Conservation of prehistoric caves and stability of their inner climate: lessons from Chauvet and other French caves.
In the last 150 years, some prehistoric painted caves suffered irreversible degradations due to misperception of conservation issues and subsequent mismanagement. These sites presented naturally an exceptional stability of their internal climate allowing conservation in situ of outstanding fragile remains, some for nearly 40,000 years. This is for a large part due to exchanges of air, CO2, heat and water with the karstic system in which these caves are included. We introduce the concept of underground confinement, based on the stability of the inner cave climate parameters, especially its temperature. Confined caves present the best conservative properties. It is emphasized that this confined state implies slow exchanges with the surrounding karst and that a stable cave cannot be viewed as a closed system. This is illustrated on four case studies of French caves of various confinement states evidenced by long term continuous monitoring and on strategies to improve their conservation properties. The Chauvet cave presents optimal conservation properties. It is wholly confined as shown by the stability of its internal parameters since its discovery in 1994. In Marsoulas cave, archeological works removed the entrance scree and let a strong opening situation of the decorated zone. Remediation is expected by adding a buffer structure at the entrance. In Pech Merle tourist cave, recurrent painting fading was related to natural seasonal drying of walls. Improvement of the cave closure system restored a confined state insuring optimal visibility of the paintings. In Gargas tourist cave, optimization of closures, lighting system and number of visitors, allowed it to gradually reach a semi-confined state that improved the conservation properties. Conclusions are drawn on the characterization of confinement state of caves and on the ways to improve their conservation properties by restoring their initial regulation mechanisms and to avoid threats to their stability.


Advances in exercise, fitness, and performance genomics.
An annual review publication of the most significant articles in exercise, fitness, and performance genomics begins with this article, which covers 2 yr, 2008 and 2009. The review emphasizes the strongest articles as defined by sample size, quality of phenotype measurements, quality of the exercise program or physical activity exposure, study design, adjustment for multiple testing, quality of genotyping, and other related study characteristics. With this avowed focus on the highest quality articles, only a small number of published articles are reviewed. Among the most significant findings reported here are a brief overview of the first genome-wide association study of the genetic differences between exercisers and nonexercisers. In addition, the latest results on the actinin alpha 3 (ACTN3) R577X nonsense polymorphism are reviewed, emphasizing that no definitive conclusion can be reached at this time. Recent studies that have dealt with mitochondrial DNA haplogroups and endurance performance are described. Published reports indicating that physical activity may attenuate the effect of the fat mass and obesity associated (FTO) gene risk allele on body mass index are reviewed. Articles that have tested the contributions of specific genes to the response of glucose and insulin metabolism traits to regular exercise or physical activity level are considered and found to be generally inconclusive at this stage. Studies examining ethnic differences in the response of blood lipids and lipoproteins to exercise training cannot unequivocally relate these to apolipoprotein E (APOE) genotypes. Hemodynamic changes with exercise training were reported to be associated to sequence variation in kinesin heavy chain (KIF5B), but no replication study is available as of yet. We conclude from this first installment that exercise scientists need to prioritize high-quality research designs and that replication studies with large sample sizes are urgently needed.


Listening and question-asking behaviors in resident and nurse handoff conversations: a prospective observational study.
To characterize interactivity during resident and nurse handoffs by investigating listening and question-asking behaviors during conversations. Resident (n = 149) and nurse (n = 126) handoffs in an inpatient medicine unit were audio-recorded. Handoffs were coded based on listening behaviors (active and passive), question types (patient status, coordination of care, clinical reasoning, and framing and alignment), and question responses. Comparisons between residents and nurses for listening and question-asking behaviors were performed using the Wilcoxon rank-sum tests. A Poisson regression model was used to investigate differences in the question-asking behaviors between residents and nurses, and the association between listening and question-asking behaviors. There were no significant differences between residents and nurses in their active (18% resident vs 39% nurse handoffs) or passive (88% resident vs 81% nurse handoffs) listening behaviors. Question-asking was common in resident and nurse handoffs (87% vs 98%) and focused primarily on patient status, co-ordination, and framing and alignment. Nurses asked significantly more questions than residents (Mresident = 2.06 and Mnurse = 5.52) by a factor of 1.76 (P < 0.001). Unit increase in listening behaviors was associated with an increase in the number of questions during resident and nurse handoffs by 7% and 12%, respectively. As suggested by the Joint Commission, question-asking behaviors were common across resident and nurse handoffs, playing a critical role in supporting resilience in communication and collaborative cross-checks during conversations. The role of listening in initiating question-asking behaviors is discussed.


Towards single cell heat shock response by accurate control on thermal confinement with an on-chip microwire electrode.
Metal electrodes with micron scale width enable the heating of less than a dozen cells in a confluent layer at predictable temperatures up to 85 °C with an accuracy of ±2 °C. Those performances were obtained by a preliminary robust temperature calibration based on biotin-rhodamine fluorescence and by controlling the temperature map on the substrate through thermal modeling. The temperature accuracy was proved by inducing the expression of heat shock proteins (HSP) in a few NIH-3T3 cells through a confined and precise temperature rise. Our device is therefore effective to locally induce a heat shock response with almost single-cell resolution. Furthermore, we show that cells heated at a higher temperature than the one of heat shock remain alive without producing HSP. Electrode deposition being one of the most common engineering processes, the fabrication of electrode arrays with a simple control circuit is clearly within reach for parallel testing. This should enable the study of several key mechanisms such as cell heat shock, death or signaling. In nanomedicine, controlled drug release by external stimuli such as for example temperature has attracted much attention. Our device could allow fast and efficient testing of thermoactivable drug delivery systems.


Treatment efficacy of pegylated interferon plus ribavirin therapy in chronic hepatitis C patients with mixed genotype 1/2 infection.
The treatment efficacy of patients with mixed hepatitis C virus (HCV) genotype 1/genotype 2 (HCV-1/2) remains unknown. We aimed to elucidate the sustained virological response (SVR) rate in patients with HCV-1/2 infection. One hundred and ten HCV-1/2 patients treated with response-guided peginterferon/ribavirin therapy (24 weeks for patients with a rapid virological response [RVR] and low viral loads; 48 weeks for patients without a RVR or high viral loads) were allocated. Two hundred HCV-1 patients were selected as a historical control. Interleukin-28B (IL-28B) rs8099917 genotype was tested for the association with an SVR. The rates of RVR, sustained virologic response (SVR), and relapse rate were 71.8%, 87.3%, and 11.1%, respectively. The SVR rate was significantly higher in patients with an abbreviated regimen as compared with those with 48-week regimen (95.5% vs 75.0%, P = 0.002), and both were similar to the HCV-1 historical control. Stepwise logistic regression analysis revealed that lower baseline viral loads were the single factor predictive of an RVR (odds ratio/95% confidence intervals [OR/CI] of 41.62/9.72-178.19, P < 0.001). The achievement of an RVR was the single best factor predictive of an SVR (OR/CI: 7.5/1.33-42.27, P = 0.02). Nevertheless, an abbreviated regimen became the single factor associated with an SVR if treatment regimen was taken into consideration (OR/CI: 11.0/1.25-96.79, P = 0.03). The SVR rate did not differ between patients with rs8099917 TT and TG/GG genotype (91.7% vs 87.5%, P = 0.63). The treatment efficacy of patients with HCV-1/2 was satisfactory. The role of IL-28B genetic variants in the population with response-guided therapy was limited.


Analytical decision model for the cost-effective management of solitary pulmonary nodules.
Multiple strategies are currently being used to manage patients who present with indeterminate solitary pulmonary nodules (SPN). We have used decision-analysis models to assess the cost-effectiveness of various strategies for the diagnosis and management of SPN. Four decision strategies were compared: a wait and watch strategy, a surgery strategy, a computed tomography (CT)-based strategy, and a CT-plus-positron emission tomography (PET) strategy. An incremental cost-effectiveness ratio (ICER) was used to compare all strategies to the wait and watch strategy. A CT-plus-PET strategy was the most cost-effective over a large pretest likelihood (probability of having a malignant nodule), with a range of 0.12 to 0.69. Furthermore, within this likelihood range, the potential cost savings of using the CT-plus-PET strategy over the CT strategy ranged from $91 to $2,200 per patient. This translates to a yearly national savings of approximately $62.7 million. Decision-analysis modeling indicates the potential cost-effectiveness of [18F]2-fluoro-2-deoxy-D-glucose (FDG)-PET in the management of SPN. Furthermore, the decision trees developed can be used to model various features of the management of SPN, including modeling the cost-effectiveness of other newly emerging technologies.


Global mental health: A call to action.
Mental health needs have been recognized as a priority area by the World Health Organization (WHO), and a Comprehensive Mental Health Action Plan (2013) was proposed to address the needs of millions of people around the world. Concerns have been raised about the degree to which current global efforts are appropriate and sufficient for promoting mental health (MH), reducing the risk for common MH disorders, and addressing the needs of individuals experiencing mental illness. This commentary expands on the presentation of the Global Alliance for Behavioral Health and Social Justice's Task Force on Global Mental Health at the 16th Biennial Conference of the Society for Community Research and Action, held in Ottawa, Ontario, Canada June 21-24, 2017, "Building Capacity to Address Mental Illness and Emotional Distress in Low-Resource Settings and Among Refugee Populations." Utilizing a socioecological framework, this commentary offers a call to action in addressing global mental health by emphasizing the need for greater investments in wellness promotion, prevention, treatment, and recovery. Importantly, such efforts need to value local knowledge and culture, harness natural existing resources and assets, and ensure equitable distribution of key resources for MH. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Buffy coat PCR for diagnosis of experimental pneumococcal pneumonia.
An immunocompetent murine model of pneumococcal pneumonia and bacteremia was used to evaluate a PCR assay based on amplification of the pneumolysin gene. Mice were treated with trovafloxacin to determine the decline in sensitivity of PCR as lung bacterial concentrations decreased and blood cultures became sterile. Forty-three mice were studied for up to 120 h after start of antibiotic treatment. PCR of buffy coat specimens was more sensitive than PCR of plasma. Only 21% of animals had a positive blood culture, whereas 77% of PCR buffy coat assays were positive. After 48 h of therapy all blood culture specimens were sterile, whereas buffy coat PCR was positive in 57.8% of specimens. PCR of buffy coat specimens was negative in all mice colonized nasally with Streptococcus pneumoniae and in rabbits with Escherichia coli bacteremia. Our results demonstrate that our PCR technique using buffy coat specimens is highly specific for invasive pneumococcal disease and remains positive in the majority of animals for at least 48 h after start of antibiotic therapy.


