The role of Cancer-Testis antigens as predictive and prognostic markers in non-small cell lung cancer.
Cancer-Testis Antigens (CTAs) are immunogenic proteins that are poor prognostic markers in non-small cell lung cancer (NSCLC). We investigated expression of CTAs in NSCLC and their association with response to chemotherapy, genetic mutations and survival. We studied 199 patients with pathological N2 NSCLC treated with neoadjuvant chemotherapy (NAC; n = 94), post-operative observation (n = 49), adjuvant chemotherapy (n = 47) or unknown (n = 9). Immunohistochemistry for NY-ESO-1, MAGE-A and MAGE-C1 was performed. Clinicopathological features, response to neoadjuvant treatment and overall survival were correlated. DNA mutations were characterized using the Sequenom Oncocarta panel v1.0. Affymetrix data from the JBR.10 adjuvant chemotherapy study were obtained from a public repository, normalised and mapped for CTAs. NY-ESO-1 was expressed in 50/199 (25%) samples. Expression of NY-ESO-1 in the NAC cohort was associated with significantly increased response rates (P = 0.03), but not overall survival. In the post-operative cohort, multivariate analyses identified NY-ESO-1 as an independent poor prognostic marker for those not treated with chemotherapy (HR 2.61, 95% CI 1.28-5.33; P = 0.008), whereas treatment with chemotherapy and expression of NY-ESO-1 was an independent predictor of improved survival (HR 0.267, 95% CI 0.07-0.980; P = 0.046). Similar findings for MAGE-A were seen, but did not meet statistical significance. Independent gene expression data from the JBR.10 dataset support these findings but were underpowered to demonstrate significant differences. There was no association between oncogenic mutations and CTA expression. NY-ESO-1 was predictive of increased response to neoadjuvant chemotherapy and benefit from adjuvant chemotherapy. Further studies investigating the relationship between these findings and immune mechanisms are warranted.


Programmable energy landscapes for kinetic control of DNA strand displacement.
DNA is used to construct synthetic systems that sense, actuate, move and compute. The operation of many dynamic DNA devices depends on toehold-mediated strand displacement, by which one DNA strand displaces another from a duplex. Kinetic control of strand displacement is particularly important in autonomous molecular machinery and molecular computation, in which non-equilibrium systems are controlled through rates of competing processes. Here, we introduce a new method based on the creation of mismatched base pairs as kinetic barriers to strand displacement. Reaction rate constants can be tuned across three orders of magnitude by altering the position of such a defect without significantly changing the stabilities of reactants or products. By modelling reaction free-energy landscapes, we explore the mechanistic basis of this control mechanism. We also demonstrate that oxDNA, a coarse-grained model of DNA, is capable of accurately predicting and explaining the impact of mismatches on displacement kinetics.


Rapid volumetric OCT image acquisition using compressive sampling.
Acquiring three dimensional image volumes with techniques such as Optical Coherence Tomography (OCT) relies on reconstructing the tissue layers based on reflection of light from tissue interfaces. One B-mode scan in an image is acquired by scanning and concatenating several A-mode scans, and several contiguous slices are acquired to assemble a full 3D image volume. In this work, we demonstrate how Compressive Sampling (CS) can be used to accurately reconstruct 3D OCT images with minimal quality degradation from a subset of the original image. The full 3D image is reconstructed from sparsely sampled data by exploiting the sparsity of the image in a carefully chosen transform domain. We use several sub-sampling schemes, recover the full 3D image using CS, and show that there is negligible effect on clinically relevant morphometric measurements of the optic nerve head in the recovered image. The potential outcome of this work is a significant reduction in OCT image acquisition time, with possible extensions to speeding up acquisition in other imaging modalities such as ultrasound and MRI.


Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer's disease dementia.
Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimer's disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.


IS6110 transposition and evolutionary scenario of the direct repeat locus in a group of closely related Mycobacterium tuberculosis strains.
In recent years, various polymorphic loci and multicopy insertion elements have been discovered in the Mycobacterium tuberculosis genome, such as the direct repeat (DR) locus, the major polymorphic tandem repeats, the polymorphic GC-rich repetitive sequence, IS6110, and IS1081. These, especially IS6110 and the DR locus, have been widely used as genetic markers to differentiate M. tuberculosis isolates and will continue to be so used, due to the conserved nature of the genome of M. tuberculosis. However, little is known about the processes involved in generating these or of their relative rates of change. Without an understanding of the biological characteristics of these genetic markers, it is difficult to use them to their full extent for understanding the population genetics and epidemiology of M. tuberculosis. To address these points, we identified a cluster of 7 isolates in a collection of 101 clinical isolates and investigated them with various polymorphic genetic markers, which indicated that they were highly related to each other. This cluster provided a model system for the study of IS6110 transposition, evolution at the DR locus, and the effects of these on the determination of evolutionary relationships among M. tuberculosis strains. Our results suggest that IS6110 restriction fragment length polymorphism patterns are useful in grouping closely related isolates together; however, they can be misleading if used for making inferences about the evolutionary relationships between closely related isolates. DNA sequence analysis of the DR loci of these isolates revealed an evolutionary scenario, which, complemented with the information from IS6110, allowed a reconstruction of the evolutionary steps and relationships among these closely related isolates. Loss of the IS6110 copy in the DR locus was noted, and the mechanisms of this loss are discussed.


Tissue microarray profiling in human heart failure.
Tissue MicroArrays (TMAs) are a versatile tool for high-throughput protein screening, allowing qualitative analysis of a large number of samples on a single slide. We have developed a customizable TMA system that uniquely utilizes cryopreserved human cardiac samples from both heart failure and donor patients to produce formalin-fixed paraffin-embedded sections. Confirmatory upstream or downstream molecular studies can then be performed on the same (biobanked) cryopreserved tissue. In a pilot study, we applied our TMAs to screen for the expression of four-and-a-half LIM-domain 2 (FHL2), a member of the four-and-a-half LIM family. This protein has been implicated in the pathogenesis of heart failure in a variety of animal models. While FHL2 is abundant in the heart, not much is known about its expression in human heart failure. For this purpose, we generated an affinity-purified rabbit polyclonal anti-human FHL2 antibody. Our TMAs allowed high-throughput profiling of FHL2 protein using qualitative and semiquantitative immunohistochemistry that proved complementary to Western blot analysis. We demonstrated a significant relative reduction in FHL2 protein expression across different forms of human heart failure.


Looming auditory collision warnings for driving.
A driving simulator was used to compare the effectiveness of increasing intensity (looming) auditory warning signals with other types of auditory warnings. Auditory warnings have been shown to speed driver reaction time in rear-end collision situations; however, it is not clear which type of signal is the most effective. Although verbal and symbolic (e.g., a car horn) warnings have faster response times than abstract warnings, they often lead to more response errors. Participants (N=20) experienced four nonlooming auditory warnings (constant intensity, pulsed, ramped, and car horn), three looming auditory warnings ("veridical," "early," and "late"), and a no-warning condition. In 80% of the trials, warnings were activated when a critical response was required, and in 20% of the trials, the warnings were false alarms. For the early (late) looming warnings, the rate of change of intensity signaled a time to collision (TTC) that was shorter (longer) than the actual TTC. Veridical looming and car horn warnings had significantly faster brake reaction times (BRT) compared with the other nonlooming warnings (by 80 to 160 ms). However, the number of braking responses in false alarm conditions was significantly greater for the car horn. BRT increased significantly and systematically as the TTC signaled by the looming warning was changed from early to veridical to late. Looming auditory warnings produce the best combination of response speed and accuracy. The results indicate that looming auditory warnings can be used to effectively warn a driver about an impending collision.


RANTES chemokine expression in diseased and normal human tissues.
RANTES is a member of a large family of cytokines, called chemokines, which are thought to play a regulatory role in inflammatory processes. We have made recombinant human RANTES protein which was used to generate a panel of anti-RANTES monoclonal antibodies. Following characterization, select anti-RANTES monoclonal antibodies were used for immunohistologic staining of a large panel of normal, diseased and fetal tissue sections. Diseased tissues included eleven lymphomas and eight renal tumors. Most tissues were also tested in parallel for RANTES mRNA by in situ hybridization using RANTES mRNA specific oligomeric probes. As expected, most normal adult tissues contain few, if any, RANTES positive cells. In contrast, RANTES expression dramatically increases in inflammatory sites. In addition, megakaryocytes, some tumours, and select fetal tissues express high levels of RANTES message and protein. These results indicate a wider expression of RANTES than previously appreciated and suggest multiple physiologic roles for this soluble factor.


Direct and mediated associations between religious coping, spirituality, and youth violence in El Salvador.
To examine the direct and mediated relationships between religious coping, spirituality, social developmental factors, and violence among high-risk and gang-involved youth in a high-crime, Latin American country. Using a community sample of 290 high-risk and gang-involved youth in San Salvador, El Salvador, structural equation modeling was employed to examine the relationships between religious coping, spirituality, social developmental factors (e.g., antisocial bond and antisocial beliefs), and violence. Religious coping (β = - 0.14, P < 0.05) and spirituality (β = - 0.20, P < 0.01) were both significantly associated with antisocial bond. Antisocial bond, in turn, was directly associated with violence (β = 0.70, P < 0.001) and was associated with antisocial beliefs (β = 0.54, P < 0.001); however, the path from antisocial beliefs to violence was not statistically significant. No direct paths were identified from religiosity and spirituality to violence. The goodness-of-fit statistics (root mean square error of approximation, 0.034; comparative fit index, 0.974; and Tucker-Lewis index, 0.966) suggest that the final model had acceptable fit. This study is among the first to shed light on the relationship between religiosity, spirituality, and youth violence in the Latin American context. Elevated levels of religious coping and spirituality are associated with less antisocial bonding, which, in turn, is associated with lower levels of violent behavior among high-risk and gang-involved Salvadoran youth. Study findings suggest that religious coping and spirituality are indirectly protective for youth violence among this high-risk population.


