Prevention of herpes simplex virus type 2 transmission with antiviral therapy.
Worldwide, herpes simplex virus type 2 (HSV-2) infection is the biggest cause of genital ulcer disease, and is responsible for the majority of cases of genital herpes. The risk of transmitting genital herpes to a partner is one of the leading causes of psychological distress for those with the disease. Antiviral compounds available for the treatment of genital herpes are known to reduce clinical recurrence rates and HSV shedding. This understanding provided impetus for a randomized, placebo-controlled study to assess the ability to interrupt transmission of HSV using oral valaciclovir therapy (500 mg, once daily). The study enrolled 1484 immunocompetent, heterosexual, monogamous couples in stable relationships where both partners were aware of the source partner's infection and the source partner had symptomatic genital herpes. Valaciclovir reduced the risk of transmitting HSV-2 infection by 48%. Furthermore, valaciclovir reduced the risk of clinical disease in the susceptible partner by 75%. As a result, the International Herpes Management Forum (IHMF) now recommends that physicians offer suppressive valaciclovir therapy to immunocompetent individuals concerned about transmitting genital herpes to a heterosexual partner, and advises safer sex behaviour, including the use of condoms, to prevent genital herpes transmission.


Introducing loupes to clinical practice: dental hygienists experiences and opinions.
Recent literature has identified a number of potential advantages in wearing loupes for dental hygienists, including improved quality of care and ergonomics. The aim of the study was to determine dental hygienists' opinions about wearing loupes. A short online survey was distributed to all dental hygienists who had recently participated in a study investigating the efficacy of loupes on musculoskeletal disorders; all had only worn loupes for a 6-month period, and prior to the study had not worn loupes. All of those invited completed the survey (n = 12), achieving a 100% response rate. The majority of respondents noted that the loupes were adaptable to wear; however, only one-quarter of hygienists surveyed were wearing them often following the study. Respondents identified that the biggest advantage to loupes was calculus removal (91.7%), and most indicated that they felt the quality of their work increased when wearing loupes (75%). The biggest disadvantage to wearing loupes was the adjustment period (50%), with limited depth of vision, headache, vertigo and infection control noted by at least one-third of respondents. This study revealed that hygienists identify both benefits and limitations to wearing loupes, and therefore, ongoing support may be required for hygienists adopting their use in clinical practice.


Timing of Dysphagia Screening in Alzheimer's Dementia.
Dysphagia is an important and frequent symptom in Alzheimer's dementia (AD). We hypothesized that dysphagia could be seen in the early stages of AD and sarcopenia presence rather than the severity of the AD affecting dysphagia. The main aim of this study was to investigate swallowing functions in AD patients according to stages. The second aim was to investigate the correlation between sarcopenia and dysphagia in AD. This study involved 76 probable AD patients. For all participants, diagnosis of sarcopenia was based on definitions from the revised version of European Working Group on Sarcopenia in Older People at 2018. Dysphagia symptom severity was evaluated by the Turkish version of the Eating Assessment Tool, a videofluoroscopic swallowing study (VFSS) was performed for instrumental evaluation of swallowing. The patients were divided into 3 groups according to the clinical dementia rating (CDR) scale as CDR 1 (mild dementia), CDR 2 (moderate dementia), and CDR 3 (severe dementia). Swallowing evaluation parameters were analyzed between these groups. Mean age was 78.9 ± 6.4 years, and 56.4% were female. Twenty-six patients had mild dementia, 31 patients had moderate dementia, 19 patients had severe dementia (CDR 3). We found that sarcopenia rates were similar between AD stages according to CDR in our study population and dysphagia could be seen in every stage of AD. In a multivariate analysis, polypharmacy and sarcopenia were found to be independently associated factors for dysphagia, irrespective of stage of AD (OR: 6.1, CI: 1.57-23.9, P = 0.009; OR: 4.9, CI: 1.24-19.6, P = 0.023, respectively). Aspirations may be subtle so that AD patients and caregivers may not be aware of swallowing difficulties. Therefore, all AD patients, especially those who have polypharmacy and/or sarcopenia (probable-sarcopenia-severe sarcopenia), should be screened for dysphagia in every stage.


Transformation by polyoma virus middle T antigen.
The transforming protein of polyoma virus, middle T antigen, is a membrane-associated phosphoprotein. Middle T forms a complex with, and is phosphorylated by, a cellular tyrosine kinase pp60c-src. Mutant analysis suggests that formation of this complex is critical to transformation by polyoma. Middle T binding causes pp60c-src to autophosphorylate at novel sites in its amino terminus, and increases the specific activity of the enzyme. However, at least one non-transforming mutant of middle T, dl1015, can also activate pp60c-src in these ways. This suggests that properties of middle T other than the ability to activate pp60c-src are also necessary for transformation. These properties may include the ability to associate with a phosphatidylinositol kinase, and/or with a protein of 61 kDa. The mechanism by which middle T activates pp60c-src may involve its ability to alter the phosphorylation state of the enzyme, and thus interfere with the regulation of pp60c-src activity in vivo. Polyoma virus transformed cells might then be a good model system for investigating the control of pp60c-src activity as well as defining substrates of the enzyme.


Low-key marketing--Craig Hospital. Consistent focus on the patient's healing.
Craig Hospital, in suburban Denver, was pushed into the limelight when survivors of the Columbine High School shootings were patients for rehabilitation. But high-profile cases are treated the same as all others by this world-renowned traumatic brain and spinal cord injury center: the well-being and recovery of the patient is never compromised for the sake of publicity. Ongoing marketing practices are decidedly low-key.


Long-term prognosis of patients with achilles tendinopathy. An observational 8-year follow-up study.
To determine the long-term outcome of patients treated nonoperatively for acute or subchronic (duration of the symptoms before initiation of the treatment less than 6 months) Achilles tendinopathy, we performed a follow-up analysis on 83 of 107 patients an average 8 +/- 2 (SD) years after the initial contact. The analysis included a questionnaire, clinical examination, performance tests, muscle strength measurement, and ultrasonographic examination. Twenty-four of the 83 patients (29%) had to be operated on during the follow-up period. Seventy patients (84%) had full recovery of their activity level, and at 8 years' follow-up 78 patients (94%) were asymptomatic or had only mild pain with strenuous exercise. However, a clear side-to-side difference between the involved and the uninvolved sides was observed on the performance test, clinical examination, and ultrasonography. Also, 34 patients (41%) started to suffer from overuse symptoms in the initially uninvolved Achilles tendon. The results of our 8-year follow-up showed that the long-term prognosis of patients with acute-to-subchronic Achilles tendinopathy is favorable as determined by subjective and functional assessments. In the clinical and ultrasonographic examinations, mild-to-moderate changes were observed rather frequently in both the involved and initially uninvolved Achilles tendons, but the occurrence of these changes was not clearly related to the patients' symptoms.


