both the right and left sides to determine whether there was any difference between the two sides. The mean onset latency (± SD) of the right compound muscle action potentials (CMAPs) (5.99±0.39 msec) was significantly shorter than that of the left CMAPs (6.45±0.50 msec). The mean peak latency was significantly shorter in the right CMAPs (10.22±1.33 msec) than the left CMAPs (12.48±2.02 msec). The mean (± SD) amplitude was significantly lower in the left CMAPs (0.42±0.11 mV) than the right CMAPs (0.49±0.10 mV). The difference between the length of the nerve on the right and left sides might have affected the difference in latency between the two sides.


Antibiotics and the ribosome.
The ribosome is one of the main antibiotic targets in the cell. Recent years brought important insights into the mode of interaction of antibiotics with the ribosome and mechanisms of antibiotic action. Ribosome crystallography provided a detailed view of the interactions between antibiotics and rRNA. Advances in biochemical techniques let us better understand how the binding of small organic molecules can interfere with functions of an enzyme four orders of magnitude larger than the inhibitor. These and other achievements paved the way for the development of new ribosome-targeting antibiotics, some of which have already entered medical practice. The recent progress, problems and new directions of research of ribosome-targeting antibiotics are discussed in this review.


Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.
Heterologous prime/boost regimens have the potential for raising high levels of immune responses. Here, we report that DNA priming followed by a recombinant modified vaccinia Ankara (rMVA) booster has controlled a highly pathogenic immunodeficiency virus challenge in a Rhesus macaque model. Both the DNA and rMVA components of the vaccine expressed multiple immunodeficiency virus proteins. Two DNA inoculations at 0 and 8 weeks and a single rMVA booster at 24 weeks effectively controlled an intrarectal challenge administered 7 months after the booster. These highly promising findings provide hope that a relatively simple multiprotein DNA/MVA vaccine can help to control the AIDS epidemic.


Correlation between Breast Arterial Calcification and the 10-year fatal cardiovascular risk by means of the SCORE Risk System.
The aim of this study was to investigate the relationship between Breast Arterial Calcification (BAC) on mammography and the 10-year fatal Cardiovascular Disease (CVD) risk by using SCORE risk system. The study was conducted from September 2013 to July 2014. A total of 66 women with BAC and 66 age-matched controls without BAC were analyzed. The groups were compared with respect to demographics, clinical, reproductive, laboratory parameters, and 10-year fatal CVD risk. The mean ages of the women in the study was 54.0 years (40-85 years). Hypertension, systolic blood pressure, levels of serum total cholesterol and the calculated SCORE risk were higher in the BAC (+) group than in the BAC (-) group (p=0.04, p=0.031, p=0.046, and p=0.038 respectively). Multivariate analysis showed that none of them was independent factor of BAC on mammograms, only the 10-year fatal CVD risk was close to being statistically significant (OR:1.17, CI:0.98-1.38, p=0.06). BAC on mammography was found to be related to the 10-year fatal CVD risk as calculated by the SCORE risk score system. Additional large-scale prospective studies are required to further assess whether BAC can be considered a useful screening tool for CVD risk prediction in women who screened for breast cancer by mammography.


The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs.
For the purposes of drug approval, the interchangeability of a generic drug and the corresponding brand-name drug is based on the criterion of "essential similarity," which requires that the generic drug have the same amount and type of active principle, the same route of administration, and the same therapeutic effectiveness as the original drug, as demonstrated by a bioequivalence study. However, bioequivalence and therapeutic effectiveness are not necessarily the same. This review summarizes available data comparing the bioequivalence and therapeutic efficacy of brand-name psychoactive drugs with those of the corresponding generic products. Relevant information was identified through searches of MEDLINE, Current Contents/Clinical Medicine, and EMBASE for English-language articles and English abstracts of articles in other languages published between 1975 and the present. The search terms used were generic drug, branded drug, safety, toxicity, adverse events, clinical efficacy, bioequivalence, bioavailability, psychoactive drugs, and excipients. Few publications compared the bioequivalence and efficacy of brand-name and generic psychoactive drugs. Those that were identified revealed differences in the efficacy and tolerability of brand-name and generic psychoactive drugs that had not been noted in the original bioequivalence studies. Specifically, l study found that plasma levels of phenytoin were 31% lower after a switch from a brand-name to a generic product. Several controlled studies of carbamazepine showed a recurrence of convulsions after the shift to a generic formulation. After a sudden recurrence of seizures when generic valproic acid was substituted for the brand-name product, an investigation by the US Food and Drug Administration found a difference in bioavailability between the 2 formulations. Statistically significant differences in pharmacokinetic variables have been reported in favor of brand-name versus generic diazepam (P < 0.001). Finally, a case report involving paroxetine mesylate cast doubt on the tolerability and efficacy of the generic formulation. The essential-similarity requirement should be extended to include more rigorous analyses of tolerability and efficacy in actual patients as well as in healthy subjects.


[THE INFLUENCE OF GLUTEN ON THE SHARPNESS OF VISION].
An eighty five old male was diagnosed with celiac disease. Six months before the diagnosis he complained of difficulties in his sight. In an optimetrical examination a decline in sharpness of sight was found: Right (R) - 6/19, Left (L) - 6/12. Following a few months of a gluten-free diet his situation improved and the signs of celiac disease disappeared. The sharpness of sight was re-examined and good improvement was found: L - 6/9, R - 6/12. This means that gluten might influence the sharpness of sight.


An analysis of caring.
Although 'caring' is now commonly discussed in nursing, the literature appears divided about the 'caring' concept. Some think it is at the centre of nursing and should therefore become part of nursing's paradigm. Others argue that although nursing is one form of caring, caring is not unique to nursing, so nursing cannot lay claim to being the form of caring. This paper aims to understand more fully what the concept 'caring' is, before any meaningful conclusions can be drawn about such a polarized debate. In order to achieve this aim, Wilson's 3rd step of concept analysis, as discussed by Walker and Avant, will be used to clarify the 'caring' concept. This requires the identification of all uses of the concept that can be discovered. Eight uses of the concept 'caring' found in the nursing literature will be discussed. These are: ethics; instrumental and affective; traits; patients' and nurses' perceptions of caring; holism: humanism; organizational; and quality.


Rootless tephra stratigraphy and emplacement processes.
Volcanic rootless cones are the products of thermohydraulic explosions involving rapid heat transfer from active lava (fuel) to external sources of water (coolant). Rootless eruptions are attributed to molten fuel-coolant interactions (MFCIs), but previous studies have not performed systematic investigations of rootless tephrostratigraphy and grain-size distributions to establish a baseline for evaluating relationships between environmental factors, MFCI efficiency, fragmentation, and patterns of tephra dispersal. This study examines a 13.55-m-thick vertical section through an archetypal rootless tephra sequence, which includes a rhythmic succession of 28 bed pairs. Each bed pair is interpreted to be the result of a discrete explosion cycle, with fine-grained basal material emplaced dominantly as tephra fall during an energetic opening phase, followed by the deposition of coarser-grained material mainly as ballistic ejecta during a weaker coda phase. Nine additional layers are interleaved throughout the stratigraphy and are interpreted to be dilute pyroclastic density current (PDC) deposits. Overall, the stratigraphy divides into four units: unit 1 contains the largest number of sediment-rich PDC deposits, units 2 and 3 are dominated by a rhythmic succession of bed pairs, and unit 4 includes welded layers. This pattern is consistent with a general decrease in MFCI efficiency due to the depletion of locally available coolant (i.e., groundwater or wet sediments). Changing conduit/vent geometries, mixing conditions, coolant and melt temperatures, and/or coolant impurities may also have affected MFCI efficiency, but the rhythmic nature of the bed pairs implies a periodic explosion process, which can be explained by temporary increases in the water-to-lava mass ratio during cycles of groundwater recharge.