Reporting of Adherence in the VOICE Trial: Did Disclosure of Product Nonuse Increase at the Termination Visit?
VOICE-a phase 2B, placebo-controlled, randomized trial testing daily use of an antiretroviral tablet (tenofovir or Truvada) or daily use of tenofovir gel in 5029 women from South Africa, Uganda, and Zimbabwe-found none of the drug regimens effective in reducing HIV-1 acquisition in the intent-to-treat analysis. More than half of women assigned to active products in a case cohort sample had no drug detected in any plasma specimens tested during the trial. Yet, in response to questions asked of participants during the trial, ≥90 % of doses were reportedly taken. To explore factors associated with low adherence, a behavioral termination visit questionnaire was developed after early closure of the oral tenofovir and vaginal gel arms. We hypothesized that participants would be more forthcoming about nonuse after they exited the trial than during monthly/quarterly follow-up visits. Comparison of adherence reporting at routine follow-up visits with reporting at trial termination, however, indicates that disclosure of product nonadherence did not increase at the termination visit as anticipated. In resource-limited settings where women value the ancillary benefits provided by trial participation and are concerned that disclosure of nonuse may jeopardize trial participation, objective measures of adherence may yield more meaningful data regarding the inability or reluctance to use than measures of product use derived from self-report.


Induction and inhibition of human cytochrome P4501 by oxygenated polycyclic aromatic hydrocarbons.
Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) are found in the environment together with PAHs. However, less is known concerning their biological activity including their impact on aryl hydrocarbon receptor (AHR) signalling and the subsequent modulation of the cytochrome P450 monooxygenases (CYP). In this study, the effects of 15 environmentally relevant oxy-PAHs on the induction and activity of the CYP1 enzymes were determined in vitro by measuring gene expression levels and enzyme activity. We found that nine of the tested oxy-PAHs significantly induced CYP1A1 and CYP1B1 gene expression in human keratinocytes (HaCaT cells) while only five of these also were potent inducers of CYP1-dependent ethoxyresorufin-O-deethylase (EROD) activity suggesting that some of the oxy-PAHs are both activators of AHR signalling and inhibitors of CYP1 function. Using a recombinant human CYP1A1 enzyme we showed that eleven of the oxy-PAHs potently inhibited enzyme activity with benz[a]anthracene-7,12-quinone (7,12-BAQ) and benzo[a]fluorenone (BFLO) being the most potent inhibitors (IC50 = 0.037 and 0.061 μM, respectively). We further exposed HaCaT cells to binary mixtures of oxy-PAHs and the model AHR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to investigate potential interaction effects. The results showed that oxy-PAHs can interfere with the TCDD-mediated effects leading to reduced CYP1A1 and 1B1 expression and EROD activity. These data represent the first demonstration that oxy-PAHs can be potent inhibitors of CYP1 expression and function and make important contributions towards understanding the mechanisms through which oxy-PAHs can contribute to the overall risk of polycyclic aromatic compounds.


Atlas of Electroencephalography, 3rd Edition.
Electroencephalography (EEG) is the recording of the electrical activity of the brain. EEG is a reliable test to assess cerebral function. It aids in diagnosis, classification, and management of patients with epilepsy. It also has practical uses in conditions other than epilepsy. Moreover, it is harmless and inexpensive. EEG is an important tool for evaluating patients with epilepsy. It may help classify the syndrome, identify the likely source of focal seizures, and confirm a diagnosis of status epilepticus. EEG is therefore helpful when selecting appropriate antiepileptic drugs for patients with epilepsy, is valuable for diagnosis and management of status epilepticus as well as predicting the prognosis in epilepsy syndromes, and, is finally useful when localizing an area for resection in surgery candidates. In addition, despite advances in neuroimaging, EEG remains a valuable tool in the evaluation of stuporous and comatose patients. A systematic approach is essential for EEG interpretation, and when combined with good clinical judgment, it will improve diagnostic sensitivity and specificity and may improve therapeutic outcomes. This EEG atlas is designed as a practical guide for neurology residents, neurologists, and epileptologists, so that they may appropriately identify normal and abnormal findings, while reading an EEG. By reading and reviewing the relevant chapter of this well-organized atlas, that includes many EEG images, the reader will also learn how to report an EEG finding. We hope that this atlas fills an unmet need, and leads to improved patient care.


Initial conservative management strategy of HeartWare left ventricular assist device thrombosis with intravenous heparin or bivalirudin.
Pump thrombosis is a serious left ventricular assist device complication, though there are no guidelines regarding its treatment. The main aim of this study was to describe a strategy of intravenous anticoagulation as the initial treatment in these patients and then to compare intravenous heparin with bivalirudin. All consecutive patients who received a HeartWare left ventricular assist device from July 2009 to March 2019 were retrospectively analysed. Patients developing a pump thrombosis were selected, and treatment, outcomes and complications were recorded. During this period of time (116 months), 220 patients underwent HeartWare left ventricular assist device implantation and 57 developed pump thrombosis, with an incidence rate of first pump thrombosis of 0.17 events per patient-year of support (incidence rate of all episodes of pump thrombosis: 0.30 events per patient-year of support). All the patients were initially treated medically, predominantly with either intravenous heparin (n = 26) or bivalirudin (n = 16). Patients treated with bivalirudin during the first pump thrombosis episode had less subsequent re-thrombosis episodes (18.7% vs 57.7%, p < 0.05). In addition, percentage time in therapeutic range was greater for bivalirudin compared with heparin (68.5% ± 16.9% vs 37.4% ± 31.0%, p < 0.01). During the first pump thrombosis episode, 26.3% of the patients needed surgery (left ventricular assist device exchange (n = 8), transplant (n = 6) or decommissioning (n = 1)). The overall survival at 1 year was 61.4%, and there was no significant difference in survival. Left ventricular assist device thrombosis is a serious life-threatening complication; hence, we propose an initial conservative management of pump thrombosis with enhanced intravenous anticoagulation with either intravenous heparin or bivalirudin, with surgery reserved for refractory cases.


Emergence of fluoroquinolone resistance in the native Campylobacter coli population of pigs exposed to enrofloxacin.
The effect of a single 5 day enrofloxacin treatment on the native Campylobacter coli population in conventionally weaned 5-week-old pigs was investigated. Twelve pigs were split into two groups of six: one group was treated with a therapeutic dose (15 mg/pig/day) of enrofloxacin and the other remained untreated to act as the control. Campylobacter coli were isolated from faecal samples and tested for ciprofloxacin resistance by measuring MIC values. Mutations in the quinolone resistance-determining region (QRDR) of the gyrA gene of resistant isolates were identified by sequencing and denaturing HPLC. Levels of enrofloxacin and its primary metabolite ciprofloxacin in the pig faeces were also measured by HPLC. No quinolone-resistant C. coli (n = 867) were detected in any of the pigs prior to treatment, indicating <0.1% resistance in the group. Resistant C. coli were isolated from pigs for up to 35 days after treatment with a therapeutic dose. These resistant C. coli had MIC values of 128 mg/L and 8-16 mg/L for nalidixic acid and ciprofloxacin, respectively, and the same single point mutation causing a Thr-86 to Ile substitution in the QRDR was identified in each. The concentration of enrofloxacin in the pig faeces was 2-4 micro g/g faeces for the duration of the 5 day therapeutic treatment and was detected up to 10 days post-treatment. Ciprofloxacin was also measured and peaked at 0.6 micro g/g faeces in the treated group. This study provides evidence that a single course of enrofloxacin treatment contributes directly to the emergence and persistence of fluoroquinolone resistance in C. coli.


Cortical deficits of emotional face processing in adults with ADHD: its relation to social cognition and executive function.
Although it has been shown that adults with attention-deficit hyperactivity disorder (ADHD) have impaired social cognition, no previous study has reported the brain correlates of face valence processing. This study looked for behavioral, neuropsychological, and electrophysiological markers of emotion processing for faces (N170) in adult ADHD compared to controls matched by age, gender, educational level, and handedness. We designed an event-related potential (ERP) study based on a dual valence task (DVT), in which faces and words were presented to test the effects of stimulus type (faces, words, or face-word stimuli) and valence (positive versus negative). Individual signatures of cognitive functioning in participants with ADHD and controls were assessed with a comprehensive neuropsychological evaluation, including executive functioning (EF) and theory of mind (ToM). Compared to controls, the adult ADHD group showed deficits in N170 emotion modulation for facial stimuli. These N170 impairments were observed in the absence of any deficit in facial structural processing, suggesting a specific ADHD impairment in early facial emotion modulation. The cortical current density mapping of N170 yielded a main neural source of N170 at posterior section of fusiform gyrus (maximum at left hemisphere for words and right hemisphere for faces and simultaneous stimuli). Neural generators of N170 (fusiform gyrus) were reduced in ADHD. In those patients, N170 emotion processing was associated with performance on an emotional inference ToM task, and N170 from simultaneous stimuli was associated with EF, especially working memory. This is the first report to reveal an adult ADHD-specific impairment in the cortical modulation of emotion for faces and an association between N170 cortical measures and ToM and EF.


Limits to human performance: elevated risks on high mountains.
In 1950, Maurice Herzog and Louis Lachenal became the first climbers to reach the summit of an 8000m peak (Annapurna, 8091m). In the half century since that pioneering climb, mountaineers have increasingly sought to climb the fourteen '8K peaks' of the Himalayas and Karakoram, with remarkable success; they have made 5085 ascents of those peaks up to the year 2000. While seeking adventure on those great peaks, mountaineers are inevitably exposed to hypoxia, cold and dehydration as well as to the physical hazards of climbing. Those few mountaineers who successfully summit an 8K peak are likely to be at or near their physiological limits and probably confront an elevated probability of dying during their descent. We will briefly review some of the physiological challenges climbers face at extreme elevation and then compare success rates and death rates on mountains of different heights (Rainer, Foraker, Denali, K2, Everest). Success rates decline with summit height, but overall death rates and death rates during descent from the summit increase with summit height. Although these patterns are based on non-experimental and uncontrolled data, our findings are consistent with the hypothesis that increasing altitude is associated with decreased success and with increased risk of death.