Microbe-derived uremic solutes enhance thrombosis potential in the host.
p-Cresol sulfate (pCS) and indoxyl sulfate (IS), gut microbiome-derived metabolites, are traditionally associated with cardiovascular disease (CVD) risks in the setting of impaired kidney function. While pharmacologic provision of pCS or IS can promote pro-thrombotic phenotypes, neither the microbial enzymes involved nor direct gut microbial production have been linked to CVD. Untargeted metabolomics was performed on a discovery cohort (n = 1,149) with relatively preserved kidney function, followed by stable isotope-dilution mass spectrometry quantification of pCS and IS in an independent validation cohort (n = 3,954). Genetic engineering of human commensals to produce p-cresol and indole gain-of-function and loss-of-function mutants, followed by colonization of germ-free mice, and studies on host thrombosis were performed. Systemic pCS and IS levels were independently associated with all-cause mortality. Both in vitro and within colonized germ-free mice p-cresol productions were recapitulated by collaboration of two organisms: a Bacteroides strain that converts tyrosine to 4-hydroxyphenylacetate, and a Clostridium strain that decarboxylates 4-hydroxyphenylacetate to p-cresol. We then engineered a single organism, Bacteroides thetaiotaomicron, to produce p-cresol, indole, or both metabolites. Colonizing germ-free mice with engineered strains, we show the gut microbial genes for p-cresol (hpdBCA) and indole (tryptophanase) are sufficient to confer a pro-thrombotic phenotype in vivo. Moreover, human fecal metagenomics analyses show that abundances of hpdBCA and tryptophanase are associated with CVD. These studies show that pCS and IS, two abundant microbiome-derived metabolites, play a broader potential role in CVD than was previously known. They also suggest that therapeutic targeting of gut microbial p-cresol- and indole-producing pathways represent rational targets for CVD.IMPORTANCEAlterations in gut microbial composition and function have been linked to numerous diseases. Identifying microbial pathways responsible for producing molecules that adversely impact the host is an important first step in the development of therapeutic interventions. Here, we first use large-scale clinical observations to link blood levels of defined microbial products to cardiovascular disease risks. Notably, the previously identified uremic toxins p-cresol sulfate and indoxyl sulfate were shown to predict 5-year mortality risks. After identifying the microbes and microbial enzymes involved in the generation of these uremic toxins, we used bioengineering technologies coupled with colonization of germ-free mice to show that the gut microbial genes that generate p-cresol and indole are sufficient to confer p-cresol sulfate and indoxyl sulfate formation, and a pro-thrombotic phenotype in vivo. The findings and tools developed serve as a critical step in both the study and targeting of these gut microbial pathways in vivo.


Hearing with the mouthparts: behavioural responses and the structural basis of ultrasound perception in acherontiine hawkmoths
In contrast to previous assumptions, mouthparts form hearing organs not only in choerocampine hawkmoths but also in some distantly related acherontiine hawkmoth species. Four of the six acherontiine species studied revealed responses to ultrasonic sounds when stimulated during tethered flight. The responses included changes in flight speed and non-directional turns. Individuals from two species also responded by emitting sound. The minimum thresholds of the flight pattern changes were approximately 70 dB in all species studied, with species-specific best frequencies between 30 and 70 kHz. Some acherontiine species also move their tongue in a stereotyped way when stimulated acoustically. The activity of the muscles involved in this tongue reflex was characterized in the present study and used in combination with ablation experiments to localize the hearing organ. These experiments revealed auditory functions of the labial palps and the labral pilifers similar to those found in Choerocampina. The palp contributes a 20-25 dB rise in sensitivity, whereas the pilifer appears to contain the sensory organ. Structural differences suggest a convergent evolution of hearing in hawkmoths: in the place of the swollen palps of Choerocampina, acherontiine species capable of hearing possess a scale-plate of the palps that interacts with an articulating pilifer, while this modification is absent in closely related non-hearing species.


Effects of herpes simplex virus on mRNA stability.
Herpes simplex virus virions contain one or more functions which mediate shutoff of host protein synthesis, disaggregation of host polyribosomes, and degradation of host mRNA. We studied aspects of the host shutoff mechanism by using herpes simplex virus type 1 mutants deficient in virion-induced shutoff of host protein synthesis (G. S. Read and N. Frenkel, J. Virol. 46:498-512, 1983). Shutoff of host protein synthesis by the wild-type virus was associated with degradation of host mRNAs, including beta-actin, alpha-tubulin, and heat shock protein 70. In contrast, the virion host shutoff (vhs) mutants were deficient to various degrees in their ability to induce host mRNA degradation; the extent of mRNA degradation correlated well with the extent of inhibition of host protein synthesis. This finding suggests that inhibition of host protein synthesis and degradation of host mRNA were mediated by the same virion-associated function. Virion-induced degradation of host mRNA was not prevented by inhibitors of ribosome translocation, nor could it be augmented, for mutant vhs-1, by drugs which disaggregate polyribosomes. This suggests that mRNA in polyribosomes, as well as nonpolyribosomal mRNA, is susceptible to virion-induced degradation. Finally, the half-life of viral transcripts was also prolonged in cells infected with the vhs-1 mutant virus, suggesting that the vhs function indiscriminately decreased the half-lives of both host and viral mRNAs. The vhs function may thus play a dual role in virus infection. (i) It inhibits host gene expression, and (ii) it enables rapid transitions in the expression of viral genes which are sequentially transcribed as infection progresses.


In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen-specific prothrombin activation.
Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.


CPA tumors with normal routine audiometry and positive reflex and BSER tests.
Recently, in a ten-day-period, three patients whose hearing was within normal limits with good speech discrimination were found to have large cerebellopontine angle tumors. There were neurologic symptoms in only one patient. In these three cases, stapedius reflexes were absent with the affected ear stimulated. Brain stem evoked responses (BSER) were clearly abnormal in the three cases. Postoperative brain stem testing showed essentially no change in the nonoperated ear owing to brain stem manipulation. In two cases hearing was preserved. In one patient, the brain stem recordings returned to near-normal after surgery. In another, brain stem responses remained the same and the stapedius reflexes returned to normal. It appears that stapedius reflex testing and the BSER are highly useful tools that can be used to diagnose an acoustic neuroma before it grossly affects hearing.


Specific mesenchymal/epithelial induction of olfactory receptor, vomeronasal, and gonadotropin-releasing hormone (GnRH) neurons.
We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs), and gonadotropin-releasing hormone (GnRH) neurons, the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions specify the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons.


[Participation of peripheral sensory structures of autonomic nervous system in the mechanisms of neuroimmune interactions].
On the basis of the electrophysiological research carried out with immunohystochemical methods on rats, it is found, that introduction of products of mast cell degranulation into blood as well as endogenous release of mast cell mediators with either the compound 48/80 or introduction of egg albumin to presensitized rats, enhances activity of mesenteric afferent nerve fibers. The obtained data provide evidence that intestinal afferents contribute an early signal to the brain regarding potential pathogens. The question of whether or not the intrinsic enteric neurons are involved in these processes, however, has not been carefully studied. So we investigated this problem and found that the enteric neurons express receptor of innate immunity TLR4 and nociceptive vanilloid receptor TRPV1, by means ofimmunohistochemical method. The analysis of neurons distribution revealed that vanilloid receptors are expressed by neurons localized mainly in myenteric plexus whereas TLR4-immunoreactive neurons generally are present in submucous plexus. It is also established coexpression of both receptors in the single intrinsic enteric neuron. In conclusion, our findings indicate that sensory terminals of external afferent fibers as well as intrinsic neurons of intestine can modulate reactions of the organism to endotoxins and thus may be involved in reception of inflammatory and immune responses.


Structure of the defect perovskite Ce1/3NbO3: a redetermination by electron and neutron powder diffraction
The crystal structure of the defect perovskite Ce1/3NbO3, cerium niobium oxide, has been re-examined by neutron powder and electron diffraction. The results of a powder neutron Rietveld refinement indicate that the structure is monoclinic: space group P2/m with Z = 4, a = 5.5267 (3), b = 7.8824 (2), c = 5.5245 (3) A, beta = 90.294 (1)degrees, V= 240.67 (2) A3 at 298 K with chi2 = 2.570. Previous reports have described the Ce1/3NbO3 structure in a smaller (V/2) orthorhombic cell based solely upon X-ray powder diffraction data. The presence of weak reflections in the electron diffraction pattern provides conclusive evidence for a monoclinic superstructure of the orthorhombic cell. While these superlattice reflections are barely detectable with X-ray radiation, they are clearly visible in the neutron diffraction experiments. The superlattice reflections are shown to arise from a tilting of the NbO6 octahedra which results in the reduction of symmetry from orthorhombic to monoclinic. It is also found that the Ce3+ and Nb5+ cations are displaced from the centres of their respective polyhedra to accommodate the bond-valence requirements of the crystal structure. It is likely that distortions of this type are present in other Ln1/3NbO3 and Ln1/3TaO3 defect perovskites.


