Control of aldosterone secretion by pituitary hormones.
Pro-gamma-melanotropins (pro-gamma-MSH) are implicated in the control of aldosterone secretion by the normal adrenal cortex and in idiopathic hyperaldosteronism. In contrast with other melanotropins (alpha- and beta-MSH), the pro-gamma-MSH increase aldosterone secretion by normal adrenals only in the presence of adrenocorticotrophic hormone (ACTH). However, in aldosteronoma cells this stimulatory effect of the pro-gamma-MSH is not ACTH-dependent. The mechanism of pro-gamma-MSH action on aldosterone biosynthesis may involve activation of cholesteryl ester hydrolase in zona glomerulosa, resulting in an increased provision of cholesterol for steroidogenesis.


Exposure to Upper Arm Elevation During Work Compared to Leisure Among 12 Different Occupations Measured with Triaxial Accelerometers.
Regarding prevention of neck and shoulder pain (NSP), unsupported arm elevation is one factor that should be taken into account when performing work risk assessment. Triaxial accelerometers can be used to measure arm elevation over several days but it is not possible to differentiate between supported and unsupported arm elevation from accelerometers only. Supported arm elevation is more likely to exist during sitting than standing. The aim of the study was to evaluate the use of whole workday measurements of arm elevation with accelerometers to assess potentially harmful work exposure of arm elevation, by comparing arm elevation at work with arm elevation during leisure, in a population with diverse work tasks, and to assess how the exposure parameters were modified when upper arm elevation during sitting time was excluded. The participants, 197 workers belonging to 12 occupational groups with diverse work tasks, wore triaxial accelerometers on the dominant arm, hip, and back for 1-4 days to measure arm elevation and periods of sitting. None of the groups were found to have higher exposure to arm elevation during work compared to leisure. Even though some occupations where known to have work tasks that forced them to work with elevated arms to a large extent. A high proportion of arm elevation derived from sitting time, especially so during leisure. When arm elevation during sitting time was excluded from the analysis, arm elevation was significantly higher at work than during leisure among construction workers, garbage collectors, manufacturing workers, and domestic cleaners. Together this illustrates that it is not suitable to use whole workday measurments of arm elevation with accelerometer as a sole information source when assessing the risk for NSP due to arm elevation. Information on body posture can provide relevant contextual information in exposure assessments when it is known that the potential harmful exposure is performed in standing or walking.


Four decades of experience of prosthetic valve endocarditis reflect a high variety of diverse pathogens.
Prosthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future.


Hierarchically encapsulating enzymes with multi-shelled metal-organic frameworks for tandem biocatalytic reactions.
Biocatalytic transformations in living organisms, such as multi-enzyme catalytic cascades, proceed in different cellular membrane-compartmentalized organelles with high efficiency. Nevertheless, it remains challenging to mimicking biocatalytic cascade processes in natural systems. Herein, we demonstrate that multi-shelled metal-organic frameworks (MOFs) can be used as a hierarchical scaffold to spatially organize enzymes on nanoscale to enhance cascade catalytic efficiency. Encapsulating multi-enzymes with multi-shelled MOFs by epitaxial shell-by-shell overgrowth leads to 5.8~13.5-fold enhancements in catalytic efficiencies compared with free enzymes in solution. Importantly, multi-shelled MOFs can act as a multi-spatial-compartmental nanoreactor that allows physically compartmentalize multiple enzymes in a single MOF nanoparticle for operating incompatible tandem biocatalytic reaction in one pot. Additionally, we use nanoscale Fourier transform infrared (nano-FTIR) spectroscopy to resolve nanoscale heterogeneity of vibrational activity associated to enzymes encapsulated in multi-shelled MOFs. Furthermore, multi-shelled MOFs enable facile control of multi-enzyme positions according to specific tandem reaction routes, in which close positioning of enzyme-1-loaded and enzyme-2-loaded shells along the inner-to-outer shells could effectively facilitate mass transportation to promote efficient tandem biocatalytic reaction. This work is anticipated to shed new light on designing efficient multi-enzyme catalytic cascades to encourage applications in many chemical and pharmaceutical industrial processes.


Anthropometry in Long-Term Survivors of Acute Lymphoblastic Leukemia in Childhood and Adolescence.
Body mass index (BMI) is an inadequate measure of nutritional status in children and adolescents with cancer as it does not distinguish muscle from adipose tissue. However, arm anthropometry offers simple assessments of fat mass and lean body mass; especially valuable in low- and middle-income countries where the great majority of young people with cancer live and access to sophisticated expensive measures of body composition is markedly limited. The nutritional status of 75 long-term survivors of acute lymphoblastic leukemia was assessed by arm anthropometry, in addition to BMI, in a cross-sectional cohort study. Normal ranges for triceps skin fold thickness (TSFT, a surrogate for fat mass) and mid-upper arm circumference (MUAC, a surrogate for lean body mass) were between the 15th and 85th percentiles for age and sex. Overweight/obesity was classified as a TSFT >85th percentile and sarcopenia as an MUAC <15th percentile. Height normalized indices for TSFT and MUAC were also calculated. Overweight/obesity was identified in 1/3 of subjects by a BMI >25 and by TSFT; and 20% of the subjects had a TSFT >95th percentile. Only two subjects were sarcopenic. None met the combined criteria for sarcopenic obesity. TSFT and MUAC/height indices did not add sensitivity to identification of sarcopenia or obesity. TSFT is a useful measure of overweight/obesity in this population, but MUAC does not identify a notable proportion with sarcopenia. Further resolution may be provided by more sophisticated measures of body composition.


High spatial and temporal resolution mobile incoherent Doppler lidar for sea surface wind measurements.
A mobile Doppler lidar based on an injection-seeded diode-pumped Nd:YAG pulsed laser with a high repetition rate was developed to measure the sea surface wind (SSW) with high spatial and temporal resolution. The system was operated during the 2007 Qingdao International Regatta to measure the distribution of SSW in the racing area in real time with 50-100 m horizontal resolution and 2-10 min temporal resolution. An observation of nonuniform distribution of SSW is presented. The lidar results are compared with both buoy and wind tower measurements, which show good agreement. This lidar can be used advantageously for the 2008 Olympic sailing games as well as for observing mesoscale and microscale meteorology processes.


Altering cancer transcriptomes using epigenomic inhibitors.
Due to the hyper-activation of WNT signaling in a variety of cancer types, there has been a strong drive to develop pathway-specific inhibitors with the eventual goal of providing a chemotherapeutic antagonist of WNT signaling to cancer patients. A new category of drugs, called epigenetic inhibitors, are being developed that hold high promise for inhibition of the WNT pathway. The canonical WNT signaling pathway initiates when WNT ligands bind to receptors, causing the nuclear localization of the co-activator β-catenin (CTNNB1), which leads to an association of β-catenin with a member of the TCF transcription factor family at regulatory regions of WNT-responsive genes. The TCF/β-catenin complex then recruits CBP (CREBBP) or p300 (EP300), leading to histone acetylation and gene activation. A current model in the field is that CBP-driven expression of WNT target genes supports proliferation whereas p300-driven expression of WNT target genes supports differentiation. The small molecule inhibitor ICG-001 binds to CBP, but not to p300, and competitively inhibits the interaction of CBP with β-catenin. Upon treatment of cancer cells, this should reduce expression of CBP-regulated transcription, leading to reduced tumorigenicity and enhanced differentiation. We have compared the genome-wide effects on the transcriptome after treatment with ICG-001 (the specific CBP inhibitor) versus C646, a compound that competes with acetyl-coA for the Lys-coA binding pocket of both CBP and p300. We found that both drugs cause large-scale changes in the transcriptome of HCT116 colon cancer cells and PANC1 pancreatic cancer cells and reverse some tumor-specific changes in gene expression. Interestingly, although the epigenetic inhibitors affect cell cycle pathways in both the colon and pancreatic cancer cell lines, the WNT signaling pathway was affected only in the colon cancer cells. Notably, WNT target genes were similarly downregulated after treatment of HCT116 with C646 as with ICG-001. Our results suggest that treatment with a general HAT inhibitor causes similar effects on the transcriptome as does treatment with a CBP-specific inhibitor and that epigenetic inhibition affects the WNT pathway in HCT116 cells and the cholesterol biosynthesis pathway in PANC1 cells.


Development of a guideline for the management of the unanticipated difficult airway in pediatric practice.
Most airway problems in children are identified in advance; however, unanticipated difficulties can arise and may result in serious complications. Training for these sporadic events can be difficult. We identified the need for a structured guideline to improve clinical decision making in the acute situation and also to provide a guide for teaching. Guidelines for airway management in adults are widely used; however, none have been previously devised for national use in children. We aimed to develop guidelines for the management of the unanticipated difficult pediatric airway for use by anesthetists working in the nonspecialist pediatric setting. We reviewed available guidelines used in individual hospitals. We also reviewed research into airway management in children and graded papers for the level of evidence according to agreed criteria. A Delphi panel comprising 27 independent consultant anesthetists considered the steps of the acute airway management guidelines to reach consensus on the best interventions to use and the order in which to use them. If following the literature review and Delphi feedback, there was insufficient evidence or lack of consensus, regarding inclusion of a particular point; this was reviewed by a Second Specialist Group comprising 10 pediatric anesthetists. Using the Delphi group's deliberations and feedback from the Second Specialist Group, we developed three guidelines for the acute airway management of children aged 1-8 years. This paper provides the background, available evidence base, and justification for each step in the resultant guidelines and gives a rationale for their use.