Broadband cavity enhanced absorption spectroscopy as a detector for HPLC.
The first demonstration of a cavity enhanced absorption spectroscopy (CEAS) based technique, applied to HPLC detection is reported. Broadband cavity enhanced absorption spectroscopy (BBCEAS) has been used for detection in a HPLC system (HPLC-BBCEAS). Measurements were made on the dyes rhodamine 6G and rhodamine B between 450 and 600 nm. The sensitivity of the measurements as determined by the minimum detectable change in the absorption coefficient, alpha(min), were 2.9 x 10(-5) cm(-1) at 527 nm and 1.9 x 10(-5) cm(-1) at 556 nm, the peak absorption wavelengths of rhodamine 6G and rhodamine B, respectively. The limits of detection (LOD) for the two dyes were 426 and 271 pM, respectively. The LOD of the HPLC-BBCEAS setup was found to be between 54 and 77 times lower than with a Perkin-Elmer HPLC (series 200) comprising a 200EP photodiode array detector. The sensitivity of the developed setup also compared favorably with the previous single wavelength HPLC-CRDS studies while using a considerably lower cost experimental setup and simpler experimental methodology. The use of BBCEAS detection also allowed the discrimination following an isocratic HPLC separation of the nearly co-eluting dyes rhodamine 6G and rhodamine B.


Biomarkers of systemic inflammation and risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial.
The authors conducted a nested case-control study of serum inflammatory markers and risk of symptomatic benign prostatic hyperplasia (BPH), using data from the placebo arm of the Prostate Cancer Prevention Trial (1993-2003). Incident BPH (n = 676) was defined as treatment, report of 2 International Prostate Symptom Score (IPSS) values >14, or 2 increases of > or = 5 from baseline values with at least one value > or = 12. Controls (n = 683) were men who reported no BPH treatment or IPSS values >7 over the 7-year trial. Baseline serum was analyzed for C-reactive protein, tumor necrosis factor alpha (monomer), soluble tumor necrosis factor receptors I and II (sTNF-RI and sTNF-RII), interleukin 6, and interferon gamma. Controlled for age and race, a high C-reactive protein concentration was associated with increased BPH risk (for quartile 4 vs. quartile 1, odds ratio (OR) = 1.40, 95% confidence interval (CI): 1.04, 1.88); this was attenuated after control for body mass index (OR = 1.30, 95% CI: 0.95, 1.75). Low sTNF-RII and high interleukin 6 concentrations were associated with increased BPH risk (for quartile 4 vs. quartile 1, sTNF-RII: OR = 0.61, 95% CI: 0.46, 0.82; interleukin 6: OR = 1.79, 95% CI: 1.32, 2.42); these associations were only in men aged <65 years. Results suggest that systemic inflammation or lower levels of soluble receptors that bind inflammatory cytokines increase BPH risk.


Phosphorylation of ribosomal proteins by the vaccinia virus B1R protein kinase.
Two proteins of the 40S ribosomal subunit were shown to be phosphorylated in vitro by a vaccinia virus-encoded serine/threonine protein kinase. These were identified by two-dimensional gel electrophoresis as ribosomal proteins Sa and S2 and were shown by phosphoamino acid analysis to both be phosphorylated on serine and threonine residues. The three phosphorylated forms of S2 produced by the B1R protein kinase in vitro matched the phosphorylated forms of S2 previously observed in cells infected with vaccinia virus. These data strongly suggest that this enzyme is responsible for the phosphorylation of S2 and Sa which occurs early during vaccinia virus infection.


Cellular transformation by human papillomaviruses: lessons learned by comparing high- and low-risk viruses.
The oncogenic potential of papillomaviruses (PVs) has been appreciated since the 1930s yet the mechanisms of virally-mediated cellular transformation are still being revealed. Reasons for this include: a) the oncoproteins are multifunctional, b) there is an ever-growing list of cellular interacting proteins, c) more than one cellular protein may bind to a given region of the oncoprotein, and d) there is only limited information on the proteins encoded by the corresponding non-oncogenic PVs. The perspective of this review will be to contrast the activities of the viral E6 and E7 proteins encoded by the oncogenic human PVs (termed high-risk HPVs) to those encoded by their non-oncogenic counterparts (termed low-risk HPVs) in an attempt to sort out viral life cycle-related functions from oncogenic functions. The review will emphasize lessons learned from the cell culture studies of the HPVs causing mucosal/genital tract cancers.


A sub-nanomolar real-time nitric oxide probe: in vivo nitric oxide release in heart.
Amperometric nitric oxide probes are critical in evaluating real-time nitric oxide levels. This valuable tool enables one to measure spontaneous baseline levels of nitric oxide as well as 'puffs' of the gaseous signal molecule that may last for only seconds to minutes. However, in the past, many probes suffered from a lack of sensitivity, durability and reliability, causing investigators to design numerous controls to support their data. Our laboratory evaluated the new ISO-NOPF100 NO probe manufactured by World Precision Instruments of Sarasota, Florida. An invertebrate in vivo heart preparation was used, which presents a high degree of difficuly in obtaining nitric oxide measurements due to space limitations, resulting in physical contact of the probe with tissues. Additionally, we used in vitro invertebrate ganglionic preparations as a comparison since this tissue releases spontaneous and low levels of NO. Calibration of the new probe demonstrated high linearity and sensitivity. The detection limit for this new probe was determined to be approximately two times lower than probes previously used in our laboratory. Basal nitric oxide fluctuations in Mytilus edulis heart and excised ganglia were able to be resolved in the sub-nanomolar range. The ISO-NOPF100 NO probe represents a significant advancement for measuring nitric oxide in real-time.


Lysophosphatidic acid 5 receptor induces activation of Na(+)/H(+) exchanger 3 via apical epidermal growth factor receptor in intestinal epithelial cells.
Na(+) absorption is a vital process present in all living organisms. We have reported previously that lysophosphatidic acid (LPA) acutely stimulates Na(+) and fluid absorption in human intestinal epithelial cells and mouse intestine by stimulation of Na(+)/H(+) exchanger 3 (NHE3) via LPA(5) receptor. In the current study, we investigated the mechanism of NHE3 activation by LPA(5) in Caco-2bbe cells. LPA(5)-dependent activation of NHE3 was blocked by mitogen-activated protein kinase kinase (MEK) inhibitor PD98059 and U0126, but not by phosphatidylinositol 3-kinase inhibitor LY294002 or phospholipase C-β inhibitor U73122. We found that LPA(5) transactivated the epidermal growth factor receptor (EGFR) and that inhibition of EGFR blocked LPA(5)-dependent activation of NHE3, suggesting an obligatory role of EGFR in the NHE3 regulation. Confocal immunofluorescence and surface biotinylation analyses showed that LPA(5) was located mostly in the apical membrane. EGFR, on the other hand, showed higher expression in the basolateral membrane. However, inhibition of apical EGFR, but not basolateral EGFR, abrogated LPA-induced regulation of MEK and NHE3, indicating that LPA(5) selectively activates apical EGFR. Furthermore, transactivation of EGFR independently activated the MEK-ERK pathway and proline-rich tyrosine kinase 2 (Pyk2). Similarly to MEK inhibition, knockdown of Pyk2 blocked activation of NHE3 by LPA. Furthermore, we showed that RhoA and Rho-associated kinase (ROCK) are involved in activation of Pyk2. Interestingly, LPA(5) did not directly activate RhoA but was required for transactivation of EGFR. Together, these results unveil a pivotal role of apical EGFR in NHE3 regulation by LPA and show that the RhoA-ROCK-Pyk2 and MEK-ERK pathways converge onto NHE3.


Safety of chromium-enriched biomass of Yarrowia lipolytica as a novel food pursuant to Regulation (EU) 2015/2283.
Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on chromium-enriched biomass of Yarrowia lipolytica as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The NF is the dried and heat-killed chromium-enriched biomass of Y. lipolytica. This yeast species is widespread in nature, can be found in the environment and in foods, and was attributed the qualified presumption of safety (QPS) status for production purposes in 2018, including food and feed products based on biomass of the yeast. The production process, fermentation in the presence of chromium chloride, includes a heat-killing step of the yeast, resulting in the absence of viable Y. lipolytica in the NF. The maximum total chromium content of the NF is 23 μg Cr/g, with the chromium present as Cr(III). The applicant proposed to use the NF as a food supplement. The target population proposed by the applicant is the general population from 3 years of age onwards, with maximum proposed use levels of 2 g/day for children from 3 to 9 years of age and 4 g/day thereafter. At the proposed use levels of the NF, the combined intake of chromium provided by the NF, in addition to a background diet high in chromium, would result in total chromium intakes well below the tolerable daily intake (TDI) for chromium(III) for all target population groups. The Panel concludes that the NF, chromium-enriched biomass of Y. lipolytica, is safe under the proposed conditions of use.


Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids.
High plasma level of cholesterol is a well-known risk factor for atherosclerotic diseases. Oxidized LDL induces cellular and nuclear damage that leads to apoptotic cell death. We tested the hypothesis that flavonoids may function as antioxidants with regard to LDL incubated with 5 microm-Cu(2+) alone or in combination with human umbilical vein endothelial cells (HUVEC). Cytotoxicity and formation of thiobarbituric acid-reactive substances induced by Cu(2+)-oxidized LDL were examined in the presence of various subtypes of flavonoid. Flavanols, flavonols and flavanones at a non-toxic dose of 50 microm markedly inhibited LDL oxidation by inhibiting the formation of peroxidative products. In contrast, the flavones luteolin and apigenin had no such effect, with >30 % of cells killed after exposure to 0.1 mg LDL/ml. Protective flavonoids, especially (-)-epigallocatechin gallate, quercetin, rutin and hesperetin, inhibited HUVEC nuclear condensation and fragmentation induced by Cu(2+)-oxidized LDL. In addition, immunochemical staining and Western blot analysis revealed that anti-apoptotic Bcl-2 expression was enhanced following treatment with these protective flavonoids. However, Bax expression and caspase-3 cleavage stimulated by 18 h incubation with oxidized LDL were reduced following treatment with these protective flavonoids. The down-regulation of Bcl-2 and up-regulation of caspase-3 activation were reversed by the cytoprotective flavonoids, (-)-epigallocatechin gallate, quercetin and hesperetin, at >/=10 microm. These results suggest that flavonoids may differentially prevent Cu(2+)-oxidized LDL-induced apoptosis and promote cell survival as potent antioxidants. Survival potentials of certain flavonoids against cytotoxic oxidized LDL appeared to stem from their disparate chemical structure. Furthermore, dietary flavonoids may have therapeutic potential for protecting the endothelium from oxidative stress and oxidized LDL-triggered atherogenesis.