Predicting the Need for Surgery in Patients with Lumbar Disc Herniation: A New Internally Validated Scoring System.
Prospective study. To propose a scoring system for predicting the need for surgery in patients with lumbar disc herniation (LDH). The indications for surgery in patients with LDH are well established. However, the exact timing of surgery is not. According to surgeons, patients with failed conservative treatment who underwent delayed surgery, often after 6 months postsymptom initiation, have poor functional recovery and outcome. The current study included patients with symptomatic LDH. Patients with an indication for emergent surgery such as profound or progressive motor deficit, cauda equina syndrome, and diagnoses other than single-level LDH were excluded from the analysis. All patients followed a conservative treatment regimen (a combination of physical therapy, pain medications, and/or spinal epidural steroid injections). Surgery was indicated for patients who continuously experienced pain despite maximal conservative therapy. In total, 134 patients met the inclusion and exclusion criteria. Among them, 108 (80.6%) responded to conservative management, and 26 (19.4%) underwent unilateral laminotomy and microdiscectomy. The symptom duration, disc degeneration grade on magnetic resonance imaging (Pfirrmann disc grade), herniated disc location and type, fragment size, and thecal sac diameter significantly differed between patients who responded to conservative treatment and those requiring surgery. The area under the receiver operating characteristic curve of the scoring system based on the anteroposterior size of the herniated disc fragment and herniated disc location and type was 0.81. A scoring system based on herniated disc/fragment size, location, and type can be applied to predict the need for surgery in patients with LDH. In the future, this tool can be used to prevent unnecessarily prolonged conservative management (>4-8 weeks).


Blocking α4β7 integrin delays viral rebound in SHIVSF162P3-infected macaques treated with anti-HIV broadly neutralizing antibodies.
Anti-HIV broadly neutralizing antibodies (bNAbs) may favor development of antiviral immunity by engaging the immune system during immunotherapy. Targeting integrin α4β7 with an anti-α4β7 monoclonal antibody (Rh-α4β7) affects immune responses in SIV/SHIV-infected macaques. To explore the therapeutic potential of combining bNAbs with α4β7 integrin blockade, SHIVSF162P3-infected, viremic rhesus macaques were treated with bNAbs only (VRC07-523LS and PGT128 anti-HIV antibodies) or a combination of bNAbs and Rh-α4β7 or were left untreated as a control. Treatment with bNAbs alone decreased viremia below 200 copies/ml in all macaques, but seven of eight macaques (87.5%) in the bNAbs-only group rebounded within a median of 3 weeks (95% CI: 2 to 9). In contrast, three of six macaques treated with a combination of Rh-α4β7 and bNAbs (50%) maintained a viremia below 200 copies/ml until the end of the follow-up period; viremia in the other three macaques rebounded within a median of 6 weeks (95% CI: 5 to 11). Thus, there was a modest delay in viral rebound in the macaques treated with the combination antibody therapy compared to bNAbs alone. Our study suggests that α4β7 integrin blockade may prolong virologic control by bNAbs in SHIVSF162P3-infected macaques.


In situ expression of the IL-1-alpha and TNF-alpha genes by Reed-Sternberg cells in Hodgkin's disease.
The histopathologic pattern of tissues involved by Hodgkin's disease (HD) suggests excessive activation of environmental cells by cytokines released by Hodgkin-Reed-Sternberg (HRS) cells, which are considered as the neoplastic component of HD lesions. This hypothesis has been supported by many studies performed in vitro using HD cell lines. In this study, we have tried to demonstrate the cytokine-producing cells in an environment as close as possible to the in vivo conditions, using in situ hybridization onto frozen sections of HD samples. [35S]-labelled single-stranded RNA probes were prepared by transcribing human cDNA fragments of the TNF-alpha and IL-1 alpha genes subcloned into appropriate vectors. A total of 19 specimens of HD lesions, including 7 cases of nodular sclerosing (NS) type and 12 cases of mixed cellularity (MC), were tested with both types of probes. Clinical stages included stage I (6 cases), stage II (4 cases), stage III (6 cases) and stage IV (3 cases). TNF-alpha and/or IL-1 alpha expression was observed in 12 among 19 HD cases. However, neither the histological type nor the clinical status of the patients was correlated with the profile of cytokine secretion. Most of the cytokine-producing cells could be identified as HRS cells due to their morphological appearance. In 3 cases, simultaneous analysis by immunohistochemistry and in situ hybridization showed that IL-1 alpha/TNF-alpha mRNA-producing cells simultaneously expressed the CD30 antigen, thereby confirming the HRS nature of these cells.


The Online Patient Satisfaction Index for Patients With Low Back Pain: Development, Reliability, and Validation Study.
Low back pain is highly prevalent, and most often, a specific causative factor cannot be identified. Therefore, for most patients, their low back pain is labeled as nonspecific. Patient education and information are recommended for all these patients. The internet is an accessible source of medical information on low back pain. Approximately 50% of patients with low back pain search the internet for health and medical advice. Patient satisfaction with education and information is important in relation to patients' levels of inclination to use web-based information and their trust in the information they find. Although patients who are satisfied with the information they retrieve use the internet as a supplementary source of information, dissatisfied patients tend to avoid using the internet. Consumers' loyalty to a product is often applied to evaluate their satisfaction. Consumers have been shown to be good ambassadors for a service when they are willing to recommend the service to a friend or colleague. When consumers are willing to recommend a service to a friend or colleague, they are also likely to be future users of the service. To the best of our knowledge, no multi-item instrument exists to specifically evaluate satisfaction with information delivered on the web for people with low back pain. This study aims to report on the development, reliability testing, and construct validity testing of the Online Patient Satisfaction Index to measure patients' satisfaction with web-based information for low back pain. This is a cross-sectional validation study of the Online Patient Satisfaction Index. The index was developed with experts and assessed for face validity. It was subsequently administered to 150 adults with nonspecific low back pain. Of these, 46% (70/150) were randomly assigned to participate in a reliability test using an intraclass correlation coefficient of agreement. Construct validity was evaluated by hypothesis testing based on a web app (MyBack) and Wikipedia on low back pain. The index includes 8 items. The median score (range 0-24) based on the MyBack website was 20 (IQR 18-22), and the median score for Wikipedia was 12 (IQR 8-15). The entire score range was used. Overall, 53 participants completed a retest, of which 39 (74%) were stable in their satisfaction with the home page and were included in the analysis for reliability. Intraclass correlation coefficient of agreement was estimated to be 0.82 (95% CI 0.68-0.90). Two hypothesized correlations for construct validity were confirmed through an analysis using complete data. The index had good face validity, excellent reliability, and good construct validity and can be used to measure satisfaction with the provision of web-based information regarding nonspecific low back pain among people willing to access the internet to obtain health information. ClinicalTrials.gov NCT03449004; https://clinicaltrials.gov/ct2/show/NCT03449004.