The interaction of polyphenols with bilayers: conditions for increasing bilayer adhesion.
Because proteins and other molecules with a high polyphenol content are commonly involved in adhesion processes, we are investigating the interactions between polyphenols and biological materials. A naturally occurring polyphenol that binds a variety of proteins and lipids is tannic acid (TA), which contains five digallic acid residues covalently linked to a central D-glucose. A previous study has shown that TA increases the adhesion between apposing phosphatidylcholine (PC) bilayers and over a very narrow concentration range collapses the interbilayer fluid space from about 15 A to 5 A. To determine the chemical requirements a polyphenolic molecule must possess to increase bilayer adhesion, we have synthesized several simpler TA analogs that vary in their size, shape, and number of gallic acid and hydroxyl groups. X-ray diffraction, absorbance, binding, and differential scanning calorimetry measurements were used to investigate the interaction of these polyphenolic molecules with egg PC (EPC) and dipalmitoyl PC (DPPC) bilayers. Of these synthetic polyphenols, only penta-O-galloyl-alpha-D-glucose (PGG) was able to completely mimic the effects of TA by collapsing the interbilayer fluid space from 15 A to 5 A, decreasing the dipole potential by about 300 mV, increasing the transition enthalpy of DPPC liposomes, and inducing an interdigitated phase in DPPC. Binding studies indicated that the fluid space was reduced to 5 A at an EPC:PGG mole ratio of 5:1. We conclude that these polyphenols collapse the fluid space of PC bilayers because they 1) are amphipathic and partition into the bilayers interfacial region, 2) are long enough to span the interbilayer space, 3) contain several gallic acids distributed so that they can partition simultaneously into apposing bilayers, and 4) have sufficient gallic acid residues to interact with all lipid headgroups and cover the bilayer surface. Under these conditions we conclude that the polyphenols from interbilayer bridges. We argue that these bridges are stabilized by increased adhesion arising from an increased van der Waals interaction between apposing bilayers, electrostatic interactions between the pi electrons in the phenol ring and the -(N+CH3)3 groups on the PC headgroups, decreased hydration repulsion between bilayers, and hydrogen bonds between the H-bond-donating moieties on the polyphenols and H-bond-accepting groups in the bilayer.


Investigation of Triamcinolone Instillation in the Long-term Rate of Anterior Urethral Strictures' Recurrence.
Previous publications confirmed that after internal urethrotomy success rates in the short-term (less than 6 months) are varied (70-80%) and in the long-term results are generally low. In this study, the efficacy of triamcinolone instillation based on a newly introduced protocol on the rate of recurrence in patients with anterior urethral strictures was evaluated. A total of 66 patients were divided into treatment group (n = 33), in which triamcinolone was instilled on urethra after removing of Foley catheter and control group (n = 33) that not received any intervention. Each 40 mg/1 ml of triamcinolone vial was dissolved in 9 ml of distilled water and then a 2 ml of diluted solution was used for each instillation and 8 ml was kept in 4°C. Triamcinolone was instilled based on daily in week 1, every other day for week 2 and then every Monday and Friday for 2 months. Penile clamp was used after instillation for 1 hour. Treatment failure was based on urine flow rate, rate of recurrence and time to appearance of recurrence. There were not any significant differences regrading to age (p = 0.09), length (p = 0.41) and diameter (p = 0.36) of stricture between 2 groups. Time to appearance of recurrence showed significantly in the treatment group when compared with that in the control group (1,350 ± 900 vs. 124.3 ±112 days; p < 0.01). In the treatment group, 88% had reasonable consequence, while in control 48%. There were 3 patients with a mean length-diameter of stricture around 0.3-5 cm who showed recurrence free with the mean of 720 days after intervention. Administration of triamcinolone instillation in urethra is associated with a decreased risk of stricture recurrence. Superior outcomes were seen in patients with a stricture length of more than 2 cm and this may in part reflect the increasing efficacy of the instillation method in the management of urethral strictures. These findings help identify patients with aggressive features of strictures in urethra who may benefit from intensified treatment efficacy of triamcinolone instillation.


Finding the moral heart of treatment: mental health care in a French prison.
Morality is one of the most important elements of social actions, specifically in medical settings. Unfortunately, in social science, morality is often undertheorized and can lead to moralism. The aim of the paper is to test the "moral economy theory" which highlights the link between some local moral evaluations and a political context. We focus on "treatment" as therapeutic tool and as moral regulation of patients in a French remand centre. On the basis of an ethnography of forms of care for prisoners (2009-2010), and semi-directed interviews with working mental health professionals (n = 10), we analyse their engagement and their moral expectations of the prisoners under their care. Firstly, we show how prisoners are selected and then converted into patients deserving of attention (expectations of honesty, sincerity and compliance). Secondly, we show how these patients are divided into three main intervention categories, in which the treatment is both therapeutic and moral (expectations of responsibility, recognition of guilt, and self-esteem). Finally, we discuss these moral criteria within a new moral economy of vulnerability.


Passive transfer of immunoglobulin Y antibody to Streptococcus mutans glucan binding protein B can confer protection against experimental dental caries.
Active immunization with Streptococcus mutans glucan binding protein B (GBP-B) has been shown to induce protection against experimental dental caries. This protection presumably results from continuous secretion of salivary antibody to GBP-B, which inhibits accumulation of S. mutans within the oral biofilm. The purpose of this study was to explore the influence of short-term (9- or 24-day) passive oral administration of antibody to S. mutans GBP-B on the longer-term accumulation and cariogenicity of S. mutans in a rat model of dental caries. Preimmune chicken egg yolk immunoglobulin Y (IgY) or IgY antibody to S. mutans GBP-B was supplied in lower (experiment 1) and higher (experiment 2) concentrations in the diet and drinking water of rats for 9 (experiment 1) or 24 (experiment 2) days. During the first 3 days of IgY feeding, all animals were challenged with 5 x 10(6) streptomycin-resistant S. mutans strain SJ-r organisms. Rats remained infected with S. mutans for 78 days, during which rat molars were sampled for the accumulation of S. mutans SJ-r bacteria and total streptococci. Geometric mean levels of S. mutans SJ-r accumulation on molar surfaces were significantly lower in antibody-treated rats on days 16 and 78 of experiment 2 and were lower on all but the initial (day 5) swabbing occasions in both experiments. Relative to controls, the extent of molar dental caries measured on day 78 was also significantly decreased. The decrease in molar caries correlated with the amount and duration of antibody administration. This is the first demonstration that passive antibody to S. mutans GBP-B can have a protective effect against cariogenic S. mutans infection and disease. Furthermore, this decrease in infection and disease did not require continuous antibody administration for the duration of the infection period. This study also indicates that antibody to components putatively involved only in cellular aggregation can have a significant effect on the incorporation of mutans streptococci in dental biofilm.


B-Raf activation cooperates with PTEN loss to drive c-Myc expression in advanced prostate cancer.
Both the PI3K → Akt → mTOR and mitogen-activated protein kinase (MAPK) signaling pathways are often deregulated in prostate tumors with poor prognosis. Here we describe a new genetically engineered mouse model of prostate cancer in which PI3K-Akt-mTOR signaling is activated by inducible disruption of PTEN, and extracellular signal-regulated kinase 1/2 (ERK1/2) MAPK signaling is activated by inducible expression of a BRAF(V600E) oncogene. These tissue-specific compound mutant mice develop lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Activation of PI3K → Akt → mTOR and MAPK signaling pathways in these prostate tumors cooperate to upregulate c-Myc. Accordingly, therapeutic treatments with rapamycin and PD0325901 to target these pathways, respectively, attenuate c-Myc levels and reduce tumor and metastatic burden. Together, our findings suggest a generalized therapeutic approach to target c-Myc activation in prostate cancer by combinatorial targeting of the PI3K → Akt → mTOR and ERK1/2 MAPK signaling pathways.


Predicting economic losses from the continued spread of the Mexican rice borer (Lepidoptera: Crambidae).
The Mexican rice borer, Eoreuma loftini (Dyar) (Lepidoptera: Crambidae), is an invasive species that originated from Mexico, and it is threatening to cause major economic losses to sugarcane, Saccharum spp., and rice, Oryza sativa L., industries in Louisiana. The insect is expected to reach sugarcane and rice production areas in Louisiana by 2008, and infest all of Louisiana sugarcane and rice industries by 2035. When all sugarcane in Louisiana becomes infested, annual yield losses of $220 million would be expected for a cultivar of comparable susceptibility to LCP 85-384 (assuming this cultivar is planted on 100% of the production area). This also assumes the use of the current practice of rainfed production and one application of insecticide, which is presently used by farmers in Louisiana. Irrigation with 30 cm of water is predicted to reduce estimated losses by 29%, whereas four applications of a biorational insecticide such as tebufenozide are expected to reduce the loss in revenue by 53%. The use of the resistant 'HoCP 85-845' would reduce the projected loss in revenue by 24%. Combining all three management tactics on sugarcane, anticipated net loss in revenue would decrease by 66%. The rice industry in Louisiana is projected to suffer from a loss in revenue of $45 million when the entire state is infested. A 77% reduction in loss in revenue is expected with one application of lambda-cyhalothrin. A quarantine on east Texas sugarcane is estimated to save the Louisiana industry between $1.1 billion and $3.2 billion (depending on management) during the time needed for the insect to fully invade the state's sugarcane and rice producing area by natural migration rather than by accidental introduction. The rapid deployment of appropriate management tactics will have a key role in reducing the anticipated economic impact of E. loftini once it becomes a pest in Louisiana sugarcane and rice.


FDA drug approval summaries: pemetrexed (Alimta).
The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.


The Use of Patient-Reported Outcomes in Patients Treated With Maintenance Hemodialysis: A Perspective.
There is increasing interest in the integration of patient-reported outcomes (PROs) into health care research and clinical practice for the benefit of patients with end-stage kidney disease receiving hemodialysis. In a research setting, PROs can be used as a patient-centered primary or secondary outcome in clinical studies. In routine care, PRO data may be used to support service delivery through benchmarking and audit or inform and enhance the care of the individual patient by improving patient-clinician communication. Despite evidence demonstrating the potential benefits of PROs and prioritization of these outcomes by patients, their use in kidney disease remains limited. Although there are significant methodological and operational challenges for the widespread integration of PROs, there is now consensus that this area should be at the forefront of clinical research and implementation science. We discuss the current use of PROs for patients with end-stage kidney disease receiving hemodialysis and identify a roadmap for increasing the evidence base and introducing PROs into mainstream clinical practice.


