Axillary hidradenitis.
The magnitude of the social, economic, and medical problems confronting patients with chronic suppurative axillary hidradenitis is not generally recognized. Nonoperative treatment is disappointing. Total excision of all apocrine-bearing axillary tissue with primary closure is the treatment of choice. Operative treatment can be safely accomplished even when draining sinuses are present. Twenty-six patients representing 47 operated axillae are presented.


A review of the cost-effectiveness of face-to-face behavioural interventions for smoking, physical activity, diet and alcohol.
To assess the evidence for the cost-effectiveness of health behaviour interventions that address the major behavioural risk factors for chronic disease, including smoking, physical inactivity, poor diet, and alcohol misuse. Medical and economic databases were searched for relevant economic evaluations. Studies were critically appraised using a published 35-point checklist, and the results are described using a narrative approach, noting methodological limitations. The review included 64 studies from 1995-2005, including 17 reports on multiple behaviour interventions. There was considerable variation among the studies by target populations, intervention components, primary outcomes, and economic methods, but the reported incremental cost-effectiveness ratios were consistently low (e.g. <14,000 Euros per quality-adjusted life-year gained for smoking-cessation programmes in 2006 Euros) as compared to certain preventive pharmaceutical and invasive interventions. Interventions targeting high-risk-population subgroups were relatively better value for money as compared to those targeting general populations. In general, the results of this review demonstrate favourable cost-effectiveness for smoking interventions, physical activity interventions and multiple behaviour interventions in high-risk groups. Although alcohol and dietary interventions appeared to be economically favourable, it is difficult to draw conclusions because of the variety in study outcomes. However, methodological limitations weaken the generalizability of findings, and suggest that the results of any given study should be considered carefully when being used to inform resource allocation.


Sulfur K-edge X-ray absorption spectroscopy and density functional theory calculations on superoxide reductase: role of the axial thiolate in reactivity.
Superoxide reductase (SOR) is a non-heme iron enzyme that reduces superoxide to peroxide at a diffusion-controlled rate. Sulfur K-edge X-ray absorption spectroscopy (XAS) is used to investigate the ground-state electronic structure of the resting high-spin and CN- bound low-spin FeIII forms of the 1Fe SOR from Pyrococcus furiosus. A computational model with constrained imidazole rings (necessary for reproducing spin states), H-bonding interaction to the thiolate (necessary for reproducing Fe-S bond covalency of the high-spin and low-spin forms), and H-bonding to the exchangeable axial ligand (necessary to reproduce the ground state of the low-spin form) was developed and then used to investigate the enzymatic reaction mechanism. Reaction of the resting ferrous site with superoxide and protonation leading to a high-spin FeIII-OOH species and its subsequent protonation resulting in H2O2 release is calculated to be the most energetically favorable reaction pathway. Our results suggest that the thiolate acts as a covalent anionic ligand. Replacing the thiolate with a neutral noncovalent ligand makes protonation very endothermic and greatly raises the reduction potential. The covalent nature of the thiolate weakens the FeIII bond to the proximal oxygen of this hydroperoxo species, which raises its pKa by an additional 5 log units relative to the pKa of a primarily anionic ligand, facilitating its protonation. A comparison with cytochrome P450 indicates that the stronger equatorial ligand field from the porphyrin results in a low-spin FeIII-OOH species that would not be capable of efficient H2O2 release due to a spin-crossing barrier associated with formation of a high-spin 5C FeIII product. Additionally, the presence of the dianionic porphyrin pi ring in cytochrome P450 allows O-O heterolysis, forming an FeIV-oxo porphyrin radical species, which is calculated to be extremely unfavorable for the non-heme SOR ligand environment. Finally, the 5C FeIII site that results from the product release at the end of the O2- reduction cycle is calculated to be capable of reacting with a second O2-, resulting in superoxide dismutase (SOD) activity. However, in contrast to FeSOD, the 5C FeIII site of SOR, which is more positively charged, is calculated to have a high affinity for binding a sixth anionic ligand, which would inhibit its SOD activity.


Transcriptomic study of ciprofloxacin resistance in Streptomyces coelicolor A3(2).
Soil organisms exhibit resistance to a wide range of antibiotics as they either need to protect themselves from endogenous antibiotics or from those present in their soil environment. The soil could serve as a reservoir for resistance mechanisms that have already emerged or have the potential to emerge in clinically important bacteria. Streptomyces coelicolor, a non-pathogenic soil-dwelling organism, is thus used as a model for the study of intrinsic resistance. Preliminary screening of several compounds showed that S. coelicolor had high intrinsic resistance for the fluoroquinolone group of antibiotics. We subjected the bacteria to sub-inhibitory concentrations of ciprofloxacin and studied the transcriptomic response using microarrays. The data were supported with various biochemical and phenotypic assays. Ciprofloxacin treatment leads to differential expression of many genes with enhanced mRNA expression of its target, DNA gyrase gene. High induction of DNA repair pathways was also observed and many transporters were upregulated. Ciprofloxacin was found to induce ROS formation in a dose dependent manner. Reduction of ROS via anti-oxidants increased the effective MIC of the drug in the bacteria. The regulation of antibiotic resistance in S. coelicolor was studied systematically and contribution of different mechanisms in the development of resistance was assessed. Our data suggest that multiple mechanisms work in coordination to facilitate the cell to combat the stress due to ciprofloxacin.


Bedside Rationing Under Resource Constraints-A National Survey of Ethiopian Physicians' Use of Criteria for Priority Setting.
In low-income settings resource constraints force clinicians to make harsh choices. We examine the criteria Ethiopian physicians use in their bedside rationing decisions through a national survey at 49 public hospitals in Ethiopia. Substantial variation in weight given to different criteria were reported by the 587 participating physicians (response rate 91.7%). Young age, primary prevention, or the patient being the family's economic provider increased likelihood of offering treatment to a patient, while small expected benefit or low chance of success diminished likelihood. More than 50% of responding physicians were indifferent to patient's position in society, unhealthy behavior, and residence, while they varied widely in weight they gave to patient's poverty, ability to work, and old age. While the majority of Ethiopian physicians reported allocation of resources that was compatible with national priorities, more contested criteria were also frequently reported. This might affect distributional justice and equity in health care access.


BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes.
To compare genetic test results for deleterious mutations of BRCA1 and BRCA2 with estimated probabilities of carrying such mutations; to assess sensitivity of genetic testing; and to assess the relevance of other susceptibility genes in familial breast and ovarian cancer. Data analyzed were from six high-risk genetic counseling clinics and concern individuals from families for which at least one member was tested for mutations at BRCA1 and BRCA2. Predictions of genetic predisposition to breast and ovarian cancer for 301 individuals were made using BRCAPRO, a statistical model and software using Mendelian genetics and Bayesian updating. Model predictions were compared with the results of genetic testing. Among the test individuals, 126 were Ashkenazi Jewish, three were male subjects, 243 had breast cancer, 49 had ovarian cancer, 34 were unaffected, and 139 tested positive for BRCA1 mutations and 29 for BRCA2 mutations. BRCAPRO performed well: for the 150 probands with the smallest BRCAPRO carrier probabilities (average, 29.0%), the proportion testing positive was 32.7%; for the 151 probands with the largest carrier probabilities (average, 95.2%), 78.8% tested positive. Genetic testing sensitivity was estimated to be at least 85%, with false-negatives including mutations of susceptibility genes heretofore unknown. BRCAPRO is an accurate counseling tool for determining the probability of carrying mutations of BRCA1 and BRCA2. Genetic testing for BRCA1 and BRCA2 is highly sensitive, missing an estimated 15% of mutations. In the populations studied, breast cancer susceptibility genes other than BRCA1 and BRCA2 either do not exist, are rare, or are associated with low disease penetrance.


CLC Chloride Channels and Transporters: Structure, Function, Physiology, and Disease.
CLC anion transporters are found in all phyla and form a gene family of eight members in mammals. Two CLC proteins, each of which completely contains an ion translocation parthway, assemble to homo- or heteromeric dimers that sometimes require accessory β-subunits for function. CLC proteins come in two flavors: anion channels and anion/proton exchangers. Structures of these two CLC protein classes are surprisingly similar. Extensive structure-function analysis identified residues involved in ion permeation, anion-proton coupling and gating and led to attractive biophysical models. In mammals, ClC-1, -2, -Ka/-Kb are plasma membrane Cl- channels, whereas ClC-3 through ClC-7 are 2Cl-/H+-exchangers in endolysosomal membranes. Biological roles of CLCs were mostly studied in mammals, but also in plants and model organisms like yeast and Caenorhabditis elegans. CLC Cl- channels have roles in the control of electrical excitability, extra- and intracellular ion homeostasis, and transepithelial transport, whereas anion/proton exchangers influence vesicular ion composition and impinge on endocytosis and lysosomal function. The surprisingly diverse roles of CLCs are highlighted by human and mouse disorders elicited by mutations in their genes. These pathologies include neurodegeneration, leukodystrophy, mental retardation, deafness, blindness, myotonia, hyperaldosteronism, renal salt loss, proteinuria, kidney stones, male infertility, and osteopetrosis. In this review, emphasis is laid on biophysical structure-function analysis and on the cell biological and organismal roles of mammalian CLCs and their role in disease.


Genetic basis of falling risk susceptibility in the UK Biobank Study.
Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual's fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (Pcombined ≤ 5 × 10-8). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics.


Hygiene hypothesis and autoimmune diseases.
Throughout the twentieth century, there were striking increases in the incidences of many chronic inflammatory disorders in the rich developed countries. These included autoimmune disorders such as Type 1 diabetes and multiple sclerosis. Although genetics and specific triggering mechanisms such as molecular mimicry and viruses are likely to be involved, the increases have been so rapid that any explanation that omits environmental change is incomplete. This chapter suggests that a series of environmental factors, most of them microbial, have led to a decrease in the efficiency of our immunoregulatory mechanisms because we are in a state of evolved dependence on organisms with which we co-evolved (and that had to be tolerated) as inducers of immunoregulatory circuits. These organisms ("Old Friends") are depleted from the modern urban environment. Rather than considering fetal programming by maternal microbial exposures, neonatal programming, the hygiene hypothesis, gut microbiota, and diet as separate and competing hypotheses, I attempt here to integrate these ideas under a single umbrella concept that can provide the missing immunoregulatory environmental factor that is needed to explain the recent increases in autoimmune disease.