Common skin problems in the community and primary care.
Skin problems can be hard to diagnose, leaving clinicians frustrated and patients incorrectly treated, but rashes and lesions can be markers of systemic disease and infections. However, by using simple history-taking and mnemonics, safety and correct diagnoses can be achieved. This article will consider some common problems encountered in primary and community care, issues that need to be excluded, resources that will help with diagnosis and some management guidelines. This is not an exhaustive guide, and advice should be sought from learned colleagues in specific cases. Pressure area care and the use of compression bandaging will not be discussed unless it is of relevance to the subject of rashes and lesions.


Manipulation of both virus- and cell-specific factors is required for robust transient replication of a hepatitis C virus genotype 3a sub-genomic replicon.
Hepatitis C virus (HCV) genotype (GT) 3 is the second most prevalent of the seven HCV genotypes and exhibits the greatest resistance to the highly potent, direct-acting antivirals (DAAs) that are currently in use. Previously a stable cell line harbouring the S52 GT3 sub-genomic replicon (SGR) was established, but this SGR was unable to robustly replicate transiently. As transient SGRs are a critical tool in the development of DAAs, and in the study of viral resistance, we sought to establish a transient SGR system based on S52. Next-generation sequencing was used to identify putative culture-adaptive substitutions that had arisen during long-term selection of the S52 SGR. A subset of these substitutions was built back into the S52 SGR in the context of a CpG/UpA-low luciferase reporter, with a single point mutation in NS4A conferring the greatest replication capability upon S52. Modification of the innate immune-sensing pathways of Huh7.5 hepatoma cells by expression of the parainfluenza virus type 5 V protein and SEC14L2 resulted in a further enhancement of S52 replication. Furthermore, this transiently replicating SGR showed genotype-specific differences in sensitivity to two clinically relevant NS5A DAAs. In conclusion, we report that a single substitution in NS4A, coupled with host cell modifications, enabled robust levels of transient replication by the GT3 S52 SGR. This system will have beneficial uses in both basic research into the unique aspects of GT3 biology and drug discovery.


Use of carvedilol in hypertension: an update.
β-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular morbidity and mortality as a consequence of blood pressure reduction in patients with hypertension. However, evidence from recent meta-analyses have demonstrated no benefit afforded by atenolol compared with placebo in risk of mortality, myocardial infarction, or stroke, and a higher risk of mortality and stroke with atenolol/propranolol compared with other antihypertensive drug classes. Thus, the effect of these agents on cardiovascular morbidity and mortality in hypertensive patients, especially their use in uncomplicated hypertension, has remained largely controversial. However, it is recognized that the clinical studies used in these meta-analyses were mainly based on the older second-generation β-blockers, such as atenolol and metoprolol. Actually, considerable heterogeneity in, eg, pharmacokinetic, pharmacological, and physicochemical properties exists across the different classes of β-blockers, particularly between the second-generation and newer third-generation agents. Carvedilol is a vasodilating noncardioselective third-generation β-blocker, without the negative hemodynamic and metabolic effects of traditional β-blockers, which can be used as a cardioprotective agent. Compared with conventional β-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. Studies have also shown that carvedilol exhibits favorable effects on metabolic parameters, eg, glycemic control, insulin sensitivity, and lipid metabolism, suggesting that it could be considered in the treatment of patients with metabolic syndrome or diabetes. The present report provides an overview of the main clinical studies concerning carvedilol administered as either monotherapy or in combination with another antihypertensive or more frequently a diuretic agent, with particular focus on the additional benefits beyond blood pressure reduction.


Physiological studies of an oligosporogenous strain of Bacillus popilliae.
A relatively small but consistent increase in the frequency of spore formation by an oligosporogenous strain of Bacillus popilliae (NRRL B-2309M) was obtained by adding 0.1% sodium pyruvate to the sporulation medium. The frequency of spore formation was essentially the same when a low level of glucose, trehalose, or glucose-6-phosphate or a high level of alpha-methyl-d-mannoside was added as the carbon and energy source. Many other variations in the cultural medium and cultural conditions failed to enhance spore formation of 2309M, and no spores were found in four asporogenic strains under any of the conditions tried. There were no significant differences between the 2309M strain and three nonsporeforming cultures with respect to (i) the rate and extent of growth, (ii) the rates of glucose utilization, or (iii) volatile acid production and utilization. None of the cultures tested was found to produce detectable levels of extracellular protease or an antibiotic. The only consistent marker found associated with spore formation was the development of catalase activity, and this activity was stimulated by heating at 80 C for 10 min. This was not found unless morphological evidence of spore formation was observed. The germination of the spores formed by 2309M in vitro was stimulated by heat shock and by the addition of pyruvate to the germination medium.


Epidemiology of acute and chronic hepatitis B virus infection in Norway, 1992-2009.
Norway is classified as a low prevalence country for hepatitis B virus infection. Vaccination is only recommended for risk groups (intravenous drug users (IDUs), Men who have Sex with Men (MSM), immigrants and contacts of known carriers). We describe the epidemiology of reported cases of hepatitis B in Norway, during the years 1992-2009 in order to assess the validity of current risk groups and recommend preventive measures. We used case based data from the national surveillance system on acute and chronic hepatitis B. The Norwegian Statistics Bureau provided population and migration data and the Norwegian Institute for Alcohol and Drug Research the estimated number of active IDUs between 2002-2007. Incidence rates (IR) and incidence rate ratios (IRR) for acute hepatitis B and notification rates (NR) and notification rate ratios (NRR) for chronic hepatitis B with 95% confidence intervals were calculated. The annual IR of acute hepatitis B ranged from 0.7/100,000 (1992) to 10.6/100,000 (1999). Transmission occurred mainly among IDUs (64%) or through sexual contact (24%). The risk of acquiring acute hepatitis B was highest in people aged 20-29 (IRR = 6.6 [3.3-13.3]), and in males (IRR = 2.4 [1.7-3.3]). We observed two peaks of newly reported chronic hepatitis B cases in 2003 and 2009 (NR = 17.6/100,000 and 17.4/100,000, respectively). Chronic hepatitis B was more likely to be diagnosed among immigrants than among Norwegians (NRR = 93 [71.9-120.6]), and among those 20-29 compared to those 50-59 (NRR = 5.2 [3.5-7.9]). IDUs remain the largest risk group for acute hepatitis B. The observed peaks of chronic hepatitis B are related to increased immigration from high endemic countries and screening and vaccination of these groups is important to prevent further spread of infection. Universal screening of pregnant women should be introduced. A universal vaccination strategy should be considered, given the high cost of reaching the target populations. We recommend evaluating the surveillance system for hepatitis B as well as the effectiveness of screening and vaccinating immigrant populations.