Ichthyosiform mycosis fungoides with alopecia and atypical membranous nephropathy.
We describe here a rare case of variant of mycosis fungoides (MF): ichthyosiform MF with alopecia and atypical membranous nephropathy. The diagnosis was made based on the following findings: generalized ichthyosis-like eruption, alopecia, enlarged superficial lymph nodes, proteinuria, and hematuria, the histological features of the skin biopsy from both ichthyotic and alopecic lesions with immunohistochemical staining, and the renal biopsy examination with immunofluorescence. The histological examination of ichthyotic and alopecic lesions displayed a predominant infiltration of atypical lymphocytes in the upper dermis with the characteristics of epidermotropism and folliculotropism. Immunohistochemical studies demonstrated that most infiltrated atypical lymphocytes were CD3, CD4, and CD45RO positive, whereas negative for CD5, CD7, CD20, CD30, and CD56. A renal biopsy examination revealed atypical membranous nephropathy with deposition of immunoglobulin G (IgG), IgM, IgA, C1q, and C3. In this case atypical membranous nephropathy was involved, which is very uncommon and has never been presented in the literature to date. Although ichthyosiform MF usually features a relatively favorable course, diffuse alopecia and the renal involvement in this case might indicate aggressive disease and poor prognosis.


Effect of vasodilation and vasoconstriction on microvascular pressures in skeletal muscle.
The effect of topically applied papaverine (PAP) and norepinephrine (NE), on the microvascular pressure distribution was studied in the cremaster muscle of anesthetized rats. The cremaster muscle was exteriorized into a tissue bath containing Krebs bicarbonate buffer, and microvessel diameters and pressures were measured using a video caliper and the resistance servo-null method, respectively. Pressures were measured in the 1st through 4th branch order arterioles (1A to 4A) and 1st through 4th branch order venules (1V to 4V). Resistances were calculated across each segment from pressure gradients and 1A blood flow which was estimated from red cell velocities. PAP (10 microM) produced approximately a 15% decrease in arteriolar pressures with a concomitant increase in venular pressures of between 15 and 50%. In contrast, NE (0.1 microM) significantly increased arteriolar pressure by approximately 30% and decreased venular pressure by about 25%. Changes in systemic pressure during treatment with PAP and NE were small or insignificant and could not account for the observed changes in microvascular pressure. Significant dilation was observed in 3A, 4A, and 3V vessels after papaverine. In comparison, NE caused significant constriction in all vessel orders except 4V. PAP decreased resistance across all segments between 1A and 4V by 22-42% and increased venular resistance by almost 400%. NE increased resistance in all microvascular segments with the largest changes occurring in 2A to 3A (+276%) and 4A to 4V (+277%) segments. These data demonstrate that PAP and NE induce significant and opposite changes in arteriolar and venular pressures. Such network alterations in microvascular pressure should be considered when evaluating microvascular reactivity and exchange in the presence of vasoactive agents.


Is it too soon for mesenchymal stem cell trials in people with ALS?
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting primarily the motor neurons. Stem cell therapy is under development as a possible treatment approach. A pilot study of intraspinal injections of mesenchymal stem cells (MSC) was conducted in 9 participants. We review this paper, the rationale, preclinical data and study design.


Integrated cytogenetic, ecological, and DNA barcode study reveals cryptic diversity in Simulium (Gomphostilbia) angulistylum (Diptera: Simuliidae).
An integrated approach based on cytogenetics, molecular genetics, and ecology was used to examine diversity in the black fly Simulium angulistylum Takaoka & Davies in Thailand. Cytological analysis revealed three cytoforms (A, B, and C) of S. angulistylum differentiated by fixed chromosome inversions. Distributions of these cytoforms were associated with ecology. Cytoforms A and B were found in low-altitude habitats (<600 m above sea level), whereas cytoform C occurred at high altitudes (>1000 m above sea level). Mitochondrial DNA sequences of the cytochrome oxidase subunit I barcoding region revealed significant genetic differentiation among the cytoforms. The mitochondrial DNA haplotype network revealed divergent lineages within cytoforms, indicating additional hidden diversity. Therefore, integrated approaches are necessary for fully understanding black fly biodiversity. Population genetic analysis revealed high genetic structuring that could be due to the habitat preferences of S. angulistylum. Phylogeographic analyses indicated population demographic expansion at the mid-Pleistocene (900 000 years ago), which is older than for other black flies and insects in the Southeast Asian mainland. The high level of genetic structure and diversity, therefore, could also be due to the long demographic history of S. angulistylum.


Phagotrophic Protists and Their Associates: Evidence for Preferential Grazing in an Abiotically Driven Soil Ecosystem.
The complex relationship between ecosystem function and soil food web structure is governed by species interactions, many of which remain unmapped. Phagotrophic protists structure soil food webs by grazing the microbiome, yet their involvement in intraguild competition, susceptibility to predator diversity, and grazing preferences are only vaguely known. These species-dependent interactions are contextualized by adjacent biotic and abiotic processes, and thus obfuscated by typically high soil biodiversity. Such questions may be investigated in the McMurdo Dry Valleys (MDV) of Antarctica because the physical environment strongly filters biodiversity and simplifies the influence of abiotic factors. To detect the potential interactions in the MDV, we analyzed the co-occurrence among shotgun metagenome sequences for associations suggestive of intraguild competition, predation, and preferential grazing. In order to control for confounding abiotic drivers, we tested co-occurrence patterns against various climatic and edaphic factors. Non-random co-occurrence between phagotrophic protists and other soil fauna was biotically driven, but we found no support for competition or predation. However, protists predominately associated with Proteobacteria and avoided Actinobacteria, suggesting grazing preferences were modulated by bacterial cell-wall structure and growth rate. Our study provides a critical starting-point for mapping protist interactions in native soils and highlights key trends for future targeted molecular and culture-based approaches.


Selective expression of CYP2A13 in human pancreatic α-islet cells.
Exposure to cigarette smoke is an etiological factor of human pancreatic cancer and has been associated with an increased risk of pancreatic diseases, including pancreatitis and diabetes. The toxicants in cigarette smoke can reach pancreatic tissue, and most of the toxicants require cytochrome P450 (P450)-mediated metabolic activation to exert their toxicity. Among all the human P450 enzymes, CYP2A13 is the most efficient enzyme in the metabolic activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a major tobacco-specific toxicant and a suspected human carcinogen. It also metabolically activates 4-aminobiphenyl, another toxicant in cigarette smoke. Immunohistochemical analysis in this study demonstrated that CYP2A13 was selectively expressed in the islets but not in the exocrine portion of adult human pancreas. Further study using dual immunofluorescence labeling technique showed that CYP2A13 protein was mainly expressed in the α-islet but not in β-islet cells. The selective expression of CYP2A13 in human pancreatic α-islet cells suggests that these islet cells could be damaged by the toxicants existing in cigarette smoke through CYP2A13-mediated in situ metabolic activation. Our result provides a mechanistic insight for human pancreatic diseases that have been associated with cigarette smoke exposure.


Alterations of conjunctival microbiota associated with orthokeratology lens wearing in myopic children.
Orthokeratology (OK) lens wear increases the risk of bacterial infection, but little is known about the microbiota of the conjunctival sac in myopic children wearing OK lenses. This study aimed to investigate the changes of conjunctival microbiota in children after treatment with OK lenses using 16 S rDNA sequencing. Twenty-eight myopic children who had been continuously wearing OK lenses for 12 to 13 months were enrolled in this prospective study. Twenty-two gender- and age-matched myopic children who had not worn OK lenses or discontinued OK lens wear at least 1 year ago were recruited as controls. Conjunctival swabs from each participant were collected for exploration of the microbiota profiles, targeting the V3-V4 regions of the 16 S rRNA gene by MiSeq sequencing. The differences in the microbial community structure and diversity were also compared between groups. The bacterial alpha diversity indices in the OK lens group were not different from those in the non-wearer group (P > 0.05, Wilcoxon test), while beta diversity examined using principle coordinate analysis of unweighted UniFrac divided the two groups into different clusters. Proteobacteria, Bacteroidetes, and Firmicutes were the abundant phyla in the conjunctival sac microbiota in both groups (P < 0.05, Mann-Whitney U test). Among children in the OK lens group, the Linear discriminant analysis Effect Size identified the compositional changes in OK lens-associated bacteria. Key functional genera such as Blautia, Parasutterella, and Muribaculum were enriched, whereas Brevundimonas, Acinetobacter, Proteus, and Agathobacter decreased significantly (P < 0.05, Mann-Whitney U test). Phylogenetic investigation of communities by reconstruction of unobserved states also showed altered bacterial metabolic pathways in OK lens-associated microbiota. Moreover, using receiver operating characteristic curves, Brevundimonas, Acinetobacter, Proteus, and Agathobacter alone (the area under the curve was all > 0.7500) or in combination (the area under the curve was 0.9058) were revealed to discriminate OK lens wearers from controls. The relative abundance of the microbial community in the conjunctival sac of myopic children can alter after OK lens wear. Brevundimonas, Acinetobacter, Proteus, and Agathobacter may be candidate biomarkers to distinguish between OK lens wearers and non-wearers.


[Role of technogenic pollution as a risk factor in morbidity of preschool children].
The paper shows it adequate to apply a systems approach to assessing the role of technogenic pollution of the environment in the system of socio-hygienic and biomedical factors that affect the morbidity among pre-school children by using the epidemiological survey in the area of the Revdinsk-Pervouralsk industrial center as an example.


Evaluation of an enzyme immunosorbent assay for the diagnosis of Argentine haemorrhagic fever.
To elaborate a set of serological tests for the diagnosis of Argentine haemorrhagic fever (AHF), an enzyme-linked immunosorbent assay (ELISA) for detection of specific anti-Junin virus (JV) IgG is described, and its performance is compared with that of the plaque reduction neutralization test (PRNT). The reproducibility, sensitivity, specificity, and confidence limits for positive and negative results for ELISA were statistically analysed. The value of 800 was demonstrated as the lowest positive titer. Titers > or = 800 varied within one (two-fold) dilution in 95.6% of the tests, while the sensitivity and specificity were 99.2% and 98.8%, respectively. The assay yielded 1% of false positives and 0.05% of false negatives. A comparison of ELISA to PRNT in detecting the seroconversion for JV was studied by the chi square test (comparison of proportions in paired samples) and the K parameter for agreement proportion. Comparison of ELISA to PRNT showed no significant difference in the proportions of positive and negative results of these assays (P < 0.01), demonstrating an equivalent performance (K = 0.98) in the diagnosis of AHF. In addition, the simplicity and safety of the procedures involved make this ELISA the most suitable test to detect natural human JV infections.