Amelioration of neurobehavioral and cognitive abilities of F1 progeny following dietary supplementation with Spirulina to protein malnourished mothers.
Early life adversities (stress, infection and mal/undernutrition) can affect neurocognitive, hippocampal and immunological functioning of the brain throughout life. Substantial evidence suggests that maternal protein malnutrition contributes to the progression of neurocognitive abnormalities and psychopathologies in adolescence and adulthood in offspring. Maternal malnutrition is prevalent in low and middle resource populations. The present study was therefore undertaken to evaluate the effects of dietary Spirulina supplementation of protein malnourished mothers during pregnancy and lactation on their offspring's reflex, neurobehavioral and cognitive development. Spirulina is a Cyanobacterium and a major source of protein and is being used extensively as a dynamic nutraceutical against aging and neurodegeneration. Sprague Dawley rats were switched to low protein (8% protein) or normal protein (20% protein) diet for 15 days before conception. Spirulina was orally administered (400 mg/kg/b.wt.) to subgroups of pregnant females from the day of conception throughout the lactational period. We examined several parameters including reproductive performance of dams, physical development, postnatal reflex ontogeny, locomotor behavior, neuromuscular strength, anxiety, anhedonic behavior, cognitive abilities and microglia populations in the F1 progeny. The study showed improved reproductive performance of Spirulina supplemented protein malnourished dams, accelerated acquisition of neurological reflexes, better physical appearance, enhanced neuromuscular strength, improved spatial learning and memory and partly normalized PMN induced hyperactivity, anxiolytic and anhedonic behavior in offspring. These beneficial effects of Spirulina consumption were also accompanied by reduced microglial activation which might assist in restoring the behavioral and cognitive skills in protein malnourished F1 rats. Maternal Spirulina supplementation is therefore proposed as an economical nutraceutical/supplement to combat malnutrition associated behavioral and cognitive deficits.


Existing data sources for clinical epidemiology: Aarhus University Prescription Database.
Population-based prescription databases in Nordic countries have become a mainstay of epidemiologic research. Denmark has both national and regional population-based prescription databases. Aarhus University Prescription Database collects data on reimbursed medications dispensed at all community pharmacies of the North Denmark Region and the Central Denmark Region. The regions have a combined population of 1.8 million inhabitants, or one-third of the Danish population. Denmark's primary health care sector, which includes general practitioners, specialists, and dentists, generates about 96% of the prescription sales, most of which are reimbursable and are dispensed by the community pharmacies. The Aarhus University Prescription Database combines the region's pharmacy records in a single database, maintained and updated for research purposes. Each dispensation record contains patient-, drug-, and prescriber-related data. Dispensation records retain patients' universal personal identifier, which allows for individual-level linkage to all Danish registries and medical databases. The linked data have many applications in clinical epidemiology, including drug utilization studies, safety monitoring, etiologic research, and validation studies.


The influence of systemic lupus erythematosus on fetal development: cognitive, behavioral, and health trends.
In 1985, Gualtieri and Hicks proposed the immunoreactive theory to explain the higher prevalence of childhood neurodevelopmental disorders in males. The theory claimed that male fetuses are more antigenic to mothers, resulting in increased immunologic attack on the developing central nervous system, and increased probability of atypical brain development. Individuals with systemic lupus erythematosus (SLE) provide a unique situation in which to investigate this theory. We evaluated the parent-reported prevalence of five developmental problems (stuttering, other speech problems, hyperactivity, attention deficit, and reading problems) in two groups: 154 individuals ages 8-20 years born to women with SLE, drawn from six cities, and 154 controls of comparable age and sex whose mothers did not have SLE. Controls were drawn from a comparison group ascertained from randomly selected schools in one of the cities. Questions about handedness, immune disorders, and pregnancy and birth complications were also evaluated. Children of SLE mothers were shown to have more evidence of developmental difficulties, immune related disorders, and nonrighthandedness. For developmental problems, these findings were most marked in male children of SLE mothers. These results suggest that maternal immunoreactivity, as represented by women with SLE, may present a special risk factor for subsequent learning difficulties in their children, particularly males.


Comparison of the immune response elicited by infectious and inactivated foot-and-mouth disease virus in mice.
The immune response to foot-and-mouth disease virus (FMDV) elicited by infection or immunization with inactivated virus in adult mice was examined. A model of adoptive transfer of immunocompetent cells was used for this purpose. The results presented here indicate that both short- and long-term secondary immune responses elicited by high doses of inactivated virus are indistinguishable, at the humoral or cellular level, from that observed after infection. The responses to inactivated or infectious virus were both efficiently mediated by B cells. However, immunization with low doses of inactivated virus induced a response which, although effective in aborting infection, was fully dependent on FMDV-specific T cell cooperation. These findings suggest that the different immune responses observed after infection and immunization are mainly the result of the different viral mass presented to the immune system in each case.


The Important Role of Intermuscular Adipose Tissue on Metabolic Changes Interconnecting Obesity, Ageing and Exercise: A Systematic Review.
As age increases, adipose tissue infiltrates muscle tissue and leads to sarcopenia. When excessive accumulation of adipose tissue accompanied progressive decrease in lean body mass especially visceral fat, termed as sarcopenic obesity (SO) and related metabolic intermuscular adipose tissue (IMAT) is an ectopic tissue found between muscle groups, and is distinct from subcutaneous adipose tissue. Until now, the association between IMAT and metabolic health was not understood. This study is the first systematic review assessing the association between IMAT and metabolic health. The PubMed, Science Direct and Cochrane databases were searched for studies reporting IMAT and metabolic risk. The descriptions of the extracted data are guided by the Preferred Reporting Items for Systematic Reviews (PRISMA) statement with a Grading of Recommendations Assessment, Development and Evaluation approach. This study is registered at PROSPERO (identifier: CRD42022337518). Six studies were pooled and reviewed using critical appraisal by the Newcastle Ottawa Scale and Centre for Evidence-Based Medicine checklist. Two clinical trials and four observational trials were included. Our results reveal that IMAT is associated with metabolic risk, especially in older adults and patients with obesity. However, in a person with abdominal obesity, VAT has a more significant role in metabolic risk than IMAT. The largest decrease in IMAT was achieved by combining aerobic with resistance training.


Melasma: successful treatment with pidobenzone 4% (K5lipogel).
Melasma (a term derived from the Greek word "melas" meaning black) is an acquired blotchy, irregularly patterned, brown or sometimes gray brown hypermelanosis of the face and occasionally the neck. Its etiology is poorly understood but mainly related to sunlight and genetic predisposition. Melasma seems to be more frequent in darker skinned people, especially women. Its treatment is always difficult and the condition usually relapses. The treatment with pidobenzone 4% (K5 lipogel), twice per day for 16 weeks has proved to be safe and effective. Pidobenzone 4% lipogel, according to the present study, seems also to represent a useful, reliable, and safe treatment of the different types of melasma.


Protein kinase C bound to the Golgi apparatus supports the formation of constitutive transport vesicles.
Constitutive secretion of heparan sulphate proteoglycans (HSPGs) was stimulated in human hepatoma HepG2 cells by phorbol 12-myristate 13-acetate (PMA) and inhibited by calphostin C, a specific inhibitor of protein kinase C (PKC). To delineate more closely the site of PKC action, the packaging in vitro of 35SO4-labelled HSPGs into transport vesicles was investigated. Formation of transport vesicles at the trans-Golgi network was stimulated by PMA and inhibited by calphostin C or Ro 31-8220 by using a post-nuclear supernatant. Treatment of either isolated Golgi-enriched membranes or cytosolic proteins with calphostin C provided evidence that membrane-bound PKC forms strongly supported vesicle formation, whereas cytosolic PKC forms showed a marginal effect. The PKC isoforms PKC-alpha and PKC-zeta were attached to highly purified Golgi membranes, as shown by Western blotting. Both isoforms were localized by confocal immunofluorescence microscopy in the Golgi area of HepG2 cells. Immunoelectron microscopy of ultrathin cryosections of HepG2 cells showed that PKC-zeta predominantly attaches to the trans-Golgi region, whereas PKC-alpha binds to the cis- and trans-Golgi area.


