Concerted effects of heterogeneous nuclear ribonucleoprotein C1/C2 to control vitamin D-directed gene transcription and RNA splicing in human bone cells.
Traditionally recognized as an RNA splicing regulator, heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC1/C2) can also bind to double-stranded DNA and function in trans as a vitamin D response element (VDRE)-binding protein. As such, hnRNPC1/C2 may couple transcription induced by the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) with subsequent RNA splicing. In MG63 osteoblastic cells, increased expression of the 1,25(OH)2D target gene CYP24A1 involved immunoprecipitation of hnRNPC1/C2 with CYP24A1 chromatin and RNA. Knockdown of hnRNPC1/C2 suppressed expression of CYP24A1, but also increased expression of an exon 10-skipped CYP24A1 splice variant; in a minigene model the latter was attenuated by a functional VDRE in the CYP24A1 promoter. In genome-wide analyses, knockdown of hnRNPC1/C2 resulted in 3500 differentially expressed genes and 2232 differentially spliced genes, with significant commonality between groups. 1,25(OH)2D induced 324 differentially expressed genes, with 187 also observed following hnRNPC1/C2 knockdown, and a further 168 unique to hnRNPC1/C2 knockdown. However, 1,25(OH)2D induced only 10 differentially spliced genes, with no overlap with differentially expressed genes. These data indicate that hnRNPC1/C2 binds to both DNA and RNA and influences both gene expression and RNA splicing, but these actions do not appear to be linked through 1,25(OH)2D-mediated induction of transcription.


Reduced Postburn Hypertrophic Scarring and Improved Physical Recovery With Yearlong Administration of Oxandrolone and Propranolol.
Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P < 0.05) occurred in OxProp-treated scars. With OxProp, scar severity was attenuated and pliability increased (both P < 0.05). Analyses of patient-reported outcomes showed improved general and emotional health within the OxProp-treated group (P < 0.05). Here, we have shown improvements in objective and subjective measures of scarring and an increase in overall patient-reported physical function. The combined administration of OxProp for up to a year after burn injury should be considered for the reduction of postburn scarring and improvement of long-term psychosocial outcomes in children with massive burns.


Prevalence and correlates of psychopathic traits in the household population of Great Britain.
There are no previous surveys of psychopathy and psychopathic traits in representative general population samples using standardized instruments. This study aimed to measure prevalence and correlates of psychopathic traits, based on a two-phase survey using the Psychopathy Checklist: Screening Version (PCL: SV) in 638 individuals, 16-74 years, in households in England, Wales and Scotland. The weighted prevalence of psychopathy was 0.6% (95% CI: 0.2-1.6) at a cut score of 13, similar to the noncriminal/nonpsychiatric sample described in the manual of the PCL: SV. Psychopathy scores correlated with: younger age, male gender; suicide attempts, violent behavior, imprisonment and homelessness; drug dependence; histrionic, borderline and adult antisocial personality disorders; panic and obsessive-compulsive disorders. This survey demonstrated that, as measured by the PCL: SV, psychopathy is rare, affecting less than 1% of the household population, although it is prevalent among prisoners, homeless persons, and psychiatric admissions. There is a half-normal distribution of psychopathic traits in the general population, with the majority having no traits, a significant proportion with non-zero values, and a severe subgroup of persons with multiple associated social and behavioral problems. This distribution has implications for research into the etiology of psychopathy and its implications for society.


Hematologic and systemic metabolic alterations due to Mediterranean class II G6PD deficiency in mice.
Deficiency of glucose-6-phosphate dehydrogenase (G6PD) is the single most common enzymopathy, present in approximately 400 million humans (approximately 5%). Its prevalence is hypothesized to be due to conferring resistance to malaria. However, G6PD deficiency also results in hemolytic sequelae from oxidant stress. Moreover, G6PD deficiency is associated with kidney disease, diabetes, pulmonary hypertension, immunological defects, and neurodegenerative diseases. To date, the only available mouse models have decreased levels of WT stable G6PD caused by promoter mutations. However, human G6PD mutations are missense mutations that result in decreased enzymatic stability. As such, this results in very low activity in red blood cells (RBCs) that cannot synthesize new protein. To generate a more accurate model, the human sequence for a severe form of G6PD deficiency, Med(-), was knocked into the murine G6PD locus. As predicted, G6PD levels were extremely low in RBCs, and deficient mice had increased hemolytic sequelae to oxidant stress. Nonerythroid organs had metabolic changes consistent with mild G6PD deficiency, consistent with what has been observed in humans. Juxtaposition of G6PD-deficient and WT mice revealed altered lipid metabolism in multiple organ systems. Together, these findings both establish a mouse model of G6PD deficiency that more accurately reflects human G6PD deficiency and advance our basic understanding of altered metabolism in this setting.


Discovery of 16-Demethylrifamycins by Removing the Predominant Polyketide Biosynthesis Pathway in Micromonospora sp. Strain TP-A0468.
A number of strategies have been developed to mine novel natural products based on biosynthetic gene clusters and there have been dozens of successful cases facilitated by the development of genomic sequencing. During our study on biosynthesis of the antitumor polyketide kosinostatin (KST), we found that the genome of Micromonospora sp. strain TP-A0468, the producer of KST, contains other potential polyketide gene clusters, with no encoded products detected. Deletion of kst cluster led to abolishment of KST and the enrichment of several new compounds, which were isolated and characterized as 16-demethylrifamycins (referred to here as compounds 3 to 6). Transcriptional analysis demonstrated that the expression of the essential genes related to the biosynthesis of compounds 3 to 6 was comparable to the level in the wild-type and in the kst cluster deletion strain. This indicates that the accumulation of these compounds was due to the redirection of metabolic flux rather than transcriptional activation. Genetic disruption, chemical complementation, and bioinformatic analysis revealed that the production of compounds 3 to 6 was accomplished by cross talk between the two distantly placed polyketide gene clusters pks3 and M-rif This finding not only enriches the analogue pool and the biosynthetic diversity of rifamycins but also provides an auxiliary strategy for natural product discovery through genome mining in polyketide-producing microorganisms.IMPORTANCE Natural products are essential in the development of novel clinically used drugs. Discovering new natural products and modifying known compounds are still the two main ways to generate new candidates. Here, we have discovered several rifamycins with varied skeleton structures by redirecting the metabolic flux from the predominant polyketide biosynthetic pathway to the rifamycin pathway in the marine actinomycetes species Micromonospora sp. strain TP-A0468. Rifamycins are indispensable chemotherapeutics in the treatment of various diseases such as tuberculosis, leprosy, and AIDS-related mycobacterial infections. This study exemplifies a useful method for the discovery of cryptic natural products in genome-sequenced microbes. Moreover, the 16-demethylrifamycins and their genetically manipulable producer provide a new opportunity in the construction of novel rifamycin derivates to aid in the defense against the ever-growing drug resistance of Mycobacterium tuberculosis.


Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress.
Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6) hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.


Nephrin Signaling Results in Integrin β1 Activation.
Patients with certain mutations in the gene encoding the slit diaphragm protein Nephrin fail to develop functional slit diaphragms and display severe proteinuria. Many adult-onset glomerulopathies also feature alterations in Nephrin expression and function. Nephrin signals from the podocyte slit diaphragm to the Actin cytoskeleton by recruiting proteins that can interact with C3G, a guanine nucleotide exchange factor of the small GTPase Rap1. Because Rap activity affects formation of focal adhesions, we hypothesized that Nephrin transmits signals to the Integrin receptor complex, which mediates podocyte adhesion to the extracellular matrix. To investigate Nephrin's role in transmitting signals to the Integrin receptor complex, we conducted genetic studies in Drosophila nephrocytes and validated findings from Drosophila in a cultured human podocyte model. Drosophila nephrocytes form a slit diaphragm-like filtration barrier and express the Nephrin ortholog Sticks and stones (Sns). A genetic screen identified c3g as necessary for nephrocyte function. In vivo, nephrocyte-specific gene silencing of sns or c3g compromised nephrocyte filtration and caused nephrocyte diaphragm defects. Nephrocytes with impaired Sns or C3G expression displayed an altered localization of Integrin and the Integrin-associated protein Talin. Furthermore, gene silencing of c3g partly rescued nephrocyte diaphragm defects of an sns overexpression phenotype, pointing to genetic interaction of sns and c3g in nephrocytes. We also found that activated Nephrin recruited phosphorylated C3G and resulted in activation of Integrin β1 in cultured podocytes. Our findings suggest that Nephrin can mediate a signaling pathway that results in activation of Integrin β1 at focal adhesions, which may affect podocyte attachment to the extracellular matrix.


Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3.
Genome-wide association studies have confirmed the involvement of non-coding angiopoietin-like 3 (ANGPTL3) gene variants with coronary artery disease, levels of low-density lipoprotein cholesterol (LDL-C), triglycerides and ANGPTL3 mRNA transcript. Extensive linkage disequilibrium at the locus, however, has hindered efforts to identify the potential functional variants. Using regulatory annotations from ENCODE, combined with functional in vivo assays such as allele-specific formaldehyde-assisted isolation of regulatory elements, statistical approaches including eQTL/lipid colocalisation, and traditional in vitro methodologies including electrophoretic mobility shift assay and luciferase reporter assays, variants affecting the ANGPTL3 regulome were examined. From 253 variants associated with ANGPTL3 mRNA expression, and/or lipid traits, 46 were located within liver regulatory elements and potentially functional. One variant, rs10889352, demonstrated allele-specific effects on DNA-protein interactions, reporter gene expression and chromatin accessibility, in line with effects on LDL-C levels and expression of ANGPTL3 mRNA. The ANGPTL3 gene lies within DOCK7, although the variant is within non-coding regions outside of ANGPTL3, within DOCK7, suggesting complex long-range regulatory effects on gene expression. This study illustrates the power of combining multiple genome-wide datasets with laboratory data to localise functional non-coding variation and provides a model for analysis of regulatory variants from GWAS.