Regulation of endothelial barrier function by the cAMP-dependent protein kinase.
Elevation of cAMP promotes the endothelial cell (EC) barrier and protects the lung from edema development. Thus, we tested the hypothesis that both increases and decreases in PKA modulate EC function and coordinate distribution of regulatory, adherence, and cytoskeletal proteins. Inhibition of PKA activity by RpcAMPS and activation by cholera toxin was verified by assay of kemptide phosphorylation in digitonin permeabilized EC. Inhibition of PKA by RpcAMPS or overexpression of the endogenous inhibitor, PKI, decreased monolayer electrical impedance and exacerbated the decreases produced by agonists (thrombin and PMA). RpcAMPS directly increased F-actin content and organization into stress fibers, increased co-staining of actin with both phosphatase 2B and myosin light chain kinase (MLCK), caused reorganization of focal adhesions, and decreased catenin at cell borders. These findings are similar to those evoked by thrombin. In contrast, cholera toxin prevented the agonist-induced resistance decrease and protein redistribution. Although PKA activation attenuated thrombin-induced myosin light chain (MLC) phosphorylation, PKA inhibition per se did not cause MLC phosphorylation or affect [Ca2+]i. These studies indicate that a decrease in PKA activity alone can produce disruption of barrier function via mechanisms not involving MLCK and support a central role for cAMP/PKA in regulation of cytoskeletal and adhesive protein function in EC which correlates with altered barrier function.


Experiences of relatives with outpatient palliative care: a cross-sectional study.
The authors aimed to evaluate the experiences of the relatives of dying people, both in regard to benefits and special needs, when supported by a mobile palliative care bridging service (MPCBS), which exists to enable dying people to stay at home and to support patients' relatives. A cross-sectional survey. A standardised survey was performed, asking 106 relatives of dying people about their experiences with the MPCBS (response rate=47.3%). Descriptive statistics were analysed using SPSS 23. Many relatives (62.5%) reported that their dying relations when discharged from a facility to stay at home were not symptom-free. The MPCBS helped relatives maintain home care, and this was reported to be helpful. Support provided by the MPCBS made it easier for 77.6% of relatives to adjust care as soon as situations changed, and helped ensure that symptoms could be better controlled, at least for 68.2% of relatives. Younger relatives felt more encouraged by the MPCBS to care for their relatives dying at home.


V1-V2-V3-V4 T wave inversion: left or right ventricle?
An 84-year-old woman, affected by Alzheimer's disease, presented to the emergency department with intense dyspnoea. Since ECG was showing T wave inversion in anterior leads and troponin-T was high, the patient was admitted to our unit with a diagnosis of anterior non-ST elevation myocardial infarction. However, the patient's medical history and a further review of the ECG led us to suspect a pulmonary embolism (PE) as a possible differential clinical diagnosis. We tested this alternative hypothesis: echocardiography as well as contrast-enhanced CT scan confirmed the diagnosis of PE. We describe these misleading ECG findings together with a brief discussion of electrocardiographical changes in pulmonary embolism.


A myogenic factor from sea urchin embryos capable of programming muscle differentiation in mammalian cells.
Using the basic helix-loop-helix domain of the myogenic factor myogenin as a probe, we identified a clone from a sea urchin cDNA library with considerable sequence similarity to the vertebrate myogenic factors. This cDNA, sea urchin myogenic factor 1 (SUM-1), transactivated a muscle creatine kinase-chloramphenicol acetyltransferase reporter gene in 10T1/2 fibroblasts to a level comparable to that of the vertebrate myogenic factors. In addition, bacterially expressed beta-galactosidase-SUM-1 fusion protein interacted directly with the kappa E-2 site in the muscle creatine kinase enhancer core as assayed by electrophoretic mobility shift assays. Stably transfected SUM-1 activated the muscle differentiation program and converted 10T1/2 cells from fibroblasts to myotubes. In sea urchin embryos, SUM-1 RNA was not detected before gastrulation. It accumulated to its highest levels during the prism stage when myoblasts were first detected by myosin immunostaining and then diminished as myocytes differentiated. SUM-1 protein was localized in secondary mesenchyme cells when they could first be identified as muscle cells by myosin immunostaining. These results implicate SUM-1 as a regulatory factor involved in the early decision of a pluripotent secondary mesenchyme cell to convert to a myogenic fate. SUM-1 is an example of an invertebrate myogenic factor that is capable of functioning in mammalian cells.


Retrotransposons represent the most labile fraction for genomic rearrangements in polyploid plant species.
Understanding how increased genome size and diversity within polyploid genomes impacts plant evolution and breeding continues to be challenging. Although historical studies by McClintock suggested the importance of transposable elements mediated by polyploidisation on genomic changes, data from plant crosses remain scarce. Despite the absence of a conclusive proof regarding autonomous retrotransposon movement in synthetic allopolyploids, the transposition of retrotransposons and their ubiquitous dispersion in all plant species might explain the positive correlation between the genome size of plants and the prevalence of retrotransposons. Here, we address polyploidisation-mediated rearrangements of retrotransposon-associated sequences and discuss a tendency for a preferential restructuring of large ancestral genomes after polyploidisation. A comparative analysis of the frequency of modifications of retrotransposon-associated sequences in synthetic polyploids with marked differences in genome sizes is presented. Such analyses suggest the absence of a significant difference in the rates of rearrangements despite vast dissimilarities in the retrotransposon copy number between species, which emphasises the high plasticity of this genomic feature. See also the sister article focusing on animals by Arkhipova and Rodriguez in this themed issue.


Invasion by extremes: population spread with variation in dispersal and reproduction.
For populations having dispersal described by fat-tailed kernels (kernels with tails that are not exponentially bounded), asymptotic population spread rates cannot be estimated by traditional models because these models predict continually accelerating (asymptotically infinite) invasion. The impossible predictions come from the fact that the fat-tailed kernels fitted to dispersal data have a quality (nondiscrete individuals and, thus, no moment-generating function) that never applies to data. Real organisms produce finite (and random) numbers of offspring; thus, an empirical moment-generating function can always be determined. Using an alternative method to estimate spread rates in terms of extreme dispersal events, we show that finite estimates can be derived for fat-tailed kernels, and we demonstrate how variable reproduction modifies these rates. Whereas the traditional models define spread rate as the speed of an advancing front describing the expected density of individuals, our alternative definition for spread rate is the expected velocity for the location of the furthest-forward individual in the population. The asymptotic wave speed for a constant net reproductive rate R0 is approximated as (1/T)(piuR)/2)(1/2) m yr(-1), where T is generation time, and u is a distance parameter (m2) of Clark et al.'s 2Dt model having shape parameter p = 1. From fitted dispersal kernels with fat tails and infinite variance, we derive finite rates of spread and a simple method for numerical estimation. Fitted kernels, with infinite variance, yield distributions of rates of spread that are asymptotically normal and, thus, have finite moments. Variable reproduction can profoundly affect rates of spread. By incorporating the variance in reproduction that results from variable life span, we estimate much lower rates than predicted by the standard approach, which assumes a constant net reproductive rate. Using basic life-history data for trees, we show these estimated rates to be lower than expected from previous analytical models and as interpreted from paleorecords of forest spread at the end of the Pleistocene. Our results suggest reexamination of past rates of spread and the potential for future response to climate change.


A Francisella virulence factor catalyses an essential reaction of biotin synthesis.
We recently identified a gene (FTN_0818) required for Francisella virulence that seemed likely involved in biotin metabolism. However, the molecular function of this virulence determinant was unclear. Here we show that this protein named BioJ is the enzyme of the biotin biosynthesis pathway that determines the chain length of the biotin valeryl side-chain. Expression of bioJ allows growth of an Escherichia coli bioH strain on biotin-free medium, indicating functional equivalence of BioJ to the paradigm pimeloyl-ACP methyl ester carboxyl-esterase, BioH. BioJ was purified to homogeneity, shown to be monomeric and capable of hydrolysis of its physiological substrate methyl pimeloyl-ACP to pimeloyl-ACP, the precursor required to begin formation of the fused heterocyclic rings of biotin. Phylogenetic analyses confirmed that distinct from BioH, BioJ represents a novel subclade of the α/β-hydrolase family. Structure-guided mapping combined with site-directed mutagenesis revealed that the BioJ catalytic triad consists of Ser151, Asp248 and His278, all of which are essential for activity and virulence. The biotin synthesis pathway was reconstituted reaction in vitro and the physiological role of BioJ directly assayed. To the best of our knowledge, these data represent further evidence linking biotin synthesis to bacterial virulence.


Photoacoustic Spectroscopy-Based Breath Analysis for SIBO.
Breath hydrogen (H2) and methane (CH4) monitoring play an important role in the diagnosis of gastrointestinal disorders, such as lactose intolerance and small intestinal bacterial overgrowth (SIBO). In this paper, the photoacoustic spectroscopy method is used for H2 gas and CH4 gas detection. We present a novel approach for H2 gas concentration measurement, which is the linear relationship between the resonant frequency of breath carbon dioxide (CO2) and the H2 concentration in a resonant photoacoustic cell. Experimental results show that the minimum detectable limits of H2, CH4, and CO2 are calculated to be 8.86, 0.56, and 145.14 ppm, respectively, which can meet the requirements of breath diagnosis.