Cyclodextrin-based nanocarriers containing a synergic drug combination: A potential formulation for pulmonary administration of antitubercular drugs.
Tuberculosis (TB) remains a major global health problem. The use of ethionamide (ETH), a main second line drug, is associated to severe toxic side-effects due to its low therapeutic index. In this challenging context, "booster" molecules have been synthetized to increase the efficacy of ETH. However, the administration of ETH/booster pair is mostly hampered by the low solubility of these drugs and the tendency of ETH to crystallize. Here, ETH and a poorly water-soluble booster, so-called BDM43266, were simultaneously loaded in polymeric β-cyclodextrin nanoparticles (pβCyD NPs) following a "green" protocol. The interaction of ETH and BDM43266 with pβCyD NPs was investigated by complementary techniques. Remarkably, the inclusion of ETH and BDM43266 pβCyD NPs led to an increase of their apparent solubility in water of 10- and 90-fold, respectively. Competition studies of ETH and BDM43266 for the CyD cavities of pβCyD NPs corroborated the fact that the drugs did not compete with each other, confirming the possibility to simultaneously co-incorporate them in NPs. The drug-loaded NP suspensions could be filtered through 0.22μm filters. Finally, the drug-loaded NPs were passed through a Microsprayer® to evaluate the feasibility to administer pβCyD NPs by pulmonary route. Each spray delivered a constant amount of both drugs and the NPs were totally recovered after passage through the Microsprayer®. These promising results pave the way for a future use of pβCyD NPs for the pulmonary delivery of the ETH/BDM43266 pair.


Investigating the potential of human placenta-derived extracellular matrix sponges coupled with amniotic membrane-derived stem cells for osteochondral tissue engineering.
Osteochondral injuries are challenging to repair due to their complex tissue anatomy and restricted self-repairing ability associated with a limited blood supply. Osteochondral tissue engineering is an important clinical aspect of the management and treatment of cartilage and underlying bone. In the present study, we fabricated human placenta-derived extracellular matrix sponges (PEMS) for repair of osteochondral tissue through a decellularization process. There were no significant cellular components present in the PEMS; hematoxylin & eosin/DAPI staining, DNA quantification and agarose gel electrophoresis were used to evaluate the extent of decellularization. Moreover, no significant alteration to the collagen and glycosaminoglycan (native extracellular matrix) content of the PEMS was observed. PEMS in vitro provided a non-cytotoxic environment rich in bioactive cues for human amniotic membrane-derived stem cells (HAMSCs) to proliferate in and differentiate into chondrogenic and osteogenic lineages under induction. Histological analysis at 28 days after the PEMS were subcutaneously implanted demonstrated no severe immune response in the host and supported the formation of blood vessels. To assess the osteochondral tissue repair ability of PEMS, cell-free PEMS (CFP) and cell-seeded PEMS (CSP) were implanted at osteochondral defect sites in a rabbit model. Histological scores indicated that osteochondral regeneration was more successful in the defects filled with CSP compared to those filled with CFP and empty defects (ED) after 60 days of implantation. In summary, a naturally derived biocompatible scaffold composed of extracellular matrix from human placenta has been successfully developed for osteochondral tissue engineering.


Carboxyl-truncated STAT5beta is generated by a nucleus-associated serine protease in early hematopoietic progenitors.
Hematopoiesis is tightly controlled by a family of cytokines that signal through a related set of receptors. The pleiotropic and overlapping response of a cell to different cytokines is reflected in the number and complex pattern of activated signal transducers. Of special interest is STAT5, which is stimulated by a large and diverse set of cytokines. In addition to the two highly homologous proteins, STAT5A and STAT5B, encoded by duplicated genes, expression and activation of a dominant-negative, carboxyl-truncated form has also been described in early hematopoietic progenitors. We show here that a protease expressed in early hematopoietic cells cleaves the alpha forms of STAT5A/5B (p96/p94) to generate carboxyl-truncated beta forms (p80/p77). Inhibition studies assigned this protease to the serine class of endopeptidases. Cell fractionation experiments showed that the protease is associated with the nucleus in a constitutively activated form and does not require an activated STAT5 substrate. The ability of a protease to modulate the specificity of an activated transcription factor is unprecedented and underlines the importance of proteases in regulation of cell functions.


Fighting with Spirits: Migration Trauma, Acculturative Stress, and New Sibling Transition-A Clinical Case Study of an 8-Year-Old Girl with Absence Epilepsy.
In this article, we discuss the impact of migration and acculturation processes on the cultural, personal identity, and mental health of children who immigrate to a Western, multicultural environment, and the challenges clinicians in such environments face, when confronted with non-Western idioms of distress and healing practices. We do that by presenting a challenging clinical case of an 8-year-old girl who presented with very disorganized behavior, which matches a culturally accepted construct of spirit possession, in the context of migration trauma, acculturative stress, and new sibling transition. We identify cultural conflict in school and bullying as major mediators between acculturative stress and mental distress. We also aim at identifying vulnerability, risk and protective factors, and the importance of cultural coping resources. We explore in depth the patient's cultural background and the family's belief system and culturally shaped narratives, in order to arrive at a cultural formulation, which focuses on the significance of idioms of distress in shaping psychopathology and influencing the personal and interpersonal course of trauma- and stress-related disorders. We also call attention to the finding that in children, idioms of distress may manifest themselves in a somatic manner. We argue, together with other researchers, that spirit possession deserves more interest as an idiom of distress and a culture-specific response to traumatizing events. We finally emphasize the importance of an anti-reductionist clinical stance, that is able to use different levels of understanding processes of distress and healing, and seeks to reconciliate cultural divides and integrate different explanatory frameworks and help-seeking practices.


Adenovirally mediated gene transfer of functional human tissue-type plasminogen activator to murine lungs.
As several forms of lung injury are associated with alveolar fibrin deposition, and fibrin has been pathogenically implicated in the lung fibrotic response, we sought to develop an in vivo gene transfer model of fibrinolytic protease overexpression. To this end, human tissue-type plasminogen activator (t-PA) possesses a high degree of specificity for proteolytic activation of fibrin-bound plasminogen to its active form, plasmin. To construct an effective vector, the cDNA for human t-PA was inserted downstream of a cytomegalovirus early enhancer-promoter into the E1 position of a replication-deficient adenovirus. The adenovirally expressed t-PA was found to be of the expected size and appropriate functional activity both in vitro and in vivo. A single intratracheal instillation of the adenoviral-t-PA construct resulted in a dose- dependent, tissue-specific expression of increased levels of t-PA antigen (100-fold) and t-PA protease activity (4-fold) for at least 2 wk in whole lung lysates. The expressed protein localized to the bronchiolar epithelium and peribronchiolar alveolar cells and did not result in increases in total lung protein or alveolar cell counts at 3 d after instillation. In conclusion, a single intratracheal instillation of adenoviral-cytomegalovirus-t-PA construct will generate dramatic bronchoalveolar compartment overexpression of functional recombinant human t-PA for at least 2 wk. This vector can now be utilized for the determination of the therapeutic potential of t-PA in a number of in vivo model systems.