Murine cytomegalovirus reactivation concomitant with acute graft-versus-host disease is controlled by antibodies.
Reactivation of human cytomegalovirus (HCMV) from latency is a frequent complication following hematopoietic stem cell transplantation (HSCT). The development of acute graft-versus-host disease (GVHD) is a significant risk factor for HCMV disease. Using a murine GVHD model in animals latently infected with murine CMV (MCMV), we studied preventive and therapeutic interventions in this high-risk scenario of HSCT. Mice latently infected with MCMV experienced reactivated MCMV and developed disseminated MCMV infection concomitant with the manifestations of GVHD. Dissemination was accompanied by accelerated mortality. We demonstrate that MCMV reactivation and dissemination was modulated by MCMV-specific antibodies, thus demonstrating in vivo protective activity of antiviral antibodies. However, the efficacy of serum therapy required repetitive doses of high-titer immune serum secondary to the shortened serum half-life of IgG in animals with GVHD. In a complementary approach, treatment of GVHD by adoptive transfer of donor-derived Tregs facilitated production of MCMV-specific antibodies from newly developing donor-derived B cells. Together, our findings strongly suggest that antibodies play a major role in controlling recurrent MCMV infection that follows GVHD, and they argue for reassessing the potential of antibody treatments as well as therapeutic strategies that enhance de novo antibody development against HCMV.


Alexithymia, Psychological Distress, and Social Impairment in Patients with Hidradenitis Suppurativa.
Hidradenitis suppurativa (HS) is a rare, chronic, inflammatory skin disease characterized by deep-seated nodules, abscesses, and draining fistulas. HS has a substantial adverse impact on patients' lives. Only a few studies investigated the relationship between health-related quality of life, psychological distress, and emotional dysregulation in patients with HS. Alexithymia, namely the difficulty in describing or recognizing emotions, has been associated with various psychological disorders, such as anxiety, depression, and psychological distress. The aim of this study was to examine the prevalence of alexithymia in patients with HS and its association with demographic and clinical variables, quality of life indices, and psychological distress. Ninety outpatients with HS completed the 20-item Toronto Alexithymia Scale, the 12-item General Health Questionnaire (GHQ-12), the Dermatology Life Quality Index, the Skindex-17, and the 36-Item Short-Form Health Survey. Information on sociodemographic and clinical variables was retrieved from clinical records. Alexithymia or borderline alexithymia was observed in 44.4% of patients with HS, with a higher prevalence of the alexithymic trait in women than in men (51.7 vs. 31.2%). We did not find any association between alexithymia and clinical variables. Of the entire sample analyzed, 46.1% reported high psychological distress; among them, 78% reported alexithymia or borderline alexithymia compared to 16.7% among GHQ noncases. Furthermore, HS patients with alexithymia or borderline alexithymia showed significantly higher scores on the Skindex-17 psychosocial scale and the Dermatology Life Quality Index, and a lower score on the mental component of the 36-item Short-Form Health Survey, than nonalexithymic patients. Dermatologists should consider alexithymia in the diagnosis and treatment of HS patients, given its important role in psychological and psychosocial distress.


STITCH 4: integration of protein-chemical interactions with user data.
STITCH is a database of protein-chemical interactions that integrates many sources of experimental and manually curated evidence with text-mining information and interaction predictions. Available at http://stitch.embl.de, the resulting interaction network includes 390 000 chemicals and 3.6 million proteins from 1133 organisms. Compared with the previous version, the number of high-confidence protein-chemical interactions in human has increased by 45%, to 367 000. In this version, we added features for users to upload their own data to STITCH in the form of internal identifiers, chemical structures or quantitative data. For example, a user can now upload a spreadsheet with screening hits to easily check which interactions are already known. To increase the coverage of STITCH, we expanded the text mining to include full-text articles and added a prediction method based on chemical structures. We further changed our scheme for transferring interactions between species to rely on orthology rather than protein similarity. This improves the performance within protein families, where scores are now transferred only to orthologous proteins, but not to paralogous proteins. STITCH can be accessed with a web-interface, an API and downloadable files.


Symptom severity 1 to 4 months after thoracotomy for lung cancer.
Information about the severity of symptoms during recovery from surgery for lung cancer can be useful in planning and anticipating needs for recovery. To describe symptom severity during the first 4 months after thoracotomy for non-small cell lung cancer and factors associated with overall symptom severity at 1 and 4 months. Ninety-four patients were assessed at 1, 2, and 4 months after thoracotomy by using the Lung Cancer Symptom Scale, Brief Pain Inventory, Schwartz Fatigue Scale, Dyspnea Index, and Center for Epidemiology Studies-Depression Scale (CES-D). Clinically meaningful changes, decrease in the proportion of patients with severe symptoms, and relationships among symptoms were determined. Mixed effects models for repeated measures were used to evaluate changes in severity. Multiple regression models were used to examine correlates of overall symptoms. Mean symptom severity significantly decreased over time for most symptoms. Only disrupted appetite, pain, and dyspnea had clinically meaningful improvement at 4 months. Severe symptoms included fatigue (57%), dyspnea (49%), cough (29%), and pain (20%). Prevalence of depressed mood decreased at 4 months. Most patients (77%) had comorbid conditions. Number of comorbid conditions and CES-D explained 54% of the variance in symptom severity at 1 month; comorbid conditions, male sex, neoadjuvant treatment, and CES-D score explained 50% of the variance at 4 months. Severe symptoms continued 4 months after surgery for some patients, indicating the need for support during recovery, especially for patients with multiple comorbid conditions and depressed mood.


Maintenance of large subpopulations of differentiated CD8 T-cells two years after cytomegalovirus infection in Gambian infants.
In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28(-)CD62L(-)Bcl-2(low)CD95(+)perforin(+)) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNgamma response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. CONCLUSIONS / SIGNIFICANCE: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant.


PDGF induction of alpha 2 integrin gene expression is mediated by protein kinase C-zeta.
Platelet-derived growth factor (PDGF) stimulates fibroblasts to move over collagen and contract three-dimensional collagen gels, processes important in wound repair and fibrocontractive diseases. These processes depend on alpha 2 beta 1 integrin ligation of collagen and PDGF induces the expression of this integrin. Several lines of evidence presented here suggest that PKC-zeta plays a role in alpha 2 integrin gene expression. The induction was blocked by chemical inhibitors for protein tyrosine kinases (PTK), genistein, and protein kinase C (PKC), chelerythrine, and bisindolylmaleimide GF 109203X. Cells depleted of phorbol 12-myristate 13-acetate (PMA)-inducible PKCs by chronic treatment with PMA still demonstrated an alpha 2 response to PDGF indicating that a non-PMA-sensitive PKC isoform was required. PDGF induced kinase activity in PKC-zeta immunoprecipitates. Antisense oligonucleotides complementary to 5' end of PKC-zeta mRNA sequences blocked the PDGF-induced increase of alpha 2 mRNA levels up to 70%, indicating PKC-zeta, a non-PMA-sensitive PKC isoform, is a component of the PDGF stimulatory pathway for alpha 2 mRNA synthesis. A 961-base pair (bp) upstream region of alpha 2 gene/CAT construct transfected into human dermal fibroblasts was positively regulated by PDGF as judged by CAT enzymatic levels. Both PTK and PKC inhibitors blocked PDGF-stimulation of the alpha 2 promoter fragment/CAT construct, indicating that the phosphorylation requirement occurred at alpha 2 promoter-directed transcription level. Therefore, we propose that PDGF-stimulatory pathway of alpha 2 integrin gene expression involves multiple cellular protein kinases, one of which is PKC-zeta.


Antidiabetic "gliptins" affect biofilm formation by Streptococcus mutans.
Streptococcus mutans, a dental caries causing odontopathogen, produces X-prolyl dipeptidyl peptidase (Sm-XPDAP, encoded by pepX), a serine protease known to have a nutritional role. Considering the potential of proteases as therapeutic targets in pathogens, this study was primarily aimed at investigating the role of Sm-XPDAP in contributing to virulence-related traits. Dipeptidyl peptidase (DPP IV), an XPDAP analogous enzyme found in mammalian tissues,is a well known therapeutic target in Type II diabetes. Based on the hypothesis that gliptins, commonly used as anti-human-DPP IV drugs, may affect bacterial growth upon inhibition of Sm-XPDAP, we have determined their ex vivo antimicrobial and anti-biofilm activity towards S. mutans. All three DPP IV drugs tested reduced biofilm formation as determined by crystal violet staining. To link the observed biofilm inhibition to the human-DPP IV analogue present in S. mutans UA159, a pepX isogenic mutant was generated. In addition to reduced biofilm formation, CLSM studies of the biofilm formed by the pepX isogenic mutant showed these were comparable to those formed in the presence of saxagliptin, suggesting a probable role of this enzyme in biofilm formation by S. mutans UA159. The effects of both pepX deletion and DPP IV drugs on the proteome were studied using LC-MS/MS. Overall, this study highlights the potential of Sm-XPDAP as a novel anti-biofilm target and suggests a template molecule to synthesize lead compounds effective against this enzyme.


[Headache].
Circadian rhythm has important implications in primary headache disorders. Migraine attacks are known to be triggered by either excess or lack of sleep. Cluster headache is clinically characterized by headache attacks that recur in chronologically similar patterns and the presence of the cluster period. Recent epidemiological data have disclosed that there is a tendency that migraine attacks occur during the daytime. A marked seasonal variation of attack frequency is noted in migraine with aura. Functional imaging and voxel-based morphometric assay revealed abnormalities in the hypothalamus in patients with cluster headache. Besides, the serum melatonin level is reduced in cluster headache. A polymorphism of the orexin receptor 2 gene has been identified as a risk factor for developing cluster headache. Orexin may be a key molecule closely implicated in both biological rhythm and nociception. As hypnic headache exhibits a strictly chronological pattern of headache attacks, this unique headache disorder is referred to also as "alarm clock headache". As with cluster headache, structural abnormalities of the hypothalamus have been detected by voxel-based morphometric assay. From the anatomical perspective, there are close fiber connections between the hypothalamus and the trigeminal nucleus caudalis, thus reinforcing the importance of diurnal rhythm disturbance in the pathophysiology of headache disorders.