The UK Expert Patients Program: lessons learned and implications for cancer survivors' self-care support programs.
Globally, the enablement of self-care is increasingly being recognised as an essential component of chronic disease management. Within the UK a key self-care policy initiative is the Expert Patients Program. Developed from the Chronic Disease Self-Management Program, this is a 6 week self-management education program for people with different chronic diseases, facilitated by lay volunteers. As an example of a major public health initiative designed to enhance self-management in long-term conditions, this paper draws on evaluations of the EPP and CDSMP and analyzes the implications for the development of similar programs for cancer survivors. There are a number of evaluations of the CDSMP which suggest significant improvement in participants' chronic disease management self-efficacy and some evidence of healthcare utilization reduction. However, whilst the national evaluation of the EPP demonstrated similar improvements in self-efficacy and health status, there was no significant effect on healthcare utilization. Trials of such programs need to be treated with some caution as participants are often not typical of the general population, and as a complex intervention effectiveness is inherently difficult to assess. Qualitative evaluations revealed that the EPP's strength was derived mainly through peer support and learning. Nevertheless, a number of contextual problems were identified including recruitment, clinicians' lack of engagement with the program and inflexible course materials. Lay-led self-care support programs such as the EPP have a significantly positive effect on self-efficacy which could be of benefit to cancer survivors. However, a number of lessons should be learned from the EPP when developing similar initiatives for cancer survivors.


Malignant tracheal necrosis and fistula formation following palliative chemoradiotherapy: a case report.
Concurrent chemoradiotherapy is an essential treatment strategy for inoperable locally advanced non-small cell lung cancer (NSCLC). Although supportive care has improved, unexpected complications due to the disease or treatment can occur. Tracheomediastinal fistulas are very rare but can be a serious problem. Herein, we report a case of severe chondronecrosis of the distal trachea with formation of a fistula into a metastatic lymphadenopathy in a patient with stage IIIB NSCLC. The patient received external beam radiotherapy with a total dose of 35 Gy in 14 fractions, which was approximately half of the conventional therapeutic radiotherapy dose, along with concurrent cisplatin based chemotherapy. Careful evaluation, early detection, and timely intervention are essential to prevent and appropriately treat chondronecrosis, even in cases of low-dose radiotherapy application to central tumors.


Economic Evaluation of Cinacalcet in the United States: The EVOLVE Trial.
Previous economic evaluations of cinacalcet in patients with secondary hyperparathyroidism (sHPT) relied on the combination of surrogate end points in clinical trials and epidemiologic studies. The objective was to conduct an economic evaluation of cinacalcet on the basis of the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial from a US payer perspective. We developed a semi-Markov model to assess the cost-effectiveness of cinacalcet in addition to conventional therapy, compared with conventional therapy alone, in patients with moderate-to-severe sHPT receiving hemodialysis. We used treatment effect estimates from the unadjusted intent-to-treat (ITT) analysis and prespecified covariate-adjusted ITT analysis as our main analyses. We assessed model sensitivity to variations in individual inputs and overall decision uncertainty through probabilistic sensitivity analyses. The incremental cost-effectiveness ratio (ICER) for cinacalcet was $61,705 per life-year and $79,562 per quality-adjusted life-year (QALY) gained using the covariate-adjusted ITT analysis. Probabilistic sensitivity analysis suggested a 73.2% chance of the ICER being below a willingness-to-pay threshold of $100,000. Treatment effects from unadjusted ITT analysis yielded an ICER of $115,876 per QALY. The model was most sensitive to the treatment effect on mortality. In the unadjusted ITT analysis, cinacalcet does not represent a cost- effective use of health care resources when applying a willingness-to-pay threshold of $100,000 per QALY. When using the covariate-adjusted ITT treatment effect, which represents the least biased estimate, however, cinacalcet is a cost-effective therapy for patients with moderate-to-severe sHPT on hemodialysis.


Characteristics of avoidant/restrictive food intake disorder in children and adolescents: a "new disorder" in DSM-5.
To evaluate the DSM-5 diagnosis of Avoidant/Restrictive Food Intake Disorder (ARFID) in children and adolescents with poor eating not associated with body image concerns. A retrospective case-control study of 8-18-year-olds, using a diagnostic algorithm, compared all cases with ARFID presenting to seven adolescent-medicine eating disorder programs in 2010 to a randomly selected sample with anorexia nervosa (AN) and bulimia nervosa (BN). Demographic and clinical information were recorded. Of 712 individuals studied, 98 (13.8%) met ARFID criteria. Patients with ARFID were younger than those with AN (n = 98) or BN (n = 66), (12.9 vs. 15.6 vs. 16.5 years), had longer durations of illness (33.3 vs. 14.5 vs. 23.5 months), were more likely to be male (29% vs. 15% vs. 6%), and had a percent median body weight intermediate between those with AN or BN (86.5 vs. 81.0 and 107.5). Patients with ARFID included those with selective (picky) eating since early childhood (28.7%); generalized anxiety (21.4%); gastrointestinal symptoms (19.4%); a history of vomiting/choking (13.2%); and food allergies (4.1%). Patients with ARFID were more likely to have a comorbid medical condition (55% vs. 10% vs. 11%) or anxiety disorder (58% vs. 35% vs. 33%) and were less likely to have a mood disorder (19% vs. 31% vs. 58%). Patients with ARFID were demographically and clinically distinct from those with AN or BN. They were significantly underweight with a longer duration of illness and had a greater likelihood of comorbid medical and/or psychiatric symptoms.


Efficacy and safety of flexibly dosed paliperidone palmitate in Chinese patients with acute schizophrenia: an open-label, single-arm, prospective, interventional study.
This open-label, single-arm, multicenter, 13-week, prospective study explored the efficacy, safety, and tolerability of paliperidone palmitate (150 milligram equivalents [mg eq] [day 1], 100 mg eq [day 8], both deltoid injections; 75-150 mg eq, deltoid/gluteal injection) in Chinese patients with acute schizophrenia (Positive and Negative Syndrome Scale [PANSS] total score ≥70), who previously had unsatisfactory therapeutic effect following oral antipsychotic treatment (without washout period). Primary efficacy endpoint was percentage of patients with ≥30% improvement in the PANSS total score at the end of 13 weeks. Secondary efficacy endpoints included change from baseline to end of week 13 in PANSS total score, PANSS subscale scores, Marder factor scores, Clinical Global Impressions-Severity score, and Personal and Social Performance Scale scores. Overall, 477/610 enrolled patients (full analysis set, 78.2%) completed the study (men: 55.1%; women: 44.9%; mean age: 31.5 years). Total, 443/610 (72.6%, full analysis set) patients achieved primary endpoint (mean [standard deviation] change from baseline: -30.9 [19.51]). All secondary endpoints demonstrated significant improvement at the end of 13 weeks. One death occurred during this acute phase. The most common (>5%) treatment-emergent adverse events were extrapyramidal disorders (8.4%). The efficacy and safety data are consistent with other short-term, placebo-controlled studies of paliperidone palmitate conducted in similar populations.


TAF10 (TAF(II)30) is necessary for TFIID stability and early embryogenesis in mice.
TAF10 (formerly TAF(II)30), is a component of TFIID and the TATA box-binding protein (TBP)-free TAF-containing complexes (TFTC/PCAF/STAGA). To investigate the physiological function of TAF10, we disrupted its gene in mice by using a Cre recombinase/LoxP strategy. Interestingly, no TAF10(-/-) animals were born from intercrosses of TAF10(+/-) mice, indicating that TAF10 is required for embryogenesis. TAF10(-/-) embryos developed to the blastocyst stage, implanted, but died shortly after ca. 5.5 days postcoitus. Surprisingly, trophoblast cells from TAF10(-/-) blastocysts were viable, whereas inner cell mass cells failed to survive, highlighting that TAF10 is not generally required for transcription in all cells. TAF10-deficient cells express normal levels of TBP and TAFs other than TAF10 but contain only partially formed TFIID, are endocycle arrested, and have undetectable levels of transcription. Thus, our results demonstrate that TAF10 is required for TFIID stability, cell cycle progression, and transcription in the early mouse embryo.


International periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis syndrome cohort: description of distinct phenotypes in 301 patients.
The aims of this study were to describe the clinical features of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) and identify distinct phenotypes in a large cohort of patients from different countries. We established a web-based multicentre cohort through an international collaboration within the periodic fevers working party of the Pediatric Rheumatology European Society (PReS). The inclusion criterion was a diagnosis of PFAPA given by an experienced paediatric rheumatologist participating in an international working group on periodic fever syndromes. Of the 301 patients included from the 15 centres, 271 had pharyngitis, 236 cervical adenitis, 171 oral aphthosis and 132 with all three clinical features. A total of 228 patients presented with additional symptoms (131 gastrointestinal symptoms, 86 arthralgias and/or myalgias, 36 skin rashes, 8 neurological symptoms). Thirty-one patients had disease onset after 5 years and they reported more additional symptoms. A positive family history for recurrent fever or recurrent tonsillitis was found in 81 patients (26.9%). Genetic testing for monogenic periodic fever syndromes was performed on 111 patients, who reported fewer occurrences of oral aphthosis or additional symptoms. Twenty-four patients reported symptoms (oral aphthosis and malaise) outside the flares. The CRP was >50 mg/l in the majority (131/190) of the patients tested during the fever. We describe the largest cohort of PFAPA patients presented so far. We confirm that PFAPA may present with varied clinical manifestations and we show the limitations of the commonly used diagnostic criteria. Based on detailed analysis of this cohort, a consensus definition of PFAPA with better-defined criteria should be proposed.