Exploring the Behavioral and Metabolic Phenotype Generated by Re-Introduction of the Ghrelin Receptor in the Ventral Tegmental Area.
Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-RVTA mice) to specifically study the importance of the constitutively active Ghr-R for VTA neuronal signaling. Our results showed that re-introduction of the Ghr-R in the VTA had no impact on body weight or food intake under basal conditions. However, during novel environment stress Ghr-RVTA mice showed increased food intake and energy expenditure compared to Ghr-R knockout mice, demonstrating the significance of Ghr-R signaling in the response to stress. Ghr-RVTA mice also showed increased cocaine-induced locomotor activity compared to Ghr-R knockout mice, highlighting the importance of ghrelin signaling for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress.


Size-mediated non-trophic interactions and stochastic predation drive assembly and dynamics in a seabird community.
Theoretical and empirical evidence suggests that body size is a major life-history trait impacting on the structure and functioning of complex food webs. However, long-term analyses of size-dependent interactions within simpler network modules, for instance, competitive guilds, are scant. Here, we model the assembly dynamics of the largest breeding seabird community in the Mediterranean basin during the last 30 years. This unique data set allowed us to test, through a "natural experiment," whether body size drove the assembly and dynamics of an ecological guild growing from very low numbers after habitat protection. Although environmental stochasticity accounted for most of community variability, the population variance explained by interspecific interactions, albeit small, decreased sharply with increasing body size. Since we found a demographic gradient along a body size continuum, in which population density and stability increase with increasing body size, the numerical effects of interspecific interactions were proportionally higher on smaller species than on larger ones. Moreover, we found that the per capita interaction coefficients were larger the higher the size ratio among competing species, but only for the set of interactions in which the species exerting the effect was greater. This provides empirical evidence for long-term asymmetric interspecific competition, which ultimately prompted the local extinction of two small species during the study period. During the assembly process stochastic predation by generalist carnivores further triggered community reorganizations and global decays in population synchrony, which disrupted the pattern of interspecific interactions. These results suggest that the major patterns detected in complex food webs can hold as well for simpler sub-modules of these networks involving non-trophic interactions, and highlight the shifting ecological processes impacting on assembling vs. asymptotic communities.


Training prosthesis users to switch between modes of a multi-articulating prosthetic hand.
Producing triggers to switch between modes of myoelectric prosthetic hands has proven to be difficult. We evaluated whether digital training methods were feasible in individuals with an upper limb defect (ULD), whether myosignals in these individuals differ from those of non-impaired individuals and whether acquired skills transfer to prosthesis use. Two groups participated in a 9-day pre-test-post-test design study with seven 45-minute training sessions. One group trained using a serious game, the other with their myosignals digitally displayed. Both groups also trained using a prosthesis. The pre- and post-tests consisted of an adapted Clothespin Relocation Test and the spherical subset of the Southampton Hand Assessment Procedure. After the post-test, the System Usability Scale (SUS) was administered. Clinically relevant performance measures and myosignal features were analysed. Four individuals with a ULD participated. SUS-scores deemed both training methods feasible. Three participants produced only a few correct triggers. Myosignals features indicated larger variability for individuals with a ULD compared to non-impaired individuals (previously published data [1]). Three participants indicated transfer of skill. Even though both training methods were deemed feasible and most participants showed transfer, seven training sessions were insufficient to learn reliable switching behaviour.Trial registration: The study was approved by the medical ethics committee of the University Medical Center Groningen (METc 2018.268).Implications for rehabilitationSwitching between pre-programmed modes of a myoelectric prosthetic hand can be learned, however it does require training.Serious games can be considered useful training tools for trigger production in early phases of myoelectric prosthesis control training.In order to evoke transfer of skill from training to daily life both task-specificity and focus of attention during training should be taken into account.


Confronting actual practice with practice guidelines in oncology.
Improving health care quality requires the availability of data to identify and eliminate unnecessary variations in the care process. Variations can be caused by an ineffective implementation of research findings or by obstacles to the translation of research into clinical practice. The analysis of current patterns of care by the use of routine data from electronic patient records or clinical registries may help highlight these deficiencies in actual care. The growing infrastructure of information technologies and the knowledge about clinically relevant variations of routine practice may help us understand the mechanisms that are impeding the translation of research into practice. There is a need to scrutinize these variations of practice and the barriers to guideline implementation. We think that an understanding and open discussion of such reasons may help, to continuously improve the quality of patient care. This process facilitates efforts and strategies to implement evidence-based medicine in the daily routine.


Promoting the health of people with chronic obstructive pulmonary disease: patients' and carers' views.
The aim of this study was to generate in-depth insights into patients' and family members' understanding of the causation, progression and prevention of chronic obstructive pulmonary disease and the role of health promotion with this population. In particular, we were interested in identifying the ways patients and family members considered that they could maximise their (patients') health, in the presence of this disease. Chronic obstructive pulmonary disease is highly prevalent and a significant cause of morbidity and mortality, impacting on quality of life and healthcare expenditure. Health promotion is, therefore, an important consideration. There are few examples in the literature of health promotion programmes for this population, including those directed at smoking cessation, which also focus on the family or significant others. An exploratory, descriptive design was employed. Semi-structured, audio-recorded interviews were conducted with 14 patients and 12 family caregivers. Interviews were transcribed verbatim and thematically analysed using content analysis procedures which captured the meaning of the data. The three main themes were 'health promotion: what's that?', 'community resources for health promotion' and 'it wasn't just the smoking'. Many participants seemed unaware that their health might benefit from a healthier life style and provided little spontaneous information on any activities they carried out to maintain or improve their health. This study highlighted a dearth of health promoting activity amongst people affected by chronic obstructive pulmonary disease. The reality for most patients was to manage the day-to-day demands that the symptoms of the disease imposed on them. Our data suggest that a more wide-ranging approach, encompassing aspects of health promotion, might be welcomed by many patients and their family carers. The findings from this study highlight gaps in patients' and carers' understanding of the potential role of health promotion in chronic obstructive pulmonary disease and areas for intervention by health professionals. With the increase in smoking rates of women and predicted future increases in chronic obstructive pulmonary disease, it is imperative that health professionals find effective ways to provide support and health promotive care for patients and families.


Differential ability of the dorsal and ventral rat hippocampus to exhibit group I metabotropic glutamate receptor-dependent synaptic and intrinsic plasticity.
The hippocampus is critically involved in learning and memory processes. Although once considered a relatively homogenous structure, it is now clear that the hippocampus can be divided along its longitudinal axis into functionally distinct domains, responsible for the encoding of different types of memory or behaviour. Although differences in extrinsic connectivity are likely to contribute to this functional differentiation, emerging evidence now suggests that cellular and molecular differences at the level of local hippocampal circuits may also play a role. In this study, we have used extracellular field potential recordings to compare basal input/output function and group I metabotropic glutamate receptor-dependent forms of synaptic and intrinsic plasticity in area CA1 of slices taken from the dorsal and ventral sectors of the adult rat hippocampus. Using two extracellular electrodes to simultaneously record field EPSPs and population spikes, we show that dorsal and ventral hippocampal slices differ in their basal levels of excitatory synaptic transmission, paired-pulse facilitation, and EPSP-to-Spike coupling. Furthermore, we show that slices taken from the ventral hippocampus have a greater ability than their dorsal counterparts to exhibit long-term depression of synaptic transmission and EPSP-to-Spike potentiation induced by transient application of the group I mGluR agonist (RS)-3,5-dihydroxyphenylglycine. Together, our results provide further evidence that the information processing properties of local hippocampal circuits differ in the dorsal and ventral hippocampal sectors, and that these differences may in turn contribute to the functional differentiation that exists along the hippocampal longitudinal axis.