Perceptual proxies for extracting averages in data visualizations.
Across science, education, and business, we process and communicate data visually. One bedrock finding in data visualization research is a hierarchy of precision for perceptual encodings of data (e.g., that encoding data with Cartesian positions allows more precise comparisons than encoding with sizes). But this hierarchy has only been tested for single-value comparisons, under the assumption that those lessons would extrapolate to multivalue comparisons. We show that when comparing averages across multiple data points, even for pairs of data points, these differences vanish. Viewers instead compare values using surprisingly primitive perceptual cues (e.g., the summed area of bars in a bar graph). These results highlight a critical need to study a broader constellation of visual cues that mediate the patterns that we can see in data, across visualization types and tasks.


Immunization information systems: a decade of progress in law and policy.
This article reports on a study of laws, regulations, and policies governing Immunization Information Systems (IIS, also known as "immunization registries") in states and selected urban areas of the United States. The study included a search of relevant statutes, administrative codes and published attorney general opinions/findings, an online questionnaire completed by immunization program managers and/or their staff, and follow-up telephone interviews.The legal/regulatory framework for IIS has changed considerably since 2000, largely in ways that improve IIS' ability to perform their public health functions while continuing to maintain strict confidentiality and privacy controls. Nevertheless, the exchange of immunization data and other health information between care providers and public health and between entities in different jurisdictions remains difficult due in part to ongoing regulatory diversity.To continue to be leaders in health information exchange and facilitate immunization of children and adults, IIS will need to address the challenges presented by the interplay of federal and state legislation, regulations, and policies and continue to move toward standardized data collection and sharing necessary for interoperable systems.


[The characteristics of the causative agents of suppurative-inflammatory complications in hemophiliacs].
Morphological-cultural and physiological-biochemical properties of 24 strains of microorganisms agents of pyo-inflammatory complications of different localization in patients with hemophilia have been studied. Microorganisms strains presented by the following species: Staphylococcus aureus, S. epidermidis, S. saprophyticus, Proteus vulgaris, P. morganii, Hafnia alvei, Serratia marcescens, have been identified. It was found out that in monoculture staphylococci prove to be the leading etiological agent (60.9%), gram-negative enterobacteria (52.2%) and bacterial associations (8.7%) occur more rarely. Special attention was paid to the study of resistance of antibiotics, circulation and pathogenicity factors that had a direct effect on the main disease severity. It was ascertained that high activity of enzymes and presence of pathogenicity factors were the peculiarities of microorganisms isolated from pyo-septic sites in patients with hemophilia. All the strains possessed multiple resistance to antibiotics.


Carbon source regulation of gene expression in Methylosinus trichosporium OB3b.
Gene expression in methanotrophs has been shown to be affected by the availability of a variety of metals, most notably copper regulating expression of alternative forms of methane monooxygenase. Here, we show that growth substrate also affects expression of genes encoding for enzymes responsible for the oxidation of methane to formaldehyde and the assimilation of carbon. Specifically, in Methylosinus trichosporium OB3b, expression of genes involved in the conversion of methane to methanol (pmoA and mmoX) and methanol to formaldehyde (mxaF, xoxF1, and xoxF2) as well as in carbon assimilation (fae1, fae2, metF, and sga) decreased when this strain was grown on methanol vs. methane, indicating that methanotrophs manipulate gene expression in response to growth substrate as well as the availability of copper. Interestingly, growth of M. trichosporium OB3b on methane vs. methanol was similar despite such large changes in gene expression. Finally, methanol-grown cultures of M. trichosporium OB3b also exhibited the "copper-switch." That is, expression of pmoA increased and mmoX decreased in the presence of copper, indicating that copper still controlled the expression of alternative forms of methane monooxygenase in M. trichosporium OB3b even though methane was not provided. Such findings indicate that methanotrophs can sense and respond to multiple environmental parameters simultaneously.


[Genetic and epidemiological investigation of a birth cohort of boxers].
The aim of this project, which ran from 1 January 1994 to 1 January 1999 (and which will be continued up to 2004), was to study mortality, disease incidence, and risk factors in a birth cohort of purebred boxer dogs born between January 1994 and February 1995 in the Netherlands (n = 2629). The ancestry of the boxer dogs in the cohort was considered a major risk factor. Special attention was given to genetic disorders, because a system for genetic counselling was being planned; however, non-genetic risk factors were also studied. Participation by breeders and owners of boxer dogs was very high. Pup mortality was 22% and was mainly caused by individual pup factors. Between 2 months and 4 years of age, 123 (7.5%) dogs died; the survival rate was 92.5%. The main causes of death were epilepsy (n = 23), heart disease (n = 22), and traffic injury (n = 13). Over the same age range, on average a boxer dog suffered about 4.25 times from a non-serious disease, mainly of the gastro-intestinal tract, upper respiratory tract, or locomotion system, but 20% had a serious, chronic disease. A relatively high heritability estimate (h2) was found for four diseases: cheilo-palatoschisis (h2 = 0.27), cryptorchism (h2 = 0.24), lesions of cruciate ligaments and menisci (h2 = 0.28), epilepsy (h2 = 0.36). Selection by means of genetic counselling, according to a programme developed on the basis of the results of this study, can reduce the frequency of these genetic diseases in purebred populations of boxer dogs. This genetic counselling programme will also be effective in other breeds of dog because it is based on linking specific pedigree and health information with a generally applicable method of estimating breeding values.


Methods and motivations for buprenorphine diversion from public opioid substitution treatment clinics.
This study aimed to develop a better understanding of the motives for suspected buprenorphine diversion during supervised dosing. Structured interviews were conducted with clients after 71 episodes of diversion at 3 opioid substitution treatment clinics in Sydney, Australia. Interviews were conducted by the clinic manager. An equivalent number of suspected episodes involved diversion via removal of buprenorphine from the mouth (n = 35), and secretion of buprenorphine in the mouth (n = 32). Denial of diversion occurred in 45% of suspected episodes and was significantly associated with secretion of buprenorphine in the mouth (P < .0001), suggesting a possible misunderstanding between clinicians and clients to what constitutes diversion. Motivations for diversion included "stockpiling" for later sublingual use (n = 15), discarding buprenorphine (n = 11), and giving it to another person (n = 5). A consistent definition of diversion of supervised dosed of buprenorphine is required. Diversion of supervised doses may represent a single episode of nonadherence to dosing instructions or more significant ambivalence over treatment. Responses to suspected diversion should aim to minimise harm and maximise treatment outcomes.


Upregulation of EphA receptor expression in the injured adult rat spinal cord.
After spinal cord injury (SCI), the inability of supraspinal neurons to regenerate or reform functional connections is likely due to proteins in the surrounding microenvironment restricting regeneration. EphAs are a family of receptor tyrosine kinases that are involved in axonal guidance during development. These receptors and their ligands, the Ephrins, act via repulsive mechanisms to guide growing axons towards their appropriate targets and allow for the correct developmental connections to be made. In the present study, we investigated whether EphA receptor expression changed after a thoracic contusion SCI. Our results indicate that several EphA molecules are upregulated after SCI. Using semiquantitative RT-PCR to investigate mRNA expression after SCI, we found that EphA3, A4, and A7 mRNAs were upregulated. EphA3, A4, A6, and A8 receptor immunoreactivity increased in the ventrolateral white matter (VWM) at the injury epicenter. EphA7 had the highest level of immunoreactivity in both control and injured rat spinal cord. EphA receptor expression in the white matter originated from glial cells as coexpression in both astrocytes and oligodendrocytes was observed. In contrast, gray matter expression was localized to neurons of the ventral gray matter (motor neurons) and dorsal horn. After SCI, specific EphA receptor subtypes are upregulated and these increases may create an environment that is unfavorable for neurite outgrowth and functional regeneration.


Mechanisms of pathogenicity of influenza A (H5N1) viruses in mice.
Avian-like H5N1 influenza viruses isolated from humans in 1997 were shown to have two distinct pathogenic phenotypes in BALB/c mice, after intranasal inoculation and without prior adaptation to this host. To further understand the mechanisms of H5N1 pathogenicity, we investigated the consequences of the mute of viral inoculation on morbidity and mortality, viral replication in pulmonary and systemic organs, and lymphocyte depletion. This study demonstrates the importance of extrapulmonary spread and replication, particularly in the brain, for the lethality of H5N1 viruses.


Mild Coarctation of Aorta is an Independent Risk Factor for Exercise-Induced Hypertension.
Exercise-induced hypertension is a predictor of cardiovascular events in patients with coarctation of aorta (COA). However, it is unclear whether mild COA diagnosis is an independent risk factor of exercise-induced hypertension. We hypothesized that for every unit increase in exercise, patients with COA (without hemodynamically significant coarctation) will have a higher rise in systolic blood pressure (SBP) compared with matched controls. One hundred forty-nine patients with COA (aortic coarctation peak velocity <2 m/s) who underwent exercise testing were matched 1:1 to controls using propensity score method based on age, sex, body mass index, hypertension diagnosis, and SBP at rest. We compared exercise-induced change in SBP between patients with COA and controls and also assessed the correlation between Doppler-derived aortic vascular function indices (effective arterial elastance index and total arterial compliance index) and exercise-induced changes in SBP. Compared with controls, patients with COA had a greater change in SBP per unit metabolic equivalent (β=2.86; 95% CI, 1.96-4.77 versus 1.07, 95% CI, -0.15 to 1.75; P=0.018) and per unit oxygen pulse (β=4.57; 95% CI, 2.97-7.12 versus 1.45, 95% CI, -0.79 to 2.09, P<0.001). There was a correlation between SBPpeak-SBPrest and elastance index (r=0.38, P=0.032) and between SBPpeak-SBPrest and total arterial compliance index (r=-0.51, P=0.001), suggesting an association between vascular dysfunction and exercise-induced BP changes. Patients with COA, without significant obstruction, had higher exercise-induced changes in SBP after adjustment for other risk factors for hypertension. Considering the already known prognostic importance of exercise-induced hypertension, the current study highlights the potential role of exercise testing for risk stratification of patients with mild COA.