Foot and ankle somatosensory deficits in children with cerebral palsy: A pilot study.
To investigate foot and ankle somatosensory function in children with cerebral palsy (CP). Ten children with spastic diplegia (age 15 ± 5 y; GMFCS I-III) and 11 typically developing (TD) peers (age 15 ± 10 y) participated in the study. Light touch pressure and two-point discrimination were assessed on the plantar side of the foot by using a monofilament kit and an aesthesiometer, respectively. The duration of vibration sensation at the first metatarsal head and medial malleolus was tested by a 128 Hz tuning fork. Joint position sense and kinesthesia in the ankle joint were also assessed. Children with CP demonstrated significantly higher light touch pressure and two-point discrimination thresholds compared to their TD peers. Individuals with CP perceived the vibration stimulus for a longer period compared to the TD participants. Finally, the CP group demonstrated significant impairments in joint position sense but not in kinesthesia of the ankle joints. These findings suggest that children with CP have foot and ankle tactile and proprioceptive deficits. Assessment of lower extremity somatosensory function should be included in clinical practice as it can guide clinicians in designing more effective treatment protocols to improve functional performance in CP.


Influence of prior influenza vaccination on antibody and B-cell responses.
Currently two vaccines, trivalent inactivated influenza vaccine (TIV) and live attenuated influenza vaccine (LAIV), are licensed in the USA. Despite previous studies on immune responses induced by these two vaccines, a comparative study of the influence of prior influenza vaccination on serum antibody and B-cell responses to new LAIV or TIV vaccination has not been reported. During the 2005/6 influenza season, we quantified the serum antibody and B-cell responses to LAIV or TIV in adults with differing influenza vaccination histories in the prior year: LAIV, TIV, or neither. Blood samples were collected on days 0, 7-9 and 21-35 after immunization and used for serum HAI assay and B-cell assays. Total and influenza-specific circulating IgG and IgA antibody secreting cells (ASC) in PBMC were detected by direct ELISPOT assay. Memory B cells were also tested by ELISPOT after polyclonal stimulation of PBMC in vitro. Serum antibody, effector, and memory B-cell responses were greater in TIV recipients than LAIV recipients. Prior year TIV recipients had significantly higher baseline HAI titers, but lower HAI response after vaccination with either TIV or LAIV, and lower IgA ASC response after vaccination with TIV than prior year LAIV or no vaccination recipients. Lower levels of baseline HAI titer were associated with a greater fold-increase of HAI titer and ASC number after vaccination, which also differed by type of vaccine. Our findings suggest that the type of vaccine received in the prior year affects the serum antibody and the B-cell responses to subsequent vaccination. In particular, prior year TIV vaccination is associated with sustained higher HAI titer one year later but lower antibody response to new LAIV or TIV vaccination, and a lower effector B-cell response to new TIV but not LAIV vaccination.


Indigenous Infant Mortality by Age and Season of Birth, 1800-1899: Did Season of Birth Affect Children's Chances for Survival?
This paper focuses on the influence of season of birth on infant mortality among the Sami and non-Sami populations in northern Sweden during the nineteenth century. The source material is a set of data files from the Demographic Data Base at Umeå University, making it possible to combine age at death (in days), month of death, and month of birth over the course of the entire century. Cox regression models reveal that for the first week of life, season of birth had no influence on the risk of mortality. For the Sami, the results showed that being born during winter was related to a higher risk of neonatal mortality, and being born during summer was related to a higher risk of mortality after six months of age. Furthermore, for the Sami, the neonatal mortality showed a U-shaped pattern with a minimum in June-August, whereas the corresponding pattern among the non-Sami was flatter. The findings shed light on vulnerability in two populations sharing the same environment, but diverging in terms of social, economic, and cultural factors.


2.4 g Mesalamine (Asacol 400 mg tablet) Once Daily is as Effective as Three Times Daily in Maintenance of Remission in Ulcerative Colitis: A Randomized, Noninferiority, Multi-center Trial.
The noninferiority of pH-dependent release mesalamine (Asacol) once daily (QD) to 3 times daily (TID) administration was investigated. This was a phase 3, multicenter, randomized, double-blind, parallel-group, active-control study, with dynamic and stochastic allocation using central registration. Patients with ulcerative colitis in remission (a bloody stool score of 0, and an ulcerative colitis disease activity index of ≤2), received the study drug (Asacol 2.4 g/d) for 48 weeks. The primary efficacy endpoint of the nonrecurrence rate was assessed on the full analysis set. The noninferiority margin was 10%. Six hundred and four subjects were eligible and were allocated; 603 subjects received the study drug. The full analysis set comprised 602 subjects (QD: 301, TID: 301). Nonrecurrence rates were 88.4% in the QD and 89.6% in the TID. The difference between nonrecurrence rates was -1.3% (95% confidence interval: -6.2, 3.7), confirming noninferiority. No differences in the safety profile were observed between the two treatment groups. On post hoc analysis by integrating the QD and the TID, nonrecurrence rate with a mucosal appearance score of 0 at determination of eligibility was significantly higher than the score of 1. The mean compliance rates were 97.7% in the QD and 98.1% in the TID. QD dosing with Asacol is as effective and safe as TID for maintenance of remission in patients with ulcerative colitis. Additionally, this study indicated that maintaining a good mucosal state is the key for longer maintenance of remission.


Clinically relevant characteristics associated with early treatment drug use versus abstinence.
This study describes early treatment drug use status and associated clinical characteristics in a diverse sample of patients entering outpatient substance abuse psychosocial counseling treatment. The goal is to more fully characterize those entering treatment with and without active use of their primary drug in order to better understand associated treatment needs and resilience factors. We examined baseline data from a NIDA Clinical Trials Network (CTN) study (Web-delivery of Treatment for Substance Use) with an all-comers sample of patients (N = 494) entering 10 outpatient treatment centers. Patients were categorized according to self-identified primary drug of abuse (alcohol, cocaine/stimulants, opioids, marijuana) and by baseline drug use status (positive/negative) based on urine testing or self-reports of recent use (alcohol). Characteristics were examined by primary drug and early use status. Classified as drug-negative were 84%, 76%, 62%, and 33% of primary opioid, stimulant, alcohol, and marijuana users; respectively. Drug-positive versus -negative patients did not differ on demographics or rates of substance abuse/dependence diagnoses. However, those negative for active use had better physical and mental health profiles, were less likely to be using a secondary drug, and were more likely to be attending 12-step self-help meetings. Early treatment drug abstinence is common among substance users entering outpatient psychosocial counseling programs, regardless of primary abused drug. Abstinence (by negative UA) is associated with better health and mental health profiles, less secondary drug use, and more days of 12-step attendance. These data highlight differential treatment needs and resiliencies associated with early treatment drug use status. NCT01104805.


A novel TMPRSS3 missense mutation in a DFNB8/10 family prevents proteolytic activation of the protein.
Pathogenic mutations in TMPRSS3, which encodes a transmembrane serine protease, cause non-syndromic deafness DFNB8/10. Missense mutations map in the low density-lipoprotein receptor A (LDLRA), scavenger-receptor cysteine-rich (SRCR), and protease domains of the protein, indicating that all domains are important for its function. TMPRSS3 undergoes proteolytic cleavage and activates the ENaC sodium channel in a Xenopus oocyte model system. To assess the importance of this gene in non-syndromic childhood or congenital deafness in Turkey, we screened for mutations affected members of 25 unrelated Turkish families. The three families with the highest LOD score for linkage to chromosome 21q22.3 were shown to harbor P404L, R216L, or Q398X mutations, suggesting that mutations in TMPRSS3 are a considerable contributor to non-syndromic deafness in the Turkish population. The mutant TMPRSS3 harboring the novel R216L missense mutation within the predicted cleavage site of the protein fails to undergo proteolytic cleavage and is unable to activate ENaC, thus providing evidence that pre-cleavage of TMPRSS3 is mandatory for normal function.


What is a cure and how do we get there?
The absence of adequate treatment for most of the world's 400 000 individuals with haemophilia makes the development of a cure compelling. Advances in the basic molecular sciences over the past 20 years have resulted in the feasibility of curing haemophilia through the application of gene therapy. However, the reality of this therapeutic strategy is highly complex. In addition, challenges to achieving a cure exist beyond the basic scientific hurdles. Thoughtful attention must also be given to a number of interrelated issues, including ethical considerations in patient recruitment, informed consent and geographical variables of global clinical trials. The global inequalities in healthcare mean that the ethics of international medical research, especially when it includes countries where people usually do not receive quality care, become much more complicated. The majority of haemophiliacs lives in developing countries and is a valuable resource of human subjects who could be enrolled in clinical trials. When recruiting subjects globally, investigators must be ever mindful that the patient population is a precious resource, which must be treated with respect and care. This presents a major challenge for investigators engaged in trials of haemophilia gene therapy to ensure that the informed consent process is current and comprehensive, that therapeutic misconceptions are appropriately managed, and that the roles of the researcher and physician are clear. Global clinical gene-therapy trials are an important and appropriate component in the quest to achieve a cure for haemophilia. When trials follow identical internationally accepted standards, a successful outcome can be achieved for trials including developing countries, if country specific cultural and economic aspects are considered.