Structural studies on the RNA-recognition motif of NELF E, a cellular negative transcription elongation factor involved in the regulation of HIV transcription.
The elongation of transcription of HIV RNA at the TAR (transactivation-response element) is highly regulated by positive and negative factors. The cellular negative transcription elongation factor NELF (negative elongation factor) was suggested to be involved in transcriptional regulation of HIV-1 (HIV type 1) by binding to the stem of the viral TAR RNA which is synthesized by cellular RNA polymerase II at the viral long terminal repeat. NELF is a heterotetrameric protein consisting of NELF A, B, C or the splice variant D, and E. In the present study, we determined the solution structure of the RRM (RNA-recognition motif) of the RNA-binding subunit NELF E and studied its interaction with the viral TAR RNA. Our results show that the separately expressed recombinant NELF E RRM has alpha-helical and beta-strand elements adopting a betaalphabetabetaalphabeta fold and is able to bind to TAR RNA. Fluorescence equilibrium titrations with fluorescently labelled double- and single-stranded oligoribonucleotides representing the TAR RNA stem imply that NELF E RRM binds to the single-stranded TAR RNAs with K(d) values in the low-micromolar range.


Characterizing percolative materials by straining.
Carrier transport in a wide range of nanomaterial assemblies proceeds by percolation through discontinuous networks of constituents. Improving percolative nanomaterials could enhance transparent conductors, sensors, and electronic devices. A significant obstacle in optimizing percolative materials is the challenge in their characterization. The critical connection pathways which determine a percolative material's conductivity are not easily accessible with existing metrology tools and traditional investigation approaches rely on indirect methods based on many samples and on simplifying assumptions. We here demonstrate the direct extraction of characteristic parameters from a single sample by analyzing the strain-dependent resistance of percolative materials. An analytical model is derived that can explain experimental data for various percolative materials, morphologies, and straining conditions. The relationship of the extracted parameters with previously introduced figures of merit allows us to compare nanostructures of diverse dimensionalities and compositions for applications such as strain gauges and transparent conductors.


Deconvolution of gene expression from cell populations across the C. elegans lineage.
Knowledge of when and in which cells each gene is expressed across multicellular organisms is critical in understanding both gene function and regulation of cell type diversity. However, methods for measuring expression typically involve a trade-off between imaging-based methods, which give the precise location of a limited number of genes, and higher throughput methods such as RNA-seq, which include all genes, but are more limited in their resolution to apply to many tissues. We propose an intermediate method, which estimates expression in individual cells, based on high-throughput measurements of expression from multiple overlapping groups of cells. This approach has particular benefits in organisms such as C. elegans where invariant developmental patterns make it possible to define these overlapping populations of cells at single-cell resolution. We implement several methods to deconvolve the gene expression in individual cells from population-level data and determine the accuracy of these estimates on simulated data from the C. elegans embryo. These simulations suggest that a high-resolution map of expression in the C. elegans embryo may be possible with expression data from as few as 30 cell populations.


The effect of endurance running training on asthmatic adults.
Nine mild to moderate asthmatic adults (three males, six females) and six non-asthmatics (one male, five females) underwent endurance running training three times per week for five weeks, at self selected running speeds on a motorized treadmill. After training, the asthmatic group had a significantly higher maximum oxygen uptake, significantly lower blood lactate and heart rate in submaximal running, and significantly reduced time to complete a two mile treadmill run, partly attributable to the ability to exercise at a higher % VO2 max after training. These training induced changes of the asthmatic group were generally of a greater magnitude than those shown by the non-asthmatic group. Although seven of the nine asthmatics did show a reduction in the post-exercise fall in FEV1 after the five week training period, this was not statistically significant for the asthmatic group as a whole. The results of this study therefore suggest that endurance running training can improve the aerobic fitness of asthmatic adults, and may reduce the severity of exercise-induced asthma.


Cerebral gumma. Case report.
A case of focal cerebral syphilitic gumma of the right temporal lobe is reported. Angiography showed moderate focal hypervascularity with stretched vessels, and irregularity of the vessel walls. Plain computerized tomography revealed an area of low density that enhanced strongly after intravenous administration of contrast medium.


Highly efficient nanoplasmonic SERS on cardboard packaging substrates.
This work reports on highly efficient surface enhanced Raman spectroscopy (SERS) constructed on low-cost, fully recyclable and highly reproducible cardboard plates, which are commonly used as disposable packaging material. The active optical component is based on plasmonic silver nanoparticle structures separated from the metal surface of the cardboard by a nanoscale dielectric gap. The SERS response of the silver (Ag) nanoparticles of various shapes and sizes were systematically investigated, and a Raman enhancement factor higher than 106 for rhodamine 6G detection was achieved. The spectral matching of the plasmonic resonance for maximum Raman enhancement with the optimal local electric field enhancement produced by 60 nm-sized Ag NPs predicted by the electromagnetic simulations reinforces the outstanding results achieved. Furthermore, the nanoplasmonic SERS substrate exhibited high reproducibility and stability. The SERS signals showed that the intensity variation was less than 5%, and the SERS performance could be maintained for up to at least 6 months.


Risk factors for impaired wound healing in sirolimus-treated renal transplant recipients.
As sirolimus has been implicated in impaired wound healing, the aim of this study was to evaluate risk factors for wound complications after renal transplantation in patients treated with this drug de novo. This single center retrospective review of wound complications included 194 renal transplant recipients, all of whom received sirolimus immunosuppression in combination with reduced doses of cyclosporine (CsA) and corticosteroids de novo. A wound complication was defined as an infection, incisional hernia, or lymphocele. The overall incidence of wound complications within the first year post-transplantation was 36% (n = 70) including infection in 12% (n = 23), lymphocele formation in 18% (n = 34), and incisional hernia in 18% (n = 34) of patients. Seventeen patients suffered more than one wound complication. A multivariate analysis showed that independent risk factors for the development of wound complications were recipients over the age of 40 yr (odds ratio 2.536, p = 0.011), subjects with body mass index (BMI) >26 (odds ratio 2.498, p = 0.027) and especially BMI >30 (odds ratio 3.738, p = 0.007), the use of thymoglobulin for induction immunosuppression (odds ratio 3.627, p = 0.002), and a cumulative dose of sirolimus of at least 35 mg by post-transplant day 4 (odds ratio 2.694, p = 0.023). African-American (odds ratio 0.139, p < 0.001) or Hispanic recipients (odds ratio 0.337, p = 0.014) were less likely to experience a wound problem than Caucasian recipients. A number of potentially modifiable risk factors independently increase the incidence of wound complications among renal transplant recipients receiving sirolimus-based immunosuppression de novo.


Dexamethasone-inhibited pertechnetate uptake in metastatic carcinoma of the cerebellum.
Two sodium pertechnetate Tc 99m brain scans, done within several days of each other, demonstrated inhibition of pertechnetate localization in a cerebellar lesion after dexamethasone therapy for cerebral edema. The lesion, a metastasis from a bronchogenic mucinous adenocarcinoma, was clearly present in the first scan, which was done before treatment.


Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response.
Despite advances toward understanding the prevention and treatment of many cancers, patients who suffer from oral squamous cell carcinoma (OSCC) confront a survival rate that has remained unimproved for more than 2 decades, indicating our ability to treat them pharmacologically has reached a plateau. In an ongoing effort to improve the clinical outlook for this disease, we previously reported that an essential component of the mechanism by which the proteasome inhibitor bortezomib (PS-341, Velcade) induced apoptosis in OSCC required the activation of a terminal unfolded protein response (UPR). Predicated on these studies, the authors hypothesized that high-throughput screening (HTS) of large diverse chemical libraries might identify more potent or selective small-molecule activators of the apoptotic arm of the UPR to control or kill OSCC. They have developed complementary cell-based assays using stably transfected CHO-K1 cell lines that individually assess the PERK/eIF2α/CHOP (apoptotic) or the IRE1/XBP1 (adaptive) UPR subpathways. An 66 K compound collection was screened at the University of Michigan Center for Chemical Genomics that included a unique library of prefractionated natural product extracts. The mycotoxin methoxycitrinin was isolated from a natural extract and found to selectively activate the CHOP-luciferase reporter at 80 µM. A series of citrinin derivatives was isolated from these extracts, including a unique congener that has not been previously described. In an effort to identify more potent compounds, the authors examined the ability of citrinin and the structurally related mycotoxins ochratoxin A and patulin to activate the UPR. Strikingly, it was found that patulin at 2.5 to 10 µM induced a terminal UPR in a panel of OSCC cells that was characterized by an increase in CHOP, GADD34, and ATF3 gene expression and XBP1 splicing. A luminescent caspase assay and the induction of several BH3-only genes indicated that patulin could induce apoptosis in OSCC cells. These data support the use of this complementary HTS strategy to identify novel modulators of UPR signaling and tumor cell death.


Fentanyl epidemic in Chicago, Illinois and surrounding Cook County.
Epidemics related to illicit fentanyl abuse have been reported and the potential exists for a national epidemic associated with high mortality. This report describes emergency department visits for opioid toxicity and a recent outbreak of illicit fentanyl fatalities in Chicago, Illinois and surrounding Cook County. Retrospective chart review of opioid-related overdoses seen in our emergency department and a retrospective review of data from the Cook County Medical Examiner's Office Fentanyl Fatality Database from April 2005 through December 2006. Our emergency department treated 43 patients with a total of 55 emergency department visits during this time. Paramedic transport was utilized for 83.6% of the emergency department visits and naloxone was administered during 80.4% of transports. Naloxone was administered during 47.3% of emergency department visits with total doses ranging from 0.4 mg to 12 mg. Eighty percent of cases were treated and discharged from the emergency department. During this same time frame, the Medical Examiner's office identified 342 fentanyl-related fatalities. In 2006, illicit fentanyl fatalities represented 6.9% of all Medical Examiner cases for that year. Approximately 80% of deaths occurred in Chicago. A peak in fentanyl-related deaths occurred in the spring of 2006 and again in the fall of 2006 while the number of emergency department visits peaked during May of 2006. Chicago and surrounding Cook County experienced an outbreak of 342 fentanyl-related deaths between April 2005 and December 2006. The experience demonstrated a clear need for an interdisciplinary approach to identifying, communicating, and managing an outbreak.


First analysis of the safety and efficacy of UGN-101 in the treatment of ureteral tumors.
UGN-101 has been approved for the chemoablation of low-grade upper tract urothelial cancer (UTUC) involving the renal pelvis and calyces. Herein is the first reported cohort of patients with ureteral tumors treated with UGN-101. We performed a retrospective review of patients treated with UGN-101 for UTUC at 15 high-volume academic and community centers focusing on outcomes of patients treated for ureteral disease. Patients received UGN-101 with either adjuvant or chemo-ablative intent. Response rates are reported for patients receiving chemo-ablative intent. Adverse outcomes were characterized with a focus on the rate of ureteral stenosis. In a cohort of 132 patients and 136 renal units, 47 cases had tumor involvement of the ureter, with 12 cases of ureteral tumor only (8.8%) and 35 cases of ureteral plus renal pelvic tumors (25.7%). Of the 23 patients with ureteral involvement who received UGN-101 induction with chemo-ablative intent, the complete response was 47.8%, which did not differ significantly from outcomes in patients without ureteral involvement. Fourteen patients (37.8%) with ureteral tumors had significant ureteral stenosis at first post-treatment evaluation, however, when excluding those with pre-existing hydronephrosis or ureteral stenosis, only 5.4% of patients developed new clinically significant stenosis. UGN-101 appears to be safe and may have similar efficacy in treating low-grade urothelial carcinoma of the ureter as compared to renal pelvic tumors.


Extending in Silico Protein Target Prediction Models to Include Functional Effects.
In silico protein target deconvolution is frequently used for mechanism-of-action investigations; however existing protocols usually do not predict compound functional effects, such as activation or inhibition, upon binding to their protein counterparts. This study is hence concerned with including functional effects in target prediction. To this end, we assimilated a bioactivity training set for 332 targets, comprising 817,239 active data points with unknown functional effect (binding data) and 20,761,260 inactive compounds, along with 226,045 activating and 1,032,439 inhibiting data points from functional screens. Chemical space analysis of the data first showed some separation between compound sets (binding and inhibiting compounds were more similar to each other than both binding and activating or activating and inhibiting compounds), providing a rationale for implementing functional prediction models. We employed three different architectures to predict functional response, ranging from simplistic random forest models ('Arch1') to cascaded models which use separate binding and functional effect classification steps ('Arch2' and 'Arch3'), differing in the way training sets were generated. Fivefold stratified cross-validation outlined cascading predictions provides superior precision and recall based on an internal test set. We next prospectively validated the architectures using a temporal set of 153,467 of in-house data points (after a 4-month interim from initial data extraction). Results outlined Arch3 performed with the highest target class averaged precision and recall scores of 71% and 53%, which we attribute to the use of inactive background sets. Distance-based applicability domain (AD) analysis outlined that Arch3 provides superior extrapolation into novel areas of chemical space, and thus based on the results presented here, propose as the most suitable architecture for the functional effect prediction of small molecules. We finally conclude including functional effects could provide vital insight in future studies, to annotate cases of unanticipated functional changeover, as outlined by our CHRM1 case study.


Exploring Perspectives on Antimicrobial Use in Livestock: A Mixed-Methods Study of UK Pig Farmers.
Increasing levels of antimicrobial resistance in human and veterinary medicine have raised concerns over the irresponsible use of antimicrobials. The role of administering antimicrobials in food producing animals most frequently falls to the farmer, therefore it is essential that their use of antimicrobials is both optimal and responsible. This study sought in-depth information on the drivers behind antimicrobial use behaviors and farmer attitudes to responsible use using a mixed-methodological approach. Initially, in-depth semi-structured interviews were conducted with a purposively selected sample of farmers (n = 22). A thematic analysis approach was taken to identify key themes from these qualitative data. The generalizability and variation of these themes was then tested on a larger randomly selected sample of pig farmers through a questionnaire study (n = 261). The influences behind antimicrobial use were complex with multiple drivers motivating decisions. There was no consensual opinion on what farming systems resulted in either a low or high antimicrobial requirement however, farmers reported that good management practices, low stocking densities, and a high health status were associated with low antimicrobial use. Farmers expressed desire to avoid the long-term use of in-feed antimicrobials, but identified barriers to discontinuing such behaviors, such as pig morbidity, mortality, and economic losses. The high cost of antimicrobials was described as a motivation toward seeking alternative methods of controlling disease to prophylactic use; however, this expense was balanced against the losses from an increased burden of disease. The high financial costs involved in pig production alongside the economic uncertainty of production and pressure from retailers, were identified as limiting the scope for improvements in pig accommodation and facilities which could reduce the antimicrobial requirements on farm. Long-term, sustainable and economically stable relationships between retailers and farmers may allow farmers to make necessary investments in improving management and housing in order to reduce antimicrobial use. Greater use and more widespread deployment of effective vaccinations were highlighted by farmers as being a feasible alternative to antimicrobial use in preventing disease.