Continuing decline of memory skills with significant recovery of intellectual function following severe carbon monoxide exposure: clinical, psychometric, and neuroimaging findings.
Extensive clinical, psychometric, and neuroimaging data are presented and interpreted with regard to a 35-year-old, White male college graduate who was exposed to severe carbon monoxide (CO) poisoning. The patient was comatose for 21 days following the exposure. Several other people, who were in the same room as the patient, died due to the toxic effects of the CO. The patient was employed premorbidly as a systems level lead computer programmer. The patient received medical and neuropsychological follow-up for 3 years post-CO exposure. Neuropsychological evaluations revealed a gradual, but incomplete recovery of general intellectual function. The patient continued to exhibit severe memory deficits with some evidence for small additional memory decline over time. Characteristic and permanent vestibular and gait disturbances were also noted, along with a variety of neuropsychological deficits that improved over time with the exception of memory function. The patient also experienced significant affective and personality changes. Neuroimaging studies reveal a generalized cortical atrophy as shown by significantly enlarged ventricles and a ventricle-to-brain ratio that exceeded 4 standard deviations above the norm. The observed atrophic changes are consistent with CO-induced anoxic type injury, which was also accompanied by bilateral lesions of the globus pallidus, caudate, and hippocampus. Despite obtaining average levels of general intellectual functioning over time, significant memory impairments, depression, and personality disturbances severely impaired the patients' vocational recovery and ability to return to work.


Extracellular Vesicles as Markers and Mediators in Sepsis.
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a highly lethal condition in which current tools for early diagnosis and therapeutic decision-making are far from ideal. Extracellular vesicles (EVs), 30 nm to several micrometers in size, are released from cells upon activation and apoptosis and express membrane epitopes specific for their parental cells. Since their discovery two decades ago, their role as biomarkers and mediators in various diseases has been intensively studied. However, their potential importance in the sepsis syndrome has gained attention only recently. Sepsis and EVs are both complex fields in which standardization has long been overdue. In this review, several topics are discussed. First, we review current studies on EVs in septic patients with emphasis on their variable quality and clinical utility. Second, we discuss the diagnostic and therapeutic potential of EVs as well as their role as facilitators of cell communication via micro RNA and the relevance of micro-organism-derived EVs. Third, we give an overview over the potential beneficial but also detrimental roles of EVs in sepsis. Finally, we focus on the role of EVs in selected intensive care scenarios such as coagulopathy, mechanical ventilation and blood transfusion. Overall, the prospect for EV use in septic patients is bright, ranging from rapid and precise (point-of-care) diagnostics, prevention of harmful iatrogenic interventions, to using EVs as guides of individualized therapy. Before the above is achieved, however, the EV research field requires reliable standardization of the current methods and development of new analytical procedures that can close the existing technological gaps.


Low pH, aluminum, and phosphorus coordinately regulate malate exudation through GmALMT1 to improve soybean adaptation to acid soils.
Low pH, aluminum (Al) toxicity, and low phosphorus (P) often coexist and are heterogeneously distributed in acid soils. To date, the underlying mechanisms of crop adaptation to these multiple factors on acid soils remain poorly understood. In this study, we found that P addition to acid soils could stimulate Al tolerance, especially for the P-efficient genotype HN89. Subsequent hydroponic studies demonstrated that solution pH, Al, and P levels coordinately altered soybean (Glycine max) root growth and malate exudation. Interestingly, HN89 released more malate under conditions mimicking acid soils (low pH, +P, and +Al), suggesting that root malate exudation might be critical for soybean adaptation to both Al toxicity and P deficiency on acid soils. GmALMT1, a soybean malate transporter gene, was cloned from the Al-treated root tips of HN89. Like root malate exudation, GmALMT1 expression was also pH dependent, being suppressed by low pH but enhanced by Al plus P addition in roots of HN89. Quantitative real-time PCR, transient expression of a GmALMT1-yellow fluorescent protein chimera in Arabidopsis protoplasts, and electrophysiological analysis of Xenopus laevis oocytes expressing GmALMT1 demonstrated that GmALMT1 encodes a root cell plasma membrane transporter that mediates malate efflux in an extracellular pH-dependent and Al-independent manner. Overexpression of GmALMT1 in transgenic Arabidopsis, as well as overexpression and knockdown of GmALMT1 in transgenic soybean hairy roots, indicated that GmALMT1-mediated root malate efflux does underlie soybean Al tolerance. Taken together, our results suggest that malate exudation is an important component of soybean adaptation to acid soils and is coordinately regulated by three factors, pH, Al, and P, through the regulation of GmALMT1 expression and GmALMT1 function.


Effects of postoperative rehabilitation on limb function after cranial cruciate ligament repair in dogs.
To determine the effects of early postoperative rehabilitation on limb function in dogs after surgery for ruptured cranial cruciate ligament (RCCL). Prospective clinical study. 51 client-owned dogs. Dogs weighing between 20 and 40 kg (44 to 88 lb) that had RCCL and medial meniscal injury were studied. After removal of the RCCL and complete medial meniscectomy, the stifle joint was stabilized by use of a lateral retinacular stabilization technique. Twenty-five dogs were included in a postoperative rehabilitation group, and 26 dogs were included in an exercise-restricted group. Limb function (peak vertical force [PVF] and vertical impulse [VI]) was determined before surgery and 6 months after surgery, using force platform gait analysis. Prior to surgery, mean PVF and VI in affected limbs were similar between groups. Six months after surgery, PVF and VI were significantly increased in dogs of both groups. However, PVF and VI in dogs in the rehabilitation group were significantly greater than those of dogs in the exercise-restricted group. At this time, differences in limb function (as measured by PVF and VI) between the repaired and normal limbs were not evident in dogs in the rehabilitation group. Conversely, limb function in the repaired limb of dogs in the exercise-restricted group was still significantly less than that of the normal limb. Dogs that have surgery for RCCL and a torn medial meniscus benefit from postoperative rehabilitation; rehabilitation should be considered part of the postoperative management of these patients.


Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus.
Constitutive activation of the PI3K/AKT/mTOR-pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus-resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus-sensitive and -resistant cell lines showed significant upregulation of PI3K/AKT/mTor-, RAS signaling- and the RTK-dependent PDGFR-, FGFR-, Met- and ALK-signaling-pathways in the resistant cells. Furthermore, MET, known as important proto-oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of MET plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance.


Quality of Basic Life Support - A Comparison between Medical Students and Paramedics.
Poor survival rates after cardiac arrest can partly be explained by poor basic life support skills in medical professionals. This study aimed to assess quality of basic life support in medical students and paramedics. We conducted a prospective observational study with 100 early medical students (group A), 100 late medical students (group B) and 100 paramedics (group C), performing a 20-minute basic life support simulation in teams of two. Average frequency and absolute number of chest compressions per minute (mean (±SD)), chest decompression (millimetres of compression remaining, mean (±SD)), hands-off-time (seconds/minute, mean (±SD)), frequency of switching positions between ventilation and chest compression (per 20 minutes) and rate of sufficient compressions (depth ≥50mm) were assessed as quality parameters of CPR. In groups A, B and C the rates of sufficiently deep chest compressions were 56%, 42% and 52%, respectively, without significant differences. Male gender and real-life CPR experience were significantly associated with deeper chest compression. Frequency and number of chest compressions were within recommended goals in at least 96% of all groups. Remaining chest compressions were 6 mm (±2), 6 mm (±2) and 5 mm (±2) with a significant difference between group A and C (p=0.017). Hands-off times were 6s/min (±1), 5s/min (±1) and 4s/min (±1), which was significantly different across all three groups. Overall, paramedics tended to show better quality of CPR compared to medical students. Though, chest compression depth as an important quality characteristic of CPR was insufficient in almost 50% of participants, even in well trained paramedics. Therefore, we suggest that an effort should be made to find better ways to educate health care professionals in BLS.


A Reproducible Cartilage Impact Model to Generate Post-Traumatic Osteoarthritis in the Rabbit.
Post-traumatic osteoarthritis (PTOA) is responsible for 12% of all osteoarthritis cases in the United States. PTOA can be initiated by a single traumatic event, such as a high-impact load acting on articular cartilage, or by joint instability, as occurs with anterior cruciate ligament rupture. There are no effective therapeutics to prevent PTOA currently. Developing a reliable animal model of PTOA is necessary to better understand the mechanisms by which cartilage damage proceeds and to investigate novel treatment strategies to alleviate or prevent the progression of PTOA. This protocol describes an open, drop tower-based rabbit femoral condyle impact model to induce cartilage damage. This model delivered peak loads of 579.1 ± 71.1 N, and peak stresses of 81.9 ± 10.1 MPa with a time-to-peak load of 2.4 ± 0.5 ms. Articular cartilage from impacted medial femoral condyles (MFCs) had higher rates of apoptotic cells (p = 0.0058) and possessed higher Osteoarthritis Research Society International (OARSI) scores of 3.38 ± 1.43 compared to the non-impacted contralateral MFCs (0.56 ± 0.42), and other cartilage surfaces of the impacted knee (p < 0.0001). No differences in OARSI scores were detected among the non-impacted articular surfaces (p > 0.05).


Comprehensive qPCR profiling of gene expression in single neuronal cells.
A major challenge in neuronal stem cell biology lies in characterization of lineage-specific reprogrammed human neuronal cells, a process that necessitates the use of an assay sensitive to the single-cell level. Single-cell gene profiling can provide definitive evidence regarding the conversion of one cell type into another at a high level of resolution. The protocol we describe uses Fluidigm Biomark dynamic arrays for high-throughput expression profiling from single neuronal cells, assaying up to 96 independent samples with up to 96 quantitative PCR (qPCR) probes (equivalent to 9,216 reactions) in a single experiment, which can be completed within 2-3 d. The protocol enables simple and cost-effective profiling of several hundred transcripts from a single cell, and it could have numerous utilities.