The occurrence of Achlya recurva (Saprolegniales, Oomycetes) in hydrocarbon-polluted soil from Argentina.
Saprolegniaceae are ubiquitous filamentous water molds. They occur as saprotrophs or parasitic on aquatic and terrestial plants and on aquatic animals, and a number of interesting fungi belonging to the Saprolegniaceae have been isolated from the soil. In the course of an investigation of the water molds in Argentina, an unusual species of Achlya was isolated once from soil collections. Brassica napus seeds were used as bait as well as for the maintenance of this fungus in gross water cultures. Achlya recurva Cornu (Saprolegniales, Oomycetes), was isolated from a hydrocarbon-polluted soil (crude oil) in the neighborhood of an oil tank from a distillery (Ensenada, Buenos Aires Province). This species is reported, described and illustrated for the first time from Argentina. Remarks on the habitat are also made because it was never found in polluted areas.


alpha-1-Antitrypsin ameliorates cigarette smoke-induced emphysema in the mouse.
Serine elastase inhibitors have been proposed as a treatment for cigarette smoke-induced emphysema, but little is known about whether such agents actually are effective. We recently reported that a synthetic serine elastase inhibitor, ZD0892, provided some protection against emphysema in a guinea pig model. For these experiments, we used transgenic mice that expressed extremely low levels of human alpha-1-antitrypsin (A1AT) but were tolerant of exogenous human A1AT. Mice were exposed to daily cigarette smoke for up to 6 months; some animals received 20 mg of human A1AT (Prolastin) every 48 hours. Treatment with A1AT produced an approximate twofold increase in serum A1AT levels and elastase inhibitory capacity and abolished smoke-induced elevations in lavage neutrophils and matrix breakdown products (desmosine and hydroxyproline) measured from 2 to 30 days of smoke exposure. A1AT oxidized to remove antiproteolytic activity did not increase serum elastase inhibitory capacity but did prevent neutrophil influx. Treatment with A1AT for 6 months provided 63% protection against increased airspace size (emphysema) and abolished smoke-mediated increases in plasma tumor necrosis factor-alpha. We conclude that A1AT therapy ameliorates smoke-induced inflammation and matrix breakdown, possibly via an antiinflammatory mechanism related to tumor necrosis factor-alpha suppression, and provides partial protection against emphysema.


Epidemiology and outcomes of in-hospital cardiopulmonary resuscitation in the United States, 2000-2009.
To examine temporal trends in the epidemiology and outcomes of in-hospital cardiopulmonary resuscitation (CPR) recipients at a population level. Retrospective analysis of temporal trends in CPR incidence, survival to discharge, discharge disposition, hospital length of stay, and cost of hospitalization for CPR recipients (age ≥ 18 years) captured in the Nationwide Inpatient Sample (2000-2009) in the United States. Between years 2000 and 2009, CPR incidence increased by 33.7%, from 1 case per 453 to 1 case per 339 hospitalized patients (annual percentage increase: 4.3%, 95% CI: 3.4-5.2%, p<0.001). Compared to CPR recipients in years 2000-2001, those in 2008-2009 were more often younger (age<65 years: 33.4% vs. 40.0%), non-white (29.3% vs. 36.4%), and higher comorbidity scores (score ≥ 4: 22.2% vs. 27.1%) (all p<0.001). Rates of neurologic compromise, mechanical ventilator, and feeding tube use increased by 37.7, 28.2, and 58.5%, respectively (all p<0.001). Adjusted rate of survival to discharge increased by 41.3% (20.6-29.1%, p<0.001). Compared to survivors in 2000, those discharged in 2009 were more often discharged to hospice (0.4% vs. 7.1%, p<0.001); a 35% decrease in discharge to home was noted (36.4% vs. 23.8%, p<0.001). Mean cost of hospitalization per day increased for both survivors ($2742-$3462, p=0.006) and decedents ($3159-$4212, p<0.001). The rate of in-hospital CPR in the U.S. increased, and CPR recipients have become younger and sicker over time. Survival to discharge has improved by 41.3%. Functional outcomes after in-hospital CPR appear to have worsened, with considerable clinical and economic implications.


Significance of Antisolvents on Solvation Structures Enhancing Interfacial Chemistry in Localized High-Concentration Electrolytes.
Localized high-concentration electrolytes (LHCEs) provide a new way to expand multifunctional electrolytes because of their unique physicochemical properties. LHCEs are generated when high-concentration electrolytes (HCEs) are diluted by antisolvents, while the effect of antisolvents on the lithium-ion solvation structure is negligible. Herein, using one-dimensional infrared spectroscopy and theoretical calculations, we explore the significance of antisolvents in the model electrolyte lithium bis(fluorosulfonyl)imide/dimethyl carbonate (LiFSI/DMC) with hydrofluoroether. We clarify that the role of antisolvent is more than dilution; it is also the formation of a low-dielectric environment and intensification of the inductive effect on the C=O moiety of DMC caused by the antisolvent, which decrease the binding energy of the Li+···solvent and Li+···anion interactions. It also has beneficial effects on interfacial ion desolvation and Li+ transport. Furthermore, antisolvents also favor reducing the lowest unoccupied molecular orbital (LUMO) energy level of the solvated clusters, and FSI- anions show a decreased reduction stability. Consequently, the influence of antisolvents on the interfacial chemical and electrochemical activities of solvation structures cannot be ignored. This finding introduces a new way to improve battery performance.


HER2 Gene Protein Assay Is Useful to Determine HER2 Status and Evaluate HER2 Heterogeneity in HER2 Equivocal Breast Cancer.
Approximately 15% of breast cancers show equivocal human epidermal growth factor receptor 2 (HER2) results on HER2 immunohistochemistry (IHC) and are reflexed for fluorescence in situ hybridization (FISH). However, some cases remain equivocal. In this study, we evaluated these double-equivocal cases by using a novel gene protein assay (GPA), which can simultaneously assess HER2 gene copy number and protein on a single slide using bright-field microscopy. GPA was performed on 42 HER2 IHC and FISH double-equivocal cases. GPA was negative for amplification in 28 cases, equivocal in three cases, and positive in 11 cases. The GPA results showed excellent concordance with either repeat FISH using a chromosome 17 centromere probe or FISH using an alternative probe. Furthermore, HER2 heterogeneity was identified in three of 11 GPA-positive cases. HER2 GPA performs accurately and is very useful to determine HER2 status in HER2 IHC and FISH double-equivocal breast cancer cases and identify HER2 heterogeneity.


Heterogeneity of COVID-19 symptoms and associated factors: Longitudinal analysis of laboratory-confirmed COVID-19 cases in San Antonio.
Few studies have examined heterogeneous associations of risk factors with Coronavirus Disease-2019 (COVID-19) symptoms by type. The objectives of this study were to estimate the prevalence of and risk factors associated with COVID-19 symptoms and to investigate whether the associations differ by the type of symptoms. This study obtained longitudinal data over 6 months from laboratory-confirmed COVID-19 cases in a citywide sample in San Antonio. Sixteen symptoms of COVID-19 infection, measured at baseline and three follow-up times (1, 3, and 6 months), were analyzed using generalized estimating equations (GEE) to investigate potential risk factors while accounting for the repeated measurements. The risk factors included time in months, sociodemographic characteristics, and past or current medical and psychiatric conditions. To obtain interpretable results, we categorized these sixteen symptoms into five categories (cardiopulmonary, neuro-psychological, naso-oropharyngeal, musculoskeletal, and miscellaneous). We fitted GEE models with a logit link using each category as the outcome variable. Our study demonstrated that the associations were heterogeneous by the categories of symptoms. The time effects were the strongest for naso-oropharyngeal symptoms but the weakest for neuro-psychological symptoms. Female gender was associated with increased odds of most of the symptoms. Hispanic ethnicity was also associated with higher odds of neuro-psychological, musculoskeletal, and miscellaneous symptoms. Depression was the most robust psychiatric condition contributing to most of the symptoms. Different medical conditions seemed to contribute to different symptom expressions of COVID-19 infection.


The evolution of ScotRIGHT: The first pan-Scotland physician trainee research network.
Scotland has a distinguished track record in foundational clinical research. From the completion of the first clinical trial undertaken in scurvy to cloning the world's first whole mammal, Scottish basic and clinical research is world leading. More recently, challenges in access to research skills, funding and programmes by clinical trainees led to the development of alternatives to these typical avenues of accessing research opportunities. Trainee networks evolved to meet the needs of trainees looking to access projects and collaboratives beyond audit and quality improvement commonly performed during structured training. These networks have enjoyed enormous success and have succeeded in progressing projects which have impactful outputs for patients, and improving clinical services. Here, we describe the foundation of the first pan-Scotland physician trainee research network; Scottish Trainees Research In Gastroterology and Hepatology (ScotRIGHT). We outline the foundational efforts, requisites and foundations required to develop a research network.


Justifying quarantine in preventing the spread of COVID-19 in healthcare.
The first COVID-19-positive patient was identified in Ireland on 29 February 2020 (Department of Health, Government of Ireland; https://www.gov.ie/en/pressrelease/2f75fd-statement-from-the-national-public-healthemergency-team-sat-29-feb/). Healthcare worker (HCW) quarantining became a core intervention for those identified as 'close contacts' to reduce onward transmission within the workplace to patients and colleagues. Whether a quarantining strategy could be justified at a time when there was an increased demand for the services of HCWs remained unknown. To establish whether quarantining staff away from a healthcare setting during a pandemic is justified. This retrospective study examined close contacts of COVID-19-positive index cases (both residents and HCWs) in a community hospital over a 4-week period from 1 to 28 April 2020. Close contacts were identified in accordance with national guidelines. Zones of the hospital were examined to determine the number of COVID-positive index cases and their close contacts. A cumulative result for the hospital was recorded. While outcomes varied over time, per zone and per HCW category, the overall conversion rate from close contact to an index case was 30%. This study vindicates the policy of quarantining close contact HCWs from their workplaces as they pose a significant threat to both their patients and fellow workers.