Adverse drug events associated with disorders of coagulation.
Disorders of coagulation are common adverse drug events encountered in critically ill patients and present a serious concern for intensive care unit (ICU) clinicians. Dosing strategies for medications used in the ICU are typically developed for use in noncritically ill patients and, therefore, do not account for the altered pharmacokinetic and pharmacodynamic properties encountered in the critically ill as well as the increased potential for drug-drug interactions, given the far greater number of medications ordered. This substantially increases the risk for coagulation-related adverse reactions, such as a bleeding or prothrombotic events. Although many medications used in the ICU have the potential to cause coagulation disorders, the exact incidence will vary based on the specific medication, dose, concomitant drug therapy, ICU setting, and patient-specific comorbidities. Clinicians must strongly consider these factors when evaluating the risk/benefit ratio for a particular therapy. This review surveys recent literature documenting the risk for adverse drug reactions specific to bleeding and/or clotting with commonly used medications in the ICU.


Enhancement of synchronization between hippocampal and amygdala theta waves associated with pontine wave density.
Theta waves in the amygdala are known to be synchronized with theta waves in the hippocampus. Synchronization between amygdala and hippocampal theta waves is considered important for neuronal communication between these regions during the memory-retrieval process. These theta waves are also observed during rapid eye movement (REM) sleep. However, few studies have examined the mechanisms and functions of theta waves during REM sleep. This study examined correlations between the dynamics of hippocampal and amygdala theta waves and pontine (P) waves in the subcoeruleus region, which activates many brain areas including the hippocampus and amygdala, during REM sleep in rats. We confirmed that the frequency of hippocampal theta waves increased in association with P wave density, as shown in our previous study. The frequency of amygdala theta waves also increased with in associated with P wave density. In addition, we confirmed synchronization between hippocampal and amygdala theta waves during REM sleep in terms of the cross-correlation function and found that this synchronization was enhanced in association with increased P wave density. We further studied theta wave synchronization associated with P wave density by lesioning the pontine subcoeruleus region. This lesion not only decreased hippocampal and amygdala theta frequency, but also degraded theta wave synchronization. These results indicate that P waves enhance synchronization between regional theta waves. Because hippocampal and amygdala theta waves and P waves are known to be involved in learning and memory processes, these results may help clarify these functions during REM sleep.


Traditional cardiovascular disease risk factors in dialysis patients compared with the general population: the CHOICE Study.
Although atherosclerotic cardiovascular disease (ASCVD) risk in end-stage renal disease (ESRD) is 5 to 30 times that of the general population, few data exist comparing ASCVD risk factors among new dialysis patients to the general population. This cross-sectional study of 1041 dialysis patients describes the prevalence of ASCVD risk factors at the beginning of ESRD compared with estimates of ASCVD risk factors in the adult US population derived from the Third National Health and Nutrition Examination (NHANES III). CHOICE Study participants had a high prevalence of diabetes (54%), hypertension (96%), left ventricular hypertrophy by electrocardiogram (EKG) criteria (22%), low physical activity (80%), hypertriglyceridemia (36%), and low HDL cholesterol (33%). CHOICE participants were more likely to be older, black, and male than NHANES III participants. After adjustment for age, race, gender, and ASCVD (defined as myocardial infarction, revascularization procedure, stroke, carotid endarterectomy, and amputation in CHOICE; and as myocardial infarction and stroke in NHANES III), the prevalence of diabetes, hypertension, left ventricular hypertrophy by EKG, low physical activity, low HDL cholesterol, and hypertriglyceridemia were still more common in CHOICE participants. Smoking, obesity, hypercholesterolemia, and high LDL cholesterol, however, were less common in CHOICE than NHANES III participants. The projected 5-yr ASCVD risk based on the Framingham Risk Equation among those older than 40 yr without ASCVD was higher in CHOICE Study participants (13%) than in the NHANES III participants (6%). In summary, many ASCVD risk factors are more prevalent in ESRD than in the general population and may explain some, but probably not all, of the increased ASCVD risk in ESRD.


The Rho family G proteins play a critical role in muscle differentiation.
The Rho family GTP-binding proteins play a critical role in a variety of cytoskeleton-dependent cell functions. In this study, we examined the role of Rho family G proteins in muscle differentiation. Dominant negative forms of Rho family proteins and RhoGDI, a GDP dissociation inhibitor, suppressed transcription of muscle-specific genes, while mutationally activated forms of Rho family proteins strongly activated their transcription. C2C12 cells overexpressing RhoGDI (C2C12RhoGDI cells) did not differentiate into myotubes, and expression levels of myogenin, MRF4, and contractile protein genes but not MyoD and myf5 genes were markedly reduced in C2C12RhoGDI cells. The promoter activity of the myogenin gene was suppressed by dominant negative mutants of Rho family proteins and was reduced in C2C12RhoGDI cells. Expression of myocyte enhancer binding factor 2 (MEF2), which has been reported to be required for the expression of the myogenin gene, was reduced at the mRNA and protein levels in C2C12RhoGDI cells. These results suggest that the Rho family proteins play a critical role in muscle differentiation, possibly by regulating the expression of the myogenin and MEF2 genes.


Hyperthermia Sensitizes Glioma Stem-like Cells to Radiation by Inhibiting AKT Signaling.
Glioma stem-like cells (GSC) are a subpopulation of cells in tumors that are believed to mediate self-renewal and relapse in glioblastoma (GBM), the most deadly form of primary brain cancer. In radiation oncology, hyperthermia is known to radiosensitize cells, and it is reemerging as a treatment option for patients with GBM. In this study, we investigated the mechanisms of hyperthermic radiosensitization in GSCs by a phospho-kinase array that revealed the survival kinase AKT as a critical sensitization determinant. GSCs treated with radiation alone exhibited increased AKT activation, but the addition of hyperthermia before radiotherapy reduced AKT activation and impaired GSC proliferation. Introduction of constitutively active AKT in GSCs compromised hyperthermic radiosensitization. Pharmacologic inhibition of PI3K further enhanced the radiosensitizing effects of hyperthermia. In a preclinical orthotopic transplant model of human GBM, thermoradiotherapy reduced pS6 levels, delayed tumor growth, and extended animal survival. Together, our results offer a preclinical proof-of-concept for further evaluation of combined hyperthermia and radiation for GBM treatment.


Prevalence of orthostatic hypotension in the unselected ambulatory population of persons aged 65 years old and above.
The diagnostic recommendation for orthostatic hypotension (OH) is to measure blood pressure during the first 3 min after getting up from a lying position. There are no clear definitions as to the amount of time that the patient should lie down before this, and the number of measurements to be taken in lying and standing positions. The aim of this study was to identify the optimal time to measure blood pressure when lying and standing. This was a prospective study of 99 patients aged 65 years and above in an urban primary care clinic. Blood pressure was measured at 1 min intervals over 10 min in the lying position and 7 min standing. OH was found in 37 patients (37.4%). Of these, 56.8% were identified in the 1st minute, 67.6% after 2 min and 83.8% after 3 min of standing. In all cases, participants with OH were asymptomatic. In the lying position, blood pressure stabilized after 7 min, but when the 7th minute was used as a reference for OH many cases were lost. To optimize the identification of OH, blood pressure should be measured at 1 min intervals over the first 3 min after standing up. The amount of time that patients should lie down before blood pressure is measured standing up still has to be determined.