Rectification of EMG in low force contractions improves detection of motor unit coherence in the beta-frequency band.
Rectification of surface EMG before spectral analysis is a well-established preprocessing method used in the detection of motor unit firing patterns. A number of recent studies have called into question the need for rectification before spectral analysis, pointing out that there is no supporting experimental evidence to justify rectification. We present an analysis of 190 records from 13 subjects consisting of simultaneous recordings of paired single motor units and surface EMG from the extensor digitorum longus muscle during middle finger extension against gravity (unloaded condition) and against gravity plus inertial loading (loaded condition). We directly examine the hypothesis that rectified surface EMG is a better predictor of the frequency components of motor unit synchronization than the unrectified (or raw) EMG in the beta-frequency band (15-32 Hz). We use multivariate analysis and estimate the partial coherence between the paired single units using both rectified and unrectified surface EMG as a predictor. We use a residual partial correlation measure to quantify the difference between raw and rectified EMG as predictor and analyze unloaded and loaded conditions separately. The residual correlation for the unloaded condition is 22% with raw EMG and 3.5% with rectified EMG and for the loaded condition it is 5.2% with raw EMG and 1.4% with rectified EMG. We interpret these results as strong supporting experimental evidence in favor of using the preprocessing step of surface EMG rectification before spectral analysis.


Preparation and Optimization of Moxifloxacin Microspheres for Colon Targeted Delivery Using Quality by Design Approach: In Vitro and In Vivo Study.
Gut microbiota has a significant role in the pathogenesis of diabetes. Colonic microflora modulation using an antibiotic might have an emerging role to treat the metabolic disorders. The present study was aimed to optimize the Moxifloxacin loaded chitosan microspheres (MCMs) by emulsion cross linking method for colon targeted delivery to alter the microflora. Preliminary optimization of MCMs was carried out using Placket-Burman design (PBD) following by final optimization with Box-Behnken design (BBD). Optimized MCMs were evaluated for yield, particle size, entrapment efficiency and in vitro/ in vivo antimicrobial activities. FTIR spectroscopy of MCMs confirms the absence of chemical interactions during the formulation. MCMs were found to be smooth, spherical with particle size around 20μm. An enteric coating of MCMs prevented the drug release in the acidic environment of the stomach and ileum with complete release at the colon. MCMs had followed the korsmeyer - peppas model of drug release, indicating the drug release by non-fickian diffusion pattern. MCMs showed significant in vitro antimicrobial activity against Lactobacillus casei and Escherichia coli. In vivo results of MCMs exhibited prolonged antimicrobial effect of drug in the cecal content of rats. Significant protective activity observed in the ileum and colon histology in rats treated with MCMs compared to the pure drug. MCMs were formulated by emulsion cross linking method using QBD approach. An enteric coating around the microspheres prevented the premature drug release at upper gastrointestinal tract, while chitosan cross linking has provided the sustain release of the drug in the colonic region over the time.


Positive control of colanic acid synthesis in Escherichia coli by rmpA and rmpB, two virulence-plasmid genes of Klebsiella pneumoniae.
In Klebsiella pneumoniae, the mucoid phenotype, which is a virulence factor, is distinct from capsule production. It is positively controlled by a plasmid gene, designated rmpA. When introduced into certain Escherichia coli strains, rmpA induces expression of a mucoid phenotype, which results from overproduction of colanic acid at 30 degrees C but not at 37 degrees C. In E. coli, production of colanic acid is regulated by three genes: rcsA and rcsB which act as positive regulators, and rcsC which is a negative effector. In this work we present evidence that the rmpA gene complemented an rcsA, Ion double mutant of E. coli, but not an rcsA, Ion+ isolate. This leads to the suggestion that rmpA expressed an rcsA-like activity and like rcsA, was negatively controlled at post-transcriptional level by the Lon protease. The nucleotide sequence of rmpA is reported. No homology could be found between the 27 kiloDalton RcsA protein and the deduced amino acid sequence of the 15.5 kiloDalton RmpA protein. Another gene, rmpB, which was required in E. coli recA isolates for full expression of rmpA at 30 degrees C, has been identified on the K. pneumoniae virulence plasmid and shown to encode a 37 kiloDalton protein. Although rmpB was closely linked to rmpA, it was not present on the same transcriptional unit. These results suggested that induction of colanic acid synthesis by the K. pneumoniae virulence gene rmpA, was, at least in E. coli, under the control of the RecA network via rmpB, which may act as a positive regulator of rmpA. We conclude that these plasmid genes may function in K. pneumoniae as regulatory genes controlling the mucoid phenotype, which is itself encoded by the chromosome.


Echinomycin did not affect the safety of fracture healing: an experimental pilot study on a murine femur fracture model.
There is a need for effective drugs in the prevention and treatment of heterotopic ossifications (HO) after fractures. Echinomycin has been shown to prevent formation of HO in an animal model. However, before it may be considered as an option against HO, it needs to be studied whether it prevents fracture healing similar to non-steroidal anti-inflammatory drugs (NSAIDS). Therefore, the hypothesis was that echinomycin prevents fracture healing and callus formation. In an experimental murine pilot study, standard blunt femur fractures were induced and retrograde intramedullary compression fixation of the femur was performed. The treatment group (n = 8) received echinomycin (0.3 mg/kg body weight) and the control group (n = 8) did not receive echinomycin. The fractures and implant positions were verified by conventional X-rays immediately postoperatively. As the primary outcome variable, fracture healing (osseous consolidation) was evaluated by conventional X-rays and micro-computed tomography (CT) scans after ten weeks and graded as healed, partial or complete pseudarthrosis. The secondary outcome, callus formation, was graded semi-quantitatively from 0 (mostly absent) to 3 (maximum). Fracture healing was present in all living cases after ten weeks concerning the treatment group. Partial pseudarthrosis was seen in two cases, one in the treatment and another one in the control group. Complete pseudarthrosis was seen in one case of the control group after an open fracture. Callus formation was similar in both groups with a mean grade of 1.5 within each group. Two cases of the treatment group died. As a novel finding, echinomycin did not inhibit fracture healing or callus formation in this in vivo murine standard femur fracture model pilot study. Further studies involving a larger number of cases, quantitative assessment with CT scans and histopathological analysis are needed before generalizing the results of this pilot study.


Physics and device applications of optical microcavities.
Optical microcavities are resonators that have at least one dimension on the order of a single optical wavelength. These structures enable one to control the optical emission properties of materials placed inside them. They can, for example, modify the spatial distribution of radiation power, change the spectral width of the emitted light, and enhance or suppress the spontaneous emission rate. In addition to being attractive for studying the fundamental physics of the interaction between materials and vacuum field fluctuations, optical microcavities hold technological promise for constructing novel kinds of light-emitting devices. One of their most dramatic potential features is thresholdless lasing. In this way and others, controlled spontaneous emission is expected to play a key role in a new generation of optical devices.


Umbilical cord blood: a guide for primary care physicians.
Umbilical cord blood stem cell transplants are used to treat a variety of oncologic, genetic, hematologic, and immunodeficiency disorders. Physicians have an important role in educating, counseling, and offering umbilical cord blood donation and storage options to patients. Parents may donate their infant's cord blood to a public bank, pay to store it in a private bank, or have it discarded. The federal government and many state governments have passed laws and issued regulations regarding umbilical cord blood, and some states require physicians to discuss cord blood options with pregnant women. Five prominent medical organizations have published recommendations about cord blood donation and storage. Current guidelines recommend donation of umbilical cord blood to public banks when possible, or storage through the Related Donor Cord Blood Program when a sibling has a disease that may require a stem cell transplant. Experts do not currently recommend private banking for unidentified possible future use. Step-by-step guidance and electronic resources are available to physicians whose patients are considering saving or donating their infant's umbilical cord blood.


Usefulness of 64-slice multidetector computed tomography as an initial diagnostic approach in patients with acute chest pain.
Recently, multidetector computed tomography (MDCT) has been proposed as an accurate diagnostic tool to evaluate for coronary artery disease. However, the role of MDCT as part of the initial diagnostic for evaluating acute chest pain is less well established. We prospectively enrolled patients presenting with acute chest pain to the emergency department (ED) and risk stratified them based on the pretest probability for an acute coronary syndrome (ACS): (1) very low, (2) low, (3) intermediate, (4) high, and (5) very high or definite. After exclusion of very low and very high risk patients, 268 patients were randomized to either immediate 64-slice cardiac MDCT or a conventional diagnostic strategy. Number of admissions, ED and hospital length of stay (LOS), and major adverse cardiac events over 30 days of follow-up were compared between the strategies based on the pretest probability for ACS. The number of patients ultimately diagnosed with an ACS did not differ between the 2 strategies. Emergency department LOS and total admissions were not different between strategies. Patients in the MDCT-based strategy had a decreased hospital LOS (P = .049) and fewer admissions deemed unnecessary (P = .007). Reductions in unnecessary admissions were more prominent in intermediate-risk patients (P = .015). None of the patients discharged from the ED in the MDCT-based strategy experienced major adverse cardiac events at follow-up. Use of an MDCT-based strategy in the ED as part of the initial diagnostic approach for patients presenting with acute chest pain is safe and efficiently reduces avoidable admissions in patients with an intermediate pretest probability for ACS.