HIV-positive women with anal high-grade squamous intraepithelial lesions: a study of 153 cases with long-term anogenital surveillance.
Women living with HIV (WLHIV) are at increased risk for human papillomavirus (HPV)-associated anal cancer. Given the "field effect" of HPV pathogenesis, some recommend that anal cancer screening should be limited to WLHIV with prior genital disease. This study aimed to characterize the relationship between anal and genital disease in WLHIV in order to better inform anal cancer screening guidelines. We retrospectively studied 153 WLHIV with biopsy-proven anal high-grade squamous intraepithelial lesions (AHSIL) and long-term evaluable cervical/vaginal/vulvar histopathology. Based on the absence or presence of genital HSIL, subjects were categorized as having isolated AHSIL or multicentric HSIL. Demographics, HIV parameters and cervical/anal HPV status were recorded. Chi-square test was used for bivariate analyses. Of 153 WLHIV with AHSIL, 110 (72%) had isolated AHSIL, while 43 (28%) had multicentric HSIL (28 cervical, 16 vulvar, and 8 vaginal HSIL). The median genital surveillance was 8 years (range 1-27). Cervical HPV16/18 infection was associated with multicentric disease (P = 0.001). Overall, 53% of multicentric cases presented genital HSIL preceding AHSIL with median interval 13 years (range 2-23). Paired anal and cervical high-risk HPV results were available for 60 women within 12 months of AHSIL diagnosis: 30 (50%) had anal infection alone, while 30 (50%) had anal/cervical coinfection by 16/18 (15%), non-16/18 (13%), or different types (22%). In conclusion, WLHIV frequently develop AHSILs without pre-existing genital disease or after long latency following a genital HSIL diagnosis. Our findings support anal cancer screening for WLHIV irrespective of prior genital disease.


Do patients with multiple endocrine neoplasia syndrome type 1 benefit from periodical screening?
To determine the benefit of periodical clinical screening of carriers of a mutation in the multiple endocrine neoplasia type 1 (MEN-1) gene, because any useful discussion requires more concrete data. Our study population consisted of all the patients with MEN-1 (n=58) who were treated at the University Medical Centre Utrecht, The Netherlands, during the period 1975-2003, and their affected relatives (n=29). Records of affected individuals who died were analysed for morbidity, cause of death and age at death. We discuss our results in the light of the literature on MEN-1 regarding the benefit of screening. Over a period of 28 Years, we identified 87 individuals affected with MEN-1, from 16 families. A mutation in the MEN-1 gene was detected in 57%, 18% were obligate carriers, and in 24% the diagnosis was only clinically confirmed. Thirty individuals died, 17 from MEN-1-related causes, including malignancies (n=12: pancreatic islet cell tumours n=6 and carcinoid tumours n=6), the Zollinger-Ellison syndrome (n=4) and Cushing's disease (n=1). The remaining patients died of causes probably related to MEN-1 (n=3), unrelated to MEN-1 (n=7) or of unknown causes. Mean ages at death from MEN-1 were 55.4 Years for men and 46.8 Years for women, in both cases significantly lower than the mean age at death in the average Dutch population (P<0.05). We feel that the significantly increased risk of premature death found in patients with MEN-1 justifies the periodical clinical screening of carriers of the MEN-1 gene mutation. Early detection and treatment of abnormalities will probably reduce this risk.


A scoping review of live wildlife trade in markets worldwide.
Wet markets sell fresh food and are a global phenomenon. They are important for food security in many regions worldwide but have come under scrutiny due to their potential role in the emergence of infectious diseases. The sale of live wildlife has been highlighted as a particular risk, and the World Health Organisation has called for the banning of live, wild-caught mammalian species in markets unless risk assessment and effective regulations are in place. Following PRISMA guidelines, we conducted a global scoping review of peer-reviewed information about the sale of live, terrestrial wildlife in markets that are likely to sell fresh food, and collated data about the characteristics of such markets, activities involving live wildlife, the species sold, their purpose, and animal, human, and environmental health risks that were identified. Of the 56 peer-reviewed records within scope, only 25% (n = 14) focussed on disease risks; the rest focused on the impact of wildlife sale on conservation. Although there were some global patterns (for example, the types of markets and purpose of sale of wildlife), there was wide diversity and huge epistemic uncertainty in all aspects associated with live, terrestrial wildlife sale in markets such that the feasibility of accurate assessment of the risk of emerging infectious disease associated with live wildlife trade in markets is currently limited. Given the value of both wet markets and wildlife trade and the need to support food affordability and accessibility, conservation, public health, and the social and economic aspects of livelihoods of often vulnerable people, there are major information gaps that need to be addressed to develop evidence-based policy in this environment. This review identifies these gaps and provides a foundation from which information for risk assessments can be collected.


Detection of brain amyloid-β deposits due to the repetitive head trauma in a former karate player.
Head trauma is a well-established epidemiological risk factor for Alzheimer's disease, but a study of early detection of its pathology has not yet been performed in human patients in vivo. To address this issue, we performed 11 C-labelled Pittsburgh compound B-positron emission tomography on a right-handed 30-year-old man with cognitive deterioration after repetitive head trauma during karate matches. Structural magnetic resonance imaging was also performed on this patient. The same positron emission tomography analysis was performed on elderly healthy controls (15 men, mean age: 70.7 ± 6.2 years). To analyze grey matter volume, structural magnetic resonance imaging was performed on age-matched healthy controls (15 men, mean age: 28.5 ± 3.6 years). The cognitive deterioration in our patient was fixed and partially improved in the 10 years after the repetitive head trauma. However, Pittsburgh compound B-non-displaceable binding potential was significantly elevated in the patient. Volume reduction was shown in the medial temporal region, cerebellum, and the basal frontal cortex, while amyloid-β increase was shown in the bilateral prefrontal cortex. This is the first study to show an early degenerative process due to head trauma in the prefrontal cortex, where structural damage is not yet visible. Early recognition of the degenerative pathology due to repetitive head trauma by amyloid and possibly tau imaging would help clinicians determine how to treat those with early symptoms.


Influence of Intramyocardial Adipose Tissue on the Accuracy of Endocardial Contact Mapping of the Chronic Myocardial Infarction Substrate.
Recent studies have demonstrated that intramyocardial adipose tissue (IMAT) may contribute to ventricular electrophysiological remodeling in patients with chronic myocardial infarction. Using an ovine model of myocardial infarction, we aimed to determine the influence of IMAT on scar tissue identification during endocardial contact mapping and optimal voltage-based mapping criteria for defining IMAT dense regions. In 7 sheep, left ventricular endocardial and transmural mapping was performed 84 weeks (15-111 weeks) post-myocardial infarction. Spearman rank correlation coefficient was used to assess the relationship between endocardial contact electrogram amplitude and histological composition of myocardium. Receiver operator characteristic curves were used to derive optimal electrogram thresholds for IMAT delineation during endocardial mapping and to describe the use of endocardial mapping for delineation of IMAT dense regions within scar. Endocardial electrogram amplitude correlated significantly with IMAT (unipolar r=-0.48±0.12, P<0.001; bipolar r=-0.45±0.22, P=0.04) but not collagen (unipolar r=-0.36±0.24, P=0.13; bipolar r=-0.43±0.31, P=0.16). IMAT dense regions of myocardium reliably identified using endocardial mapping with thresholds of <3.7 and <0.6 mV, respectively, for unipolar, bipolar, and combined modalities (single modality area under the curve=0.80, P<0.001; combined modality area under the curve=0.84, P<0.001). Unipolar mapping using optimal thresholding remained significantly reliable (area under the curve=0.76, P<0.001) during mapping of IMAT, confined to putative scar border zones (bipolar amplitude, 0.5-1.5 mV). These novel findings enhance our understanding of the confounding influence of IMAT on endocardial scar mapping. Combined bipolar and unipolar voltage mapping using optimal thresholds may be useful for delineating IMAT dense regions of myocardium, in postinfarct cardiomyopathy.