Antithrombotic drugs in secondary stroke prevention among a community dwelling older population.
Patients who suffer a cerebrovascular event are at high risk of a recurrence. Secondary prevention is crucial in reducing the burden of cerebrovascular disease. To estimate the percentage of stroke survivors receiving antiplatelet or anticoagulant drugs and to identify factors associated with such treatment. Cross sectional retrospective cohort study. Data were analysed from a large collaborative observational study, the Italian "silver network" home care project, which collected data (from 1997 to 2001) on patients admitted to home care programmes (n = 5372). Twenty two home health agencies participated in evaluating the implementation of the minimum dataset for home care (MDS-HC) instrument. For the present study, 648 individuals with a diagnosis of stroke were selected and the initial MDS-HC assessment reported. 70% of stroke survivors did not receive any antiplatelet or anticoagulant drugs (95% confidence interval (CI), 66.5 to 73.5). Among all age categories, aspirin and ticlopidine were the two most commonly prescribed drugs. Living alone (odds ratio (OR), 0.49 (95% CI, 0.24 to 0.89)), dependency in activities of daily living (0.66 (0.40 to 0.99)), cognitive impairment (0.58 (0.38 to 0.86)), and low educational level (0.58 (0.34 to 0.98)) were associated with a reduced likelihood of receiving secondary stroke prevention treatment. Cardiac arrhythmias, coronary artery disease, heart failure, and peripheral vascular disease were associated with the use of antiplatelet or anticoagulant treatment. Negative attitudes among physicians with respect to secondary stroke prevention are prevalent and reinforce the need for increased awareness of existing data on the risks and benefits for elderly individuals. Social problems and functional impairment may be issues concerning physicians when deciding whether or not the risks of treatment exceed the benefit.


Rapid NK cell differentiation in a population with near-universal human cytomegalovirus infection is attenuated by NKG2C deletions.
Natural killer (NK) cells differentiate and mature during the human life course; human cytomegalovirus (HCMV) infection is a known driver of this process. We have explored human NK cell phenotypic and functional maturation in a rural African (Gambian) population with a high prevalence of HCMV. The effect of age on the frequency, absolute number, phenotype, and functional capacity of NK cells was monitored in 191 individuals aged from 1 to 49 years. Increasing frequencies of NK cells with age were associated with increased proportions of CD56dim cells expressing the differentiation marker CD57 and expansion of the NKG2C+ subset. Frequencies of NK cells responding to exogenous cytokines declined with age in line with a decreased proportion of CD57- cells. These changes coincided with a highly significant drop in anti-HCMV IgG titers by the age of 10 years, suggesting that HCMV infection is brought under control as NK cells differentiate (or vice versa). Deletion at the NKG2C locus was associated with a gene dose-dependent reduction in proportions of CD94+ and CD57+ NK cells. Importantly, anti-HCMV IgG titers were significantly elevated in NKG2C-/- children, suggesting that lack of expression of NKG2C may be associated with altered control of HCMV in childhood.


Effect of tetramethylammonium ion on the helix-to-coil transition of poly(deoxyadenylylthymidine): a nuclear magnetic resonance and calorimetric investigation.
Differential scanning calorimetry, temperature-dependent NMR, and UV spectroscopy are used to investigate the helix-to-coil transition of poly(deoxyadenylylthymidine) [poly(dA-dT)] in 1 M NaCl and 1 M Me4NCl (tetramethylammonium chloride). All three methods reveal that the polymer has a melting temperature, tm, that is approximately 6 degree C higher in 1 M Me4NCl than in 1 M NaCl. The NMR data show that this increased stability does not result from fundamental changes in base stacking or base pairing in going from 1 M NaCl to 1 M Me4NCl. Consistent with this observation, the calorimetric measurements yield essentially equal enthalpies for the helix-to-coil transition under the two salt conditions (6.8 kcal per base pair in 1 M NaCl and 7.0 kcal per base pair in M Me4NCl). Analysis of the shapes of the calorimetric curves shows that the transition is more cooperative in Me4NCl than in NaCl. Comparison of the calorimetric and van't Hoff enthalpies allows specification of the size of the cooperative unit: 27 base pairs in 1 M NaCl and 32 base pairs in 1 M Me4NCl. The NMR data reveal that the major Me4NCl-induced structural alterations (relative to NaCl) are a change in one glycosidic torison angle and a partial resolution of the two phosphates. The calorimetric experiments indicate that in the absence of fortuitous compensation these conformational changes are not accompanied by a significant enthalpy effect. On the basis of these data, we suggest that in 1 M NaCl poly(dA-dT) assumes predominantly a B-DNA-like conformation where the symmetry repeat occurs every base pair. By contrast, in 1 M Me4NCl the predominant conformation exhibits a dinucleotide repeat consistent with a right-handed alternating B-DNA structure.


Effect of 1,25(OH)2 D3 and 20(OH)D3 on interleukin-1β-stimulated interleukin-6 and -8 production by human gingival fibroblasts.
Vitamin D-1,25(OH)2 D3 or 1,25D3-maintains healthy osseous tissue, stimulates the production of the antimicrobial peptide cathelicidin and has anti-inflammatory effects, but it can cause hypercalcemia. Evidence links diminished serum levels of 1,25D3 with increased gingival inflammation. Periodontitis progression is associated with increased local production of inflammatory mediators by immune cells and gingival fibroblasts. These include interleukin (IL)-6, a regulator of osteoclastic bone resorption, and the neutrophil chemoattractant IL-8, both regulated by signaling pathways, including NF-κB and MAPK/AP-1. The objectives were to determine the effects of 1,25D3 or a non-calcemic analog, 20-hydroxyvitamin D3 -20(OH)D3 or 20D3-on IL-1β-stimulated IL-6 and IL-8 production, and NF-κB and MAPK/AP-1 activation, by human gingival fibroblasts. Human gingival fibroblasts were incubated ± IL-1β, with or without exposure to 1,25D3 or 20D3. IL-6 and IL-8 in culture supernatants were measured by enzyme-linked immunosorbent assay. NF-κB (p65) and AP-1 (phospho-cJun) and were measured in nuclear extracts via binding to specific oligonucleotides. Data were analyzed using ANOVA and Scheffe's F procedure for post hoc comparisons. IL-1β-stimulated IL-6 and IL-8 levels were both significantly inhibited (40%-60%) (P<.045) by 1,25D3, but not 20D3 (0%-15% inhibition, not statistically significant). Both 1,25D3 and 20D3 significantly and similarly inhibited IL-1β-stimulated nuclear levels of p65 and phospho-cJun (P<.02). Reduction of the activation of NF-κB and AP-1 alone is not able to inhibit strongly the IL-1β stimulated IL-6 and IL-8 gene expression. 1,25D3 but not 20D3 may affect some of the many other factors/processes/pathways that in turn regulate the expression of these genes. However, the results suggest that topical application of ligands of the vitamin D receptor may be useful in the local treatment of periodontitis while reducing adverse systemic effects.