Efficacy and Safety of the 3-Month Formulation of Paliperidone Palmitate vs Placebo for Relapse Prevention of Schizophrenia: A Randomized Clinical Trial.
Treatment nonadherence and relapse are common problems in patients with schizophrenia. The long-acting 3-month formulation of paliperidone palmitate, owing to its extended elimination half-life, may offer a valuable therapeutic option for these patients. To evaluate the efficacy and safety of the 3-month formulation of paliperidone palmitate vs placebo in delaying time to relapse of schizophrenia symptoms. This randomized, multicenter trial conducted from April 26, 2012, through April 9, 2014, in 8 countries consisted of 4 phases: 3-week screening phase, flexible-dose 17-week open-label transition phase, 12-week open-label maintenance phase, and open-ended double-blind (DB) phase. Of the 506 patients enrolled (aged 18-70 years; DSM-IV-TR diagnosis of schizophrenia), 305 were randomized to 3-month paliperidone palmitate (n = 160) or placebo (n = 145) in the DB phase. Patients received once-monthly doses of the 1-month formulation of paliperidone palmitate (50, 75, 100, or 150 mg eq) during the transition phase, followed by a single dose of the 3-month formulation (3.5 times the stabilized dose of once-monthly paliperidone palmitate) during the maintenance phase. Stabilized patients were randomized to receive either a fixed dose of 3-month paliperidone palmitate (175, 263, 350, or 525 mg eq) or placebo once every 3 months during the DB phase. Time from randomization to the first relapse event (time to relapse) in the DB phase. In the interim analysis, time to first relapse was significantly different in favor of the paliperidone palmitate group vs the placebo group (hazard ratio = 3.45; 95% CI, 1.73-6.88; P < .001); median time to relapse was 274 days for placebo but not estimable for 3-month paliperidone palmitate. An independent data monitoring committee recommended early study termination due to efficacy. In the DB phase, 183 of 305 patients (62% with 3-month paliperidone palmitate; 58% with placebo) had at least 1 treatment-emergent adverse event; those noted more frequently in the group receiving paliperidone palmitate than in the placebo group were headache (9% vs 4%), weight increased (9% vs 3%), nasopharyngitis (6% vs 1%), and akathisia (4% vs 1%). Compared with placebo, the 3-month formulation of paliperidone palmitate administered 4 times yearly significantly delayed time to relapse in patients with schizophrenia. The 3-month formulation was generally tolerable and has a safety profile consistent with other marketed paliperidone formulations. clinicaltrials.gov Identifier:NCT01529515.


Hyaluronan within fascia in the etiology of myofascial pain.
The layers of loose connective tissue within deep fasciae were studied with particular emphasis on the histochemical distribution of hyaluronan (HA). Samples of deep fascia together with the underlying muscles were taken from neck, abdomen and thigh from three fresh non-embalmed cadavers. Samples were stained with hematoxylin-eosin, Azan-Mallory, Alcian blue and a biotinylated HA-binding protein specific for HA. An ultrasound study was also performed on 22 voluntary subjects to analyze the thickness of these deep fasciae and their sublayers. The deep fascia presented a layer of HA between fascia and the muscle and within the loose connective tissue that divided different fibrous sublayers of the deep fascia. A layer of fibroblast-like cells that stained prominently with Alcian blue stain was observed. It was postulated that these are cells specialized for the biosynthesis of the HA-rich matrix. These cells we have termed "fasciacytes", and may represent a new class of cells not previously recognized. The ultrasound study highlighted a mean thickness of 1.88 mm of the fascia lata, 1.68 mm of the rectus sheath, and 1.73 mm of the sternocleidomastoid fascia. The HA within the deep fascia facilitates the free sliding of two adjacent fibrous fascial layers, thus promoting the normal function associated with the deep fascia. If the HA assumes a more packed conformation, or more generally, if the loose connective tissue inside the fascia alters its density, the behavior of the entire deep fascia and the underlying muscle would be compromised. This, we predict, may be the basis of the common phenomenon known as "myofascial pain."


Osteoradionecrosis of the mandibula in patients treated with different fractionations.
The incidence of osteonecrosis of the mandibula (ON) after irradiation using modern three-dimensional planning as well as hyperfractionation or moderately accelerated irradiation has been evaluated and compared with the incidence of the preceding period. The records of 268 head and neck cancer patients irradiated between January 1, 1980 and December 31, 1998 with a dose to the mandibula of at least 60 Gy were retrospectively analyzed. All patients had CT-based treatment planning, computerized dose calculation with isodose charts also in several off-axis planes, and regular verification films. The long-term cumulative incidence of ON needing mandibular resection was as follows: after conventional fractionation 6.2% (between 60 and 66.6 Gy target dose) or 20.1% (between > 66.6 and 72 Gy); after hyperfractionated irradiation with a target dose between 72 and 78.8 Gy 6.6%; after concomitant boost irradiation according to the MDA/Houston regime with a dose between 63.9 and 70.5 Gy: no case; after 6 x 2 Gy/week or 7 x 1.8 Gy/week and a total target dose between 66 and 72 Gy approximately 17% or higher (small patient number). Comparison of the incidence of ON during the period between 1980 and 1990 with the following period between 1990 and 1998 shows a decrease in risk to a value of approximately 5% using modern three-dimensional techniques as well as hyperfractionation or moderately accelerated fractionation.


Applied comparative anatomy of the avian middle ear.
The anatomy of the middle ear has been studied in nine species of birds, with particular reference to the structure of the ossicle and its relationship to the tympanic membrane. The morphology of the avian middle ear has been compared to that of the reconstructed human middle ear. Drum to stapes foot plate assemblies created during ossiculoplasty operations differ from the pattern found in the avian middle ear in a number of important respects and this may help to explain why they are often unsuccessful. It is not technically feasible to reproduce the avian middle ear pattern exactly in the human middle ear and developments in reconstructive technique should therefore be directed towards reproducing the three ossicle pattern of the mammalian ear.


Atomic structures of a bactericidal contractile nanotube in its pre- and postcontraction states.
R-type pyocins are representatives of contractile ejection systems, a class of biological nanomachines that includes, among others, the bacterial type VI secretion system (T6SS) and contractile bacteriophage tails. We report atomic models of the Pseudomonas aeruginosa precontraction pyocin sheath and tube, and the postcontraction sheath, obtained by cryo-EM at 3.5-Å and 3.9-Å resolutions, respectively. The central channel of the tube is negatively charged, in contrast to the neutral and positive counterparts in T6SSs and phage tails. The sheath is interwoven by long N- and C-terminal extension arms emanating from each subunit, which create an extensive two-dimensional mesh that has the same connectivity in the extended and contracted state of the sheath. We propose that the contraction process draws energy from electrostatic and shape complementarities to insert the inner tube through bacterial cell membranes to eventually kill the bacteria.


Genomic insights on heterogeneous resistance to vancomycin and teicoplanin in Methicillin-resistant Staphylococcus aureus: A first report from South India.
Methicillin-resistant Staphylococcus aureus (MRSA) infection is an important clinical concern in patients, and is often associated with significant disease burden and metastatic infections. There is an increasing evidence of heterogeneous vancomycin-intermediate S. aureus (hVISA) associated treatment failure. In this study, we aim to understand the molecular mechanism of teicoplanin resistant MRSA (TR-MRSA) and hVISA. A total of 482 MRSA isolates were investigated for these phenotypes. Of the tested isolates, 1% were identified as TR-MRSA, and 12% identified as hVISA. A highly diverse amino acid substitution was observed in tcaRAB, vraSR, and graSR genes in TR-MRSA and hVISA strains. Interestingly, 65% of hVISA strains had a D148Q mutation in the graR gene. However, none of the markers were reliable in differentiating hVISA from TR-MRSA. Significant pbp2 upregulation was noted in three TR-MRSA strains, which had teicoplanin MICs of 16 or 32 μg/ml, whilst significant pbp4 downregulation was not noted in these strains. In our study, multiple mutations were identified in the candidate genes, suggesting a complex evolutionary pathway involved in the development of TR-MRSA and hVISA strains.


Control of the synthesis of a major polypeptide of chloroplast membranes in Chlamydomonas reinhardi.
The regulation of the synthesis of one of the major polypeptides of chloroplast membranes in Chlamydomonas reinhardi y-1 has been studied in order to determine what factors are involved in the control mechanism. The polypeptide is synthesized in the cytoplasm and previously was designated as c (J. K Hoober. 1972. J. Cell Biol.52:84). Under normal conditions the synthesis of polypeptide c appears to be coupled to the synthesis of chlorophyll. When greening cells are illuminated through a light filter opaque below 675 mmicro, the conversion of protochlorophyllide to chlorophyllide is blocked. Although this elimination of light below 675 mmicro, does not affect, in the main, protein synthesis in the chloroplast and cytoplasm, synthesis of polypeptide c is inhibited. Also, control cells synthesize neither chlorophyll nor polypeptide c in the dark. However, when cells are treated with chloramphenicol, an inhibitor of chloroplast protein synthesis, the synthesis of polypeptide c occurs in the absence of light required for chlorophyll synthesis. Chlorophyll per se does not appear to be required for synthesis of polypeptide c, since treating cells with hemin, maleate, or malonate causes an inhibition of the synthesis of chlorophyll but not of polypeptide c. The results of these experiments are discussed in terms of a proposed mechanism by which synthesis of polypeptide c is regulated at the transcriptional level by a precursor of chlorophyll, and this regulation is mediated by a protein or proteins synthesized within the chloroplast.


'Do you trust those data?'-a mixed-methods study assessing the quality of data reported by community health workers in Kenya and Malawi.
High-quality data are essential to monitor and evaluate community health worker (CHW) programmes in low- and middle-income countries striving towards universal health coverage. This mixed-methods study was conducted in two purposively selected districts in Kenya (where volunteers collect data) and two in Malawi (where health surveillance assistants are a paid cadre). We calculated data verification ratios to quantify reporting consistency for selected health indicators over 3 months across 339 registers and 72 summary reports. These indicators are related to antenatal care, skilled delivery, immunization, growth monitoring and nutrition in Kenya; new cases, danger signs, drug stock-outs and under-five mortality in Malawi. We used qualitative methods to explore perceptions of data quality with 52 CHWs in Kenya, 83 CHWs in Malawi and 36 key informants. We analysed these data using a framework approach assisted by NVivo11. We found that only 15% of data were reported consistently between CHWs and their supervisors in both contexts. We found remarkable similarities in our qualitative data in Kenya and Malawi. Barriers to data quality mirrored those previously reported elsewhere including unavailability of data collection and reporting tools; inadequate training and supervision; lack of quality control mechanisms; and inadequate register completion. In addition, we found that CHWs experienced tensions at the interface between the formal health system and the communities they served, mediated by the social and cultural expectations of their role. These issues affected data quality in both contexts with reports of difficulties in negotiating gender norms leading to skipping sensitive questions when completing registers; fabrication of data; lack of trust in the data; and limited use of data for decision-making. While routine systems need strengthening, these more nuanced issues also need addressing. This is backed up by our finding of the high value placed on supportive supervision as an enabler of data quality.