Interaction between smoking and depressive symptoms with subclinical heart disease in the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Evaluate whether smoking exposure and depressive symptoms accumulated over 25 years are synergistically associated with subclinical heart disease, measured by coronary artery calcification (CAC). Participants (baseline: 54.5% women; 51.5% Black; age range = 18-30 years) were followed prospectively from 1985 to 2010 in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Smoking status was queried yearly from Year 0 to Year 25 to compute packyears of smoking exposure. Depressive symptoms were measured on the Center for Epidemiologic Studies Depression (CES-D) scale every 5 years to compute cumulative scores from Year 5 to Year 25. A three-level multinomial logistic regression was used to evaluate the association between cumulative smoking, cumulative depressive symptoms, and their interaction with moderate-risk CAC (score 1-99) and higher-risk CAC (score ≥100) compared with no CAC (score = 0) at Year 25. Models were adjusted for sociodemographic, clinical, and behavioral covariates. Among 3,189 adults, the cumulative Smoking × Depressive Symptoms interaction was not significant for moderate-risk CAC (p = .057), but was significant for higher-risk CAC (p = .001). For adults with a 30-packyear smoking history, average CES-D scores 2, 10, and 16 were, respectively, associated with odds ratios (95% confidence intervals) 3.40 (2.36-4.90), 4.82 (3.03-7.66), and 6.25 (3.31-11.83) for higher-risk CAC (all ps < .05). Cumulative smoking exposure and cumulative depressive symptoms have a synergistic association with subclinical heart disease, where higher lifetime smoking exposure and depressive symptoms are associated with greater odds of CAC. (PsycINFO Database Record


'Borderline personality': diagnostic attitudes at the Maudsley Hospital.
About a quarter of the psychiatrists at the Maudsley Hospital use the diagnosis of 'borderline' personality. The description of the borderline patient obtained in this study does not overlap with any existing ICD personality disorder but has characteristics of the schizoid, paranoid, hysteric, explosive, anankastic and antisocial personalities. The item that discriminated best between borderlines and controls was 'brief, unsystematized , psychotic episodes', which is not included in the DSM-III definitions of borderline diagnoses. Items of the DSM-III 'schizotypal' set--e.g. 'suspiciousness' and 'ideas of reference'--discriminated better between borderline cases and controls, whereas items of the DSM-III 'borderline personality' set--e.g. 'impulsivity' or 'unpredictability'--scored more frequently in both groups. These are similar to American findings.


A low-fat yoghurt supplemented with a rooster comb extract on muscle joint function in adults with mild knee pain: a randomized, double blind, parallel, placebo-controlled, clinical trial of efficacy.
Preliminary results suggested that oral-administration of rooster comb extract (RCE) rich in hyaluronic acid (HA) was associated with improved muscle strength. Following these promising results, the objective of the present study was to evaluate the effect of low-fat yoghurt supplemented with RCE rich in HA on muscle function in adults with mild knee pain; a symptom of early osteoarthritis. Participants (n = 40) received low-fat yoghurt (125 mL d(-1)) supplemented with 80 mg d(-1) of RCE and the placebo group (n = 40) consumed the same yoghurt without the RCE, in a randomized, controlled, double-blind, parallel trial over 12 weeks. Using an isokinetic dynamometer (Biodex System 4), RCE consumption, compared to control, increased the affected knee peak torque, total work and mean power at 180° s(-1), at least 11% in men (p < 0.05) with no differences in women. No dietary differences were noted. These results suggest that long-term consumption of low-fat yoghurt supplemented with RCE could be a dietary tool to improve muscle strength in men, associated with possible clinical significance. However, further studies are needed to elucidate reasons for these sex difference responses observed, and may provide further insight into muscle function.


A Systematic Review of Virtual Reality Simulators for Robot-assisted Surgery.
No single large published randomized controlled trial (RCT) has confirmed the efficacy of virtual simulators in the acquisition of skills to the standard required for safe clinical robotic surgery. This remains the main obstacle for the adoption of these virtual simulators in surgical residency curricula. To evaluate the level of evidence in published studies on the efficacy of training on virtual simulators for robotic surgery. In April 2015 a literature search was conducted on PubMed, Web of Science, Scopus, Cochrane Library, the Clinical Trials Database (US) and the Meta Register of Controlled Trials. All publications were scrutinized for relevance to the review and for assessment of the levels of evidence provided using the classification developed by the Oxford Centre for Evidence-Based Medicine. The publications included in the review consisted of one RCT and 28 cohort studies on validity, and seven RCTs and two cohort studies on skills transfer from virtual simulators to robot-assisted surgery. Simulators were rated good for realism (face validity) and for usefulness as a training tool (content validity). However, the studies included used various simulation training methodologies, limiting the assessment of construct validity. The review confirms the absence of any consensus on which tasks and metrics are the most effective for the da Vinci Skills Simulator and dV-Trainer, the most widely investigated systems. Although there is consensus for the RoSS simulator, this is based on only two studies on construct validity involving four exercises. One study on initial evaluation of an augmented reality module for partial nephrectomy using the dV-Trainer reported high correlation (r=0.8) between in vivo porcine nephrectomy and a virtual renorrhaphy task according to the overall Global Evaluation Assessment of Robotic Surgery (GEARS) score. In one RCT on skills transfer, the experimental group outperformed the control group, with a significant difference in overall GEARS score (p=0.012) during performance of urethrovesical anastomosis on an inanimate model. Only one study included assessment of a surgical procedure on real patients: subjects trained on a virtual simulator outperformed the control group following traditional training. However, besides the small numbers, this study was not randomized. There is an urgent need for a large, well-designed, preferably multicenter RCT to study the efficacy of virtual simulation for acquisition competence in and safe execution of clinical robotic-assisted surgery. We reviewed the literature on virtual simulators for robot-assisted surgery. Validity studies used various simulation training methodologies. It is not clear which exercises and metrics are the most effective in distinguishing different levels of experience on the da Vinci robot. There is no reported evidence of skills transfer from simulation to clinical surgery on real patients.


Reestablishing patency in an occluded central venous access device.
Nurses in a full range of settings from acute to home care are increasingly exposed to the use and maintenance of central VADs. Although the advantages of central VADs are well recognized, the incidence and potential for complications associated with these devices should not be minimized. The major complication of catheter occlusion has the potential of inducing significant morbidity and mortality. The purpose of the following care plan is to familiarize the nurse with the information needed to restore catheter patency efficiently, safely, and effectively, thereby reducing the potential complications and enhancing the quality of patient care.


Investigating hypoxic tumor physiology through gene expression patterns.
Clinical evidence shows that tumor hypoxia is an independent prognostic indicator of poor patient outcome. Hypoxic tumors have altered physiologic processes, including increased regions of angiogenesis, increased local invasion, increased distant metastasis and altered apoptotic programs. Since hypoxia is a potent controller of gene expression, identifying hypoxia-regulated genes is a means to investigate the molecular response to hypoxic stress. Traditional experimental approaches have identified physiologic changes in hypoxic cells. Recent studies have identified hypoxia-responsive genes that may define the mechanism(s) underlying these physiologic changes. For example, the regulation of glycolytic genes by hypoxia can explain some characteristics of the Warburg effect. The converse of this logic is also true. By identifying new classes of hypoxia-regulated gene(s), we can infer the physiologic pressures that require the induction of these genes and their protein products. Furthermore, these physiologically driven hypoxic gene expression changes give us insight as to the poor outcome of patients with hypoxic tumors. Approximately 1-1.5% of the genome is transcriptionally responsive to hypoxia. However, there is significant heterogeneity in the transcriptional response to hypoxia between different cell types. Moreover, the coordinated change in the expression of families of genes supports the model of physiologic pressure leading to expression changes. Understanding the evolutionary pressure to develop a 'hypoxic response' provides a framework to investigate the biology of the hypoxic tumor microenvironment.


Getting help from others: the effects of demand and supply.
This article investigates whether the help with care needs that is received from others depends on the potential supply of family helpers. Data from the first round of survey data collected in the National Health and Aging Trends Study are used to create measures of whether help is received, the number of helpers, and the hours of help received. Regression analysis is used to relate these outcomes to indicators of the demand for and supply of helpers. Analyses suggest limited evidence that the receipt of help is a supply-driven phenomenon. Although the measures of child-caregiver supply are not associated with a binary indicator of help received, caregiver-supply factors are associated with the number of helpers and the total hours of help received. Findings on the total number of helpers and total hours of care have implications for the division of care labor within families and between families and nonfamily members. Foreseeable trends in the demand for and the supply of help suggest further evolution in patterns of elders' receipt of help with care needs. Even if those with needs for care continue to have their needs addressed by one or more helpers, the number of helpers, and the aggregate amount of help they provide, is likely to undergo adjustment in response to changing family patterns.