Abdominal-pelvic scanning parameters revisited: a case for Z-axis reduction in patients with clinical suspicion for acute appendicitis.
The purpose of this study was to determine if CT for appendicitis can be abbreviated to begin at the top of the L2 vertebral body level and still maintain the detection rate of appendicitis and other symptomatic pathology without omitting significant incidental findings. Retrospective review of CT abdomen-pelvis exams for suspected appendicitis over a 5-month period was performed. The Z-axis scan length of the original full scans and theoretical limited scans from the top of L2 were recorded and calculated. Images were reviewed for incidental findings above the L2 vertebral body level and categorized by severity per American College of Radiology (ACR) white paper guidelines. Final diagnoses based on imaging findings were also recorded. One hundred nineteen patients (46 males, 73 females, mean age 29 ± 14) were included. Appendicitis was present in 26 cases (22%). Using a theoretical scan beginning at the top of the L2 vertebral body, none of the findings leading to diagnosis of appendicitis would have been missed. A total of 30 incidental findings were found above the L2 vertebral body. Per ACR white paper guidelines, 26 of these findings did not require additional imaging follow-up. Additional follow-up imaging was recommended for 3 of the findings above L2, and 1 right adrenal metastasis was found above L2 in a patient with previously undiagnosed NSCLC. This patient coincidentally also had appendicitis. No symptomatic pathology would have been missed had the scans begun at the top of the L2 vertebral body. Such an abbreviated scan would have resulted in a mean Z-axis reduction of 12.9 cm (30.3%). CT using abbreviated Z-axis scan length can reduce radiation dose and provide necessary imaging needed to diagnose appendicitis or other symptomatic pathology without omitting significant incidental findings.


Etoxazole resistance in predatory mite Phytoseiulus persimilis A.-H. (Acari: Phytoseiidae): Cross-resistance, inheritance and biochemical resistance mechanisms.
Phytoseiulus persimilis of the family Phytoseiidae is an effective predatory mite species that is used to control pest mites. The LC50 and LC60 values of etoxazole were determined on P. persimilis using a leaf-disc method and spraying tower. A laboratory selection population designated ETO6 was found to have a 111.63-fold resistance to etoxazole following 6 selection cycles. This population developed low cross-resistance to spinosad, spiromesifen, acetamiprid, indoxacarb, chlorantraniliprole, milbemectin and moderate cross-resistance to deltamethrin. PBO, IBP and DEM synergised resistance 3.17-, 2.85- and 3.60-fold respectively. Crossing experiments revealed that etoxazole resistance in the ETO6 population was an intermediately dominant and polygenic. In addition, detoxifying enzyme activities were increased 2.71-fold for esterase, 3.09-fold for glutathione S-transferase (GST) and 2.76-fold for cytochrome P450 monooxygenase (P450) in the ETO6 population. Selection for etoxazole under laboratory conditions resulted in the development of etoxazole resistance in the predatory mite P. persimilis that are resistant to pesticides are considered valuable for use in resistance management programmes within integrated pest control strategies.


Severe A/H1N1 influenza in four pregnant women in Podkarpacie Province of Poland.
Pregnant women, just like the rest of the population, are at risk of the novel A/H1N1 infection. However, since they belong to a more susceptible group of patients, the risk of a severe course of the disease is significantly higher when compared to their non-pregnant counterparts. This risk is especially great when the infection is accompanied by chronic conditions such as asthma or diabetes mellitus, resulting in an increased morbidity and mortality of both the mother and the fetus. The aim of the study was to present the first four cases of A/H1N1 infection in advanced pregnancy in Podkarpacie Province of Poland that were noted in the course of six weeks in November and December 2009. Maternal age ranged between 27 to 34 years, gestational age was between 29 to 38 weeks. One patient had been at first admitted to Infectious Disease Clinic, and later on transferred to the Intensive Care Unit due to respiratory distress syndrome. The remaining three patients were hospitalized in the obstetrical unit, two of them due to respiratory tract infection and one due to amniotic fluid leakage without any respiratory failure symptoms. Three patients required artificial ventilation. One patient delivered vaginally, and the remaining three had caesarean section, one of them had an emergency c-section in agonia. The fatal outcome in this patient was the result of improper diagnosis due to a false negative stripe-test result. In case of the other three patients, properly diagnosed with Real Time RT-PCR test, an immediate antiviral therapy was introduced. Two neonates died: one delivered by the woman in agonia, and one due to intrauterine hypoxia and prematurity Diagnostic and therapeutic difficulties in A/H1N1 infections in pregnant women may have their source in that fact that an unreliable stripe test alone is used (without confirmation of the infection with Real Time RT-PCR), risk factors are not taken into the account and antiviral therapy is delayed or postponed. Early antiviral therapy and delivery in case of respiratory distress syndrome improve the prognosis for both the mother and the child.


[Excision and suture in skin and subcutaneous tissue. Basic techniques of plastic surgery are essential for optimal cosmetic results].
The basic techniques of plastic surgery are of great practical importance in achieving the best possible results when reconstructing skin and subcutaneous tissue. Knowledge of the anatomy of the skin and the normal healing process is also essential. These fundamental principles of skin surgery include appropriate methods of infiltration anesthesia. Detailed descriptions of the technique of skin incision, excision of skin lesions and control of bleeding are given. Techniques of skin suture are described, and recommendations for optimal timing of suture removal and treatment of scar tissue are provided.


Comparison of the subunit and primary structures of the pyruvate kinases from rabbit and sturgeon muscles.
The structures of the pyruvate kinases isolated from rabbit and sturgeon muscles were compared. Both enzymes are composed of subunits of 56000 mol.wt. Amino acid compositions of the two enzymes are similar, but not identical. Examination of the peptides produced by CNBr cleavage demonstrated that there are at least some highly homologous regions in the two proteins. There are only two replacements between an 18-residue portion of the polypeptide chain of rabbit muscle pyruvate kinase and a portion of the polypeptide chain of the enzyme isolated from sturgeon muscle.


Brain gray and white matter transverse relaxation time in schizophrenia.
Recent in vivo diffusion brain imaging studies of schizophrenic patients have revealed microstructural abnormalities, with low diffusion anisotropy present throughout much of cortical white matter. Brain anisotropy is produced when proton movement reflects physically restricted water movement, for example, by myelin sheaths. Conditions that increase self-diffusion, such as edema, may also alter the longitudinal and transverse relaxation time of protons, and it is possible that such changes could explain the observed anisotropy diminution seen in schizophrenia. To test this possibility, we calculated pixel-by-pixel transverse relaxation time (T2) and proton density (PD) maps for gray matter and white matter across eight 5-mm-thick axial slices of fast spin echo MRI in 10 control men (age 30-57 years) and 10 men with schizophrenia (age 32-64 years). Schizophrenics had significantly longer mean white matter T2 (84.0 vs. 81.9 ms, P<0.03) and gray matter T2 (95.1 vs. 92.2, P = 0.003); their mean white and gray matter PD values were not significantly different from those of controls. Correlations were not significant between anisotropy and T2 in either grey or white matter but were significant between anisotropy and PD in white matter. T2 relaxation times are longer in schizophrenics than in controls in both gray and white matter whereas anisotropy reduction is restricted to white matter. Taken together, these results suggest that the process producing prolonged T2 does not fully account for the abnormally low anisotropy observed selectively in white matter in this group of schizophrenic patients.


Native GELFrEE: a new separation technique for biomolecular assemblies.
The cadre of protein complexes in cells performs an array of functions necessary for life. Their varied structures are foundational to their ability to perform biological functions, lending great import to the elucidation of complex composition and dynamics. Native separation techniques that are operative on low sample amounts and provide high resolution are necessary to gain valuable data on endogenous complexes. Here, we detail and optimize the use of tube gel separations to produce samples proven compatible with native, multistage mass spectrometry (nMS/MS). We find that a continuous system (i.e., no stacking gel) with a gradient in its extent of cross-linking and use of the clear native buffer system performs well for both fractionation and native mass spectrometry of heart extracts and a fungal secretome. This integrated advance in separations and nMS/MS offers the prospect of untargeted proteomics at the next hierarchical level of protein organization in biology.