Hepatocyte growth factor (HGF) induces interleukin-11 secretion from osteoblasts: a possible role for HGF in myeloma-associated osteolytic bone disease.
Multiple myeloma is associated with unbalanced bone remodeling causing lytic bone lesions. Interleukin-11 (IL-11) promotes osteoclast formation and inhibits osteoblast activity and may, thus, be one factor involved in cancer-induced bone destruction. We have previously shown that myeloma cells produce hepatocyte growth factor (HGF). We now report that HGF induces IL-11 secretion from human osteoblast-like cells and from the osteosarcoma cell lines Saos-2 and HOS. In coculture experiments, both the myeloma cell line JJN-3 and primary myeloma cells from 3 patients induced IL-11 secretion from osteoblasts, whereas no induction was observed with the non-HGF producing myeloma cell line OH-2. Enhanced IL-11 induction was observed with physical contact between osteoblasts and myeloma cells as compared with experiments in which contact was prohibited by tissue inserts. Anti-HGF serum strongly reduced the myeloma cell-induced IL-11 secretion. Furthermore, we show that JJN-3 cells express HGF on the cell-surface. Removal of surface-bound HGF on JJN-3 cells reduced IL-11 production induced in cocultures. Transforming growth factor beta1 and IL-1 potentiated the effect of HGF on IL-11 secretion, whereas an additive effect was observed with tumor necrosis factor. Thus, myeloma-derived HGF can influence the bone marrow environment both as a soluble and a surface-bound factor. Furthermore, HGF emerges as a possible factor involved in myeloma bone disease by its ability to induce IL-11.


Microbial aetiology, outcomes, and costs of hospitalisation for community-acquired pneumonia; an observational analysis.
The aim of this study was to investigate the clinical outcome and especially costs of hospitalisation for community-acquired pneumonia (CAP) in relation to microbial aetiology. This knowledge is indispensable to estimate cost-effectiveness of new strategies aiming to prevent and/or improve clinical outcome of CAP. We performed our observational analysis in a cohort of 505 patients hospitalised with confirmed CAP between 2004 and 2010. Hospital administrative databases were extracted for all resource utilisation on a patient level. Resource items were grouped in seven categories: general ward nursing, nursing on ICU, clinical chemistry laboratory tests, microbiology exams, radiology exams, medication drugs, and other.linear regression analyses were conducted to identify variables predicting costs of hospitalisation for CAP. Streptococcus pneumoniae was the most identified causative pathogen (25%), followed by Coxiella burnetii (6%) and Haemophilus influenzae (5%). Overall median length of hospital stay was 8.5 days, in-hospital mortality rate was 4.8%.Total median hospital costs per patient were €3,899 (IQR 2,911-5,684). General ward nursing costs represented the largest share (57%), followed by nursing on the intensive care unit (16%) and diagnostic microbiological tests (9%). In multivariate regression analysis, class IV-V Pneumonia Severity Index (indicative for severe disease), Staphylococcus aureus, or Streptococcus pneumonia as causative pathogen, were independent cost driving factors. Coxiella burnetii was a cost-limiting factor. Median costs of hospitalisation for CAP are almost €4,000 per patient. Nursing costs are the main cause of these costs.. Apart from prevention, low-cost interventions aimed at reducing length of hospital stay therefore will most likely be cost-effective.


p53-independent apoptosis induced by paclitaxel through an indirect mechanism.
The efficacy of chemotherapeutic agents may be determined by a number of different factors, including the genotype of the tumor cell. The p53 tumor suppressor gene frequently is mutated in human tumors, and this may contribute to chemotherapeutic resistance. We tested the requirement for wild-type p53 in the response of tumor cells to treatment with paclitaxel (trade name Taxol), an antineoplastic agent that stabilizes cellular microtubules. Although paclitaxel is broadly effective against human tumor xenografts in mice, including some known to carry p53 mutations, we found that p53-containing mouse tumor cells were significantly more sensitive to direct treatment with this drug than were p53-deficient tumor cells. In an attempt to reconcile this apparent discrepancy, we examined the requirement for p53 in the cytotoxic effects of tumor necrosis factor alpha (TNF-alpha), a cytokine released from murine macrophages upon paclitaxel treatment. Conditioned medium from paclitaxel-treated macrophages was capable of inducing p53-independent apoptosis when applied to transformed mouse embryonic fibroblasts and was inhibitable by antibodies against TNF-alpha. Furthermore, in response to direct treatment with TNF-alpha, both wild-type and p53-deficient tumor cells underwent apoptosis to similar extents and with similar kinetics. Our results suggest that the efficacy of paclitaxel in vivo may be due not only to its microtubule-stabilizing activity, but its ability to activate local release of an apoptosis-inducing cytokine.


Alveolar bone loss in rats after immunization with Actinomyces viscosus.
We investigated a possible cause-and-effect relationship between sensitization against Actinomyces viscosus Nyl and destructive periodontal disease in RIC-Sprague-Dawley rats. Germfree rats (66) were either immunized with A. viscosus Nyl (day 20) or orally infected with A. viscosus Nyl (days 38 and 39) or both. We measured alveolar bone loss in maxillary and mandibular molars, in vitro T-lymphocyte responsiveness, and serum antibody titers. In immunized and monoassociated rats bone loss in both jaws progressed rapidly between days 37 and 72, whereas the rate of further resorption decreased until day 100. In monoassociated rats, development of bone loss was much slower, and the maximum resorption measured was, at best, half of the bone loss compared with the former group. However, no amplification of bone loss by immunization was observed in a second experiment using 63 conventional rats kept in relative gnotobiosis. Antibody titers to A. viscosus Nyl in gnotobiotic monoassociated rats were higher in immunized animals, whereas no difference was found in the respective groups of the relative gnotobiotic experiment. The fact that immunization more than doubled alveolar bone loss in gnotobiotic monoassociated rats confirms the allergic nature of the disease. The lack of such an effect under conventional conditions points to suppressor mechanisms whose decrease might convert stable periodontal lesions into progressive ones.


Preoperative terminal ileal and colonic resection histopathology predicts risk of pouchitis in patients after ileoanal pull-through procedure.
This study seeks to compare the histopathology of preoperative terminal ileal and colonic resection specimens with pouch biopsies after the ileoanal pull-through (IAPT) procedure. Pouchitis is the most frequent complication of transanal continent reservoirs in patients after IAPT. The authors conducted 751 consecutive pouch biopsies on 73 patients with inflammatory bowel disease or familial adenomatous polyposis who underwent IAPT by a single surgeon over a 10-year period. In this preliminary report, a pathologist, in blinded fashion, has graded 468 of the IAPT pouch biopsies and 67 of the patients' preoperative terminal ileal and colonic resection histopathology to date. Colonic histopathology was graded by the extent and severity of disease, terminal ileal and pouch histopathology by active inflammation, chronic inflammation, lymphocyte aggregates, intraepithelial lymphocytes, eosinophils, and villous blunting. Extent of colonic disease (gross and microscopic) was a significant predictor of active inflammation in subsequent IAPT pouch biopsy specimens. Also, the gross extent of colonic disease exhibited a significant linear association with pouch inflammation. However, the severity of colonic disease was not significantly predictive of active inflammation in subsequent IAPT pouch biopsies. Terminal ileal active and chronic inflammation were significant predictors of subsequent IAPT pouch inflammation. Although lymphocyte aggregates and intraepithelial lymphocytes were not predictive, terminal ileum eosinophils and villous blunting were significant predictors of active inflammation in subsequent IAPT pouch biopsy specimens. Preoperative terminal ileal and colonic histopathology predicts active inflammation of pouches after IAPT. Patients who are preoperatively assessed to have extensive disease of the colon, ileal disease ("backwash ileitis"), or both appear to be at greater risk for the development of pouchitis after IAPT.


Diagnostic challenges, the evaluation of antibiotic allergy.
Antibiotic allergy is commonly reported and often challenging to evaluate. This review highlights recent developments in our understanding of antibiotic allergy, primarily surrounding evaluation, and diagnosis of antibiotic allergy. We provide historical context to establish a framework, lending relevance to the latest studies. Clinicians have typically employed skin testing as a first step in the diagnosis of drug allergy, reserving drug provocation challenge, the gold standard for diagnosis, for those with negative skin tests. Although skin tests have a good negative predictive value, the positive predictive value has never been established. An increasing amount of research is demonstrating that drug provocation challenge is well tolerated as the initial evaluation in patients with non-life-threatening reactions to antibiotics. This research also calls into question the value of skin testing in these patients. Skin testing has long been used as the initial investigation in the diagnosis of drug allergy. New research supports that this may not be necessary in all patients, particularly those with non-life-threatening reactions. Further research into the validity of skin testing is required, along with the development of new diagnostic tests for antibiotic allergy.


Lack of telomerase gene expression in alternative lengthening of telomere cells is associated with chromatin remodeling of the hTR and hTERT gene promoters.
The presence of active telomere maintenance mechanisms in immortal cells allows the bypass of senescence by maintaining telomere length. In most immortal cell lines and tumors, telomere maintenance is attributable to telomerase reactivation. However, a number of immortal cell lines and tumors can achieve telomere maintenance in the absence of detectable telomerase activity by the alternative lengthening of telomere (ALT) mechanism. Epigenetic mechanisms have been implicated in the regulation of telomerase expression. We show that specific modifications within the chromatin environment of the hTR and hTERT promoters correlate with expression of hTR and hTERT in ALT, normal and telomerase-positive tumor cell lines. Lack of expression of hTR and hTERT in ALT cell lines is associated with histone H3 and H4 hypoacetylation and methylation of Lys9 histone H3. Conversely, hTR and hTERT expression in telomerase-positive cell lines is associated with hyperacetylation of H3 and H4 and methylation of Lys4 H3. Methylation of Lys20 H4 was not linked to gene expression but instead was specific to the hTR and hTERT promoters of ALT cells. This may provide an insight into the differences between ALT and telomerase-positive cells as well as a novel marker for the ALT phenotype. Treatment of normal and ALT cells with 5-azadeoxycytidine in combination with Trichostatin A caused chromatin remodeling of both promoters and reactivation of hTR and hTERT expression in ALT and normal cell lines. This data establishes a definite link between the chromatin environment of the telomerase gene promoters and transcriptional activity.


Regulation: threat to converging technologies.
This article discusses two competing principles underlying efforts to regulate technological developments converging at the nanoscale that are intended to promote human health: the internalization of social cost by use of economic cost-benefit analysis and the precautionary principle by implementation of preventative safety standards. Overemphasis of the former may lead to potential unacceptable political and ethical effects while narrow focus on the latter may lead to potential retardation of innovation by deterring private risk capital investment. Suggestions are made for reconciling these principles through legislative initiatives.