Identification of ATR-Chk1 pathway inhibitors that selectively target p53-deficient cells without directly suppressing ATR catalytic activity.
Resistance to DNA-damaging chemotherapy is a barrier to effective treatment that appears to be augmented by p53 functional deficiency in many cancers. In p53-deficient cells in which the G1-S checkpoint is compromised, cell viability after DNA damage relies upon intact intra-S and G2-M checkpoints mediated by the ATR (ataxia telangiectasia and Rad3 related) and Chk1 kinases. Thus, a logical rationale to sensitize p53-deficient cancers to DNA-damaging chemotherapy is through the use of ATP-competitive inhibitors of ATR or Chk1. To discover small molecules that may act on uncharacterized components of the ATR pathway, we performed a phenotype-based screen of 9,195 compounds for their ability to inhibit hydroxyurea-induced phosphorylation of Ser345 on Chk1, known to be a critical ATR substrate. This effort led to the identification of four small-molecule compounds, three of which were derived from known bioactive library (anthothecol, dihydrocelastryl, and erysolin) and one of which was a novel synthetic compound termed MARPIN. These compounds all inhibited ATR-selective phosphorylation and sensitized p53-deficient cancer cells to DNA-damaging agents in vitro and in vivo. Notably, these compounds did not inhibit ATR catalytic activity in vitro, unlike typical ATP-competitive inhibitors, but acted in a mechanistically distinct manner to disable ATR-Chk1 function. Our results highlight a set of novel molecular probes to further elucidate druggable mechanisms to improve cancer therapeutic responses produced by DNA-damaging drugs.


Computerized screening for novel producers of Monascus-like food pigments in Penicillium species.
Monascus pigments have been used as natural food colorants in Asia for centuries. They are not authorized for use in the European Union and the United States mainly due to the risk of coproduction of the mycotoxin citrinin by Monascus spp. In the present study, we screened for novel producers of Monascus-like pigments from ascomycetous filamentous fungi belonging to Penicillium subgenus Biverticillium that are not reported to produce citrinin or any other known mycotoxins. The screening was carried out using the X-hitting algorithm as a tool to quickly screen through chromatographic sample data files of 22 different Penicillium extracts with 12 Monascus pigment extracts as controls. The algorithm searched for the most similar UV-vis spectra of the metabolites (cross hits) present in the pigment extracts to those of the selected reference metabolites viz. monascin, rubropunctatin, rubropunctamine, and citrinin. The cross hits were then manually identified on the basis of their UV-vis and mass spectra. X-hitting was found to be a good tool in the rapid screening of crude pigment extracts. Monascus pigments were discovered in the extracts of two closely related species of Penicillium that were only distantly related to the genus Monascus. Monascorubrin, xanthomonasin A, and threonine derivatives of rubropunctatin were identified in the extract of Penicillium aculeatum IBT 14263, and monascorubrin was identified in the extract of Penicillium pinophilum IBT 13104. None of the tested Penicillium extracts showed the presence of citrinin. Thus, the present study brought out two novel promising sources of yellow, orange, and purple-red Monascus-like food pigments in the species of Penicillia that do not produce citrinin and opened the door to look for several more new promising sources of natural food colorants in the species of Penicillia.


Validation of constitutively expressed bioluminescent Pseudomonas aeruginosa as a rapid microbiological quantification tool.
Whole cell biosensors have been extensively used for monitoring toxicity and contamination of various compounds and xenobiotics in environmental biology and microbial ecology; their application in the pharmaceutical and cosmetics industries has been limited. According to several pharmacopoeias, pharmaceutical products must be tested for microbial activity using traditional viable count techniques; the use of whole cell microbial biosensors potentially provides an alternative, fast, and efficient method. However there is a lack of a validated bioluminescence method. Prototype whole cell microbial biosensors have already been developed in Pseudomonas aeruginosa ATCC 9027. Validation of the bioluminescent strains was performed in accordance with the pharmacopoeia, Parenteral Drug Association and International Organisation of Standardisation. These strains demonstrated that the bioluminescent method was accurate, precise and equivalent, as compared with plate counting at a range of 10(3)-10(7) CFU/mL. Percentage recoveries using the bioluminescent method were between 70% and 130% for all bioluminescent strains and therefore the bioluminescent method was accurate according to the criteria set in PDA technical report 33. The method was also more precise (relative standard deviation less than 15%) than the traditional plate counting method or the ATP bioluminescent method. The lower limit of detection was 10(3) CFU/mL. Two-way ANOVA showed no significant difference between the traditional plate counting and the novel bioluminescent method for all bioluminescent strains. The bioluminescent constructs passed/exceeded pharmacopoeia-specified criteria for range, limit of detection, accuracy, precision and equivalence.


Reduced-resolution synthetic-discriminant-function design by multiresolution wavelet analysis.
Several approaches to the design of reduced-resolution synthetic discriminant functions (SDF's) using multiresolution wavelet analysis (MWA) techniques are investigated. In the first approach, reducedresolution approximations of a full-resolution SDF are obtained by MWA. In the second approach, reduced-resolution approximations of the training-image Fourier transforms are obtained by MWA, and a reduced-resolution SDF is obtained directly by training on these. For both approaches, reducedresolution MICE-SDF filters were designed with MWA and conventional down-sampling techniques. Simulations showed that filters designed by the second approach with MWA techniques permitted reductions in the number of filter pixels from 128 × 128 to 32 × 32, while still satisfying the design constraints. In comparison, the performances of 32 × 32 filters designed by conventional downsampling techniques were significantly degraded.


The meaning of acute kidney injury and its relevance to intensive care and anaesthesia.
Acute kidney injury (AKI) is the new consensus term for acute renal failure. The term describes a continuum of kidney injury, a common condition in the critically ill and after major surgery, which is associated with increased mortality. The incidence of AKI in intensive care unit patients in Australia is >30% and sepsis is a major contributory factor. However, there is limited knowledge about its incidence after major surgery, except for cardiac surgery. The creation of staged AKI classification systems (RIFLE [Risk, Injury, Failure, Loss, End-stage], Acute Kidney Injury Network and the new Kidney Disease: Improving Global Outcomes criteria) has accelerated progress in critical care nephrology research by showing that even small changes in serum creatinine are associated with increased risk of death and that this risk increases progressively with severity of AKI. Recent thought and research has cast doubt over previously accepted pathophysiological views of AKI. Moreover, terms such as 'prerenal azotaemia' and 'acute tubular necrosis' are now being challenged as lacking validity, having little supportive evidence and carrying limited clinical utility. In this review, we explore the limitations of animal and human models of AKI and the implications of recent research on our current understanding of the pathophysiology of AKI. In addition, we describe conventional and novel diagnostic methods and therapies, and explore the clinical implications of the effect of fluid administration and perioperative management. Finally, we identify priorities for clinical investigations and future directions in AKI research.


Multi-Omic Data Interpretation to Repurpose Subtype Specific Drug Candidates for Breast Cancer.
Triple-negative breast cancer (TNBC), which is largely synonymous with the basal-like molecular subtype, is the 5th leading cause of cancer deaths for women in the United States. The overall prognosis for TNBC patients remains poor given that few treatment options exist; including targeted therapies (not FDA approved), and multi-agent chemotherapy as standard-of-care treatment. TNBC like other complex diseases is governed by the perturbations of the complex interaction networks thereby elucidating the underlying molecular mechanisms of this disease in the context of network principles, which have the potential to identify targets for drug development. Here, we present an integrated "omics" approach based on the use of transcriptome and interactome data to identify dynamic/active protein-protein interaction networks (PPINs) in TNBC patients. We have identified three highly connected modules, EED, DHX9, and AURKA, which are extremely activated in TNBC tumors compared to both normal tissues and other breast cancer subtypes. Based on the functional analyses, we propose that these modules are potential drivers of proliferation and, as such, should be considered candidate molecular targets for drug development or drug repositioning in TNBC. Consistent with this argument, we repurposed steroids, anti-inflammatory agents, anti-infective agents, cardiovascular agents for patients with basal-like breast cancer. Finally, we have performed essential metabolite analysis on personalized genome-scale metabolic models and found that metabolites such as sphingosine-1-phosphate and cholesterol-sulfate have utmost importance in TNBC tumor growth.


Resolved versus Active Chronic Graft-versus-Host Disease: Impact on Post-Transplantation Quality of Life.
The aim of this study was to determine whether impaired quality of life (QOL) persisted among patients who experienced resolved chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). Eligible participants were patients who were relapse-free for 3 years after allo-HCT who were age ≥16 years at the time of transplantation and age ≥20 years without relapse at the time of the survey. The Medical Outcomes Study's 36-Item Short-Form Survey (SF-36), the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), and a visual analog scale (VAS) were administered to assess QOL. Physicians evaluated the current status of chronic GVHD at survey using National Institutes of Health (NIH) criteria, and pretransplantation characteristics and history of GVHD were extracted from the national transplant registry database. Patients without currently active GVHD but with a history of chronic GVHD were categorized as having "resolved GVHD." Of 1250 patients informed of the study, 1216 provided consent and 1130 were included in the final analysis. A total of 745 patients (66%) had currently active chronic GVHD, 149 (13%) had resolved chronic GVHD, and 236 (21%) never had chronic GVHD after allo-HCT. Multivariable analyses showed that compared with patients with resolved or no chronic GVHD, those with active chronic GVHD reported significantly poorer QOL. The QOL scores were similar in patients with resolved chronic GVHD and those without chronic GVHD. Greater between-group differences were observed in SF-36 Physical component and VAS scores in patients age ≥50 years, but the differences were not statistically significant. Our data indicate that only currently active chronic GVHD has a significant impact on physical, mental, and social QOL in allo-HCT survivors, whereas previous chronic GVHD does not impair QOL if it has been resolved.