In vivo human muscle structure and function: adaptations to resistance training in old age.
This study investigated changes in elderly muscle joint angle-torque relation induced by resistance training. Older adults were assigned to either training (n = 9, age 74.3 +/- 3.5 years; mean +/-s.d.) or to control groups (n = 9, age 67.1 +/- 2 years). Leg-extension and leg-press exercises were performed three times per week for 14 weeks. Maximal isometric knee extension torque was measured across the knee joint angle range of movement. Vastus lateralis muscle architecture was examined in vivo using ultrasonography. The vastus lateralis muscle fascicle force was estimated from the measured joint torque, enabling construction of the fascicle length-force relation. Electromyographic (EMG) activity was measured from representative agonist and antagonist muscles. Training altered the angle-torque relation: (a) displacing it by 9-31% towards higher torque values (P < 0.05); and (b) shifting the optimal angle from 70 deg (corresponding torque: 121.4 +/- 61 N m) before to 60 deg (134.2 +/- 57.2 N m; P < 0.05) after training. Training also altered the fascicle length-force relation: (a) displacing it by 11-35% towards higher force values; and (b) shifting the optimal fascicle length from 83.7 +/- 8 mm (corresponding force: 847.9 +/- 365.3 N) before to 93.2 +/- 12.5 mm (939.3 +/- 347.8 N; P < 0.01) after training. The upward displacement of the angle-torque relation was mainly due to a training-induced increase in agonist activation, whilst the shift in the optimal angle was associated with changes in muscle-tendon properties.


Elevated trauma exposure and mental health burden among men who have sex with men in Vietnam.
The purpose of this study was to characterize trauma exposure and mental health burden among men who have sex with men (MSM) in Hanoi, Vietnam. Participants comprise 100 HIV-positive and 98 high-risk, HIV-negative MSM, ranging from 18 to 29 years of age. Data were collected using the Childhood Trauma Questionnaire, Traumatic Events Inventory, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and PTSD Symptom Scale. A subset of participants (n = 12) were also interviewed to evaluate community perception of the prevalence, causation, and available treatment options for mental health issues within the MSM community in Vietnam. In our sample, 23.2% reported having experienced moderate-to-severe childhood physical abuse; 18.7% physical neglect; 13.6% emotional abuse; 11.1% emotional neglect; and 26.8% sexual abuse. Such trauma exposure continued into adulthood and manifested most commonly in the form of interpersonal violence. Approximately 37.4% of the sample met the criteria for probable PTSD; 26.8% for moderate-to-severe depression; and 20.2% for moderate-to-severe anxiety. Neither exposure nor mental health burden differed by serostatus. Linear regression revealed that childhood emotional abuse was the only sub-type of trauma significantly associated with depression, anxiety, and PTSD symptoms. The majority of interviewees believed that mental health burden was higher among MSM relative to the general population and attributed this to their vulnerability to interpersonal violence and lack of available coping resources. However, few believed that these mental health issues warranted clinical attention, and only one participant was able to identify a mental health service provider. Our findings suggest that trauma exposure and mental health burden are prevalent among MSM, irrespective of serostatus, and much higher than what has been previously reported among the general population in Vietnam.


Floral resources impact longevity and oviposition rate of a parasitoid in the field.
1. The use of floral resource subsidies to improve herbivore suppression by parasitoids requires certain trophic interactions and physiological changes to occur. While the longevity and fecundity of parasitoids are positively affected by nectar subsidies in laboratory studies, the impacts of floral subsidies on the fecundity and longevity of freely foraging parasitoids have not been studied. 2. We studied the longevity and per capita fecundity of naturally occurring Diadegma insulare foraging in cabbage plots with and without borders of flowering buckwheat, Fagopyrum esculentum, as well as relationships between longevity, fecundity, sugar feeding and parasitism rates on larvae of the diamondback moth, Plutella xylostella. 3. Relative longevity was estimated by counting broken setae on the fringe of the forewing. Floral borders increased the longevity of males and females in adjacent cabbage plots. 4. The egg maturation rate of D. insulare was estimated by comparing egg loads of females collected early in the day with egg loads of females held without hosts in field cages throughout the day. Females in buckwheat cages matured 2.7 eggs per hour while females in control cages resorbed 0.27 eggs over the same time period. 5. The fecundity of females collected in the afternoon was estimated by comparing their actual egg load to the estimated egg load in the absence of oviposition for females in a given plot. Females foraging in buckwheat plots had marginally fewer eggs remaining in their ovaries, and laid marginally more eggs than females in control plots. Females from both treatments carried 30-60 eggs by the afternoon and therefore were time-limited rather than egg-limited. 6. Plots where a greater proportion of females had fed on sugar had longer-lived females. This suggests that feeding enhanced longevity of D. insulare. However, plots with longer-lived and more fecund females did not exhibit higher parasitism rates, although the power of these tests were low.


Effects of inhaled beclomethasone dipropionate and alternate-day prednisone on pituitary-adrenal function in children with chronic asthma.
Two corticosteroid regimens, alternate-day prednisone and inhaled beclomethasone dipropionate, have been more acceptable than daily oral corticosteroids for treatment of chronic asthma. To compare the effect of these regimens on hypothalamic-pituitary-adrenal function, 20 children with asthma were evaluated while receiving 20 to 40 mg of prednisone on alternate mornings or 400 to 800 microgram per day of inhaled beclomethasone dipropionate in divided daily doses; seven children requiring only non-corticosteroid medication served as controls. Early-morning serum cortisol concentration, urinary free-cortisol excretion and the 11-desoxycortisol response to metyrapone were decreased to a similar degree among children receiving both corticosteroid regimens in comparison with the control patients and were lowest when alternate-day prednisone and inhaled beclomethasone dipropionate were given together. Thus, inhaled beclomethasone dipropionate appears similar to alternate-day prednisone in its effect on hypothalamic-pituitary-adrenal function when used alone; the effect is additive when the two are used together.


Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration-Approved Drugs.
High-throughput screening (HTS) of small-molecule libraries accelerates the discovery of chemical leads to serve as starting points for probe or therapeutic development. With this approach, thousands of unique small molecules, representing a diverse chemical space, can be rapidly evaluated by biologically and physiologically relevant assays. The origins of numerous United States Food and Drug Administration-approved cancer drugs are linked to HTS, which emphasizes the value in this methodology. The National Institutes of Health Molecular Libraries Program made HTS accessible to the public sector, enabling the development of chemical probes and drug-repurposing initiatives. In this work, the impact of HTS in the field of oncology is considered among both private and public sectors. Examples are given for the discovery and development of approved cancer drugs. The importance of target validation is discussed, and common assay approaches for screening are reviewed. A rigorous examination of the PubChem database demonstrates that public screening centers are contributing to early-stage drug discovery in oncology by focusing on new targets and developing chemical probes. Several case studies highlight the value of different screening strategies and the potential for drug repurposing.


Sexual orientation and substance use trajectories in emerging adulthood.
The current study examined developmental changes in substance use behaviors (SUBS) based upon sexual orientation. The analyses also attempted to address a number of methodological limitations in the extant longitudinal literature (i.e. distinct operationalizations of sexual orientation, timing of sexual orientation assessment with respect to reports of SUBs, non-linear growth). Data were drawn from a longitudinal study of incoming first-time college students at a large public university (n = 3720). After a paper-and-pencil assessment just prior to matriculation, participants completed a web-based survey every fall and spring for 4 years (sub-sample n = 2854). Latent growth models revealed that sexual minorities demonstrated significant heterogeneity with regard to substance use trajectories. Initial levels and trajectories of the frequency of substance use for sexual minority individuals were distinct, generally, from their exclusively heterosexual peers. Methodologically, the timing of the assessment of sexual orientation influenced the results, and modeling non-linear components indicated that sexual minorities are at risk for exponential increases in their frequency of certain SUBs over time (i.e. drunkenness; cannabis use). Sexual minority and majority individuals exhibited differences in SUBs during emerging adulthood, especially when using self-identification to define sexual orientation. Individuals who endorsed a sexual minority self-identification at the onset of emerging adulthood, as opposed to 4 years later, evidenced exponential increases in rates of drunkenness and cannabis use. These results support that the timing of assessment is important and that some trajectories of sexual minority SUBs are non-linear during this developmental period.


Squaramides and Ureas: A Flexible Approach to Polymerase-Compatible Nucleic Acid Assembly.
Joining oligonucleotides together (ligation) is a powerful means of retrieving information from the nanoscale. To recover this information, the linkages created must be compatible with polymerases. However, enzymatic ligation is restrictive and current chemical ligation methods lack flexibility. Herein, a versatile ligation platform based on the formation of urea and squaramide artificial backbones from minimally modified 3'- and 5'-amino oligonucleotides is described. One-pot ligation gives a urea linkage with excellent read-through speed, or a squaramide linkage that is read-through under selective conditions. The squaramide linkage can be broken and reformed on demand, while stable pre-activated precursor oligonucleotides expand the scope of the ligation reaction to reagent-free, mild conditions. The utility of our system is demonstrated by replacing the enzymatically biased RNA-to-DNA reverse transcription step of RT-qPCR with a rapid nucleic-acid-template-dependent DNA chemical ligation system, that allows direct RNA detection.