Maspin expression in endometrial hyperplasia and carcinoma, and its relation with angiogenesis.
The purpose of this study was to evaluate the maspin expression in endometrial hyperplasia and cancer, and also to investigate its relation with angiogenesis. A total of 19 women with complex atypical hyperplasia, 44 patients with simple hyperplasia without atypia, and 67 patients with endometrial carcinoma were included. Maspin expression was assessed by immunohistochemistry (IHC), and tested for possible significant relation with age, FIGO stage, histologic type, grade, depth of myometrial invasion (MI), lymphovascular space involvement (LVSI), lymph node metastasis, and overall survival (OS). Angiogenesis was determined by vascular endothelial growth factor (VEGF) staining. Maspin expression was detected in only three patients with endometrial hyperplasia (5%). In patients with endometrial cancer, cytoplasmic and nuclear maspin expressions were detected in 36 (53.7%) and 18 (26.9%) patients, respectively. No significant relation was noted between staining localizations and prognostic variables. The five-year OS rate for patients with cytoplasmic staining was 91%, compared to 87% for patients without staining (p = 0.31). These values for nuclear expression were 100% and 87%, respectively (p = 0.16). The cytoplasmic and nuclear maspin expressions were found to be significantly correlated with VEGF (r = 0.278, p = 0.02 and r = 0.295, p = 0.01, respectively). This is the first study to demonstrate the relation between maspin expression and angiogenesis in endometrial cancer. Although no survival difference was noted for cytoplasmic or nuclear maspin expressions, a tendency was detected for nuclear staining. Further series will clarify the exact prognostic role of maspin expression in gynecological malignancies including endometrial cancer.


Care For America's Elderly And Disabled People Relies On Immigrant Labor.
As the US wrestles with immigration policy and caring for an aging population, data on immigrants' role as health care and long-term care workers can inform both debates. Previous studies have examined immigrants' role as health care and direct care workers (nursing, home health, and personal care aides) but not that of immigrants hired by private households or nonmedical facilities such as senior housing to assist elderly and disabled people or unauthorized immigrants' role in providing these services. Using nationally representative data, we found that in 2017 immigrants accounted for 18.2 percent of health care workers and 23.5 percent of formal and nonformal long-term care sector workers. More than one-quarter (27.5 percent) of direct care workers and 30.3 percent of nursing home housekeeping and maintenance workers were immigrants. Although legal noncitizen immigrants accounted for 5.2 percent of the US population, they made up 9.0 percent of direct care workers. Naturalized citizens, 6.8 percent of the US population, accounted for 13.9 percent of direct care workers. In light of the current and projected shortage of health care and direct care workers, our finding that immigrants fill a disproportionate share of such jobs suggests that policies curtailing immigration will likely compromise the availability of care for elderly and disabled Americans.


CXCR4-CXCL12-CXCR7, TLR2-TLR4, and PD-1/PD-L1 in colorectal cancer liver metastases from neoadjuvant-treated patients.
A neoadjuvant clinical trial was previously conducted in patients with resectable colorectal cancer liver metastases (CRLM). At a median follow up of 28 months, 20/33 patients were dead of disease, 8 were alive with disease and 5 were alive with no evidence of disease. To shed further insight into biological features accounting for different outcomes, the expression of CXCR4-CXCL12-CXCR7, TLR2-TLR4, and the programmed death receptor-1 (PD-1)/programmed death-1 ligand (PD-L1) was evaluated in excised liver metastases. Expression profiles were assessed through qPCR in metastatic and unaffected liver tissue of 33 CRLM neoadjuvant-treated patients. CXCR4 and CXCR7, TLR2/TLR4, and PD-1/PD-L1 mRNA were significantly overexpressed in metastatic compared to unaffected liver tissues. CXCR4 protein was negative/low in 10/31, and high in 21/31, CXCR7 was negative/low in 16/31 and high in 15/31, CXCL12 was negative/low in 14/31 and high in 17/31 CRLM. PD-1 was negative in 19/30 and positive in 11/30, PD-L1 was negative/low in 24/30 and high in 6/30 CRLM. Stromal PD-L1 expression, affected the progression-free survival (PFS) in the CRLM population. Patients overexpressing CXCR4 experienced a worse PFS and cancer specific survival (CSS) (p = 0.001 and p = 0.0008); in these patients, KRAS mutation identified a subgroup with a significantly worse CSS (p < 0.01). Thus, CXCR4 and PD-L1 expression discriminate patients with the worse PFS within the CRLM evaluated patients. Within the CXCR4 high expressing patients carrying Mut-KRAS in CRLM identifies the worst prognostic group. Thus, CXCR4 targeting plus anti-PD-1 therapy should be explored to improve the prognosis of Mut-KRAS-high CXCR4-CRLMs.


The SuperCrescent diamond knife: an innovative blade for glaucoma surgery.
Diamond blades have been used extensively in cataract surgery but their routine use in glaucoma surgery has been limited owing to the lack of controlled sharpness. The SuperCrescent knife is an ultrathin (100 μm) diamond blade that is an innovative modification of conventional blade design. Its pentium faceted trapezoidal design along with the square front surface area affords better control during dissection and has been used with success in both traditional trabeculectomies and nonpenetrating glaucoma procedures.


The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL).
[18F]fluorodeoxyglucose-positron emission tomography (PET) is emerging as a strong diagnostic and prognostic tool in follicular lymphoma (FL) patients. In a subset analysis of the FOLL05 trial (NCT00774826), we investigated the prognostic role of post-induction PET (PI-PET) scan. Patients were eligible to this study if they had a PI-PET scan carried out within 3 months from the end of induction immunochemotherapy. Progression-free survival (PFS) was the primary study end point. A total of 202 patients were eligible and analysed for this study. The median age was 55 years (range 33-75). Overall, PI-PET was defined as positive in 49 (24%) patients. Conventional response assessment with CT scan was substantially modified by PET: 15% (22/145) of patients considered as having a complete response (CR) after CT were considered as having partial response (PR) after PI-PET and 53% (30/57) patients considered as having a PR after CT were considered as a CR after PI-PET. With a median follow-up of 34 months, the 3-year PFS was 66% and 35%, respectively, for patients with negative and positive PI-PET (P<0.001). At multivariate analysis, PI-PET (hazard ratio 2.57, 95% confidence interval 1.52-4.34, P<0.001) was independent of conventional response, FLIPI and treatment arm. Also, the prognostic role of PI-PET was maintained within each FLIPI risk group. In FL patients, PI-PET substantially modifies response assessment and is strongly predictive for the risk of progression. PET should be considered in further updates of response criteria.


Beliefs and knowledge about post-traumatic stress disorder amongst resettled Afghan refugees in Australia.
Resettled refugees are at high risk of trauma-related mental health problems, yet there is low uptake of mental health care in this population. Evidence suggests poor 'mental health literacy' (MHL) may be a major factor influencing help-seeking behaviour among individuals with mental health problems. This study sought to examine the MHL of resettled Afghan refugees in Adelaide, South Australia. Interviews were completed with 150 (74 males; mean age 32.8 years, SD = 12.2) resettled Afghan refugees living in Adelaide, South Australia. A convenience sampling method was employed and participants were comprised of volunteers from the Afghan community residing in the northern suburbs of Adelaide. Following informed consent participants were presented a culturally appropriate vignette describing a fictional person suffering from posttraumatic stress disorder (PTSD). This was followed by a series of questions addressing participants' knowledge and understanding of the nature and treatment of the problem described. Self-report measures of PTSD symptoms and co-morbid psychopathology were also administered. Thirty-one per cent of the respondents identified the problem depicted in the vignette as being PTSD, while 26 per cent believed that the main problem was 'fear'. Eighteen per cent of participants believed that 'getting out and about more/finding some new hobbies' would be the most helpful form of treatment for the problem described, followed by 'improving their diet' and 'getting more exercise' (16 %). The results of this study demonstrate aspects of MHL that appear to be specific to Afghan refugees who have resettled in Australia. They indicate the need for health promotion and early intervention programs, and mental health services, to recognise that variation in MHL may be a function of both the cultural origin of a refugee population and their resettlement country. Such recognition is needed in order to bridge the gap between Western, biomedical models for mental health care and the knowledge and beliefs of resettled refugee populations.


Renin-angiotensin modulation of sympathetic reflex function in essential hypertension and in the elderly.
The renin-angiotensin system and the sympathetic nervous system are important control mechanisms in blood pressure regulation. A large body of in vitro and in vivo animal data indicate that angiotensin II regulates noradrenaline release and modifies sympathetic reflexes, although the physiological relevance of these to normal man remains unclear. It is established, however, that increasing age and hypertension independently modify autonomic responses in man. The hypothesis was therefore examined that angiotensin II exerts a pre-junctional effect on noradrenaline release and sympathetic cardiovascular function, in the elderly and in patients with essential hypertension. Inhibition of angiotensin-converting enzyme with enalapril and cilazapril, after short-term administration at doses sufficient to reduce circulating angiotensin II concentrations, did not alter sympathetically mediated orthostatic test, Valsalva's manoeuvre and cold pressor test, in young or elderly normotensives. Similarly, but in a separate study, the pressor, chronotropic and sympathoadrenal response to submaximal dynamic exercise were unchanged, following short-term converting enzyme inhibition in normal persons and essential hypertensive patients. These findings do not support a role for angiotensin II in presynaptic facilitation or post-junctional potentiation of noradrenergic transmission. It is proposed that the renin-angiotensin system exerts an independent, rather than a regulatory influence on sympathetic function in blood pressure control, in normal and hypertensive man.