One-dimensional topography underlies three-dimensional fibrillar cell migration.
Current concepts of cell migration were established in regular two-dimensional (2D) cell culture, but the roles of topography are poorly understood for cells migrating in an oriented 3D fibrillar extracellular matrix (ECM). We use a novel micropatterning technique termed microphotopatterning (microPP) to identify functions for 1D fibrillar patterns in 3D cell migration. In striking contrast to 2D, cell migration in both 1D and 3D is rapid, uniaxial, independent of ECM ligand density, and dependent on myosin II contractility and microtubules (MTs). 1D and 3D migration are also characterized by an anterior MT bundle with a posterior centrosome. We propose that cells migrate rapidly through 3D fibrillar matrices by a 1D migratory mechanism not mimicked by 2D matrices.


Do urinary tract infections affect morale among very old women?
Urinary tract infection (UTI) is among the most common bacterial infections in women of all ages but the incidence increases with older age. Despite the fact that UTI is a common problem it is still poorly investigated regarding its connection with experienced health and morale. The aim of this study was to explore the impact of a diagnosed, symptomatic urinary tract infection (UTI) with or without ongoing treatment on morale or subjective wellbeing among very old women. In a cross-sectional, population-based study, 504 women aged 85 years and older (range 84-104) were evaluated for ongoing UTI. Of these, 319 (63.3%), were able to answer the questions on the Philadelphia Geriatric Center Morale Scale (PGCMS) which was used to assess morale or subjective wellbeing. In the present study sample of 319 women, 46 (14.4%) were diagnosed as having had a UTI with or without ongoing treatment when they were assessed. Women with UTI with or without ongoing treatment had significantly lower PGCMS scores (10.4 vs 11.9, p = 0.003) than those without UTI, indicating a significant impact on morale or subjective wellbeing among very old women. Depression (p < 0.001), UTI (p = 0.014) and constipation (p = 0.018) were the medical diagnoses significantly and independently associated with low morale in a multivariate regression model. As UTI seems to be independently associated with low morale or poor subjective wellbeing, there needs to be more focus on prevention, diagnosis and treatment of UTI in old women.


Stage-Specific Transcriptome and Proteome Analyses of the Filarial Parasite Onchocerca volvulus and Its Wolbachia Endosymbiont.
Onchocerciasis (river blindness) is a neglected tropical disease that has been successfully targeted by mass drug treatment programs in the Americas and small parts of Africa. Achieving the long-term goal of elimination of onchocerciasis, however, requires additional tools, including drugs, vaccines, and biomarkers of infection. Here, we describe the transcriptome and proteome profiles of the major vector and the human host stages (L1, L2, L3, molting L3, L4, adult male, and adult female) of Onchocerca volvulus along with the proteome of each parasitic stage and of its Wolbachia endosymbiont (wOv). In so doing, we have identified stage-specific pathways important to the parasite's adaptation to its human host during its early development. Further, we generated a protein array that, when screened with well-characterized human samples, identified novel diagnostic biomarkers of O. volvulus infection and new potential vaccine candidates. This immunomic approach not only demonstrates the power of this postgenomic discovery platform but also provides additional tools for onchocerciasis control programs. The global onchocerciasis (river blindness) elimination program will have to rely on the development of new tools (drugs, vaccines, biomarkers) to achieve its goals by 2025. As an adjunct to the completed genomic sequencing of O. volvulus, we used a comprehensive proteomic and transcriptomic profiling strategy to gain a comprehensive understanding of both the vector-derived and human host-derived parasite stages. In so doing, we have identified proteins and pathways that enable novel drug targeting studies and the discovery of novel vaccine candidates, as well as useful biomarkers of active infection.


Recurrence of cervical intraepithelial lesions after thermo-coagulation in HIV-positive and HIV-negative Nigerian women.
The burden of cervical cancer remains huge globally, more so in sub-Saharan Africa. Effectiveness of screening, rates of recurrence following treatment and factors driving these in Africans have not been sufficiently studied. The purpose of this study therefore was to investigate factors associated with recurrence of cervical intraepithelial lesions following thermo-coagulation in HIV-positive and HIV-negative Nigerian women using Visual Inspection with Acetic Acid (VIA) or Lugol's Iodine (VILI) for diagnosis. A retrospective cohort study was conducted, recruiting participants from the cervical cancer "see and treat" program of IHVN. Data from 6 sites collected over a 4-year period was used. Inclusion criteria were: age ≥18 years, baseline HIV status known, VIA or VILI positive and thermo-coagulation done. Logistic regression was performed to examine the proportion of women with recurrence and to examine factors associated with recurrence. Out of 177 women included in study, 67.8 % (120/177) were HIV-positive and 32.2 % (57/177) were HIV-negative. Recurrence occurred in 16.4 % (29/177) of participants; this was 18.3 % (22/120) in HIV-positive women compared to 12.3 % (7/57) in HIV-negative women but this difference was not statistically significant (p-value 0.31). Women aged ≥30 years were much less likely to develop recurrence, adjusted OR = 0.34 (95 % CI = 0.13, 0.92). Among HIV-positive women, CD4 count <200cells/mm(3) was associated with recurrence, adjusted OR = 5.47 (95 % CI = 1.24, 24.18). Recurrence of VIA or VILI positive lesions after thermo-coagulation occurs in a significant proportion of women. HIV-positive women with low CD4 counts are at increased risk of recurrent lesions and may be related to immunosuppression.


Measurement of intraocular pressure (IOP) in chickens using a rebound tonometer: quantitative evaluation of variance due to position inaccuracies.
Intraocular pressure (IOP), an important risk factor for glaucoma, is a continuous trait determined by a complex set of genetic and environmental factors that are largely unknown. Genetic studies in laboratory animals may facilitate the identification of genes that affect IOP. We examined the use of the rebound tonometer for measuring IOP in non-anaesthetised birds, along with the device's robustness to alignment errors. Calibration curves were obtained by measuring the IOP of cannulated chicken eyes with the rebound tonometer over a range of pressures. To simulate different types of alignment errors that might be expected with measurement of IOP in alert chickens, for some calibrations the tonometer was positioned (1) at various distances from the cornea, (2) laterally displaced from the visual axis, or (3) angled away from the visual axis. In vivo measurements were taken on three-week-old alert chickens from a layer line, a broiler line, and a layer-broiler "advanced intercross line" (AIL) designed to facilitate QTL mapping. The rebound tonometer showed excellent linearity (R2=0.95-0.99) during calibration, as well as robustness to variation in the probe-to-cornea distance over the range 3-5mm and to lateral displacement over the range 0-2mm. However, the tonometer appeared less robust to off-axis misalignment over the range 0-20 degrees (P<0.05). Also, the slope of calibration curves sometimes differed between eyes (P<0.001), presumably reflecting differences in ocular structure. The IOP measured in non-anaesthetised three-week-old AIL chickens was 17.51+/-0.13 mmHg (mean+/-S.E.; N=105 birds). IOP was significantly associated with corneal thickness (P<0.05) and body weight (P<0.001) in a regression model. Replicate measurements were necessary in order to gauge IOP accurately in individual birds; a series of seven tonometry sessions over a 12-h period during the light phase of the light/dark cycle permitted IOP to be measured with a 95% CI of +/-0.7 mmHg. IOP did not differ significantly between the broiler and layer chicken lines which served as the progenitor lines for the AIL. In conclusion, the rebound tonometer permits rapid estimation of IOP in chickens and is well tolerated. The small alignment errors that are expected when taking measurements in non-anaesthetised animals are unlikely to affect accuracy. Since high IOP is a major risk factor for glaucoma, identifying QTL controlling IOP may offer future health benefits. However, our preliminary findings highlight several obstacles to mapping such QTL using the chicken advanced intercross line evaluated here.


Metabolic patterns across core features in dementia with lewy bodies.
To identify brain regions whose metabolic impairment contributes to dementia with Lewy bodies (DLB) clinical core features expression and to assess the influence of severity of global cognitive impairment on the DLB hypometabolic pattern. Brain fluorodeoxyglucose positron emission tomography and information on core features were available in 171 patients belonging to the imaging repository of the European DLB Consortium. Principal component analysis was applied to identify brain regions relevant to the local data variance. A linear regression model was applied to generate core-feature-specific patterns controlling for the main confounding variables (Mini-Mental State Examination [MMSE], age, education, gender, and center). Regression analysis to the locally normalized intensities was performed to generate an MMSE-sensitive map. Parkinsonism negatively covaried with bilateral parietal, precuneus, and anterior cingulate metabolism; visual hallucinations (VH) with bilateral dorsolateral-frontal cortex, posterior cingulate, and parietal metabolism; and rapid eye movement sleep behavior disorder (RBD) with bilateral parieto-occipital cortex, precuneus, and ventrolateral-frontal metabolism. VH and RBD shared a positive covariance with metabolism in the medial temporal lobe, cerebellum, brainstem, basal ganglia, thalami, and orbitofrontal and sensorimotor cortex. Cognitive fluctuations negatively covaried with occipital metabolism and positively with parietal lobe metabolism. MMSE positively covaried with metabolism in the left superior frontal gyrus, bilateral-parietal cortex, and left precuneus, and negatively with metabolism in the insula, medial frontal gyrus, hippocampus in the left hemisphere, and right cerebellum. Regions of more preserved metabolism are relatively consistent across the variegate DLB spectrum. By contrast, core features were associated with more prominent hypometabolism in specific regions, thus suggesting a close clinical-imaging correlation, reflecting the interplay between topography of neurodegeneration and clinical presentation in DLB patients. Ann Neurol 2019;85:715-725.