A prospective cohort for the investigation of alteration in temporal transcriptional and microbiome trajectories preceding preterm birth: a study protocol.
Preterm birth (PTB) results from heterogeneous influences and is a major contributor to neonatal mortality and morbidity that continues to have adverse effects on infants beyond the neonatal period. This protocol describes the procedures to determine molecular signatures predictive of PTB through high-frequency sampling during pregnancy, at delivery and the postpartum period. Four hundred first trimester pregnant women from either Myanmar or Thailand of either Karen or Burman ethnicity, with a viable, singleton pregnancy will be enrolled in this non-interventional, prospective pregnancy birth cohort study and will be followed through to the postpartum period. Fortnightly finger prick capillary blood sampling will allow the monitoring of genome-wide transcript abundance in whole blood. Collection of stool samples and vaginal swabs each trimester, at delivery and postpartum will allow monitoring of intestinal and vaginal microbial composition. In a nested case-control analysis, perturbations of transcript abundance in capillary blood as well as longitudinal changes of the gut, vaginal and oral microbiome will be compared between mothers giving birth to preterm and matched cases giving birth to term neonates. Placenta tissue of preterm and term neonates will be used to determine bacterial colonisation as well as for the establishment of coding and non-coding RNA profiles. In addition, RNA profiles of circulating, non-coding RNA in cord blood serum will be compared with those of maternal peripheral blood serum at time of delivery. This research protocol that aims to detect perturbations in molecular trajectories preceding adverse pregnancy outcomes was approved by the ethics committee of the Faculty of Tropical Medicine, Mahidol University in Bangkok, Thailand (Ethics Reference: TMEC 15-062), the Oxford Tropical Research Ethics Committee (Ethics Reference: OxTREC: 33-15) and the local Tak Province Community Ethics Advisory Board. The results of this cooperative project will be disseminated in multiple publications staggered over time in international peer-reviewed scientific journals. NCT02797327; Pre-results.


Intra and Inter-Rater Reliability and Convergent Validity of FIT-HaNSA in Individuals with Grade П Whiplash Associated Disorder.
Whiplash-Associated Disorders (WAD) are common following a motor vehicle accident. The Functional Impairment Test - Hand, and Neck/Shoulder/Arm (FIT-HaNSA) assesses upper extremity physical performance. It has been validated in patients with shoulder pathology but not in those with WAD. Establish the Intra and inter-rater reliability and the known-group and construct validity of the FIT-HaNSA in patients with Grade II WAD (WAD2). Twenty-five patients with WAD2 and 41 healthy controls were recruited. Numeric Pain Rating Scale (NPRS), Neck Disability Index (NDI), Disabilities of the Arm, Shoulder and Hand (DASH), cervical range of motion (CROM), and FIT-HaNSA were completed at two sessions conducted 2 to 7 days apart by two raters. Intraclass correlation coefficients (ICC) were used to describe Intra and inter-rater reliability. Spearman rank correlation coefficients (ρ) were used to quantify the associations between scores of the FIT-HaNSA and other measures in the WAD2 group (convergent construct validity). The Intra and inter-ICCs for the FIT-HaNSA scores ranged from 0.88 to 0.89 in the control group and 0.78 to 0.85 in the WAD2 group. Statistically significant differences in FIT-HaNSA performance between the two groups suggested known group construct validity (P < 0.001). The correlations between the NPRS, NDI, DASH, CROM and FIT-HaNSA were generally poor (ρ < 0.4). The study results indicate that the total FIT-HaNSA score has good Intra and inter-rater reliability and the construct validity in WAD2 and healthy controls.


Amnioinfusion for third trimester preterm premature rupture of membranes.
Preterm premature rupture of membranes (PPROM) is a leading cause of perinatal morbidity and mortality. Amnioinfusion aims to restore amniotic fluid volume by infusing a solution into the uterine cavity. The objective of this review was to assess the effects of amnioinfusion for PPROM on perinatal and maternal morbidity and mortality. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (2 December 2013). Randomised trials of amnioinfusion compared with no amnioinfusion in women with PPROM. Three review authors independently assessed trials for inclusion. Two review authors independently assessed trial quality and extracted data. Data were checked for accuracy. We included five trials, of moderate quality, but we only analysed data from four studies (with a total of 241 participants). One trial did not contribute any data to the review.Transcervical amnioinfusion improved fetal umbilical artery pH at delivery (mean difference 0.11; 95% confidence interval (CI) 0.08 to 0.14; one trial, 61 participants) and reduced persistent variable decelerations during labour (risk ratio (RR) 0.52; 95% CI 0.30 to 0.91; one trial, 86 participants).Transabdominal amnioinfusion was associated with a reduction in neonatal death (RR 0.30; 95% CI 0.14 to 0.66; two trials, 94 participants), neonatal sepsis (RR 0.26; 95% CI 0.11 to 0.61; one trial, 60 participants), pulmonary hypoplasia (RR 0.22; 95% CI 0.06 to 0.88; one trial, 34 participants) and puerperal sepsis (RR 0.20; 95% CI 0.05 to 0.84; one trial, 60 participants). Women in the amnioinfusion group were also less likely to deliver within seven days of membrane rupture (RR 0.18; 95% CI 0.05 to 0.70; one trial, 34 participants). These results should be treated with circumspection as the positive findings were mainly due to one trial with unclear allocation concealment. These results are encouraging but are limited by the sparse data and unclear methodological robustness, therefore further evidence is required before amnioinfusion for PPROM can be recommended for routine clinical practice.


Potential of entomopathogenic nematodes for the control of the banded fruit weevil, Phlyctinus callosus (Schönherr) (Coleoptera: Curculionidae).
Entomopathogenic nematodes (EPN) were evaluated for their potential use as biological control agents against Phlyctinus callosus, the banded fruit weevil (BFW). The susceptibility of larvae and adults to EPN was evaluated using 400 infective juveniles (IJ) per insect after 4 days in 24-well bioassay trays. The nematode isolates used were all able to infect BFW, although the larvae were found to be more susceptible than were the adults. The percentage mortality for BFW larvae ranged from 41 to 73% and for BFW adults from 13 to 45%. The most effective isolate, SF41 of Heterorhabditis zealandica, was used to investigate the effect of vertical movement of nematodes in sand and sandy loam soil, at specified concentration and temperature. A higher (82.2 ± 0.084%) percentage mortality rate was obtained with the sandy loam soil, than with the use of sand (67.5 ± 0.12%). The LD50 and LD90 values after 4 days of incubation were 96 and 278 IJ/50 μl, respectively. Nematodes were inactive below 15 °C, with the highest mortality of 74 ± 0.081% for BFW larvae recorded at 25 °C. Heterorhabditis zealandica was able to complete its life cycle successfully in sixth-instar BFW larvae after a period of 22 days. The study showed BFW larvae not to be as susceptible to nematode infection as they need a high concentration (400 IJ/larva) and 4 days to give effective control.


Measuring stem cell dynamics in the human colon--where there's a wiggle, there's a way.
The last decade has seen huge improvements in our understanding of intestinal stem cell biology, with major advances arising from the ability to transgenically label, and thus identify, murine stem cells and their progeny. In the human, transgenic labelling is not an available option and stem cell dynamic observations have been based on rare hereditary mutations and polymorphisms. Somatic mitochondrial DNA mutations cause a histochemically detectable, but neutrally selected, change in cytochrome c oxidase (CCO) enzyme activity and when this occurs in an intestinal stem cell, it can be used as an effective clonal marker in both health and disease. The intestinal crypt is the functional unit of the gut. Daughter cells are 'born' in the stem cell niche at the crypt base and proliferate, differentiate, and then apoptose as they migrate along the vertical crypt axis over 5-7 days. This stereotypical architecture provides a historical record of cell dynamics, as the distance travelled along the crypt axis is proportional to the time since the daughter cell was born. By staining, identifying, and carefully reconstructing crypt maps from serial en face sections of partially mutated mtDNA crypts, clonal ribbon images can be generated. 'Wiggles' in the width of the clonal ribbon reflect mtDNA mutated stem cell expansion or contraction events and these biological observations are applied in mathematical models. This clever approach is able to infer temporal evolutionary dynamics from a static, single time point measurement, in both normal and familial adenomatous polyposis tissue. As we have seen in the mouse, the simple ability to identify stem cell progeny can lead to a vast expansion in our understanding of stem cell evolution. The use of these techniques to trace recent stem cell dynamics in the human colon makes some headway into the knowledge gap in our understanding of murine and human intestinal stem cell biology. © 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Development, testing, and findings of a pediatric-focused trigger tool to identify medication-related harm in US children's hospitals.
The purposes of this study were to develop a pediatric-focused tool for adverse drug event detection and describe the incidence and characteristics of adverse drug events in children's hospitals identified by this tool. A pediatric-specific trigger tool for adverse drug event detection was developed and tested. Eighty patients from each site were randomly selected for retrospective chart review. All adverse drug events identified using the trigger tool were evaluated for severity, preventability, ability to mitigate, ability to identify the event earlier, and presence of associated occurrence report. Each trigger and the entire tool were evaluated for positive predictive value. Review of 960 randomly selected charts from 12 children's hospitals revealed 2388 triggers (2.49 per patient) and 107 unique adverse drug events. Mean adverse drug event rates were 11.1 per 100 patients, 15.7 per 1000 patient-days, and 1.23 per 1000 medication doses. The positive predictive value of the trigger tool was 3.7%. Twenty-two percent of all adverse drug events were deemed preventable, 17.8% could have been identified earlier, and 16.8% could have been mitigated more effectively. Ninety-seven percent of the identified adverse drug events resulted in mild, temporary harm. Only 3.7% of adverse drug events were identified in existing hospital-based occurrence reports. The most common adverse drug events identified were pruritus and nausea, the most common medication classes causing adverse drug events were opioid analgesics and antibiotics, and the most common stages of the medication management process associated with preventable adverse drug events were monitoring and prescribing/ordering. Adverse drug event rates in hospitalized children are substantially higher than previously described. Most adverse drug events resulted in temporary harm, and 22% were classified as preventable. Only 3.7% were identified by using traditional voluntary reporting methods. Our pediatric-focused trigger tool is effective at identifying adverse drug events in inpatient pediatric populations.