Exercise Overrides Blunted Hypoxic Ventilatory Response in Prematurely Born Men.
Pre-term birth provokes life-long anatomical and functional respiratory system sequelae. Although blunted hypoxic ventilatory response (HVR) is consistently observed in pre-term infants, it remains unclear if it persists with aging and, moreover, if it influences hypoxic exercise capacity. In addition, it remains unresolved whether the previously observed prematurity-related alterations in redox balance could contribute to HVR modulation. Twenty-one prematurely born adult males (gestational age = 29 ± 4 weeks], and 14 age matched controls born at full term (gestational age = 39 ± 2 weeks) underwent three tests in a randomized manner: (1) hypoxia chemo-sensitivity test to determine the resting and exercise poikilocapnic HVR and a graded exercise test to volitional exhaustion in (2) normoxia (FiO2 = 0.21), and (3) normobaric hypoxia (FiO2 = 0.13) to compare the hypoxia-related effects on maximal aerobic power (MAP). Selected prooxidant and antioxidant markers were analyzed from venous samples obtained before and after the HVR tests. Resting HVR was lower in the pre-term (0.21 ± 0.21 L ⋅ min-1 ⋅ kg-1) compared to full-term born individuals (0.47 ± 0.23 L ⋅ min-1 ⋅ kg-1; p < 0.05). No differences were noted in the exercise HVR or in any of the measured oxidative stress markers before or after the HVR test. Hypoxia-related reduction of MAP was comparable between the groups. These findings indicate that blunted resting HVR in prematurely born men persists into adulthood. Also, active adults born prematurely seem to tolerate hypoxic exercise well and should, hence, not be discouraged to engage in physical activities in hypoxic environments. Nevertheless, the blunted resting HVR and greater desaturation observed in the pre-term born individuals warrant caution especially during prolonged hypoxic exposures.


Medical therapy of steroid-resistant Crohn's disease.
Glucocorticosteroids are commonly used in the treatment of moderate to severe Crohn's disease and are effective for the short term amelioration of symptoms. However, not all patients respond to corticosteroid therapy. Approximately 20% of patients fail to respond to initial treatment with steroids, while 36% of patients may be considered steroid dependent. Sharp distinctions between steroid-dependent and steroid-resistant populations are difficult to draw because steroid responsiveness is often dose dependent. Clearer distinctions may be drawn between those who fail to respond to initial treatment with corticosteroids and those who have secondary failure later in the course of their disease on repeated treatment. Effective therapies for steroid-resistant Crohn's disease include azathioprine and 6-mercaptopurine, methotrexate, cyclosporine and infliximab. Limited data are available on the use of tacrolimus, mycophenolate mofetil and thalidomide. Steroid-resistant Crohn's disease, while involving a small minority of patients, continues to present a difficult therapeutic challenge.


What we talk about when we talk with medical students.
In this article, we review how we interact with medical students in our efforts to teach blood pressure regulation and systemic cardiovascular control along with related elements of respiratory and exercise physiology. Rather than provide a detailed lecture with key facts, we attempted to outline our approach to teaching integrative cardiovascular physiology to medical students, which includes five major themes. First, focus on questions versus answers and facts. We believe that this offers both the learner and teacher a number of advantages. Second, avoid teaching dogma in the name of clarity (i.e., heavy focus on teaching "facts" that have not yet been fully investigated). This is especially important because of the way knowledge evolves over time. Third, include laboratory-based experiences in human integrative physiology. Fourth, provide students with intellectual frameworks versus a list of "facts" to serve as a platform for question generation. Finally, focus on the role of integration and regulatory redundancy in physiology and the idea that physiology is a narrative that can help. In this article, we discuss the philosophy behind the themes outlined above and argue that questions, and not answers, are where the action is for both research and education.


Heat exposure in the Canadian workplace.
Exposure to excessive heat is a physical hazard that threatens Canadian workers. As patterns of global climate change suggest an increased frequency of heat waves, the potential impact of these extreme climate events on the health and well-being of the Canadian workforce is a new and growing challenge. Increasingly, industries rely on available technology and information to ensure the safety of their workers. Current Canadian labor codes in all provinces employ the guidelines recommended by the American Conference of Governmental Industrial Hygienists (ACGIH) that are Threshold Limit Values (TLVs) based upon Wet Bulb Globe Temperature (WBGT). The TLVs are set so that core body temperature of the workers supposedly does not exceed 38.0 degrees C. Legislation in most Canadian provinces also requires employers to install engineering and administrative controls to reduce the heat stress risk of their working environment should it exceed the levels permissible under the WBGT system. There are however severe limitations using the WGBT system because it only directly evaluates the environmental parameters and merely incorporates personal factors such as clothing insulation and metabolic heat production through simple correction factors for broadly generalized groups. An improved awareness of the strengths and limitations of TLVs and the WGBT index can minimize preventable measurement errors and improve their utilization in workplaces. Work is on-going, particularly in the European Union to develop an improved individualized heat stress risk assessment tool. More work is required to improve the predictive capacity of these indices.


Leptospermum scoparium essential oil is a promising source of mosquito larvicide and its toxicity is enhanced by a biobased emulsifier.
Synthetic pesticides are the cornerstone of vector-borne disease control, but alternatives are urgently needed to tackle the growing problem of insecticide resistance and concerns over environmental safety. Leptospermum scoparium J.R. Forst and G. Forst (manuka) essential oil and its four fractions were analyzed for chemical composition and toxicity against Aedes aegypti larvae. The use of bio-based amylose-N-1-hexadecylammonium chloride inclusion complexes (Hex-Am) as an emulsifier for L. scoparium essential oil was also investigated. Fraction 1 was inactive, fractions 2 (LC50 = 12.24 ppm) and 3 (LC50 = 20.58 ppm) were more toxic than the whole essential oil (LC50 = 47.97 ppm), and fraction 4 (LC50 = 35.87 ppm) had similar toxicity as the whole essential oil. Twenty-one chemical constituents were detected in L. scoparium essential oil compared to 16, 5, 19 and 25 chemical constituents in fractions, 1, 2, 3 and 4 respectively. The two most dominant chemical constituents were calamenene (17.78%) and leptospermone (11.86%) for L. scoparium essential oil, calamenene (37.73%) and ledene (10.37%) for fraction 1, leptospermone (56.6%) and isoleptospermone (19.73) for fraction 2, cubenol (24.30%) and caryophyllene oxide (12.38%) for fraction 3, and γ-gurjunene (21.62%) and isoleptospermone (7.88%) for fraction 4. Alpha-pinene, ledene, and aromandendrene were 2-7 times less toxic than the whole essential suggesting that the toxicity of L. scoparium essential oil was either due to other chemical constituents that were not tested or due synergist interactions among chemical constituents. Leptospermum scoparium essential oil-Hex-Am emulsion (LC50 = 29.62) was more toxic than the whole essential oil. These findings suggest that L. scoparium essential oil is a promising source of mosquito larvicide and that Hex-Am is an excellent emulsifier for L. scoparium essential oil for use as a larvicide.