Current role of microwave ablation in the treatment of small hepatocellular carcinomas.
Percutaneous radiofrequency ablation (RFA) can be as effective as surgical resection in terms of overall survival and recurrence-free survival rates in patients with small hepatocellular carcinoma (HCC). Effectiveness of RFA is adversely influenced by heat-sink effect. Other ablative therapies could be considered for larger tumors or for tumors located near the vessels. In this regard, recent improvements in microwave energy delivery systems seem to open interesting perspectives to percutaneous ablation, which could become the ablation technique of choice in the near future. Microwave ablation (MWA) has the advantages of possessing a higher thermal efficiency. It has high efficacy in coagulating blood vessels and is a relatively fast procedure. The time required for ablation is short and the shape of necrosis is elliptical with the older systems and spherical with the new one. There is no heat-sink effect and it can be used to ablate tumors adjacent to major vessels. These factors yield a large ablation volume, and result in good local control and fewer complications. This review highlights the most relevant updates on MWA in the treatment of small (<3 cm) HCC. Furthermore, we discuss the possibility of MWA as the first ablative choice, at least in selected cases.


Sustained efficacy and safety of bazedoxifene in preventing fractures in postmenopausal women with osteoporosis: results of a 5-year, randomized, placebo-controlled study.
In this 2-year extension of a 3-year study, bazedoxifene showed sustained efficacy in preventing new vertebral fractures in postmenopausal women with osteoporosis and in preventing non-vertebral fractures in higher-risk women. Bazedoxifene significantly increased bone mineral density and reduced bone turnover versus placebo and was generally safe and well tolerated. This study evaluated the efficacy and safety of bazedoxifene for the treatment of postmenopausal osteoporosis over 5 years. A total of 4,216 postmenopausal women with osteoporosis were enrolled in this 2-year extension of a 3-year, randomized, double-blind, placebo-controlled, phase 3 trial. In the core study (N = 7,492), subjects received bazedoxifene 20 or 40 mg/day, raloxifene 60 mg/day, or placebo. The raloxifene arm was discontinued after 3 years; subjects receiving bazedoxifene 40 mg were transitioned to bazedoxifene 20 mg after 4 years. Five-year findings are reported for bazedoxifene 20 and 40/20 mg and placebo. Endpoints included incidence of new vertebral fractures (primary) and non-vertebral fractures, and changes in bone mineral density (BMD) and bone turnover markers. At 5 years, the incidence of new vertebral fractures in the intent-to-treat population was significantly lower with bazedoxifene 20 mg (4.5%) and 40/20 mg (3.9%) versus placebo (6.8%; P < 0.05), with relative risk reductions of 35% and 40%, respectively. Non-vertebral fracture incidence was similar among groups. In a subgroup of higher-risk women (n = 1,324; femoral neck T-score ≤-3.0 and/or ≥ 1 moderate or severe or ≥ 2 mild vertebral fracture[s]), bazedoxifene 20 mg reduced non-vertebral fracture risk versus placebo (37%; P = 0.06); combined data for bazedoxifene 20 and 40/20 mg reached statistical significance (34% reduction; P < 0.05). Bazedoxifene significantly increased BMD and reduced bone turnover versus placebo (P < 0.05) and was generally safe and well tolerated. The findings support a sustained anti-fracture effect of bazedoxifene on new vertebral fractures in postmenopausal osteoporotic women and on non-vertebral fractures in the higher-risk subgroup of women.


Prospective cognition in rats.
Efforts to develop animal models of memory are critical for understanding the neural substrate of memory. Memory is essential for daily life and enables information to be stored and retrieved after seconds to years. The ability to remember episodes from the past is thought to be related to the ability to plan for the future. Here we focus on a particular aspect of prospective cognition, namely the ability to remember to take action when a future scenario occurs. This review focuses on a recently developed method to evaluate prospective memory in the rat. Available evidence suggests that rats remember to take action in the future, but little is known about the temporal specificity of such memories or about the flexibility and limitations of prospective memories. Recent studies that suggest that rats remember a specific past episode are reviewed to underscore potential approaches that may be used to explore the range and limits of prospective cognition. The review highlights some directions to explore, including the temporal specificity of prospective cognition, the range of flexibility or creativity within prospective cognition, and the constraints imposed by multiple motivational systems.


A Mouse Model for Binge-Level Methamphetamine Use.
Binge/crash cycles of methamphetamine (MA) use are frequently reported by individuals suffering from MA use disorders. A MA binge is self-reported as multiple daily doses that commonly accumulate to 800 mg/day (~10 mg/kg/day for a 170 pound human). A genetic animal model with a similar vulnerability to binge-level MA intake is missing. We used selectively bred MA high drinking (MAHDR) and low drinking (MALDR) mouse lines to determine whether several procedural variations would result in binge-level MA intake. Data were also collected in two progenitor populations of the MA drinking lines, the DBA/2J (D2) strain and the F2 cross of the D2 and C57BL/6J strains. The impact of 3 factors was examined: (1) concentration of MA in the two-bottle choice procedure used for selective breeding; (2) ratio of bottles containing MA vs. water, and (3) length of the withdrawal (or abstinence) period between MA drinking sessions. When MA concentration was progressively increased every 4 days in 20 mg/l amounts from 20 to 140 mg/l, maximum intake in MALDR mice was 1.1 mg/kg, whereas MAHDR mice consumed as much as 14.6 mg/kg. When these concentrations were tested in a multiple bottle choice procedure, the highest ratio of MA to water bottles (3:1) was associated with escalated MA intake of up to 29.1 mg/kg in MAHDR mice and 12.0 mg/kg in F2 mice; MALDR mice did not show a ratio-dependent escalation in MA intake. Finally, MAHDR and D2 mice were offered 3 bottles of MA vs. water at increasing concentrations from 20 to 80 mg/l, and tested under an intermittent 6-h withdrawal period, which was lengthened to 30 h (D2 mice) or to 30 or 78 h (MAHDR). D2 and MAHDR mice initially consumed similar amounts of 14-16 mg/kg MA, but D2 mice reduced their MA intake 3-fold after introduction of 30-h abstinence periods, whereas MAHDR mice retained their high level of intake regardless of withdrawal period. MAHDR mice provide a genetic model of binge-level MA intake appropriate for the study of associated MA-induced neurobiological changes and pharmaceutical treatments.


An intelligent health monitoring and diagnosis system based on the internet of things and fuzzy logic for cardiac arrhythmia COVID-19 patients.
During the COVID-19 pandemic, there is a global demand for intelligent health surveillance and diagnosis systems for patients with critical conditions, particularly those with severe heart diseases. Sophisticated measurement tools are used in hospitals worldwide to identify serious heart conditions. However, these tools need the face-to-face involvement of healthcare experts to identify cardiac problems. To design and implement an intelligent health monitoring and diagnosis system for critical cardiac arrhythmia COVID-19 patients. We use artificial intelligence tools divided into two parts: (i) IoT-based health monitoring; and (ii) fuzzy logic-based medical diagnosis. The intelligent diagnosis of heart conditions and IoT-based health surveillance by doctors is offered to critical COVID-19 patients or isolated in remote locations. Sensors, cloud storage, as well as a global system for mobile texts and emails for communication with doctors in case of emergency are employed in our proposal. Our implemented system favors remote areas and isolated critical patients. This system utilizes an intelligent algorithm that employs an ECG signal pre-processed by moving through six digital filters. Then, based on the processed results, features are computed and assessed. The intelligent fuzzy system can make an autonomous diagnosis and has enough information to avoid human intervention. The algorithm is trained using ECG data from the MIT-BIH database and achieves high accuracy. In real-time validation, the fuzzy algorithm obtained almost 100% accuracy for all experiments. Our intelligent system can be helpful in many situations, but it is particularly beneficial for isolated COVID-19 patients who have critical heart arrhythmia and must receive intensive care.


School-age outcomes in children who were extremely low birth weight from four international population-based cohorts.
The aim of this study was to determine whether learning and school problems in extremely low birth weight (ELBW) and reference children differ between cohorts in different countries. Participants were 4 international population-based cohorts of ELBW survivors who were 500 to 1000 g birth weight from New Jersey, central-west Ontario, Bavaria, and Holland (n = 532) and were followed longitudinally from birth. Psychometric data were collected independently and prospectively and included at least 1 measure of cognitive status and 1 measure of achievement administered to the children between the ages of 8 and 11 years. Adjustments were made for comparison of all measures based on reference norms within each country. Information on special educational assistance and grade repetition was obtained from the parents. The overall follow-up rate was 84% (range: 74%-90%; n = 436). The proportion of children who performed within the normal range (> or =85) were as follows: IQ between 44% and 62%; reading between 46% and 81%; arithmetic between 31% and 76%; and spelling between 39% and 65%. Children from New Jersey had the lowest rates of cognitive and achievement deficits, and Bavarian children did less well in achievement scores relative to their peers and other cohorts. Despite these differences, more than half of all cohorts required special educational assistance and/or repeated a grade. School difficulties were found to be a serious sequelae of ELBW in all 4 countries, an observation that has social and economic implications.


Mechanisms of increased susceptibility to angiotensin II-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats.
Previous findings have shown that hypotensive doses of losartan prevent the excess of apoptosis present in the hypertrophied left ventricle of adult spontaneously hypertensive rats (SHR). This study was designed to determine whether angiotensin II facilitates apoptosis in cardiomyocytes of adult SHR. Primary cultures of ventricular cardiomyocytes from 30-week-old normotensive Wistar-Kyoto rats (WKY) and SHR with left ventricular hypertrophy were exposed to 10(-)(9) mol/L angiotensin II for 24 hours. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase assay and confirmed by Annexin V detection. The expression of Bax-alpha, Bcl-2, p53, and caspase-3 proteins was assessed by Western blot assays. The expression of BAX gene was assessed by Northern blot. Angiotensin II increased (P<0.01) cardiomyocyte apoptosis, and this effect was higher (P<0.001) in SHR cells than in WKY cells. Whereas losartan (10(-7) mol/L) blocked the apoptotic effect of the octapeptide in cells from the two strains of rats, PD123319 (10(-7) mol/L) inhibited angiotensin II-mediated apoptosis only in SHR cells. Angiotensin II stimulated (P<0.01) Bax-alpha protein, and this effect was higher (P<0.01) in SHR cells than in WKY cells. Angiotensin II did not modify Bcl-2, p53, and BAX mRNA in cells from the two strains of rats. Angiotensin II induced a similar increase (P<0.05) in the ratio caspase-3/procaspase-3 (an index of caspase-3 activation) in cardiomyocytes from the two strains of rats. The present in vitro results indicate that SHR cardiomyocytes exhibit enhanced susceptibility to angiotensin II-induced apoptosis. Ligand binding to angiotensin II type 1 and type 2 receptors leading to changes in posttranscriptional processing of Bax-alpha and accumulation of this proapoptotic protein may be involved in the abnormal response of SHR cardiomyocytes. These data support a role for angiotensin II in apoptosis observed in the left ventricle of these rats.