Interrupted Aortic Arch Associated with AP Window and Complex Cardiac Anomalies: Multi Detector Computed Tomography Findings.
Interrupted aortic arch is a rare congenital malformation of the aortic arch defined as a loss of luminal continuity between the ascending and descending portions of the aorta. In a simple interrupted aortic arch, only a ventricular septal defect and patent ductus arteriosus are observed. We present a rare complex form of type A interrupted aorta with an aortopulmonary window, an atrial septal defect, a ventricular septal defect, and a patent ductus arteriosus on multidetector computed tomography (MDCT) imaging.


Antioxidant supplement use after breast cancer diagnosis and mortality in the Life After Cancer Epidemiology (LACE) cohort.
There is concern that antioxidant supplement use during chemotherapy and radiation therapy may decrease treatment effects, yet the effects of such supplements on recurrence and survival are largely unknown. The authors prospectively examined the associations between antioxidant use after breast cancer (BC) diagnosis and BC outcomes in 2264 women in the Life After Cancer Epidemiology (LACE) cohort. The cohort included women who were diagnosed with early stage, primary BC from 1997 to 2000 who enrolled, on average, 2 years postdiagnosis. Baseline data were collected on antioxidant supplement use since diagnosis and other factors. BC recurrence and mortality were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using delayed entry Cox proportional hazards models. All tests of statistical significance were 2-sided. Antioxidant supplement use after diagnosis was reported by 81% of women. Among antioxidant users, frequent use of vitamin C and vitamin E was associated with a decreased risk of BC recurrence (vitamin C: HR, 0.73; 95% CI, 0.55-0.97; vitamin E: HR, 0.71; 95% CI, 0.54-0.94); and vitamin E use was associated with a decreased risk of all-cause mortality (HR, 0.76; 95% CI, 0.58-1.00). Conversely, frequent use of combination carotenoids was associated with increased risk of death from BC (HR, 2.07; 95% CI, 1.21-3.56) and all-cause mortality (HR, 1.75; 95% CI, 1.13-2.71). Frequent use of vitamin C and vitamin E in the period after BC diagnosis was associated with a decreased likelihood of recurrence, whereas frequent use of combination carotenoids was associated with increased mortality. The effects of antioxidant supplement use after diagnosis likely differ by type of antioxidant.


The complex interplay between pain intensity, depression, anxiety and catastrophising with respect to quality of life and disability.
To identify subgroups of patients with chronic pain based on the occurrence of depression, anxiety and catastrophising and the duration of pain and pain intensity. In addition to this, the relationship between the subgroups with respect to background variables, diagnosis, pain-related disability and perceived quality of life are investigated. This study used 433 patients with chronic pain including 47 patients with spinal cord injury-related pain, 150 with chronic whiplash associated disorders and 236 with fibromyalgia. The participants answered a postal questionnaire that provided background data, pain intensity and duration and psychological and health-related items. On the basis of depression, anxiety, catastrophising, pain intensity and duration, we identified subgroups of patients with chronic pain that differed with respect to perceived quality of life, disability and diagnosis. The psychological factors, especially depression, significantly influenced perceived quality of life and disability. Pain intensity and duration play a minor role with respect to quality of life, although pain intensity is associated to perceived disability. The results of this study highlight the importance of not looking at patients with chronic pain as a homogenous entity. A detailed assessment, including psychological factors with emphasis on depressive symptoms, might be essential for planning and carrying through treatment and rehabilitation.


Examining the influence of health sector coordination on the efficiency of county health systems in Kenya.
Health systems are complex, consisting of multiple interacting structures and actors whose effective coordination is paramount to enhancing health system goals. Health sector coordination is a potential source of inefficiency in the health sector. We examined how the coordination of the health sector affects health system efficiency in Kenya. We conducted a qualitative cross-sectional study, collecting data at the national level and in two purposely selected counties in Kenya. We collected data using in-depth interviews (n = 37) with national and county-level respondents, and document reviews. We analyzed the data using a thematic approach. The study found that while formal coordination structures exist in the Kenyan health system, duplication, fragmentation, and misalignment of health system functions and actor actions compromise the coordination of the health sector. These challenges were observed in both vertical (coordination within the ministry of health, within the county departments of health, and between the national ministry of health and the county department of health) and horizontal coordination mechanisms (coordination between the ministry of health or the county department of health and non-state partners, and coordination among county governments). These coordination challenges are likely to impact the efficiency of the Kenyan health system by increasing the transaction costs of health system functions. Inadequate coordination also impairs the implementation of health programmes and hence compromises health system performance. The efficiency of the Kenyan health system could be enhanced by strengthening the coordination of the Kenyan health sector. This can be achieved by aligning and harmonizing the intergovernmental and health sector-specific coordination mechanisms, strengthening the implementation of the Kenya health sector coordination framework at the county level, and enhancing donor coordination through common funding arrangements and integrating vertical disease programs with the rest of the health system. The ministry of health and county departments of health should also review internal organizational structures to enhance functional and role clarity of organizational units and staff, respectively. Finally, counties should consider initiating health sector coordination mechanisms between counties to reduce the fragmentation of health system functions across neighboring counties.


Benefits, Challenges, and Potential Utility of a Gait Database for Diabetes Patients.
Gait analysis is a useful tool in understanding movement impairments, which impact on patient well-being. The use of gait analysis in patients with diabetes has led to improvements in health care including the treatment and prevention of ulceration and development of targeted exercise interventions. The current convention when analyzing gait is to address specific complications of diabetes, controlling for potential influencing conditions within a study sample to understand the effects of the few specific complications chosen for analysis. Databases allow for the storage of data in a structured format, allowing easy access to large quantities of data in a consistent, comparable manner. A database of gait analyses of patients with diabetes has the potential to include far greater sample sizes for statistical analyses, allowing multiple influencing factors to be assessed simultaneously, and relationships identified between multiple influencing factors. However, a database of this type would encounter ethical and methodological challenges in its implementation, which are discussed. This article introduces some of the potential benefits, challenges, and utility of a gait database for diabetes patients. We highlight that, whereas the creation of a database within this clinical population would be a complex process both ethically and practically, huge potential benefits could be gained, overcoming some of the limitations faced by traditional isolated gait analysis studies.


Addressing the drug-resistant tuberculosis challenge through implementing a mixed model of care in Uganda.
Worldwide, Drug-resistant Tuberculosis (DR-TB) remains a big problem; the diagnostic capacity has superseded the clinical management capacity thereby causing ethical challenges. In Sub-Saharan Africa, treatment is either inadequate or lacking and some diagnosed patients are on treatment waiting lists. In Uganda, various health system challenges impeded scale-up of DR-TB care in 2012; only three treatment initiation facilities existed, with only 41 of the estimated 1010 RR-TB/MDR-TB cases enrolled on treatment yet 300 were on the waiting list and there was no DR-TB treatment scale-up plan. To scale up care, the National TB and leprosy Program (NTLP) with partners rolled out a DR-TB mixed model of care. In this paper, we share achievements and outcomes resulting from the implementation of this mixed Model of DR-TB care. Routine NTLP DR-TB program data on treatment initiation site, number of patients enrolled, their demographic characteristics, patient category, disease classification (based on disease site and human immunodeficiency virus (HIV) status), on co-trimoxazole preventive therapy (CPT) and antiretroviral therapy (ART) statuses, culture results, smear results and treatment outcomes (6, 12, and 24 months) from 2012 to 2017 RR-TB/MDR-TB cohorts were collected from all the 15 DR-TB treatment initiation sites and descriptive analysis was done using STATA version 14.2. We presented outcomes as the number of patient backlog cleared, DR-TB initiation sites, RR-TB/DR-TB cumulative patients enrolled, percentage of co-infected patients on the six, twelve interim and 24 months treatment outcomes as per the Uganda NTLP 2016 Programmatic Management of drug-resistant Tuberculosis (PMDT) guidelines (NTLP, 2016). Over the period 2013-2015, the RR-TB/MDR-TB Treatment success rate (TSR) was sustained between 70.1% and 74.1%, a performance that is well above the global TSR average rate of 50%. Additionally, the cure rate increased from 48.8% to 66.8% (P = 0.03). The Uganda DR-TB mixed model of care coupled with early application of continuous improvement approaches, enhanced cohort reviews and use of multi-disciplinary teams allowed for rapid DR-TB program expansion, rapid clearance of patient backlog, attainment of high cumulative enrollment and high treatment success rates. Sustainability of these achievements is needed to further reduce the DR-TB burden in the country. We highly recommend this mixed model of care in settings with similar challenges.


Percutaneous cardiopulmonary support-supported percutaneous coronary intervention: a single center experience.
Percutaneous cardiopulmonary support (PCPS) has proven to be a valuable technique in high-risk coronary patients undergoing percutaneous coronary intervention (PCI). However, there have been few studies on PCI associated with PCPS in Korea. We summarized our experience with PCPS-supported PCI. We retrospectively reviewed 19 patients with PCPS-supported PCI between August 2005 and June 2009. PCPS was used as an elective procedure for 10 patients with at least two of the following conditions: left-ventricular ejection fraction <35%, target vessel(s) supplying more than 50% of the viable myocardium, high risk surgical patients, and patients who refused coronary bypass surgery. In the remaining 9 patients PCPS was used as an emergency procedure, to stabilize and even resuscitate patients with acute myocardial infarction and cardiogenic shock, in order to attempt urgent PCI. Among the 19 patients who were treated with PCPS-supported PCI, 11 (57.9%) survived and 8 (42.1%) patients did not. ST elevation myocardial infarction with cardiogenic shock was more prevalent in the non-survivors than in the survivors (75% vs. 27.3%, p=0.04). The elective PCPS-supported PCI was practiced more frequently in the survivors than in the non-survivors (72.7% vs. 25%, p=0.04). In the analysis of the event-free survival curve between elective and emergency procedures, there was a significant difference in the survival rate (p=0.025). Among the survivors there were more patients with multi-vessel disease, but a lower Thrombolysis in Myocardial Infarction grade in the culprit lesions was detected in the non-survivors, before PCI. Although we studied high-risk patients, there was no procedure-related mortality. Our experience suggests that PCPS may be helpful in high risk patients treated with PCI, especially in elective cases. More aggressive and larger scale studies of PCPS should follow.