Nucleocytoplasmic shuttling by protein nuclear import factors.
Protein nuclear import factors are not, in general, believed to function in the nuclear export of macromolecules and their reutilization therefore requires their recycling from the nucleus to the cytoplasm. Two possible mechanisms for recycling have been proposed. On the one hand, protein import factors such as importin beta and transportin (Trn) could continuously shuttle between cytoplasm and nucleoplasm. On the other hand, these proteins could penetrate into the nucleus only as far as the inner surface of the nuclear pore complex and then directly return to the cytoplasm. In this manuscript, we have used microinjection analysis in human cells, and in vitro nuclear assays, to demonstrate that importin beta, transportin and importin alpha are all nucleocytoplasmic shuttle proteins that efficiently enter and exit the cell nucleoplasm. In the case of transportin, we have mapped sequences required for nucleocytoplasmic shuttling to the carboxy-terminal 270 amino acids of this 890 amino acid import factor, thus demonstrating that nuclear export is independent of the amino-terminal Ran-binding domain of Trn. We further show that Trn shuttling is independent of nuclear RNA transcription. Overall, these data suggest that nucleocytoplasmic shuttling is likely to be a general attribute of protein nuclear import factors.


Flexible and efficient genome tiling design with penalized uniqueness score.
As a powerful tool in whole genome analysis, tiling array has been widely used in the answering of many genomic questions. Now it could also serve as a capture device for the library preparation in the popular high throughput sequencing experiments. Thus, a flexible and efficient tiling array design approach is still needed and could assist in various types and scales of transcriptomic experiment. In this paper, we address issues and challenges in designing probes suitable for tiling array applications and targeted sequencing. In particular, we define the penalized uniqueness score, which serves as a controlling criterion to eliminate potential cross-hybridization, and a flexible tiling array design pipeline. Unlike BLAST or simple suffix array based methods, computing and using our uniqueness measurement can be more efficient for large scale design and require less memory. The parameters provided could assist in various types of genomic tiling task. In addition, using both commercial array data and experiment data we show, unlike previously claimed, that palindromic sequence exhibiting relatively lower uniqueness. Our proposed penalized uniqueness score could serve as a better indicator for cross hybridization with higher sensitivity and specificity, giving more control of expected array quality. The flexible tiling design algorithm incorporating the penalized uniqueness score was shown to give higher coverage and resolution. The package to calculate the penalized uniqueness score and the described probe selection algorithm are implemented as a Perl program, which is freely available at http://www1.fbn-dummerstorf.de/en/forschung/fbs/fb3/paper/2012-yang-1/OTAD.v1.1.tar.gz.


Do seizures in patients with refractory epilepsy vary between wakefulness and sleep?
To determine the effects of sleep and wakefulness on seizures in patients with refractory epilepsy recorded while undergoing video-electroencephalography (EEG) telemetry. The video-EEG data of patients who had two or more seizures during video-EEG telemetry (n = 270) were reviewed. Fifty seven patients who had seizures both in wakefulness and sleep were identified. The video and ictal EEG data were reviewed, paying specific attention to type of seizures, duration, semiology, lateralisation and number of seizures. Three hundred and sixty two seizures were recorded; 237 seizures while awake and 125 while sleeping. Secondary generalisation occurred more often in sleep than in wakefulness (p < 0.01). Overall, there was no significant effect of sleep on the duration of seizures or ictal EEG change. Sleep and awake seizures differed in only eight patients. Secondary generalisation occurred more often in sleep than in wakefulness, perhaps due to the facilitated spread of seizures during sleep. For the most part, however, seizures recorded during sleep did not differ from those recorded during wakefulness.


Coexistence of energy diffusion and local thermalization in nonequilibrium XXZ spin chains with integrability breaking.
In this work we analyze the simultaneous emergence of diffusive energy transport and local thermalization in a nonequilibrium one-dimensional quantum system, as a result of integrability breaking. Specifically, we discuss the local properties of the steady state induced by thermal boundary driving in a XXZ spin chain with staggered magnetic field. By means of efficient large-scale matrix product simulations of the equation of motion of the system, we calculate its steady state in the long-time limit. We start by discussing the energy transport supported by the system, finding it to be ballistic in the integrable limit and diffusive when the staggered field is finite. Subsequently, we examine the reduced density operators of neighboring sites and find that for large systems they are well approximated by local thermal states of the underlying Hamiltonian in the nonintegrable regime, even for weak staggered fields. In the integrable limit, on the other hand, this behavior is lost, and the identification of local temperatures is no longer possible. Our results agree with the intuitive connection between energy diffusion and thermalization.


5-formylcytosine and 5-carboxylcytosine reduce the rate and substrate specificity of RNA polymerase II transcription.
Although the roles of 5-methylcytosine and 5-hydroxymethylcytosine in epigenetic regulation of gene expression are well established, the functional effects of 5-formylcytosine and 5-carboxylcytosine on the process of transcription are not clear. Here we report a systematic study of the effects of five different forms of cytosine in DNA on mammalian and yeast RNA polymerase II transcription, providing new insights into potential functional interplay between cytosine methylation status and transcription.


Predictors of asthma control and lung function responsiveness to step 3 therapy in children with uncontrolled asthma.
Predictors of improvement in asthma control and lung function to step 3 therapy in children with persistent asthma have not been identified despite reported heterogeneity in responsiveness. We sought to evaluate potential predictors of asthma control and lung function responsiveness to step 3 therapy. A post hoc analysis from the Best Add-On Giving Effective Response (BADGER) study tested the association between baseline biological, asthma control, pulmonary function, and demographic markers and responsiveness to step-up to a higher dose of inhaled corticosteroid (ICS step-up therapy) or addition of leukotriene receptor antagonist (LTRA step-up therapy) or long-acting β₂-agonist (LABA step-up therapy). In multivariate analyses higher impulse oscillometry reactance area was associated (P = .048) with a differential FEV₁ response favoring LABA over ICS step-up therapy, whereas higher urinary leukotriene E₄ levels were marginally (P = .053) related to a differential FEV₁ response favoring LTRA over LABA step-up therapy. Predictors of differential responses comparing ICS with LTRA step-up therapy were not apparent, probably because of suppression of allergic markers with low-dose ICS treatment. Minimal overlap was seen across FEV₁ and asthma control day predictors, suggesting distinct mechanisms related to lung function and asthma control day responses. Levels of impulse oscillometry reactance area indicating peripheral airway obstruction and urinary leukotriene E₄ levels indicating cysteinyl leukotriene inflammation can differentiate LABA step-up responses from responses to LTRA or ICS step-up therapy. Further studies with physiologic, genetic, and biological markers related to these phenotypes will be needed to predict individual responses to LABA step-up therapy.


New insights into the ageing of linseed oil paint binder: a qualitative and quantitative analytical study.
This paper presents an analytical investigation of paint reconstructions prepared with linseed oil that have undergone typical 19th century treatments in preparation for painting. The oil was mechanically extracted from the same seed lot, which was then processed by various methods: water washing, heat treatments, and the addition of driers, with and without heat. A modern process lead white (Dutch source, Schoonhoven) and a commercially available vine black were used as pigments. The reconstructions were prepared in 1999, and naturally aged from then onwards. We compared thermogravimetric analysis (TG), which yields macromolecular information, with gas chromatography-mass spectrometry (GC-MS) and direct exposure mass spectrometry (DEMS), which both provide molecular information. The study enabled us to quantitatively demonstrate, for the first time, that the parameters used to identify drying oils are deeply influenced by the history of the paint. In particular, here we show that the ratio between the relative amounts of palmitic and stearic acid (P/S), which is used as an index for differentiating between drying oils, is extremely dependent on the pigments present and the age of the paint. Moreover the study revealed that neither the P/S parameter nor the ratios between the relative amounts of the various dicarboxylic acids (azelaic over suberic and azelaic over sebacic) can be used to trace the sorts of pre-treatment undergone by the oil investigated in this study. The final results represent an important milestone for the scientific community working in the field, highlighting that further research is still necessary to solve the identification of drying oils in works of art.


Towards health equity: a framework for the application of proportionate universalism.
The finding that there is a social gradient in health has prompted considerable interest in public health circles. Recent influential works describing health inequities and their causes do not always argue cogently for a policy framework that would drive the most appropriate solutions differentially across the social gradient This paper aims to develop a practice heuristic for proportionate universalism. Through a review the proposed heuristic integrates evidence from welfare state and policy research, the literature on universal and targeted policy frameworks, and a multi-level governance approach that adopts the principle of subsidiarity. The proposed heuristic provides a more-grained analysis of different policy approaches, integral for operationalizing the concept of proportionate universalism. The proposed framework would allow governments at all levels, social policy developers and bureaucrats, public health professionals and activists to consider the appropriateness of distinctive policy objectives across distinctive population needs within universal welfare state principles.


Exercise and associated dietary extremes impact on gut microbial diversity.
The commensal microbiota, host immunity and metabolism participate in a signalling network, with diet influencing each component of this triad. In addition to diet, many elements of a modern lifestyle influence the gut microbiota but the degree to which exercise affects this population is unclear. Therefore, we explored exercise and diet for their impact on the gut microbiota. Since extremes of exercise often accompany extremes of diet, we addressed the issue by studying professional athletes from an international rugby union squad. Two groups were included to control for physical size, age and gender. Compositional analysis of the microbiota was explored by 16S rRNA amplicon sequencing. Each participant completed a detailed food frequency questionnaire. As expected, athletes and controls differed significantly with respect to plasma creatine kinase (a marker of extreme exercise), and inflammatory and metabolic markers. More importantly, athletes had a higher diversity of gut micro-organisms, representing 22 distinct phyla, which in turn positively correlated with protein consumption and creatine kinase. The results provide evidence for a beneficial impact of exercise on gut microbiota diversity but also indicate that the relationship is complex and is related to accompanying dietary extremes.