Agrobacterium tumefaciens mutants affected in attachment to plant cells.
An analysis of Agrobacterium tumefaciens mutants with Tn5 insertions in chromosomal DNA showed that the chromosome of A. tumefaciens codes for a specific ability of this bacterium to attach to plant cells. This ability is associated with tumorigenesis by A. tumefaciens, the ability of avirulent A. tumefaciens to inhibit tumorigenesis, and the ability to adsorb certain phages. A second class of chromosomal mutations affects tumorigenesis without altering the ability to attach to plant cells. The attachment of A. tumefaciens to plant cells was assayed by mixing radiolabeled bacteria with suspensions of tobacco tissue culture cells or freshly isolated Zinnia leaf mesophyll cells. Under the conditions of this assay, an avirulent Ti plasmid-cured strain attached to the same extent as the same strain containing pTiB6806. Six of eight avirulent mutants with Tn5 insertions in chromosomal DNA showed defective attachment, whereas two retained wild-type attachment ability. In contrast to the strains showing wild-type attachment, the attachment-defective mutants failed to inhibit tumorigenesis when inoculated onto Jerusalem artichoke slices before inoculation of a virulent strain and also showed a loss of sensitivity to two Agrobacterium phages. The loss of phage sensitivity appeared to be due to a loss of ability to adsorb the phages. Staining with Calcofluor indicated that the mutants retained the ability to synthesize cellulose fibrils, which have been implicated in the attachment process. Southern filter hybridizations demonstrated that each mutant contained a single Tn5 insertion, and genetic linkage between the Tn5 insertion in one mutant and the attachment phenotype has also been demonstrated.


Estrogenic phenol and catechol metabolites of PCBs modulate catechol-O-methyltransferase expression via the estrogen receptor: potential contribution to cancer risk.
Commercial PCB mixtures have been shown to induce liver tumors in female rats and this effect has been attributed to the effects of PCBs on estrogen metabolism. Catechol metabolites of PCBs are potent inhibitors of COMT activity and are likely to contribute significantly to reduced clearance of genotoxic catechol metabolites of estrogen. The effect of PCB metabolites on COMT expression in cultured cells was investigated to explore potential mechanisms by which PCB exposure alters catechol estrogen clearance. We hypothesize that estrogenic PCB metabolites may contribute to reduction of COMT expression via interaction with the estrogen receptor. To test this hypothesis, human MCF-7 cells were exposed to PCB analogues and the expression of COMT determined. Western blot analysis demonstrated that COMT protein levels were statistically significantly reduced by both the phenolic and the catechol compounds, an effect which was abolished by the anti-estrogen, ICI182780. The above suggests that COMT levels may be reduced by estrogenic PCB metabolites, via interactions between PCB metabolites and the ER. It supports the hypothesis that both phenolic and catechol metabolites of PCBs may contribute to PCB-mediated carcinogenesis through reduction of COMT levels and activities and subsequent reduction in clearance of endogenous and xenobiotic catechols.


Olfactory learning in the cricket Gryllus bimaculatus.
The olfactory learning capability of the cricket Gryllus bimaculatus was studied. Crickets were deprived of drinking water for 4 days and were individually trained to associate peppermint with water and vanilla with NaCl solution. Their odour preference was tested before and after training by allowing them to choose between peppermint or vanilla sources. The time spent visiting each source served as a measure of odour preference. Crickets exhibited an initial preference for vanilla over peppermint, but preference for the latter increased after only one training session. The olfactory memory formed by a single training session decayed with time but remained for at least 24 h. Memory formed by three training sessions was extremely robust, and did not decay significantly between 1 and 7 days after training. The preference formed was easily altered by reversal training in which vanilla was associated with water and peppermint with saline solution. This study shows that crickets have a highly developed olfactory learning capability characterized by fast acquisition, long retention and easy rewriting of memory.


Coexpression of translocated and normal c-myc oncogenes in hybrids between Daudi and lymphoblastoid cells.
Mechanisms that affect the transcription of the c-myc oncogene take part in the development of B-cell neoplasias such as Burkitt's lymphoma. Daudi Burkitt lymphoma cells, which express only the translocated c-myc oncogene, were hybridized with human lymphoblastoid cells, which express the normal c-myc gene; the hybrids were phenotypically lymphoblastoid and expressed both the translocated and the normal c-myc gene. This result contrasts with the findings that the decapitated c-myc gene, translocated to an immunoglobulin switch mu or alpha region, is transcriptionally silent in lymphoblastoid hybrids. Thus, there may be at least two distinct enhancer-like elements capable of deregulating c-myc transcription in lymphomas and leukemias with t(8;14) chromosome translocations. In addition, since the Daudi X lymphoblastoid hybrids express both the translocated and the normal c-myc gene, the c-myc gene product does not autoregulate c-myc transcription.


Stereotactic radiosurgery in patients with multiple brain metastases.
Patients with multiple brain metastases are often treated primarily with fractionated whole-brain radiation therapy (WBRT). In previous reports the authors have shown that patients with four or fewer brain metastases can benefit from stereotactic radiosurgery in addition to fractionated WBRT. In this paper the authors review their experience using linear accelerator stereotactic radiosurgery to treat patients with multiple brain metastases. Fifty-three patients with 149 brain metastases underwent stereotactic radiosurgery. The mean age of patients was 53.1 years (range 20-78 years). There were 23 men and 30 women. The primary tumor location was lung (27 patients), melanoma (10), breast (six), ovary (six), and other (four). All patients harbored at least two metastatic tumors treated with radiosurgery; 27 patients (51%) harbored two lesions, 17 (32%) three lesions, eight (15%) four lesions, and one patient (2%) harbored five lesions. The mean radiation dose administered was 19.6 Gy (range 14-30 Gy), and the mean secondary collimator size was 15.7 mm (range 7.5-40 mm). One hundred thirty-two (89%) of the 149 treated tumors were available for review on magnetic resonance (MR) imaging at 3 months posttreatment. Fifty-two percent were smaller in size, 31% were stable, 9% had increased in size, and 8% had disappeared. New metastatic tumors appeared in 12 (23%) of the 53 patients on MR imaging within 6 months posttreatment. Radiation-induced necrosis occurred at the site of eight (5.4%) of the 149 tumors at 6 months. Seven tumors (4.7%) subsequently required surgical resection for either tumor progression (four cases) or worsening edema from radiation-induced necrosis (three cases). Median actuarial survival was 9.6 months. Stereotactic radiosurgery can be used to treat patients with up to four brain metastases with a 91% rate of either decrease or stabilization in tumor size and a low rate of radiation-induced necrosis. In the authors' study only a small number of patients subsequently required surgical resection of a treated lesion.


Diagnostic accuracy of serum parathyroid hormone levels in kidney transplant recipients with moderate-to-advanced CKD.
Elevated parathyroid hormone (PTH) is used to diagnose high turnover bone disease in chronic kidney disease (CKD). The diagnostic accuracy of PTH in kidney transplant recipients with CKD is unknown. We examined kidney transplant recipients with CKD stages 3 (n = 498) and 4 (n = 141) to determine the sensitivity and specificity of the Kidney/Dialysis Outcome Quality Initiative (K/DOQI)-recommended PTH levels in detecting elevated serum β-CrossLaps (CTX) or osteocalcin (OC) levels. We performed receiver-operator curve analyses to determine CKD stage-specific PTH levels that provide optimal diagnostic accuracy. PTH below the lower limits of the K/DOQI ranges (35 and 70 pg/ml in CKD stages 3 and 4, respectively) showed sensitivity of >90% in diagnosing increases in biochemical markers. The upper limits (70 and 110 pg/ml), however, showed poor specificity. A specificity of >90% for detecting increased biochemical markers was seen with PTH of >140 and >240 pg/ml in CKD stages 3 and 4, respectively. Currently applied cutoffs for PTH in kidney transplant recipients with CKD stages 3 and 4 do not appear to adequately detect increased biochemical markers of bone turnover. Diagnostic uncertainty exists in patients with CKD stage 3 and PTH between 35 and 140 pg/ml, and CKD stage 4 and PTH between 70 and 240 pg/ml.


Establishment of two Epstein-Barr virus negative Burkitt cell lines from a patient with AIDS and B-cell lymphoma.
To analyze the pathogenesis of B-cell lymphomas in patients with acquired immunodeficiency syndrome (AIDS), we studied two cell lines, Es I and Es III, established from one such lymphoma for the presence of sequences of the Epstein-Barr virus (EBV) and the human immunodeficiency virus [HIV; lymphadenopathy-associated virus (LAV/HTLV-III)] as well as for the presence of cytogenetic abnormalities and monoclonal rearrangements of immunoglobulin and T-cell receptor genes. Both cell lines expressed the same IgM, kappa phenotype as the original lymphoma. The karyotype of Es I was 46, XY, t(8;14), 2 p+, inv (6p), 17p-, and the cells of Es III had an additional i(7q). Immunoglobulin gene studies demonstrated the identical monoclonal rearrangements in both cell lines. Neither EBV nor HIV sequences were detectable in the malignant B cells at the genomic level, leading to the conclusion that mechanisms other than transformation by EBV or HIV may have contributed to the B-cell lymphoma in this patient and possibly also to the generally increased frequency in patients with AIDS.


Theoretical considerations to the verification of dynamic multileaf collimated fields with a SLIC-type portal image detector.
The verification possibilities of dynamically collimated treatment beams with a scanning liquid ionization chamber electronic portal image device (SLIC-EPID) are investigated. The ion concentration in the liquid of a SLIC-EPID and therefore the read-out signal is determined by two parameters of a differential equation describing the creation and recombination of the ions. Due to the form of this equation, the portal image detector describes a nonlinear dynamic system with memory. In this work, the parameters of the differential equation were experimentally determined for the particular chamber in use and for an incident open 6 MV photon beam. The mathematical description of the ion concentration was then used to predict portal images of intensity-modulated photon beams produced by a dynamic delivery technique, the sliding window approach. Due to the nature of the differential equation, a mathematical condition for 'reliable leaf motion verification' in the sliding window technique can be formulated. It is shown that the time constants for both formation and decay of the equilibrium concentration in the chamber is in the order of seconds. In order to guarantee reliable leaf motion verification, these time constants impose a constraint on the rapidity of the image-read out for a given maximum leaf speed. For a leaf speed of 2 cm s(-1), a minimum image acquisition frequency of about 2 Hz is required. Current SLIC-EPID systems are usually too slow since they need about a second to acquire a portal image. However, if the condition is fulfilled, the memory property of the system can be used to reconstruct the leaf motion. It is shown that a simple edge detecting algorithm can be employed to determine the leaf positions. The method is also very robust against image noise.