Focal transformation and the Gouy phase shift of converging one-cycle surface acoustic waves excited by femtosecond laser pulses.
We studied the changes of the pulse shape and the phase of the spectral components in converging-surface acoustic wave pulses. These pulses were excited with a femtosecond laser by a thermoelastic mechanism. To produce converging acoustic pulses, the laser beam was focused with an axicon in a circle on the surface of an aluminum sample. During propagation through the focus, the shape of the pulses of the normal surface velocity changed from two to three polar. The absolute value of the phase of the spectral components experienced a change close to pi/2 rad (Gouy phase shift) after passage of the focal region. These observations were confirmed by analytical and numerical calculations based on the two-dimensional wave equation for surface acoustic waves.


Assessment of MR image deformation for stereotactic neurosurgery using a tagging sequence.
A tagging sequence is used to assess MR image deformations before a stereotactic neurosurgical procedure, in a test model and in two patients. This pulse sequence super-imposes narrow parallel orthogonal tag lines on an image, which can be used as an internal reference frame. Image deformation is directly related to surface area variations in the squares produced by the tagging-sequence pulses. Small spatial deformations of the tags can be detected on the images used for measuring stereotactic-target spatial coordinates. A threshold of 2 SD guarantees that the distortion is smaller than one pixel.


Subsurface and transcutaneous Raman spectroscopy and mapping using concentric illumination rings and collection with a circular fiber-optic array.
Different spatial separations between an illumination ring and a bundle of 50 collection fibers focused to collect light in the center of the ring were used to investigate the recovery of subsurface Raman spectra. The depth of Raman signal recovery and the preservation of spatial information in the recovered signal were investigated using polymer blocks stacked in different geometries. The illumination rings were then combined into a single data set to increase variation in the signal. Multivariate data analysis was used to recover the Raman spectra of the subsurface component. The Raman spectrum of a Delrin target was recoverable at depths up to 22.6 mm of overlying Teflon. Spatial information was lost at approximately 6.5 mm below the Teflon surface. The same protocols were used to recover canine bone spectra transcutaneously at depths up to 5 mm below the skin's surface. The recovered bone spectra were validated by exposed bone measurements.


Molecular detection and genomic characterization of diverse hepaciviruses in African rodents.
Hepatitis C virus (HCV; genus Hepacivirus) represents a major public health problem, infecting about three per cent of the human population. Because no animal reservoir carrying closely related hepaciviruses has been identified, the zoonotic origins of HCV still remain unresolved. Motivated by recent findings of divergent hepaciviruses in rodents and a plausible African origin of HCV genotypes, we have screened a large collection of small mammals samples from seven sub-Saharan African countries. Out of 4,303 samples screened, eighty were found positive for the presence of hepaciviruses in twenty-nine different host species. We, here, report fifty-six novel genomes that considerably increase the diversity of three divergent rodent hepacivirus lineages. Furthermore, we provide strong evidence for hepacivirus co-infections in rodents, which were exclusively found in four sampled species of brush-furred mice. We also detect evidence of recombination within specific host lineages. Our study expands the available hepacivirus genomic data and contributes insights into the relatively deep evolutionary history of these pathogens in rodents. Overall, our results emphasize the importance of rodents as a potential hepacivirus reservoir and as models for investigating HCV infection dynamics.


Localization of presynaptic inputs on dendrites of individually labeled neurons in three dimensional space using a center distance algorithm.
The spatial distribution of synaptic inputs on the dendritic tree of a neuron can have significant influence on neuronal function. Consequently, accurate anatomical reconstructions of neuron morphology and synaptic localization are critical when modeling and predicting physiological responses of individual neurons. Historically, generation of three-dimensional (3D) neuronal reconstructions together with comprehensive mapping of synaptic inputs has been an extensive task requiring manual identification of putative synaptic contacts directly from tissue samples or digital images. Recent developments in neuronal tracing software applications have improved the speed and accuracy of 3D reconstructions, but localization of synaptic sites through the use of pre- and/or post-synaptic markers has remained largely a manual process. To address this problem, we have developed an algorithm, based on 3D distance measurements between putative pre-synaptic terminals and the post-synaptic dendrite, to automate synaptic contact detection on dendrites of individually labeled neurons from 3D immunofluorescence image sets. In this study, the algorithm is implemented with custom routines in Matlab, and its effectiveness is evaluated through analysis of primary sensory afferent terminals on motor neurons. Optimization of algorithm parameters enabled automated identification of synaptic contacts that matched those identified by manual inspection with low incidence of error. Substantial time savings and the elimination of variability in contact detection introduced by different users are significant advantages of this method.


Immune regulation by histamine H4 receptors in skin.
The diverse effects of histamine on immune regulation appear to be due to differential expression and regulation of four types of histamine receptors and their distinct intracellular signals. The differences in cellular expression and affinities of these receptors for histamine determine the biological effects of histamine and the drugs that target histamine receptors. In this issue, Dijkstra et al., demonstrate the expression and some of the functions of histamine H(4) receptors on inflammatory dendritic cells in atopic dermatitis skin.


Glucocorticoids potentiate IL-6-induced SP-B expression in H441 cells by enhancing the JAK-STAT signaling pathway.
The respiratory distress syndrome (RDS) contributes to perinatal morbidity and mortality associated with preterm birth. Surfactant protein B (SP-B) is decreased in RDS. Both maternal antenatal steroid administration and chorioamnionitis reduce the incidence and severity of RDS. An important mediator in chorioamnionitis is IL-6 using the JAK-STAT signaling pathway for signal transduction. We hypothesized that the steroids, betamethasone (BTM) and dexamethasone (DXM), and IL-6 had synergistic effects on SP-B gene expression and STAT3 phosphorylation in H441 cells. DXM and BTM increased SP-B mRNA levels by 16.5 (13.3)-fold and IL-6 alone by 2.3-fold. After 48-h exposure of cells to DXM or BTM, IL-6 caused a significantly greater increase in SP-B mRNA levels (28.1-fold) than IL-6 or glucocorticoids alone. Whereas IL-6 stimulated tyrosine phosphorylation of STAT3 in a time- and dose-dependent way, DXM and BTM had no effect on STAT3 phosphorylation. Both DXM and BTM could potentiate IL-6-induced phosphorylation of STAT3. The synergism of glucocorticoids and IL-6 on SP-B gene expression and the effect of glucocorticoids on IL-6-induced STAT3 phosphorylation could be blocked by a JAK inhibitor. Expression level analysis showed that glucocorticoids increased the expression of the IL-6-binding α-subunit receptor (IL-6R) on mRNA and protein level. Our findings could represent an example of a pulmonary regulation system in which one role of glucocorticoids is to increase the effect of a cytokine by upregulation of its receptor. The described in vitro interaction of IL-6 and glucocorticoids could help explain the clinical observation that prenatal inflammation in preterm babies with antenatal steroid administration can attenuate severity of RDS.


Effects of minimum drinking age laws: review and analyses of the literature from 1960 to 2000.
The goal of this article is to review critically the extant minimum legal drinking age (MLDA) research literature and summarize the current state of knowledge regarding the effectiveness of this policy. Comprehensive searches of four databases were conducted to identify empirical studies of the MLDA published from 1960 to 1999. Three variables were coded for each study regarding methodological quality: (1) sampling design, (2) study design and (3) presence or absence of comparison group. We identified 241 empirical analyses of the MLDA. Fifty-six percent of the analyses met our criteria for high methodological quality. Of the 33 higher quality studies of MLDA and alcohol consumption, 11 (33%) found an inverse relationship; only 1 found the opposite. Similarly, of the 79 higher quality analyses of MLDA and traffic crashes, 46 (58%) found a higher MLDA related to decreased traffic crashes; none found the opposite. Eight of the 23 analyses of other problems found a higher MLDA associated with reduced problems; none found the opposite. Only 6 of the 64 college-specific studies (9%) were of high quality; none found a significant relationship between the MLDA and outcome measures. The preponderance of evidence indicates there is an inverse relationship between the MLDA and two outcome measures: alcohol consumption and traffic crashes. The quality of the studies of specific populations such as college students is poor, preventing any conclusions that the effects of MLDA might differ for such special populations.


Human T-lymphotropic virus type 1 mitochondrion-localizing protein p13(II) is required for viral infectivity in vivo.
Human T-lymphotropic virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia, encodes unique regulatory and accessory proteins in the pX region of the provirus, including the open reading frame II product p13(II). p13(II) localizes to mitochondria, binds farnesyl pyrophosphate synthetase, an enzyme involved in posttranslational farnesylation of Ras, and alters Ras-dependent cell signaling and control of apoptosis. The role of p13(II) in virus infection in vivo remains undetermined. Herein, we analyzed the functional significance of p13(II) in HTLV-1 infection. We compared the infectivity of a human B-cell line that harbors an infectious molecular clone of HTLV-1 with a selective mutation that prevents the translation of p13(II) (729.ACH.p13) to the infectivity of a wild-type HTLV-1-expressing cell line (729.ACH). 729.ACH and 729.ACH.p13 producer lines had comparable infectivities for cultured rabbit peripheral blood mononuclear cells (PBMC), and the fidelity of the start codon mutation in ACH.p13 was maintained after PBMC passage. In contrast, zero of six rabbits inoculated with 729.ACH.p13 cells failed to establish viral infection, whereas six of six rabbits inoculated with wild-type HTLV-1-expressing cells (729.ACH) were infected as measured by antibody responses, proviral load, and HTLV-1 p19 matrix antigen production from ex vivo-cultured PBMC. Our data are the first to indicate that the HTLV-1 mitochondrion-localizing protein p13(II) has an essential biological role during the early phase of virus infection in vivo.