Global geographical and historical overview of cyanotoxin distribution and cyanobacterial poisonings.
Cyanobacteria are photoautotrophic organisms which occur in aquatic and terrestrial environments. They have the potential to produce toxins which pose a threat to human and animal health. This review covers the global distribution of the common cyanotoxins and related poisoning cases. A total of 468 selected articles on toxic cyanobacteria, dating from the earliest records until 2018, were reviewed. Most of the articles were published after 2000 (72%; 337 out of 468), which is consistent with the recent growth in interest in the analysis, toxinology and ecotoxicology of cyanotoxins. Animal and/or human poisoning cases were described in more than a third of the overall publications (38%; 177 out of 468). The reviewed publications showed that there were 1118 recorded identifications of major cyanotoxins in 869 freshwater ecosystems from 66 countries throughout the world. Microcystins were the most often recorded cyanotoxins worldwide (63%; 699 out of 1118), followed by cylindrospermopsin (10%; 107 out of 1118), anatoxins (9%; 100 out of 1118), and saxitoxins (8%; 93 out of 1118). Nodularins were the most rarely recorded cyanotoxins (2%; 19 out of 1118); however, there were also reports where cyanotoxins were not analysed or specified (9%; 100 out of 1118). The most commonly found toxic cyanobacterial genera were Microcystis spp. (669 reports), Anabaena spp. (397 reports), Aphanizomenon spp. (100 reports), Planktothrix spp. (98 reports), and Oscillatoria spp. (75 reports). Furthermore, there were 183 recorded cyanotoxin poisonings of humans and/or animals. Out of all toxic cyanobacterial blooms reviewed in this paper, the highest percentage of associated poisonings was found in North and Central America (39%; 69 cases out of 179), then Europe (20%; 35 out of 179), Australia including New Zealand (15%; 27 out of 179), and Africa (11%; 20 out of 179), while the lowest percentage was related to Asia (8%; 14 cases out of 179) and South America (8%; 14 cases out of 179). Events where only animals were known to have been affected were 63% (114 out of 182), whereas 32% (58 out of 182) of the investigated events involved only humans. A historical overview of human and animal poisoning episodes associated with cyanobacterial blooms is presented. Further, geographical data on the occurrence of cyanotoxins and related poisonings based on the available literature are shown. Some countries (mainly European) have done very intensive research on the occurrence of toxic cyanobacteria and cyanotoxins, and reported related ecotoxicological observations, while in some countries the lack of data is apparent. The true global extent of cyanotoxins and associated poisonings is likely to be greater than found in the available literature, and it can be assumed that ecotoxicological and hygienic problems caused by toxic cyanobacteria may occur in more environments.


Evaluation of imaging technologies to correct for photon attenuation in the overlying tissue for in vivo bone strontium measurements.
The interpretation of measurements of bone strontium in vivo using energy dispersive x-ray fluorescence spectroscopy is presently hindered by overlying skin and soft-tissue absorption of the strontium x-rays. The use of imaging technologies to measure the overlying soft-tissue thickness at the index finger measuring site might allow correction of the strontium reading to estimate its concentration in bone. An examination of magnetic resonance (MR), computed tomography (CT) and high-frequency ultrasound (US) imaging technologies revealed that 55 MHz US had the smallest range of measurement uncertainty at 3.2% followed by 1 Tesla MR, 25 MHz US, 8 MHz US and CT at 4.3, 5.4, 6.6 and 7.1% uncertainty, respectively. Of these, only CT imaging appeared to underestimate total thickness (p < 0.05). Furthermore, an inter-study comparison on the accuracy of US measurements of the overlying tissue thickness at finger and ankle in nine subjects was investigated. The 8 MHz US system used in prior in vivo experiments was found to perform satisfactorily in a repeat study of ankle measurements, but indicated that finger thickness measurements may have been misread in previous studies by up to 17.7% (p < 0.025). Repeat ankle measurements were not significantly different from initial measurements at 2.2% difference.


Prevalence and Incidence of Amyotrophic Lateral Sclerosis in Japan.
Background: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown.Methods: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution.Results: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females.Conclusions: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.


Oral contraceptive use and malignancies of the genital tract. Results from the Royal College of General Practitioners' Oral Contraception Study.
Of 47,000 women followed since 1968, those who had used oral contraceptives (ever-users) had a significantly higher incidence rate of cervical cancer than never-users. After standardisation of rates by age, parity, smoking, social class, number of previously normal cervical smears, and history of sexually transmitted disease, the excess was 41 per 100,000 woman-years for carcinoma-in-situ and 8 per 100,000 woman-years for invasive cervical cancer. Incidence increased with increasing duration of use: the standardised incidence rate for cervical cancer in women who had taken the pill for more than 10 years was four times than in never-users. Ever-users had a lower incidence of other uterine cancers (deficit 5 per 100,000 woman-years); a lower incidence of ovarian cancer was also found (deficit 4 per 100,000), but was not statistically significant. Overall, ever-users had an excess incidence for genital tract cancers 37 per 100,000 woman-years. This excess was mainly from carcinoma-in-situ of the cervix; the excess incidence of invasive cervical cancer was offset by the deficits in other uterine and ovarian cancers. Standardised mortality rates from genital cancer were similar in ever-users and never-users. Of relevance to clinical practice is the substantially different distribution of primary cancer sites: cervical cancer accounted for 75% of the invasive genital cancers and 74% of deaths from genital cancer in ever-users, but only 31% of the invasive cancers and 30% of deaths in never-users.


Coupled, multi-strain epidemic models of mutating pathogens.
We introduce and analyze coupled, multi-strain epidemic models designed to simulate the emergence and dissemination of mutant (e.g. drug-resistant) pathogen strains. In particular, we investigate the mathematical and biological properties of a general class of multi-strain epidemic models in which the infectious compartments of each strain are coupled together in a general manner. We derive explicit expressions for the basic reproduction number of each strain and highlight their importance in regulating the system dynamics (e.g. the potential for an epidemic outbreak) and the existence of nonnegative endemic solutions. Importantly, we find that the basic reproduction number of each strain is independent of the mutation rates between the strains - even under quite general assumptions for the form of the infectious compartment coupling. Moreover, we verify that the coupling term promotes strain coexistence (as an extension of the competitive exclusion principle) and demonstrate that the strain with the greatest reproductive capacity is not necessarily the most prevalent. Finally, we briefly discuss the implications of our results for public health policy and planning.


Keratoacanthoma as a postoperative complication of skin cancer excision.
Keratoacanthomas usually occur spontaneously as a single rapidly growing tumor on sun-exposed skin. Multiple keratoacanthomas are rarely seen. Keratoacanthomas may also develop after trauma, laser resurfacing, radiation therapy, and at the donor site after skin grafting. We report 6 cases of keratoacanthomas that developed in and around healing and healed surgical sites after treatment of skin cancer. These tumors developed 1 to 3 months after surgery and were sometimes multiple. We performed follow-up examinations of patients' wounds after the treatment of skin cancer. Histological examination of nodules developing in the margins of healing wound sites and in the scars of healed wound sites after Mohs micrographic surgery revealed keratoacanthomas. The tumors presented as a rapidly growing nodule or nodules, with the typical morphology and pathology of keratoacanthoma. One patient developed multiple keratoacanthomas at surgical and nonsurgical sites. These nodules were treated by a combination of excision, curettage and electrodesiccation, and oral isotretinoin, 4 mg/d. Keratoacanthoma must be considered in the differential diagnosis of a rapidly growing nodule within or around the surgical site after skin cancer surgery.


Evaluation of muscle metaboreflex function through graded reduction in forearm blood flow during rhythmic handgrip exercise in humans.
Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Our aim was to determine the muscle metaboreflex threshold and gain in humans by creating an open-loop relationship between active muscle blood flow and hemodynamic responses during a rhythmic handgrip exercise. Eleven healthy subjects performed the exercise at 5 or 15% of maximal voluntary contraction (MVC) in random order. During the exercise, forearm blood flow (FBF), which was continuously measured using Doppler ultrasound, was reduced in five steps by manipulating the inner pressure of an occlusion cuff on the upper arm. The FBF at each level was maintained for 3 min. The initial reductions in FBF elicited no hemodynamic changes, but once FBF fell below a threshold, mean arterial blood pressure (MAP) and heart rate (HR) increased and total vascular conductance (TVC) decreased in a linear manner. The threshold FBF during the 15% MVC trial was significantly higher than during the 5% MVC trial. The gain was then estimated as the slope of the relationship between the hemodynamic responses and FBFs below the threshold. The gains for the MAP and TVC responses did not differ between workloads, but the gain for the HR response was greater in the 15% MVC trial. Our findings thus indicate that increasing the workload shifts the threshold for the muscle metaboreflex to higher blood flows without changing the gain of the reflex for the MAP and TVC responses, whereas it enhances the gain for the HR response.