Association of macrophage migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms in acute rheumatic fever.
Macrophage migration inhibitory factor and mannose-binding lectin-2 play important roles in the pathogenesis of several acute and chronic inflammatory/autoimmune disorders. The aim of the study was to investigate any possible association between migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms and acute rheumatic fever in children. Material and methods A total of 38 unrelated children with acute rheumatic fever and 40 age- and sex-matched healthy controls were analysed for codon 54 A/B polymorphism in mannose-binding lectin-2 gene and -173 G/C polymorphism in migration inhibitory factor gene by using the polymerase chain reaction method. Frequency of BB genotype of mannose-binding lectin-2 gene was higher in the patient group. Interestingly, children with acute rheumatic fever with AA genotype tended to have chorea compared with children with BB genotype. There was a statistically significant increase in frequency of the migration inhibitory factor -173 CC genotype in patients compared with the control subjects. The present study is the first to investigate the mannose-binding lectin-2 gene polymorphism in children with acute rheumatic fever. BB genotype of mannose-binding lectin-2 (codon 54) and CC genotype of migration inhibitory factor (-173) may have a role in the immunoinflammatory process of acute rheumatic fever.


Targeted validation: validating clinical prediction models in their intended population and setting.
Clinical prediction models must be appropriately validated before they can be used. While validation studies are sometimes carefully designed to match an intended population/setting of the model, it is common for validation studies to take place with arbitrary datasets, chosen for convenience rather than relevance. We call estimating how well a model performs within the intended population/setting "targeted validation". Use of this term sharpens the focus on the intended use of a model, which may increase the applicability of developed models, avoid misleading conclusions, and reduce research waste. It also exposes that external validation may not be required when the intended population for the model matches the population used to develop the model; here, a robust internal validation may be sufficient, especially if the development dataset was large.


Evolution and development of interhemispheric connections in the vertebrate forebrain.
Axonal connections between the left and right sides of the brain are crucial for bilateral integration of lateralized sensory, motor, and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. However, major events in the evolution of the vertebrate brain, such as the expansion of the telencephalon in tetrapods and the origin of the six-layered isocortex in mammals, resulted in the emergence and diversification of new commissural routes. These new interhemispheric connections include the pallial commissure, which appeared in the ancestors of tetrapods and connects the left and right sides of the medial pallium (hippocampus in mammals), and the corpus callosum, which is exclusive to eutherian (placental) mammals and connects both isocortical hemispheres. A comparative analysis of commissural systems in vertebrates reveals that the emergence of new commissural routes may have involved co-option of developmental mechanisms and anatomical substrates of preexistent commissural pathways. One of the embryonic regions of interest for studying these processes is the commissural plate, a portion of the early telencephalic midline that provides molecular specification and a cellular scaffold for the development of commissural axons. Further investigations into these embryonic processes in carefully selected species will provide insights not only into the mechanisms driving commissural evolution, but also regarding more general biological problems such as the role of developmental plasticity in evolutionary change.


Genetic diversity in Tanzanian Arabica coffee using random amplified polymorphic DNA (RAPD) markers.
DNA from Coffea arabica leaves was used for RAPD analysis and a total of 144 leaf samples collected from 16 provenances in five regions of Tanzania were analysed. Ten arbitrary 10 mer primers were employed in the analysis and they produced a total of 86 fragments. Fragment sizes ranged from 100-1400 bp. The resulting dissimilarity matrix revealed values ranging from 0.11 to 1, while the average was 0.66. The cophenetic matrix and the original dissimilarity matrix showed a significant correlation of 78%. Mean dissimilarity values within provenances showed a fairly uniform trend despite the large range from 0.31 to 0.65. The dendrogram based on genetic distances but showed two clusters with grouping of provenances similar to the dendrogram generated by Jaccard's coefficient. Bootstrap analysis showed low values, despite this, the resulting dendrogram grouped all provenances according to their geographical origin. The standard genetic distances were fairly uniform implying a narrow genetic base in the cultivated Arabica coffee.


daughterless is required for Drosophila photoreceptor cell determination, eye morphogenesis, and cell cycle progression.
Initiation of Drosophila peripheral nervous system (PNS) development requires the achaete-scute complex (AS-C) and the atonal (ato) genes. The AS-C and ato encode basic helix-loop-helix (bHLH) transcription factors that dimerize in vitro with another bHLH protein, daughterless (da). da has many functions during Drosophila embryonic development, as it is required for proper sex determination, oogenesis, and neurogenesis. Here, we examine the expression and function of da within the developing Drosophila eye. The use of a monoclonal antibody to the Da protein revealed that Da levels are modulated across the developing eye disc. Within the morphogenetic furrow (MF) and photoreceptor cell R8, there is a cell-by-cell correspondence between high levels of Da protein expression and Ato protein expression. Mosaic analysis of adult tissue demonstrates that da function is cell autonomous and required within R2, R3, R4, R5, and R8. Examination of gene expression in da- imaginal disc clones reveals that da regulates Ato expression in the MF, affects the progression of the MF, and is necessary for the reestablishment of the G2 and M phases of the synchronized cell cycle posterior to the MF.


Towards Personalized Lifetime Health: A Platform for Early Multimorbid Chronic Disease Risk Assessment and Mitigation.
Chronic diseases are the leading cause of morbidity, disability and mortality worldwide. It is well established that the majority of chronic diseases can be prevented by targeting modifiable lifestyle-related risk factors. Thus, early risk assessment and mitigation at the individual level can significantly reduce the health and economic burden of chronic diseases. Lifetime health has emerged as a potential paradigm to assist individuals to avoid harmful lifestyle-related habits to reduce the risk of chronic morbidity. In this paper, we leverage eHealth and Quantified Self technologies, novel health data visualizations, and artificial intelligence methods to develop a digital-based lifetime health platform (PRISM) to empower individuals to self-assess, self-monitor, and self-manage their risks for multiple chronic diseases and associated morbidities.


Can SNOMED CT Changes Be Used as a Surrogate Standard for Evaluating the Performance of Its Auditing Methods?
We introduce RGT, Retrospective Ground-Truthing, as a surrogate reference standard for evaluating the performance of automated Ontology Quality Assurance (OQA) methods. The key idea of RGT is to use cumulative SNOMED CT changes derived from its regular longitudinal distributions by the official SNOMED CT editorial board as a partial, surrogate reference standard. The contributions of this paper are twofold: (1) to construct an RGT reference set for SNOMED CT relational changes; and (2) to perform a comparative evaluation of the performances of lattice, non-lattice, and randomized relational error detection methods using the standard precision, recall, and geometric measures. An RGT relational-change reference set of 32,241 IS-A changes were constructed from 5 U.S. editions of SNOMED CT from September 2014 to September 2016, with reversals and changes due to deletion or addition of new concepts excluded. 68,849 independent non-lattice fragments, 118,587 independent lattice fragments, and 446,603 relations were extracted from the SNOMED CT March 2014 distribution. Comparative performance analysis of smaller (less than 15) lattice vs. non-lattice fragments was also given to approach the more realistic setting in which such methods may be applied. Among the 32,241 IS-A changes, independent non-lattice fragments covered 52.8% changes with 26.4% precision with a G-score of 0.373. Even though this G-score is significantly lower in comparison to those in information retrieval, it breaks new ground in that such evaluations have never performed before in the highly discovery-oriented setting of OQA.


Probabilistic models of individual and collective animal behavior.
Recent developments in automated tracking allow uninterrupted, high-resolution recording of animal trajectories, sometimes coupled with the identification of stereotyped changes of body pose or other behaviors of interest. Analysis and interpretation of such data represents a challenge: the timing of animal behaviors may be stochastic and modulated by kinematic variables, by the interaction with the environment or with the conspecifics within the animal group, and dependent on internal cognitive or behavioral state of the individual. Existing models for collective motion typically fail to incorporate the discrete, stochastic, and internal-state-dependent aspects of behavior, while models focusing on individual animal behavior typically ignore the spatial aspects of the problem. Here we propose a probabilistic modeling framework to address this gap. Each animal can switch stochastically between different behavioral states, with each state resulting in a possibly different law of motion through space. Switching rates for behavioral transitions can depend in a very general way, which we seek to identify from data, on the effects of the environment as well as the interaction between the animals. We represent the switching dynamics as a Generalized Linear Model and show that: (i) forward simulation of multiple interacting animals is possible using a variant of the Gillespie's Stochastic Simulation Algorithm; (ii) formulated properly, the maximum likelihood inference of switching rate functions is tractably solvable by gradient descent; (iii) model selection can be used to identify factors that modulate behavioral state switching and to appropriately adjust model complexity to data. To illustrate our framework, we apply it to two synthetic models of animal motion and to real zebrafish tracking data.


Influenza B outbreak in female psychiatric ward of Hospital Kuala Lumpur, Malaysia.
Influenza outbreaks in tropical countries are rarely reported. This article reports four cases of influenza within a psychiatric ward of a tertiary hospital in Malaysia. These were patients with severe mental illness who were involuntarily admitted and did not show the classical triad of influenza-like-illness (ILI) at the beginning. However, severe respiratory complications developed requiring intubation. Referral and cooperation with the infectious disease team was initiated to help manage the outbreak while continuing psychiatric treatment. Incidences of influenza among hospitalised psychiatric patients should be treated seriously with immediate multidisciplinary approach to prevent severe unwanted complications.


Expression and regulation of avian cathepsin L in the oviduct during molting.
Cathepsins (CTSs) are peptidases that have biological roles in degrading extracellular matrix, catabolism of intracellular proteins, and processing of pro-hormones. Of these, cathepsin L (CTSL) is closely associated with morphological changes in reproductive organs required for proper function in mammals, including humans and mice, but little is known about CTSL in avian species. In the present study, the expression of CTSL was investigated in the oviduct of hens during regression and recrudescence in response to molting. Our results revealed that expression of CTSL mRNA increased (P<0.001) when the oviduct underwent regression during the molting period in hens. In situ hybridization and immunohistochemial analyses detected CTSL mRNA and protein predominantly in the luminal (LE) and glandular epithelia (GE) during regression of the oviduct, but not during regeneration of the oviduct. Expression of CTSL decreased in the oviduct of chicks treated with diethylstilbestrol (DES, a synthetic estrogen agonist). Furthermore, we discovered four miRNAs including miR-23b, miR-551, miR-1464 and miR-1803 that regulate expression of the CTSL gene at the post-transcriptional level, which suggests that CTSL mRNA can be regulated by specific miRNAs via 3'-UTR in chickens. Results of the present research suggest that estrogen regulates expression of CTSL during regression of the oviduct during molting and that down-regulation of CTSL is likely a prerequisite for the normal regeneration of oviductal tissues following molting in laying hens.