Superiority of PC-SOD to other anti-COPD drugs for elastase-induced emphysema and alteration in lung mechanics and respiratory function in mice.
Bronchodilators (such as ipratropium bromide), steroids (such as fluticasone propionate), and newly developed anti-inflammatory drugs (such as roflumilast) are used for patients with chronic obstructive pulmonary disease (COPD). We recently reported that lecithinized superoxide dismutase (PC-SOD) confers a protective effect in mouse models of COPD. We here examined the therapeutic effect of the combined administration of PC-SOD with ipratropium bromide on pulmonary emphysema and compared the effect of PC-SOD to other types of drugs. The severity of emphysema in mice was assessed by various criteria. Lung mechanics (elastance) and respiratory function (ratio of forced expiratory volume in the first 0.05 s to forced vital capacity) were assessed. Administration of PC-SOD by inhalation suppressed elastase-induced pulmonary emphysema, alteration of lung mechanics, and respiratory dysfunction. The concomitant intratracheal administration of ipratropium bromide did not alter the ameliorating effects of PC-SOD. Administration of ipratropium bromide, fluticasone propionate, or roflumilast alone did not suppress the elastase-induced increase in the pulmonary level of superoxide anion, pulmonary inflammatory response, pulmonary emphysema, alteration of lung mechanics, or respiratory dysfunction as effectively as did PC-SOD. PC-SOD, but not the other drugs, showed a therapeutic effect even when the drug was administered after the development of emphysema. PC-SOD also suppressed the cigarette smoke-induced pulmonary inflammatory response and increase in airway resistance. Based on these results, we consider that the inhalation of PC-SOD would be therapeutically beneficial for COPD.


Exfoliatin-producing strains define a fourth agr specificity group in Staphylococcus aureus.
The staphylococcal virulon is activated by the density-sensing agr system, which is autoinduced by a short peptide (autoinducing peptide [AIP]) processed from a propeptide encoded by agrD. A central segment of the agr locus, consisting of the C-terminal two-thirds of AgrB (the putative processing enzyme), AgrD, and the N-terminal half of AgrC (the receptor), shows striking interstrain variation. This finding has led to the division of Staphylococcus aureus isolates into three different agr specificity groups and to the division of non-aureus staphylococci into a number of others. The AIPs cross-inhibit the agr responses between groups. We have previously shown that most menstrual toxic shock strains belong to agr specificity group III but that no strong clinical identity has been associated with strains of the other two groups. In the present report, we demonstrate a fourth agr specificity group among S. aureus strains and show that most exfoliatin-producing strains belong to this group. A striking common feature of group IV strains is activation of the agr response early in exponential phase, at least 2 h earlier than in strains of the other groups. This finding raises the question of the biological significance of the agr autoinduction threshold.


Evolution of life cycle, colony morphology, and host specificity in the family Hydractiniidae (Hydrozoa, Cnidaria).
Biased transitions are common throughout the tree of life. The class hydrozoa is no exception, having lost the feeding medusa stage at least 70 times. The family hydractiniidae includes one lineage with pelagic medusae (Podocoryna) and several without (e.g., Hydractinia). The benthic colony stage also varies widely in host specificity and in colony form. The five-gene phylogeny presented here requires multiple transitions between character states for medusae, host specificity, and colony phenotype. Significant phylogenetic correlations exist between medusoid form, colony morphology, and host specificity. Species with nonfeeding medusae are usually specialized on a single host type, and reticulate colonies are correlated with nonmotile hosts. The history of feeding medusae is less certain. Podocoryna is nested within five lineages lacking medusae. This requires either repeated losses of medusae, or the remarkable re-evolution of a feeding medusa after at least 150 million years. Traditional ancestral reconstruction favors medusa regain, but a likelihood framework testing biased transitions cannot distinguish between multiple losses versus regain. A hypothesis of multiple losses of feeding medusae requires transient selection pressure favoring such a loss. Populations of species with feeding medusae are always locally rare and lack of feeding medusae does not result in restricted species distribution around the world.


Cyclin E expression is correlated with tumor progression and predicts a poor prognosis in patients with ovarian carcinoma.
Cyclins, cyclin dependent kinases (cdks), and their inhibitors act in combination to regulate progression through the cell cycle and often are dysregulated in carcinoma. The authors hypothesized that cyclin E plays an important role in ovarian carcinogenesis and that its overexpression may be an indicator of a poor prognosis. Immunohistochemical analysis of cyclin E expression was performed by image analysis in normal ovaries, cystadenomas, tumors of low malignant potential, and 405 primary ovarian carcinomas by using tissue microarray technology. Overexpression of cyclin E was found in 63.2% of the samples and was associated with clear cell, poorly differentiated, and serous carcinoma (P < or = .001), high-grade tumors (P < or = .001), late-stage disease (P = .002), age older than 60 years at the time of diagnosis (P = .04), and suboptimal cytoreduction (P = .001). A high percentage of cyclin E-expressing cells was associated with a poor outcome in univariate and in multivariate analyses. In addition, cyclin E levels also reduced survival in the late-stage disease group and in patients who underwent suboptimal debulking. Cyclin E was identified as an independent prognostic factor in patients with ovarian carcinoma. The accumulation of cyclin E protein may be a late event in tumorigenesis and may contribute to disease progression in these patients.


AC/DC Thermal Nano-Analyzer Compatible with Bulk Liquid Measurements.
Nanocalorimetry, or thermal nano-analysis, is a powerful tool for fast thermal processing and thermodynamic analysis of materials at the nanoscale. Despite multiple reports of successful applications in the material sciences to study phase transitions in metals and polymers, thermodynamic analysis of biological systems in their natural microenvironment has not been achieved yet. Simply scaling down traditional calorimetric techniques, although beneficial for material sciences, is not always appropriate for biological objects, which cannot be removed out of their native biological environment or be miniaturized to suit instrument limitations. Thermal analysis at micro- or nano-scale immersed in bulk liquid media has not yet been possible. Here, we report an AC/DC modulated thermal nano-analyzer capable of detecting nanogram quantities of material in bulk liquids. The detection principle used in our custom-build instrument utilizes localized heat waves, which under certain conditions confine the measurement area to the surface layer of the sample in the close vicinity of the sensing element. To illustrate the sensitivity and quantitative capabilities of the instrument we used model materials with detectable phase transitions. Here, we report ca. 106 improvement in the thermal analysis sensitivity over a traditional DSC instrument. Interestingly, fundamental thermal properties of the material can be determined independently from heat flow in DC (direct current) mode, by using the AC (alternating current) component of the modulated heat in AC/DC mode. The thermal high-frequency AC modulation mode might be especially useful for investigating thermal transitions on the surface of material, because of the ability to control the depth of penetration of AC-modulated heat and hence the depth of thermal sensing. The high-frequency AC mode might potentially expand the range of applications to the surface analysis of bulk materials or liquid-solid interfaces.


Accelerating the health literacy agenda in Europe.
Health literacy can be defined as the knowledge, motivation and competence to access, understand, appraise and apply information to make decisions in terms of healthcare, disease prevention and health promotion. Health literacy is a European public health challenge that has to be taken seriously by policy-makers. It constitutes an emerging field for policy, research and practice. However, recent research has shown that health literacy advancement is still at its infancy in Europe, as reflected in the scarce scientific health literacy literature published by European authors. From a total of 569 articles published until 2011 on this subject, the first author of only 15% of them is from Europe. This article conveys recommendations of different European stakeholders on how to accelerate the health literacy agenda in Europe. A general introduction on the current status of health literacy is provided, followed by two cases applying health literacy in the areas of prevention of communicable diseases and promotion of digital health. The current EU strategies integrating health literacy are listed, followed by examples of challenges threatening the further development of health literacy in Europe. Recommendations as to how European stakeholders involved in research, policy, practice and education can promote health literacy are given. It is vital that the European Commission as well as European Union Member States take the necessary steps to increase health literacy at individual, organizational, community, regional and national levels.


Functional observational battery comparing effects of ethanol, 1,1,1-trichloroethane, ether, and flurothyl.
Several recent reports have demonstrated that acute solvent exposure in animals produces a profile of neurobehavioral effects similar to that of classical CNS depressant drugs such as the barbiturates and ethanol. The present investigation further delineated the behavioral pharmacology of three solvents [1,1,1-trichloroethane (TCE), ether, and flurothyl] using a functional observational battery (FOB) composed of 21 qualitative and quantitative measures of behavior. The profiles of acute effects produced by TCE and ether were similar to one another and similar to the profile of effects produced by the IP administration of ethanol. This profile of depressant effects included changes in posture, decreased arousal, disturbances in gait, decreased forelimb grip strength, increased landing foot splay, and impaired psychomotor coordination. Flurothyl exposure also produced dose-related effects on many of the measures in the FOB; however, unlike the depressant vapors, flurothyl did not affect measures of muscle tone and equilibrium such as forelimb grip strength and landing foot splay, or measures of sensorimotor reactivity, including the touch response and tail pinch response. In addition, flurothyl produced handling-induced convulsions in some mice. Recovery from the acute effects of these vapors was rapid and began within minutes of removal from the exposure chamber. These results provide further evidence that exposure to certain solvents produces a profile of reversible effects qualitatively similar to that produced by depressant drugs and alcohol, and that the FOB can be used to compare and contrast profiles of depressant and excitatory effects of inhalants.