Nucleotide sequence of the Yersinia enterocolitica ail gene and characterization of the Ail protein product.
The ability to enter (invade) eucaryotic cells is a property common to many pathogenic bacteria. Yersinia enterocolitica is a facultative intracellular pathogen whose primary site of multiplication is the reticuloendothelial system. In an effort to understand how Y. enterocolitica crosses the intestinal epithelial cell layer, we previously reported the cloning of two loci from Y. enterocolitica that individually conferred an invasive phenotype to the normally noninvasive Escherichia coli HB101. One of these loci, ail, is encoded by a region of DNA that is less than 650 base pairs. We have identified the ail gene product in maxicells as a 17-kilodalton membrane-associated protein. The Ail protein has been purified, and its N-terminal sequence has been determined. The nucleotide sequence of the ail gene revealed a single unique open reading frame of 178 amino acids. Comparison of amino acid sequences deduced from the gene and obtained by analysis of the purified protein identified the first 23 amino acids as a signal sequence. The site(s) at which transcription initiates on the ail gene was identified by primer extension analysis and shown to be identical in E. coli and Y. enterocolitica. Two small open reading frames downstream of ail were found and shown to exhibit considerable identity to the proposed IS3 transposase.


An exploratory study of neurohormonal responses of healthy men to massage.
This research examined the relationship between plasma oxytocin (OT), arginine vasopressin (AVP), cortisol, and anxiety before, during, and after a massage in healthy adult men. A randomized, controlled, crossover, repeated-measures, prospective experimental design with subjects acting as their own controls was used. The research was conducted at a Midwestern University. Fourteen (14) healthy men between the ages of 19 and 45 years of age were randomly assigned to the order of two conditions: a 20-minute massage (experimental condition) or a 20-minute reading period (control condition). Blood samples were collected at time intervals during each data collection session. Plasma OT, AVP, and cortisol levels were evaluated by enzyme immunoassay (EIA). The Spielberger State Anxiety Inventory (SAI) and autonomic measures were recorded pre- and postcondition. Both experimental (massage) and control (reading) conditions elicited a significant increase in plasma OT levels (p < 0.05) and a decrease in SAI score (p < 0.05) from pre- to postintervention. A significant positive correlation was detected between plasma AVP and plasma cortisol (r = 0.63, n = 24, p = 0.001) in the massage group, whereas a significant positive correlation between plasma AVP and the SAI (r = 0.47, n = 25, p = 0.016) was observed in the reading group. No significant differences were observed for the autonomic measures between conditions. The finding that plasma OT levels increased in both the massage and reading groups, suggests that tactile stimulus is not necessary for OT release. The results suggest that another unknown factor associated with reduction of anxiety may be involved.


Greater vegetable and fruit intake is associated with a lower risk of breast cancer among Chinese women.
The effect of vegetable and fruit consumption on breast cancer risk is controversial. We examined the association between vegetable and fruit intake and breast cancer risk in a hospital-based case-control study conducted in Guangdong, China. Four hundred and thirty-eight cases were frequency matched to 438 controls by age (5-year interval) and residence (rural/urban). Dietary intake was assessed by face-to-face interviews using a validated food frequency questionnaire. Multivariate logistic regression was used to estimate the odds ratios (ORs) and 95% confidence interval (CI) after adjusting for various potential confounders. Total vegetable and fruit intake was found to be inversely associated with breast cancer risk. The ORs of the highest quartile relative to the lowest quartile of total vegetable and fruit intake were 0.28 (95% CI 0.18-0.43) and 0.53 (95% CI 0.34-0.82), respectively. Consumption of individual vegetable and fruit groups such as dark green leafy vegetables, cruciferous vegetables, carrots and tomatoes, banana, watermelon/papaya/cantaloupe were all inversely and significantly related with breast cancer risk. An inverse association was also observed for vitamin A, carotene, vitamin C, vitamin E, and fiber intake. These data indicate that greater intake of vegetables and fruits is associated with a decreased risk of breast cancer among Chinese women residing in Guangdong.


Upper extremity reconstruction in the tetraplegic population, a national epidemiologic study.
More than 100,000 Americans live with the disability of tetraplegia. For these people their level of independence often is related to the function of the upper extremity. Reconstructive procedures can improve the use of the upper limb and multiple case series have shown benefit from these procedures for appropriate candidates. Discussions with patients and surgeons, however, suggest that these procedures rarely are performed. This study attempted to assess whether upper extremity reconstruction for the tetraplegic population is being used properly. Data from 2 inpatient national databases were used (the National Inpatient Sample and Veterans Affairs patient treatment files) for 1988, 1989, 1999, and 2000. Patients were selected by International Classification of Diseases (ICD-9) diagnosis codes for tetraplegia and procedure codes that could represent upper extremity reconstruction. The recommended rate of these surgeries was based on the annual incidence of tetraplegia (5,000) and expert opinion that suggests at least 50% of these people would benefit from upper extremity surgery. Our health care data analysis showed that fewer than 355 of these surgeries were performed in the United States in any year queried. The calculated recommended rate was 2,500 procedures a year, meaning that only 14% of appropriate candidates were receiving upper extremity reconstruction. We also found changes in the expected primary payor, with Medicaid paying for far fewer procedures in 2000 compared with 1988 claims. Finally over the course of time it appears that far fewer of these procedures are being performed. Functional upper extremity reconstruction for the tetraplegic population is profoundly underused in the United States. Various factors could be causing this disparity of care and we recommend further research into the potential barriers to health care for this vulnerable population.


The BRCA1 c. 5096G>A p.Arg1699Gln (R1699Q) intermediate risk variant: breast and ovarian cancer risk estimation and recommendations for clinical management from the ENIGMA consortium.
We previously showed that the BRCA1 variant c.5096G>A p.Arg1699Gln (R1699Q) was associated with an intermediate risk of breast cancer (BC) and ovarian cancer (OC). This study aimed to assess these cancer risks for R1699Q carriers in a larger cohort, including follow-up of previously studied families, to further define cancer risks and to propose adjusted clinical management of female BRCA1*R1699Q carriers. Data were collected from 129 BRCA1*R1699Q families ascertained internationally by ENIGMA (Evidence-based Network for the Interpretation of Germline Mutant Alleles) consortium members. A modified segregation analysis was used to calculate BC and OC risks. Relative risks were calculated under both monogenic model and major gene plus polygenic model assumptions. In this cohort the cumulative risk of BC and OC by age 70 years was 20% and 6%, respectively. The relative risk for developing cancer was higher when using a model that included the effects of both the R1699Q variant and a residual polygenic component compared with monogenic model (for BC 3.67 vs 2.83, and for OC 6.41 vs 5.83). Our results confirm that BRCA1*R1699Q confers an intermediate risk for BC and OC. Breast surveillance for female carriers based on mammogram annually from age 40 is advised. Bilateral salpingo-oophorectomy should be considered based on family history.


Fetal growth, early life circumstances, and risk of suicide in late adulthood.
Recent studies in Sweden and Scotland have found early life conditions to be associated with increased risk of attempted and completed suicide in adolescence and young adulthood. It is not known, however, whether early life conditions affect suicide risk throughout the life course, from adulthood into old age. We examined the effects of early life conditions, including markers of fetal growth, and social and economic characteristics in adulthood, on risk of suicide by violent and non-violent methods in women and men aged 31-87 years using Cox regression. 11,650 women and men born at the Uppsala University Hospital in Sweden between 1915 and 1929 were followed from 1960 until 2002 using linked records from obstetric archives, Census, population and mortality registries. During 435,039 person-years of follow-up 161 completed suicides (104 in males, 57 in females) were observed. An inverse association was found between lower birthweight-for-gestational age and risk of violent suicide in females, although the association did not reach the conventional level of statistical significance (minimally adjusted HR 2.02, 95% CI (0.88-4.63); Table 4). Being male, unmarried, and in the "other or unknown" social class category in adulthood were independently associated with increased rates of suicide. There was a weak association between higher maternal parity and suicide rates. Our findings suggest differences in effects of fetal growth patterns and perinatal circumstances on suicide risk later in life, and suggest that suicide in adults and in the elderly may be influenced by a different combination of factors than those that influence suicide in adolescence and young adulthood.


De Novo Mutations in EIF2B1 Affecting eIF2 Signaling Cause Neonatal/Early-Onset Diabetes and Transient Hepatic Dysfunction.
Permanent neonatal diabetes mellitus (PNDM) is caused by reduced β-cell number or impaired β-cell function. Understanding of the genetic basis of this disorder highlights fundamental β-cell mechanisms. We performed trio genome sequencing for 44 patients with PNDM and their unaffected parents to identify causative de novo variants. Replication studies were performed in 188 patients diagnosed with diabetes before 2 years of age without a genetic diagnosis. EIF2B1 (encoding the eIF2B complex α subunit) was the only gene with novel de novo variants (all missense) in at least three patients. Replication studies identified two further patients with de novo EIF2B1 variants. In addition to having diabetes, four of five patients had hepatitis-like episodes in childhood. The EIF2B1 de novo mutations were found to map to the same protein surface. We propose that these variants render the eIF2B complex insensitive to eIF2 phosphorylation, which occurs under stress conditions and triggers expression of stress response genes. Failure of eIF2B to sense eIF2 phosphorylation likely leads to unregulated unfolded protein response and cell death. Our results establish de novo EIF2B1 mutations as a novel cause of permanent diabetes and liver dysfunction. These findings confirm the importance of cell stress regulation for β-cells and highlight EIF2B1's fundamental role within this pathway.