Survey of the contamination of eyedrops of hospital inpatients and recommendations for the changing of current practice in eyedrop dispensing.
Topical ophthalmic medications used on the ward and from the outpatient area have been taken and cultured for potential bacterial contamination in the laboratory. We examined 143 bottles used by patients who had had routine cataract surgery and trabeculectomy. We also examined for bacterial contamination 216 bottles of eyedrops used in the outpatient area of the hospital. No contamination was found in the postoperative eyedrops, but five bottles were contaminated from the outpatient area (2.3%). The bacterial growth from outpatient drops was of the same order of magnitude as in previous studies. The practice in the UK for postoperative eyedrops to be discarded and fresh, separate bottles to take home is discussed. We recommend that this practice be changed so that the postoperative drops used for 72 hours or less are taken home.


Skeletal muscle pathology in endurance athletes with acquired training intolerance.
It is well established that prolonged, exhaustive endurance exercise is capable of inducing skeletal muscle damage and temporary impairment of muscle function. Although skeletal muscle has a remarkable capacity for repair and adaptation, this may be limited, ultimately resulting in an accumulation of chronic skeletal muscle pathology. Case studies have alluded to an association between long term, high volume endurance training and racing, acquired training intolerance, and chronic skeletal muscle pathology. To systematically compare the skeletal muscle structural and ultrastructural status of endurance athletes with acquired training intolerance (ATI group) with asymptomatic endurance athletes matched for age and years of endurance training (CON group). Histological and electron microscopic analyses were carried out on a biopsy sample of the vastus lateralis from 18 ATI and 17 CON endurance athletes. The presence of structural and ultrastructural disruptions was compared between the two groups of athletes. Significantly more athletes in the ATI group than in the CON group presented with fibre size variation (15 v 6; p = 0.006), internal nuclei (9 v 2; p = 0.03), and z disc streaming (6 v 0; p = 0.02). There is an association between increased skeletal muscle disruptions and acquired training intolerance in endurance athletes. Further studies are required to determine the nature of this association and the possible mechanisms involved.


Therapeutic Potential of Hydrogen-Rich Water on Muscle Atrophy Caused by Immobilization in a Mouse Model.
Skeletal muscle atrophy is associated with poor quality of life and disability. Thus, finding a new strategy for the prevention and treatment of skeletal muscle atrophy is very crucial. This study aimed to investigate the therapeutic potential of hydrogen-rich water (HRW) on muscle atrophy in a unilateral hind limb immobilization model. Thirty-six male Balb/C mice were divided into control (without immobilization), atrophy, and atrophy + hydrogen-rich water (HRW). Unilateral hind limb immobilization was induced using a splint for 7 days (atrophy) and removed for 10 days (recovery). At the end of each phase, gastrocnemius and soleus muscle weight, limb grip strength, skeletal muscle histopathology, muscle fiber size, cross-section area (CSA), serum troponin I and skeletal muscle IL-6, TNF-α and Malondialdehyde (MDA), and mRNA expression of NF-κB, BAX and Beclin-1 were evaluated. Muscle weight and limb grip strength in the H2-treated group were significantly improved during the atrophy phase, and this improvement continued during the recovery period. Treatment by HRW increased CSA and muscle fiber size and reduced muscle fibrosis, serum troponin I, IL-6, TNF-α and MDA which was more prominent in the atrophy phase. These data suggest that HRW could improve muscle atrophy in an immobilized condition and could be considered a new strategy during rehabilitation.


Aerosolized surfactant inhibits acetylcholine-induced airway obstruction in rats.
Exogenous surfactant treatment inhibits antigen-induced airway obstruction in sensitized guinea-pigs. Aerosolized surfactant also improves respiratory function in asthmatic patients. The aim of the present study was to determine whether aerosolized surfactant inhibits nonallergic airway obstruction induced by acetylcholine. Anaesthetized Wistar rats were treated by aerosol with the beta2-adrenoceptor agonist terbutaline, surfactant (Alveofact), a surfactant-terbutaline combination, or vehicle (control). Animals were then challenged by aerosolized acetylcholine to elicit receptor-mediated airway obstruction. A second group of animals was challenged with intravenous acetylcholine. Respiratory function variables were measured by body plethysmography before and after treatment, and after the acetylcholine challenge. Baseline lung function values before and after treatment were similar in all groups. Acetylcholine challenge by aerosol increased lung resistance by 64% in control animals. Pretreatment with terbutaline and surfactant significantly limited the increase of lung resistance to +36 and +34%, respectively. Simultaneous aerosolization of surfactant and terbutaline also inhibited airway obstruction but their effects were not additive. By contrast, terbutaline treatment inhibited the effects of intravenous acetylcholine, but surfactant did not. In conclusion, we suggest that surfactant aerosol may prevent acetylcholine and other pharmacological agents from reaching the airway smooth muscle from the airway lumen but not via the bloodstream.


Genetic Drift Linked to Heterogeneous Landscape and Ecological Specialization Drives Diversification in the Alpine Endemic Columbine Aquilegia thalictrifolia.
The European Alpine system is an extensive mountain range, whose heterogeneous landscape together with Quaternary climatic oscillations significantly affected organismal diversity and distribution in Europe. The model genus Aquilegia represents a textbook example of a rapid and recent radiation through the Northern hemisphere, with the majority of the European taxa occuring in the Alpine system. However, the processes governing genetic differentiation of the genus in this complex geographic area are still widely unexplored. In this work, we used 9 microsatellite loci to study the genetic structure and diversity of 11 populations of Aquilegia thalictrifolia Schott & Kotschy, an alpine taxon characterized by a marked ecological specificity. We found that, despite the endemic and fragmented distribution, A. thalictrifolia has overall high levels of heterozygosity, which is consistent to the substantial inbreeding depression that characterizes the genus. Strong spatial genetic structuring of populations suggests a historical prevalence of genetic drift over gene flow, with natural barriers and ecological niche hindering migration. An analytical comparison of fixation and population differentiation indexes allowed us to infer hypotheses of the postglacial history and more recent demographic events that have influenced the genetics of the species. Overall, our results indicate allopatry as a major force of differentiation in the European scenario, likely to underlie the development of taxonomic boundaries in a broader geographic context. This adds to previous notions on the primary evolutionary forces shaping the Aquilegia radiation in Europe.


Food consumption of five deep-sea fishes in the Balearic Basin (western Mediterranean Sea): are there daily feeding rhythms in fishes living below 1000 m?
Predation and food consumption of five deep-sea fish species living below 1000 m depth in the western Mediterranean Sea were analysed to identify the feeding patterns and food requirements of a deep-sea fish assemblage. A feeding rhythm was observed for Risso's smooth-head Alepocephalus rostratus, Mediterranean grenadier Coryphaenoides mediterraeus and Mediterranean codling Lepidion lepidion. Differences in the patterns of the prey consumed suggest that feeding rhythms at such depths are linked with prey availability. The diets of those predators with feeding rhythms are based principally on active-swimmer prey, including pelagic prey known to perform vertical migrations. The diets of Günther's grenadier Coryphaenoides guentheri and smallmouth spiny eel Polyacanthonotus rissoanus, which did not show any rhythm in their feeding patterns, are based mainly on benthic prey. Food consumption estimates were low (<1% of body wet mass day(-1) ). Pelagic feeding species showing diel feeding rhythms consumed more food than benthic feeding species with no feeding rhythms.


Assay and relationship of HT-2 toxin and T-2 toxin formation in liquid culture.
Both T-2 toxin and HT-2 toxin can be conveniently quantitated in crude extracts by using a combination of thin-layer chromatography and fluorodensitometry. This technique was used to follow the production of these toxins by liquid cultures of Fusarium poae (NRRL 3287). T-2 toxin was produced prior to HT-2 toxin and hexadeuterio-T-2 toxin was converted by the culture to trideuterio-HT-2 toxin.


Coronary Artery Ectasia Presenting as a Non-ST Elevation Myocardial Infarction in a Young Adult: Case Presentation and Literature Review.
While acute coronary syndromes most commonly occur secondary to unstable atherosclerotic plaque, coronary aneurysms, also known as coronary artery ectasia (CAE), represent a less common etiology. Whereas coronary atherosclerosis accounts for about 50% of CAE, the remaining 50% are either congenital or secondary to a host of inflammatory and connective tissue disorders, with Kawasaki disease being a well-known association. Patients with CAE have worse outcomes than the general population regardless of the presence of associated atherosclerotic coronary artery disease. We report the case of a young male presenting with chest pain, a right bundle branch block on electrocardiography, an elevated troponin level, and a regional wall motion abnormality on echocardiography who is found to have diffuse coronary artery ectasia on coronary angiography and is managed medically with dual antiplatelet therapy.


Coxsackievirus B3 infection and its mutation in Keshan disease.
To investigate coxsackievirus B(3) infection and its gene mutation in Keshan disease. The expression of Coxsackievirus B(3) RNA was detected in autopsy specimens of acute (12 cases), sub-acute (27 cases) and chronic (15 cases) Keshan disease by in situ hybridization. In sub-acute Keshan disease specimens, 3 cases with positive result by in situ hybridization were selected RT-PCR analysis. The DNA segments were then sequenced. Coxsackievirus B(3) RNA was detected in the cytoplasm of myocardiocyte. The positive rate was 83% in acute, 67% in sub-acute and 80% in chronic Keshan disease. In the conservative region of Coxsackievirus B(3) genome, there was a mutation in 234 (C-T) compared to the non-cardiovirulent strain, CVB(3/0). Coxsackievirus B(3) RNA can survive and replicate in heart muscle of Keshan disease, which may play an important role in the occurrence of Keshan disease. The possible mechanism of occurrence of Keshan disease is associated with point a mutation in Coxsackievirus B(3) genome.


Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group.
Children with high-risk neuroblastoma have a poor outcome. In this study, we assessed whether myeloablative therapy in conjunction with transplantation of autologous bone marrow improved event-free survival as compared with chemotherapy alone, and whether subsequent treatment with 13-cis-retinoic acid (isotretinoin) further improves event-free survival. All patients were treated with the same initial regimen of chemotherapy, and those without disease progression were then randomly assigned to receive continued treatment with myeloablative chemotherapy, total-body irradiation, and transplantation of autologous bone marrow purged of neuroblastoma cells or to receive three cycles of intensive chemotherapy alone. All patients who completed cytotoxic therapy without disease progression were then randomly assigned to receive no further therapy or treatment with 13-cis-retinoic acid for six months. The mean (+/-SE) event-free survival rate three years after the first randomization was significantly better among the 189 patients who were assigned to undergo transplantation than among the 190 patients assigned to receive continuation chemotherapy (34+/-4 percent vs. 22+/-4 percent, P=0.034). The event-free survival rate three years after the second randomization was significantly better among the 130 patients who were assigned to receive 13-cis-retinoic acid than among the 128 patients assigned to receive no further therapy (46+/-6 percent vs. 29+/-5 percent, P=0.027). Treatment with myeloablative therapy and autologous bone marrow transplantation improved event-free survival among children with high-risk neuroblastoma. In addition, treatment with 13-cis-retinoic acid was beneficial for patients without progressive disease when it was administered after chemotherapy or transplantation.


Normal labor and the induction and augmentation of labor.
The management of labor is based on a sound understanding of labor's biochemistry and physiology. The interaction between prostaglandin synthesis and other mechanisms postulated to control the initiation of labor shows promise, but the definitive explanation for the initiation of labor awaits further research. The procedures associated with the management of routine labor, including perineal preparation and the use of enemas, intravenous fluids, and analgesics and anesthetics, are generally best applied on the basis of individual need rather than protocol. The Friedman labor curve and intrapartum risk scoring have proved to be useful indices in the evaluation of the course of labor. Oxytocin and prostaglandin are two clinically useful agents in the induction and augmentation of labor. Currently, prostaglandin is used generally in the induction of preterm labors with oxytocin reserved for the induction of labor at term. The effects and side effects of the medications may be controlled by careful use and monitoring. A protocol for the successful use of oxytocin includes careful fetal monitoring and control of intravenous infusion with careful incremental increases in the dose of oxytocin based on uterine response.


Antimicrobial potentials of Diospyros mespiliformis (Ebenaceae).
The petroleum ether, chloroform, methanol, and water extracts of the leaves, stem bark, and root of Diospyros mespiliformis were studied for their antimicrobial activities. The crude extracts showed broad spectrum antimicrobial activities against 9 Gram-positive bacteria, 8 Gram-negative bacteria, and 6 fungal strains. Of the four extracting solvents, chloroform produced extracts with the best antimicrobial activities, while the chloroform extract of the root exhibited the highest antimicrobial activity. Some tetracycline resistant strains of Staphylococcus aureus and gentamicin resistant strains of Pseudomonas aeruginosa were sensitive to some of the extracts tested. Preliminary phytochemical screening revealed the presence of the following metabolites: anthraquinones, tannins, triterpene, saponins, steroids, and sugars and the absence of alkaloids. The antimicrobial activities observed are discussed in relation to the chemical constituents reportedly isolated from several species of this plant and their traditional uses.


Immune reconstitution in HIV infection.
The weight of the published evidence suggest that there is clinically significant immune recovery in a sizable fraction of HIV-infected patients who achieve suppression of viral replication. At the same time, it is clear that very few patients regain normal (i.e. equivalent to pre-infection) immune function, at least after the follow-up periods available so far. The experience from bone-marrow transplantation or intensive chemotherapy in adults suggests that such kind of immune reconstitution is unlikely (at least with treatments limited to stopping virus replication) once the immune system has been sufficiently damaged. It is also clear that effective immunity to HIV is not achieved in a significant proportion of patients. These findings have implications for both basic research and clinical practice. From the laboratory perspective, besides the urgent need to characterize the protective immunity to HIV (if it exists), it would be desirable to find some simple measure of the immune function of patients who receive therapy. The combination of markers of immune activation together with CD4 cell count and viral load should be further evaluated in this context. Regarding clinical practice, it is likely that prophylaxes for opportunistic infections can be discontinued uneventfully in the majority of patients responding to HAART. Although the evidence is not yet conclusive, all available data suggest this will be the case. Given that there is significant immune reconstitution even in advanced disease, it is tempting to consider if this fact can be used to support antiviral therapy recommendations that are less aggressive than the current ones. HIV eradication by pharmacologic means alone does not seem possible yet, and no effective immune response to HIV seems to be generated by starting therapy in the asymptomatic (as opposed to acute infection) stage of the disease. At the same time, the follow-up studies on prolonged antiretroviral therapy suggest that virologic failure will take place despite many months of seemingly adequate suppression. This fact, taken together with the side effects and inconvience of current antiretroviral regimens, can be used to support an argument in favor of evaluating strategies to treat later rather than earlier.


Meltwater input to the southern ocean during the last glacial maximum.
Three records of oxygen isotopes in biogenic silica from deep-sea sediment cores from the Atlantic and Indian sectors of the Southern Ocean reveal the presence of isotopically depleted diatomaceous opal in sediment from the last glacial maximum. This depletion is attributed to the presence of lids of meltwater that mixed with surface water along certain trajectories in the Southern Ocean. An increase in the drainage from Antarctica or extensive northward transport of icebergs are among the main mechanisms that could have produced the increase in meltwater input to the glacial Southern Ocean. Similar isotopic trends were observed in older climatic cycles at the same cores.


Machine learning-accelerated design and synthesis of polyelemental heterostructures.
In materials discovery efforts, synthetic capabilities far outpace the ability to extract meaningful data from them. To bridge this gap, machine learning methods are necessary to reduce the search space for identifying desired materials. Here, we present a machine learning–driven, closed-loop experimental process to guide the synthesis of polyelemental nanomaterials with targeted structural properties. By leveraging data from an eight-dimensional chemical space (Au-Ag-Cu-Co-Ni-Pd-Sn-Pt) as inputs, a Bayesian optimization algorithm is used to suggest previously unidentified nanoparticle compositions that target specific interfacial motifs for synthesis, results of which are iteratively shared back with the algorithm. This feedback loop resulted in successful syntheses of 18 heterojunction nanomaterials that are too complex to discover by chemical intuition alone, including extremely chemically complex biphasic nanoparticles reported to date. Platforms like the one developed here are poised to transform materials discovery across a wide swath of applications and industries.


High sensitivity troponin T in acute medicine; more questions than answers?
Troponin testing in acute medicine is routine. The introduction of a high sensitivity assay (hs Tn T) has created uncertainty regarding the clinical significance of 'abnormal' troponin T levels. The previous assay could not detect troponin levels <30 ng/l. To characterize those with a hs Tn T ≥14 ng/l. Prospective cohort study of consecutive admissions to an acute medical unit. Troponin was measured in 564 consecutive patients (∼50% of all admissions) over 1 month; was ≥14 ng/l in 224 (40%) of which 220 patients had demographic data for this analysis. Median (inter-quartile range) peak troponin was 47.5 ng/l (24-130) and 36% had a Tn T between 14 and 30 ng/l. Mean [standard deviation (SD)] age was 72 (12) years and 57% were male. Only 44 patients (20%) had an acute myocardial infarction, reflecting the increased sensitivity but reduced specificity of the assay. Prognosis was poor with 31% mortality at 1 year. Over a mean (SD) follow-up of 648 (61) days, there were 87 deaths (40%). Those with a primary non-cardiac diagnosis (n = 126) had poorer survival than those with a primary cardiac diagnosis (n = 94). Troponin elevation related to sepsis conferred a very poor prognosis with 24 deaths (70%) over the follow-up period. Elevated hs Tn T is very common in acute medicine, but myocardial infarction as an explanation is uncommon. Overall, the prognosis is poor with a tendency to worse outcomes in those with a primary 'non-cardiac' diagnosis.


Oropharyngeal Bleeding Due to Cannabidiol Oil Vape Use.
Vaping has become an increasingly popular alternative to smoking in recent years. We present a rare and unusual case of upper airway bleeding caused by inhalation of a cannabidiol (CBD) oil-based vape due to a chemical burn. There are no case reports of this injury in the literature, and we discuss the clinical presentation, diagnosis and our management of this potentially life-threatening injury. A 27-year-old man presented to the accident and emergency department after using a CBD oil vape. After one inhalation of the CBD oil vape, the patient experienced immediate onset pain in the oropharynx, dyspnoea, expectoration of blood and hoarseness. The patient had used a CBD oil vape four hours earlier that evening for the first time, which was procured from an unregulated online source. The patient was referred to the Ear, Nose and Throat (ENT) team where the examination of oropharynx identified a posterior pharyngeal bleeding point. Flexible nasal endoscopy was undertaken showing profound erythema and inflammation throughout the oropharynx and posterior pharyngeal wall. The mucous membranes had been detached leaving an exposed bleeding submucosa. The patient was commenced on three cycles of back-to-back adrenaline nebulisers (1:1000 adrenaline in 5ml of 0.9% NaCl), 6.6mg dexamethasone intravenously and hydrogen peroxide gargles (5ml of 3% hydrogen peroxide in 10ml of water) three times a day. There were early involvement and review of the airway by the anaesthetic and intensive care teams, which was deemed safe at the time. A plan was made for a definitive airway if bleeding reoccurred. Upper airway bleeding can present as a rare form of vape-induced injury and should be considered part of the differential diagnosis particularly in those using CBD oil vapes. History taking is pertinent and patients should be questioned on the specific vape liquids used. Airway stabilisation is the priority with early involvement of the multi-disciplinary team including anaesthetists, intensive care specialists and ENT surgeons.