Bacteroides uniformis combined with fiber amplifies metabolic and immune benefits in obese mice.
Gut microbiota represents a therapeutic target for obesity. We hypothesize that B. uniformis CECT 7771 combined with wheat bran extract (WBE), its preferred carbon source, may exert superior anti-obesity effects. We performed a 17-week intervention in diet-induced obese mice receiving either B. uniformis, WBE, or their combination to identify interactions and independent actions on metabolism and immunity. B. uniformis combined with WBE was the most effective intervention, curbing weight gain and adiposity, while exerting more modest effects separately. The combination restored insulin-dependent metabolic routes in fat and liver, although the bacterium was the primary driver for improving whole-body glucose disposal. Moreover, B. uniformis-combined with WBE caused the highest increases in butyrate and restored the proportion of induced intraepithelial lymphocytes and type-3 innate lymphoid cells in the intestinal epithelium. Thus, strengthening the first line of immune defense against unhealthy diets and associated dysbiosis in the intestine. This intervention also attenuated the altered IL22 signaling and liver inflammation. Our study shows opportunities for employing B. uniformis, combined with WBE, to aid in the treatment of obesity.


Heliox inhalation therapy for bronchiolitis in infants.
Acute viral bronchiolitis is associated with airway obstruction and turbulent gas flow. Heliox, a mixture of oxygen and the inert gas helium, may improve gas flow through high-resistance airways and decrease the work of breathing. To assess heliox in addition to standard medical care for acute bronchiolitis in infants. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2), which includes the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1966 to June 2009), EMBASE (June 2009), LILACS (May 2009) and the NIH web site (May 2009). Randomised controlled trials (RCTs) and quasi-RCTs of heliox in infants with acute bronchiolitis. Two review authors independently extracted data and assessed trial quality. We pooled data from individual trials. We included four trials involving 84 infants under two years of age with respiratory distress secondary to bronchiolitis caused by respiratory syncytial virus (RSV) and requiring paediatric intensive care unit (PICU) hospitalisation. We found that infants treated with heliox inhalation had a significantly lower mean clinical respiratory score in the first hour after starting treatment when compared to those treated with air or oxygen inhalation (mean difference (MD) -1.15, 95% confidence interval (CI) -1.98 to -0.33, P = 0.006, n = 69). There was no clinically significant reduction in the rate of intubation (risk ratio (RR) 1.38, 95% CI 0.41 to 4.56, P = 0.60, n = 58), in the need for mechanical ventilation (RR 1.11, 95% CI 0.36 to 3.38, P = 0.86, n = 58), or in the length of stay in a PICU (MD = -0.15 days, 95% CI -0.92 to 0.61, P = 0.69, n = 58). No adverse events related to heliox inhalation were reported. Current evidence suggests that the addition of heliox therapy may significantly reduce a clinical score evaluating respiratory distress in the first hour after starting treatment in infants with acute RSV bronchiolitis. Nevertheless, there was no reduction in the rate of intubation, in the need for mechanical ventilation, or in the length of PICU stay. Further studies with homogeneous logistics in their heliox application are needed. Such studies would provide necessary information as to the appropriate place for heliox in the therapeutic schedule for severe bronchiolitis.


Role of Strigolactones in the Host Specificity of Broomrapes and Witchweeds.
Root parasitic plants of the Orobanchaceae, broomrapes and witchweeds, pose a severe problem to agriculture in Europe, Asia and especially Africa. These parasites are totally dependent on their host for survival, and therefore, their germination is tightly regulated by host presence. Indeed, their seeds remain dormant in the soil until a host root is detected through compounds called germination stimulants. Strigolactones (SLs) are the most important class of germination stimulants. They play an important role in planta as a phytohormone and, upon exudation from the root, function in the recruitment of symbiotic arbuscular mycorrhizal fungi. Plants exude mixtures of various different SLs, possibly to evade detection by these parasites and still recruit symbionts. Vice versa, parasitic plants must only respond to the SL composition that is exuded by their host, or else risk germination in the presence of non-hosts. Therefore, parasitic plants have evolved an entire clade of SL receptors, called HTL/KAI2s, to perceive the SL cues. It has been demonstrated that these receptors each have a distinct sensitivity and specificity to the different known SLs, which possibly allows them to recognize the SL-blend characteristic of their host. In this review, we will discuss the molecular basis of SL sensitivity and specificity in these parasitic plants through HTL/KAI2s and review the evidence that these receptors contribute to host specificity of parasitic plants.


The Breast and Cervical Cancer Prevention and Treatment Act in Georgia: effects on time to Medicaid enrollment.
Implementation of the Breast and Cervical Cancer Prevention and Treatment Act of 2000 (BCCPTA) allowed states to extend Medicaid to any woman aged <65 without insurance screened and found to need treatment either for breast or cervical cancer or for a precancerous cervical condition through the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) or in Georgia, other provider sites. The authors used linked Georgia Comprehensive Cancer Registry (GCCR) and Medicaid data to test the: 1) likelihood of Medicaid enrollment in a given month and 2) time-to-enrollment (months) for those eventually enrolling. The authors used difference-in-differences analysis to estimate the effects of BCCPTA for breast or cervical cancer cases relative to a control group of women with other cancers. The authors controlled for sociodemographics, stage at diagnosis, year of diagnosis, and county level factors related to insurance levels in the area. Compared with the control cancer group, the hazard ratio of Medicaid enrollment for women with breast and cervical cancers increased post- vs pre-BCCPTA implementation. The estimated effect of this increase was that out of every 1000 women with breast cancer, BCCPTA led to 1.7 more (from 2.8 to 4.5 per month) enrolling in Medicaid. The results for women with local or later stages of cervical cancer indicated that of 1000 women with these cancers, the number enrolling in a given month increased by 3.4 due to BCCPTA. Results on time-to-enrollment indicated that the time between cancer diagnosis and enrollment was shortened by 7 to 8 months. The Georgia Medicaid program, in response to national legislation, increased the probability of women enrolling in Medicaid earlier and in turn, likely increased their cancer treatment options.


Hippocampal lesions induced by trimethyltin in the neonatal rat brain.
The neuropathology of trimethyltin (TMT) chloride on neonatal rat hippocampus was investigated. It was found that the development of pathological lesions in the developing hippocampus is age-dependent and the most vulnerable age period was between postnatal days (PND) 9 and 15. TMT-treated animals appeared to be significantly stunned in growth. Brains of these animals were also markedly smaller than those of age-matched controls. Histopathology and electron microscopy examination of the hippocampus on PND 15, 21 and 24 from animals exposed to 6.0 mg TMT-Cl/kg b.w. on PND 11 revealed rapid destructions of the Ammon's horn. The granule cells of fascia dentata, despite some non-specific pathological changes (swelling, lysosomal accumulation), showed only minimal necrotic activity. Pyramidal neurons of the Ammon's horn, however, displayed extensive damage. Extensive neuronal edema, accumulation of lysosomes and myelinoid membranous bodies and cellular necrosis were observed as early as 4 days (PND 15) after exposure. By PND 24, total abolishment of the Ammon's horn occurred with extensive dystrophic calcification and astrocytic gliosis of the area.


Projecting supply expenses.
This article details a simplified approach to within-the-year supply expenses projections. Each factor of the projection formulas is discussed and the final formulas given. An example clarifies the projection calculations.


Detection of myocardial infarction by dual-source coronary computed tomography angiography using quantitated myocardial scintigraphy as the reference standard.
Dual-source coronary computed tomography angiography (DS-CTA) has the potential to assess both coronary anatomy and myocardial perfusion. We studied the ability of DS-CTA to detect myocardial infarction (MI) compared to a reference standard of technetium Tc(99)m sestamibi single photon emission computed tomography (SPECT). 122 patients with suspected or known coronary artery disease (age 60 (SD 11) years, 36% females) were evaluated by both DS-CTA and SPECT. SPECT-MI size was quantitated using a threshold value of 60% of peak counts on the resting images. MI on DS-CTA was defined as transmural or subendocardial hypoenhancement (<50% of surrounding myocardium), which persisted in both diastolic and systolic reconstructions and was concordant with a coronary artery territory. The performance of DS-CTA to detect SPECT-MI was determined in a blinded, vessel-based analysis. 366 vessel territories were analysed (122 patients x3). SPECT revealed 20 vessel territories with MI (involving 17 patients). 15/20 (75%) of these vessel territories were also detected by DS-CTA. An additional seven MIs were detected by DS CTA only (considered as false positive). Thus, the sensitivity of DS-CTA for detection of SPECT-MI was 75% (95% CI 56% to 94%), specificity 98% (97% to 100%), positive predictive value 68% (49% to 88%) and negative predictive value 99% (97% to 100%). DS-CTA detected 10/11 (91%) larger MIs (involving >5% of left ventricular (LV) mass by SPECT). For the 15 concordant MIs (in both SPECT and DS-CTA) the mean difference in MI size between modalities was 0.5% (4.6%) of LV mass (95% CI -8.6% to 9.5%). DS-CTA myocardial perfusion imaging showed moderate sensitivity and positive predictive value but high specificity and negative predictive value for detection of SPECT-MI. Most large infarcts (>5% of LV mass) were detected by DS-CTA. When MI was detected by both modalities, there was a good correlation between infarct sizes quantitated by DS-CTA vs SPECT.


Ulipristal acetate in emergency contraception.
Despite the widespread availability of highly effective methods of contraception, unintended pregnancy is common. Unplanned pregnancies have been linked to a range of health, social and economic consequences. Emergency contraception reduces risk of pregnancy after unprotected intercourse, and represents an opportunity to decrease number of unplanned pregnancies and abortions. Emergency contraception pills (ECP) prevent pregnancy by delaying or inhibiting ovulation, without interfering with post fertilization events. If pregnancy has already occurred, ECPs will not be effective, therefore ECPs are not abortificants. Ulipristal acetate (17alpha-acetoxy-11beta-(4N-N,N-dymethilaminophenyl)-19-norpregna--4,9-diene-3,20-dione) is the first drug that was specifically developed and licensed for use as an emergency contraceptive. It is an orally active, synthetic, selective progesterone modulator that acts by binding with high affinity to the human progesterone receptor where it has both antagonist and partial agonist effects. It is a new molecular entity and the first compound in a new pharmacological class defined by the pristal stem. Up on the superior clinical efficacy evidence, UPA has been quickly recognized as the most effective emergency contraceptive pill, and recently recommended as the first prescription choice for all women regardless of the age and timing after intercourse. This article provides literature review of UPA and its role in emergency contraception.