[Studies and reports of Chinese cut crude drug's dosage in clinical prescription of (section of medical department)].
Study the actual dosage of clinical prescription in medical department of traditional Chinese medicine (TCM), and offer the consummate data for formulating the dosage standard of Chinese cut crude drug. We made use of the methods of stratified sampling and random sampling to investigate 269 882 broth prescriptions of Medical Department of TCM in 21 various hospitals, 18 provinces, and constructed the database, then applied Weka KDD software to analyze. We identified the frequency and clinical dosage intervals of 300 drugs, and the practical dosage of 155 drugs which dose has difference between in the actuality and in the pharmacopoeia. Most of drug's dosage centralized the four intervals: (3-6], (9-12], (12-15], (18-21], and the concrete dosage were 3, 6, 10, 12, 15, 20 g, etc. The dosages in the pharmacopoeia are not coincided with the practical dosages in internal medicine, and demand to revise. This paper will offer the consummate data for formulating the new dosage standard.


Th9 cells promote antitumor immune responses in vivo.
Th9 cells are a subset of CD4+ Th cells that produce the pleiotropic cytokine IL-9. IL-9/Th9 can function as both positive and negative regulators of immune response, but the role of IL-9/Th9 in tumor immunity is unknown. We examined the role of IL-9/Th9 in a model of pulmonary melanoma in mice. Lack of IL-9 enhanced tumor growth, while tumor-specific Th9 cell treatment promoted stronger antitumor responses in both prophylactic and therapeutic models. Th9 cells also elicited strong host antitumor CD8+ CTL responses by promoting Ccl20/Ccr6-dependent recruitment of DCs to the tumor tissues. Subsequent tumor antigen delivery to the draining LN resulted in CD8+ T cell priming. In agreement with this model, Ccr6 deficiency abrogated the Th9 cell-mediated antitumor response. Our data suggest a distinct role for tumor-specific Th9 cells in provoking CD8+ CTL-mediated antitumor immunity and indicate that Th9 cell-based cancer immunotherapy may be a promising therapeutic approach.


Clinical and cytogenetic features of a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias: rare T-cell receptor gene rearrangements are associated with poor outcome.
Clinical characteristics and cytogenetic aberrations were ascertained and reviewed in a population-based consecutive series of 285 pediatric T-cell acute lymphoblastic leukemias (T-ALLs) diagnosed between 1992 and 2006 in the Nordic countries. Informative karyotypic results were obtained in 249 (87%) cases, of which 119 (48%) were cytogenetically abnormal. Most (62%) of the aberrant T-ALLs were pseudodiploid. Structural changes were more common than numerical ones; 86% displayed at least one structural abnormality and 41% at least one numerical anomaly. The most frequent abnormalities were T-cell receptor (TCR) gene rearrangements (20%) [TCR;11p13 (10%), TCR;10q24 (3%), TCR;other (8%)], del(9p) (17%), +8 (14%), del(6q) (12%), and 11q23 rearrangements (6%). The TCR;other group comprised the rare rearrangements t(X;14)(p11;q11), t(X;7)(q22;q34), t(1;14)(p32;q11), ins(14;5)(q11;q?q?), inv(7)(p15q34), t(8;14)(q24;q11), t(7;11)(q34;p15), and t(12;14)(p13;q11). The clinical characteristics of this Nordic patient cohort agreed well with previous larger series, with a median age of 9.0 years, male predominance (male/female ratio 3.1), median white blood cell (WBC) count of 66.5 x 10(9)/l, and a high incidence of mediastinal mass and central nervous system involvement (59% and 9.5%, respectively). These features did not differ significantly among the various genetic subgroups. 5-year event-free survival (EFS) and overall survival for all patients were 0.61 (+/-0.03) and 0.67 (+/-0.03), respectively. In a multivariate analysis, two factors affected negatively the EFS, namely a WBC count of > or =200 x 10(9)/l (P < 0.001) and the presence of rare TCR rearrangements (P = 0.001). In conclusion, in this large series of childhood T-ALLs from the Nordic countries, the cytogenetic findings were not associated with risk of therapy failure with the exception of the TCR;other group. However, further prospective and collaborative investigations of this genetically heterogeneous entity are needed to confirm these results.


Closing the loop: physician communication with diabetic patients who have low health literacy.
Patients recall or comprehend as little as half of what physicians convey during an outpatient encounter. To enhance recall, comprehension, and adherence, it is recommended that physicians elicit patients' comprehension of new concepts and tailor subsequent information, particularly for patients with low functional health literacy. It is not known how frequently physicians apply this interactive educational strategy, or whether it is associated with improved health outcomes. We used direct observation to measure the extent to which primary care physicians working in a public hospital assess patient recall and comprehension of new concepts during outpatient encounters, using audiotapes of visits between 38 physicians and 74 English-speaking patients with diabetes mellitus and low functional health literacy. We then examined whether there was an association between physicians' application of this interactive communication strategy and patients' glycemic control using information from clinical and administrative databases. Physicians assessed recall and comprehension of any new concept in 12 (20%) of 61 visits and for 15 (12%) of 124 new concepts. Patients whose physicians assessed recall or comprehension were more likely to have hemoglobin A(1c) levels below the mean (< or = 8.6%) vs patients whose physicians did not (odds ratio, 8.96; 95% confidence interval, 1.1-74.9) (P =.02). After multivariate logistic regression, the 2 variables independently associated with good glycemic control were higher health literacy levels (odds ratio, 3.97; 95% confidence interval, 1.09-14.47) (P =.04) and physicians' application of the interactive communication strategy (odds ratio, 15.15; 95% confidence interval, 2.07-110.78) (P<.01). Primary care physicians caring for patients with diabetes mellitus and low functional health literacy rarely assessed patient recall or comprehension of new concepts. Overlooking this step in communication reflects a missed opportunity that may have important clinical implications.


The R3-carbon allotrope: a pathway towards glassy carbon under high pressure.
Pressure-induced bond type switching and phase transformation in glassy carbon (GC) has been simulated by means of Density Functional Theory (DFT) calculations and the Stochastic Quenching method (SQ) in a wide range of pressures (0-79 GPa). Under pressure, the GC experiences a hardening transition from sp- and sp(2)-type to sp(3)-type bonding, in agreement with previous experimental results. Moreover, a new crystalline carbon allotrope possessing R3 symmetry (R3-carbon) is predicted using the stochastic SQ method. The results indicate that R3-carbon can be regarded as an allotrope similar to that of amorphous GC. A very small difference in the heat of formation and the coherence of the radial and angular distribution functions of GC and the R3-carbon structure imply that small perturbations to this crystalline carbon allotrope may provide another possible amorphization pathway of carbon besides that of quenching the liquid melt or gas by ultra-fast cooling.


Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.
Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.


Validity of activity monitors in health and chronic disease: a systematic review.
The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n=118), with few carried out in patients with chronic diseases (n=16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (-12.07 (95%CI; -18.28 to -5.85) %) compared to triaxial (-6.85 (95%CI; -18.20 to 4.49) %, p=0.37) and were statistically significantly less accurate than multisensor devices (-3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity monitor and the activity monitor outcome. Triaxial and multisensor devices tend to be more valid monitors. Since activity monitors are less accurate at slow walking speeds and information about validated activity monitors in chronic disease populations is lacking, proper validation studies in these populations are needed prior to their inclusion in clinical trials.


Soluble CD14 in cerebrospinal fluid is associated with markers of inflammation and axonal damage in untreated HIV-infected patients: a retrospective cross-sectional study.
HIV-associated cognitive impairment has declined since the introduction of combination antiretroviral treatment (cART). However, milder forms of cognitive impairment persist. Inflammation in the cerebrospinal fluid (CSF) has been associated with cognitive impairment, and CSF neurofilament light chain protein (NFL) and CSF neopterin concentrations are increased in those patients. Microbial translocation in HIV infection has been suggested to contribute to chronic inflammation, and lipopolysaccharide (LPS) and soluble CD14 (sCD14) are markers of microbial translocation and the resulting monocyte activation, respectively. We hypothesised that microbial translocation contributes to inflammation and axonal damage in the central nervous system (CNS) in untreated HIV infection. We analyzed paired samples of plasma and CSF from 62 HIV-infected, untreated patients without cognitive symptoms from Sahlgrenska University Hospital, Gothenburg, Sweden. Measurements of neopterin and NFL in CSF were available from previous studies. Plasma and CSF sCD14 was measured using ELISA (R&D, Minneapolis, MN), and plasma and CSF LPS was measured using LAL colorimetric assay (Lonza, Walkersville, MD, USA). Univariate and multivariate regression analyses were performed. LPS in plasma was associated with plasma sCD14 (r = 0.31, P = 0.015), and plasma sCD14 was associated with CSF sCD14 (r = 0.32, P = 0.012). Furthermore, CSF sCD14 was associated with NFL (r = 0.32, P = 0.031) and neopterin (r = 0.32, P = 0.012) in CSF. LPS was not detectable in CSF. In a multivariate regression model CSF sCD14 remained associated with NFL and neopterin after adjusting for age, CD4+ cell count, and HIV RNA in CSF. In a group of untreated, HIV-infected patients LPS was associated with sCD14 in plasma, and plasma sCD14 was associated CSF sCD14. CSF sCD14 were associated with markers of CNS inflammation and axonal damage. This suggest that microbial translocation might be a driver of systemic and CNS inflammation. However, LPS was not detectable in the CSF, and since sCD14 is a marker of monocyte activation sCD14 may be increased due to other causes than microbial translocation. Further studies regarding cognitive impairment and biomarkers are warranted to fully understand causality.