Practice development for midwifery education: an innovative way forward.
Within workplaces there can be several different cultures operating, and it is widely recognised that this occurs in health services. Midwifery and maternity care has, and continues to face many challenges as services continually change and develop to meet the needs of women and their families. To help meet these challenges a practice development initiative was undertaken within a large maternity service in Australia to improve the learning and workplace culture. This service consisted of four separate units providing care for women and their families in the antenatal, birthing, postnatal and neonatal periods. The coming together of these four units as a service began with the creation of a shared values statement which was adopted by all midwifery staff. To obtain evidence of the current workplace, observations of practice, the review of women's stories, and audits of clinical data were undertaken. Nine midwives were trained and supported to facilitate critical discussions of the data. These critical discussions, reflections and analysis of the data, led to the identification of four domains or key areas the staff prioritised for change. This led to practice development groups being formed within the maternity service, who developed collaborative and creative ways of thinking about the issues or problems identified. This paper highlights how the processes of practice development were implemented to improve one of these domains "the learning and workplace culture", especially in relation to educational information and resources for women, their families and staff. The journey began over three years ago and continues to evolve.


The identification of two low-density lipoprotein receptor gene mutations in South African familial hypercholesterolaemia.
Two point mutations were discovered in the low-density lipoprotein genes of patients with familial hypercholesterolaemia (FH). Defective genes were cloned and/or amplified by the polymerase chain reaction (PCR) method and the DNA sequences determined. A guanine to adenine base transition in exon 4 was found to be the molecular defect in 20% of cases of FH in the Afrikaner population. A second mutation, a guanine to adenine base substitution in exon 9, was identified in two homozygous FH individuals. Restriction enzyme analysis of PCR-amplified DNA from blood and tissue samples now permits accurate diagnosis of these mutations.


Possible surface reactions on Mars: implications for viking biology results.
The results of two of the three biology experiments carried out on the Viking Mars landers have been simulated. The mixture of organic compounds labeled with carbon-14 used on Mars released carbon dioxide containing carbon-14 when reacted with a simulated martian surface and atmosphere exposed to ultraviolet light (labeled release experiment). Oxygen was released when metal peroxides or superoxides were treated with water (gas exchange experiment). The simulations suggest that the results of these two Viking experiments can be explained on the basis of reactions of the martian surface and atmosphere.


Whey peptides exacerbate body weight gain and perturb systemic glucose and tissue lipid metabolism in male high-fat fed mice.
Consumption of milk-derived whey proteins has been demonstrated to have insulin-sensitizing effects in mice and humans, in part through the generation of bioactive whey peptides. While whey peptides can prevent insulin resistance in vitro, it is unclear whether consumption of whey peptides can prevent obesity-induced metabolic dysfunction in vivo. We sought to determine whether whey peptides consumption can protect from high fat (HF) diet-induced obesity and dysregulation of glucose homeostasis. Male C57BL/6J mice were fed either a low or HF diet for 13 weeks. HF diet fed mice were provided drinking water with no addition (control), undigested whey protein isolate (WPI, 1 mg ml-1) or whey protein hydrolysate (WPH, 1 mg ml-1) throughout the diet regimen. Mice consuming WPH gained more body weight and were more glucose intolerant compared to those consuming WPI or water only. Despite increased body weight gain, perigonadal adipose tissue weight and lipid accumulation were unchanged. However, excess lipids accumulated ectopically in the liver and skeletal muscle in mice consuming WPH, which was associated with elevated inflammatory markers systemically and in adipose tissue, liver, and skeletal muscle. In skeletal muscle, mitochondrial fat oxidation and electron transport chain proteins were decreased with WPH consumption, indicative of mitochondrial dysfunction. Taken together, our results demonstrate that WPH, but not WPI, exacerbates HF-induced body weight gain and impairs glucose homeostasis, which is accompanied by increased inflammation, ectopic fat accumulation and mitochondrial dysfunction. Thus, our results argue against the use of dietary whey peptide supplementation as a preventative option against HF diet-induced metabolic dysfunction.


Coronary vasospasm as the underlying cause for chest pain in patients with PVB19 myocarditis.
To evaluate the incidence of coronary vasospasm as a possible pathophysiological mechanism causing chest pain symptoms in patients with clinically suspected myocarditis. Prospective study in a teaching hospital. 85 patients who presented at hospital with atypical chest pain and demonstrated clinical signs suggestive of myocarditis. Incidence of coronary vasospasm demonstrated by intracoronary acetylcholine (ACh) testing. The combined procedure of intracoronary ACh testing and endomyocardial biopsy (EMB) was performed after ruling out significant coronary artery disease (CAD). EMBs were analysed for myocardial inflammation by immunohistological methods and for virus genome persistence. Pathological biopsy results, including myocardial inflammation or detection of viral genomes, or both, were found in 55 (64.7%) patients while 30 (35.3%) patients showed neither cardiac inflammation nor viral genomes and were defined as the control group. Coronary vasospasm was demonstrated in 39/55 (70.9%) patients with pathological results compared with only 12/30 (40.0%) with normal biopsy results (p = 0.01). Patients with isolated PVB19 infection (n = 22) demonstrated a significantly higher incidence of coronary vasospasm than both those with isolated HHV6 infection (86.4% vs 46.7%; p = 0.025) and those with normal biopsy results (86.4% vs 40.0%; p<0.001). Univariate and multivariate logistic regression analysis showed that only PVB19 infection was independently correlated with coronary vasospasm (OR = 4.9, 95% CI 1.56 to 15.28, p = 0.006). Coronary vasospasm is one of the main reasons for atypical chest pain in patients with clinical signs of myocarditis and biopsy-proven PVB19 myocarditis in the absence of significant CAD.


Survival After In-Hospital Cardiac Arrest In Critically Ill Patients: Implications For The Covid-19 Pandemic?
The coronavirus disease 2019 (COVID-19) outbreak is placing a considerable strain on U.S. healthcare systems. Due to presumptions of poor outcomes in such critically ill patients, many hospitals have started considering a universal do-not-resuscitate order in patients with confirmed Covid-19 given a limited supply of intensive care unit (ICU) beds and the potential risk of transmission of infection to healthcare workers during resuscitation. However, empirical data on survival of cardiac arrest in Covid-19 patients are unavailable at this time. To inform this debate, we report survival outcomes following cardiopulmonary resuscitation in a cohort of similar critically ill patients with pneumonia or sepsis who were receiving mechanical ventilation in an ICU at the time of arrest. The probability of survival without severe neurological disability (CPC of 1 or 2) ranged from less than 3% to over 22% across key patient subgroups, For patients with an initial rhythm of asystole or PEA, who were also receiving vasopressors at the time of arrest, fewer than 10% were discharged without severe neurological disability (CPC of 1 or 2), and this number dropped to less than 3% in patients over 80 years old. In contrast, survival rates were much higher in younger patients, patients with an initial rhythm of VF or pulseless VT, and in patients receiving ventilatory support without vasopressors. Our findings suggest caution in universal resuscitation policies. Even in a cohort of critically ill patients on mechanical ventilation, survival outcomes following in-hospital resuscitation were not uniformly poor and varied markedly depending on age, co-morbidities and illness severity. We believe that these data can help inform discussions among patients, providers and hospital leaders regarding resuscitation policies and goals of care in the context of the COVID-19 pandemic.


Constructing 3D crystal templates for photonic band gap materials using holographic optical tweezers.
A simple and robust method is presented for the construction of 3-dimensional crystals from silica and polystyrene microspheres. The crystals are suitable for use as templates in the production of three-dimensional photonic band gap (PBG) materials. Manipulation of the microspheres was achieved using a dynamic holographic assembler (DHA) consisting of computer controlled holographic optical tweezers. Attachment of the microspheres was achieved by adjusting their colloidal interactions during assembly. The method is demonstrated by constructing a variety of 3-dimensional crystals using spheres ranging in size from 3 microm down to 800 nm. A major advantage of the technique is that it may be used to build structures that cannot be made using self-assembly. This is illustrated through the construction of crystals in which line defects have been deliberately included, and by building simple cubic structures.


Effect of pretreatment with artichoke extract on carbon tetrachloride-induced liver injury and oxidative stress.
Artichoke is a plant with antioxidant properties. In this study, we investigated the effect of artichoke extract pretreatment on carbon tetrachloride (CCl4)-induced oxidative stress and hepatotoxicity. Rats were given artichoke leaf extract (1.5g/kg/day) by gavage for 2 weeks and after then CCl4 (1ml/kg; i.p.) was applied. All rats were killed 24h after the CCl4 injection. CCl4 administration resulted in hepatic necrosis and significant increases in plasma transaminase activities as well as hepatic malondialdehyde (MDA) and diene conjugate (DC) levels in the liver of rats. Glutathione (GSH) and vitamin C levels decreased, but vitamin E levels increased in the liver of CCl4-treated rats. Hepatic superoxide dismutase (SOD) activities remained unchanged, but glutathione peroxidase (GSH-Px) and glutathione transferase (GST) activities decreased following CCl4 treatment. In rats pretreated with artichoke extract, significant decreases in plasma transaminase activities and amelioration in histopathological changes in the liver were observed following CCl4 treatment as compared to CCl4-treated rats. In addition, hepatic MDA and DC levels decreased, but GSH levels and GSH-Px activities increased without any change in other antioxidant parameters following CCl4 treatment in artichoke-pretreated rats. The present findings indicate that in vivo architoke extract administration may be useful for the prevention of oxidative stress-induced hepatotoxicity.


The effects of repeated thermal therapy on quality of life in patients with type II diabetes mellitus.
Decreased quality of life in diabetes is associated with poor health outcomes. Far-infrared sauna treatments improve the quality of life for those with chronic pain, chronic fatigue syndrome, depression, and congestive heart failure. The objective of this study is to determine whether far-infrared saunas have a beneficial effect on quality of life in those with type II diabetes. This was a sequential, longitudinal, interrupted time series design study. The setting was Fraser Lake BC, a rural village in central British Columbia, Canada. All patients of the Fraser Lake Community Health Center with type II diabetes were invited to participate in this study. The study consisted of 20-minute, 3 times weekly infrared sauna sessions, over a period of 3 months. To assess quality of life, subjects completed the 36-item Short-form Health Survey Version 2 (SF-36v2) questionnaire as well as "Zero-to-Ten" Visual Analogue Scales. Baseline study parameters were measured within 1 week prior to commencing sauna sessions. Postintervention measurements were collected between 1 and 3 days after the last sauna session. Physical health, general health, and social functioning indices of the SF-36v2 improved. Visual Analogue Scales for stress and fatigue improved. Far-infrared sauna use maybe associated with improved quality of life in people with type II diabetes mellitus. Uptake of infrared saunas use is greater than the uptake of other lifestyle interventions.


αB-crystallin response to a pro-oxidant non-cytotoxic environment in murine cardiac cells: An "in vitro" and "in vivo" study.
The αB-crystallin (HSPB5) protein is modulated in response to a wide variety of stressors generated by multiple physio-pathological conditions, sustained by reactive oxygen species (ROS) production. In cardiac muscle tissue, this protein regulates various cellular processes, such as protein degradation, apoptosis and the stabilization of cytoskeletal elements. In this work, we studied the role of HSPB5 expression, activation and localization in HL-1 murine cardiomyocytes exposed to pro-oxidant and non-cytotoxic H2O2 concentration, as well as in cardiac tissue isolated from mice following an acute, non-damaging endurance exercise. Our results demonstrated that HSPB5 is the most abundant HSP in both cardiac muscle tissue and HL-1 cells when compared to HSPB1 or HSPA1A (≈3-8 fold higher protein concentrations, p < 0.01). The acute exposure of cardiac muscle cells to sustainable level of H2O2 "in vitro" or to aerobic non-damaging exercise "in vivo" determined a fast and specific increase of HSPB5 phosphorylation (from 3 up to 25 fold increase, p < 0.01) correlated to an increase in lipid peroxidation (p < 0.05). In both experimental models, p-HSPB5 likely facilitated both the interaction with β-actin, desmin, and α-Filamin 1, the last one identified as new HSPB5 substrate in cardiac cells, as well as the sub-localization of HSPB5 within the same cellular compartment or the re-localization between compartments (i.e., nucleus and cytosol). Taken together, these data point out the role of "oxidative eustress" induced by physiological conditions in activating the molecular machinery devoted to cardiomyocytes' protection and candidate HSPB5 as a putative molecular mediator for the health benefits induced in cardiac tissue by exercise training.


Rapid antibody response to influenza vaccination in "at risk" groups.
Persons attending for routine influenza vaccination in an urban practice each provided three specimens of blood for evaluating their immunological response. 138 (67%) of the 206 persons were defined as "at risk" by reason of morbidity as given in the guidelines published by the Chief Medical Officer. The mean age was 67 yr and 65% were aged 65 yr or more. By day 7, 71% of 31 persons had protective H(1)N(1) titres, 61% H(3)N(2) and 42% B. These proportions were similar to those found at day 14 and at day 21 based on 159 persons. These findings suggest that an effective immune response is mounted within seven days of vaccination indicating that the vaccination of persons "at risk" is worthwhile even after an epidemic has established itself. This is not a reason to modify present policy of routine vaccination in early winter well before epidemics are likely to occur.


Men's decision-making about predictive BRCA1/2 testing: the role of family.
Men who have a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutation. Male carriers may be at increased risk of breast and prostate cancers. Relatively little is known about at-risk men's decision-making about BRCA1/2 testing. This qualitative study explores the influences on male patients' genetic test decisions. Twenty-nine in-depth interviews were undertaken with both carrier and noncarrier men and immediate family members (17 male patients, 8 female partners, and 4 adult children). These explored family members' experiences of cancer and genetic testing, decision-making about testing, family support, communication of test results within the family, risk perception and risk management. Implicit influences on men's testing decisions such as familial obligations are examined. The extent to which other family members--partners and adult children--were involved in testing decisions is also described. It is demonstrated that mothers of potential mutation carriers not only perceive themselves as having a right to be involved in making this decision, but also were perceived by their male partners as having a legitimate role to play in decision-making. There was evidence that (adult) children were excluded from the decision-making, and some expressed resentment about this. The implications of these findings for the practice of genetic counseling are discussed.


Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients.
Human herpesvirus-6 (HHV-6), Epstein-Barr virus and parvovirus B19 have been suggested as etiological agents of chronic fatigue syndrome but none of these viruses is consistently detected in all patients. However, active viral infections may be localized in specific tissues, and, therefore, are not easily detectable. The aim of this study was to investigate the presence of HHV-6, HHV-7, EBV and parvovirus B19 in the gastro-intestinal tract of CFS patients. Using real-time PCR, viral DNA loads were quantified in gastro-intestinal biopsies of 48 CFS patients and 35 controls. High loads of HHV-7 DNA were detected in most CFS and control biopsies. EBV and HHV-6 were detected in 15-30% of all biopsies. Parvovirus B19 DNA was detected in 40% of the patients versus less than 15% of the controls. Parvovirus B19 may be involved in the pathogenesis of CFS, at least for a subset of patients. The gastro-intestinal tract appears as an important reservoir of infection for several potentially pathogenic viruses.


Adolescent health and adaptation in Canada: examination of gender and age aspects of the healthy immigrant effect.
A longstanding and widely held assumption is that immigrants suffer from ill health and adaptation problems. Yet recent studies show that immigrants report the same or better state of health compared to their native-born counterparts. This phenomenon, known as the healthy immigrant effect, has been found in studies of specific health conditions of adults. The present study focuses instead on adolescents and extends its examination of the healthy immigrant effect, measuring both health and adaptation. Using data from population samples in the Canadian Community Health Survey (2007), foreign-born immigrant adolescents (n = 920) were compared to non-immigrant adolescents (n = 13,572) for their self-report to questionnaire items for health (general health, mental health, chronic illnesses with psychosomatic symptoms, and psychological illnesses) and adaptation (daily life stress, life satisfaction, and sense of belonging). Adolescents' gender, age, and length of residence were analyzed for the effects. Immigrant adolescents were better than non-immigrant peers on the four health measures, and did not differ from non-immigrants on the three adaptation measures despite having less household income and more family members in the household. Immigrant girls exhibited more resilient adaptability, while young immigrant boys and older non-immigrant girls displayed some potential vulnerability. Length of residence, on the other hand, did not contribute to differences for the health and adaptation of immigrant adolescents. The healthy immigrant effect was confirmed in a community population sample of adolescents in Canada. Foreign-born immigrant adolescents experience better health, as well as good adaptation equal to their native-born peers. These outcomes call for further research on sustaining good health and adaptation of the immigrant population, in particular by providing age-related effective services and prevention strategies.


NCCN task force report: management of neuropathy in cancer.
Neuropathy is a common, often debilitating complication of cancer and its treatment. Effective management of this disorder depends on early diagnosis and an understanding of its underlying causes in the individual patient. In January 2009, NCCN gathered a multidisciplinary group to review the literature and discuss intervention strategies currently available to patients as well as areas that require research efforts. The task force, which comprised experts in anesthesiology, medical oncology, neurology, neuro-oncology, neurophysiology, nursing, pain management, and rehabilitation, was charged with the goal of outlining recommendations for the possible prevention, diagnosis, and management of neuropathy. This report documents the proceedings of this meeting with a general background on neuropathy and neuropathy in oncology, followed by discussions on challenges and research issues, evaluation criteria, and management of different symptoms associated with this disorder.


Recent developments in drug delivery to prolong allograft survival in lung transplant patients.
Since the discovery of cyclosporine in 1971, calcineurin inhibitors have played a critical role in the therapeutic suppression of the immune response. Patients receiving solid organ transplants rely heavily on these medications to prevent the acute and chronic rejection of allografted tissue. These therapies can prove difficult because of potential toxicity, heightened risk of invasive infection, and erratic oral bioavailability, requiring frequent blood samples for monitoring of systemic levels. Added challenges are presented in immunosuppression of lung transplant patients owing to the increased susceptibility to invasive infection and extensive immune mechanisms inherent in lung tissue. With the introduction of tacrolimus, a more potent calcineurin inhibitor, clinical outcomes of transplants have continued to improve; however, little improvement has been noted in lung transplantation. While very effective upon arrival at the site of action, tacrolimus and cyclosporine present a variety of formulation challenges such as poor solubility, potential systemic toxicity, and extensive first pass metabolism. Initial attempts to improve solubility in both oral and intravenous formulations have resulted in variable drug absorption and increased systemic toxicity, respectfully, creating a need for formulation improvement. Through alternative routes of delivery and novel formulation techniques, researchers have addressed these issues and, in some cases, demonstrated improved clinical outcomes. Through enhanced solubilization, reduction in absorption variability, and more effective drug targeting with reduced systemic levels, improvements in outcomes and overall patient survival in lung and other solid organ transplantation can be expected.


Magnetic resonance imaging volumes of the hippocampus and the amygdala in women with borderline personality disorder and early traumatization.
Based on findings of stress-induced neural disturbances in animals and smaller hippocampal volumes in humans with posttraumatic stress disorder), we hypothesized that patients with borderline personality disorders (BPD), who often are victims of early traumatization, have smaller volumes of the hippocampus and the amygdala. We assumed that volumes of these brain regions are negatively correlated with traumatic experiences and with neuropsychological deficits. We studied 21 female patients with BPD and a similar group of healthy controls. We performed clinical assessments, a modified version of the Childhood Trauma Questionnaire, and magnetic resonance imaging volumetric measurements of the hippocampus, amygdala, temporal lobes, and prosencephalon. Neuropsychological testing included scales on which disturbances in BPD were previously reported. The patients with BPD had nearly 16% smaller volumes of the hippocampus (P<.001) and 8% smaller volumes of the amygdala (P<.05) than the healthy controls. The results for both hemispheres were nearly identical and were controlled for the volume of the prosencephalon and for head tilts. The volumes of the hippocampus were negatively correlated with the extent and the duration of self-reported early traumatization only when BPD and control subjects were considered together. Levels of neuropsychological functioning were associated with the severity of depression but not with the volumes of the hippocampus. In female patients with BPD, we found reduction of the volumes of the hippocampus (and perhaps of the amygdala), but the association of volume reduction and traumatic experiences remains unclear. Arch Gen Psychiatry. 2000;57:1115-1122.