Levonorgestrel only emergency contraceptive use and risk of ectopic pregnancy in Eldoret Kenya: a case-control study.
ectopic pregnancy is one of the causes of maternal morbidity and mortality in sub-Saharan Africa. Levonorgestrel (LNG) only emergency contraceptive pill is a well-established emergency contraceptive pill that is administered within 72 hours after unprotected intercourse. This study aimed at determining whether or not there is a significant association between levonorgestrel emergency contraceptive use and the occurrence of ectopic pregnancy. case-control (1:3) study among 79 women with ectopic pregnancy (cases) matched against 237 women without (controls) at Moi Teaching and Referral Hospital in Eldoret, Kenya; Sociodemographic and clinical data were collected using a questionnaire. Association between ectopic pregnancy and LNG-EC was assessed using Pearson chi-square test. The relationship between outcome and exposure (while adjusting for confounders) was assessed using logistic regression model. The mean age was 27.15 years. Both cases and controls were similar by age (p = 0.990), educational level (p = 0.850), marital status (p = 0.559), employment status (p = 0.186) and parity (p = 0.999). Seventy-eight (24.7%) participants had a history of miscarriage. A higher proportion of the cases had history of using LNG-EC compared to the controls (32.9% vs. 7.2%, p < 0.001). The use of LNG-EC portended more than nine times increased odds of ectopic pregnancy compared to other contraceptive methods {OR = 9.34 (95% CI: 3.9 - 16.0)}. levonorgestrel only emergency contraceptive use was associated with ectopic pregnancy. One of the limitations of this study is that we could not control for all confounders of ectopic pregnancy.


Q-TWiST analysis comparing ipilimumab/dacarbazine vs placebo/dacarbazine for patients with stage III/IV melanoma.
Study CA184024 was a multinational, randomised, double-blind, phase 3 study comparing ipilimumab/dacarbazine (DTIC) vs placebo/DTIC in patients with untreated stage III/IV melanoma, which showed that ipilimumab significantly improves survival in patients with metastatic melanoma. The objective of this analysis was to compare the quality-adjusted survival experience among patients in this trial. Survival time was partitioned into health states: toxicity, time before progression without toxicity, and relapse until death or end of follow-up. Q-TWiST (quality-adjusted time without symptoms of disease or toxicity of treatment) was calculated as the utility-weighted sum of the mean health state durations. Analyses were repeated over extended follow-up periods. Based on a combination of trial-based and external utility scores, the Q-TWiST difference in this trial was 0.50 months (P=0.0326) favoring ipilimumab after 1 year. The Q-TWiST difference was 1.5 months with 2 years of follow-up (P=0.0091), 2.36 months at 3 years (P=0.005) and 3.28 months at 4 years (P=0.0074). During the first year of study, there was little difference between groups in quality-adjusted survival. However, after 2, 3 and 4 years follow-up for patients with extended survival, the benefits of IPI+DTIC vs PLA+DTIC for advanced melanoma continue to accrue.


[Bone tissue in osteogenesis imperfecta: light and electron microscopic studies].
Osteogenesis imperfecta was studied by light and electron microscopic techniques in 36 cases, of them there were 10 postmortem and 26 bone biopsies. The persons' age was from 0 to 38 years. There were 25 males and 11 females. The microscopic studies indicated a decrease in the basic substance and an increase in the number of osteocytes. The electron microscopic studies revealed a reduction in the granular endoplasmic reticulum, as well as matrix swelling in the mitochondria, their crista degeneration, and the presence of mitochondrial hydroxyappatite; non-uniform mineralization of collagenous structures, their disintegration, a change in the diameter of collagenous fibril, and a decrease in their transversal lines.


Novel molecular markers for late phases of the growth cycle of Arabidopsis thaliana cell-suspension cultures are expressed during organ senescence.
In an Arabidopsis thaliana T87-C3 cell-suspension culture, entry into the growth-arrest phase is rapidly followed by a loss of cell viability. Three cDNA clones, SRG1, SRG2, and SRG3, corresponding to genes with transcripts that accumulate during these late phases, were isolated by the mRNA differential display method. Amino acid sequence analysis shows that the putative SRG1 protein is a new member of the Fe(II)/ascorbate oxidase superfamily, and that SRG2 codes for a protein with significant homology to beta-glucosidases. Significantly, all three SRG genes are expressed in senescing organs of Arbidopsis plants. Two previously characterized genes, SAG2 and SAG4, induced during natural senescence in Arabidopsis, were also found to be expressed in cell-suspension cultures and have expression kinetics similar to those observed for the SRG1 gene. Taken together these finding suggest that certain molecular events are common to both plant senescence and growth arrest in arabidopsis cell suspensions. Both internucleosomal cleavage of nDNA and an apparent compaction of chromatin, two characteristic features of programmed cell death in animal cells, have been observed in Arabidopsis cell cultures at a stage corresponding to loss of cell viability.


Circ_0000215 Exerts Oncogenic Function in Nasopharyngeal Carcinoma by Targeting miR-512-5p.
Background: Increasing circular RNAs (circRNAs) are reported to participate in cancer progression. Nonetheless, the role of circRNAs in nasopharyngeal carcinoma (NPC) has not been fully clarified. This work is aimed to probe the role of circ_0000215 in NPC. Methods: Circ_0000215 expression in NPC tissues and cell lines was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell counting kit-8 (CCK-8) assay, 5-bromo-2'-deoxyuridine (BrdU) assay, scratch healing assay and Transwell experiment were executed to investigate the regulatory function of circ_0000215 on the proliferation, migration and invasion of NPC cells. RNA immunoprecipitation (RIP), pull-down and dual-luciferase reporter experiments were utilized to determine the binding relationship between circ_0000215 and miR-512-5p, and between miR-512-5p and phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) 3'UTR. The effects of circ_0000215 on NPC growth and metastasis in vivo were examined with nude mice model. Western blot was applied to detect the regulatory effects of circ_0000215 and miR-512-5p on PIK3R1 expression. Results: Circ_0000215 was overexpressed in NPC tissues and cell lines. The functional experiments confirmed that knockdown of circ_0000215 impeded the growth and metastasis of NPC cells in vitro and in vivo. Additionally, circ_0000215 could also work as a molecular sponge to repress miR-512-5p expression. PIK3R1 was validated as a target gene of miR-512-5p, and circ_0000215 could increase the expression level of PIK3R1 in NPC cells via suppressing miR-512-5p. Conclusion: Circ_0000215 is overexpressed in NPC and exerts oncogenic effects in NPC through regulating miR-512-5p/PIK3R1 axis.


Proteomic analysis of germinating urediniospores of Phakopsora pachyrhizi, causal agent of Asian soybean rust.
Phakopsora pachyrhizi is an obligate pathogen that causes Asian soybean rust. Asian soybean rust has an unusually broad host range and infects by direct penetration through the leaf cuticle. In order to understand the early events in the infection process, it is important to identify and characterize proteins in P. pachyrhizi. Germination of the urediniospore is the first stage in the infection process and represents a critical life stage applicable to studies with this obligate pathogen. We have applied a 2-DE and MS approach to identify 117 proteins from the National Center of Biotechnology Information nonredundant protein database and a custom database of Basidiomycota EST sequences. Proteins with roles in primary metabolism, energy transduction, stress, cellular regulation and signaling were identified in this study. This data set is accessible at http://world-2dpage.expasy.org/repository/database=0018.


Machine learning material properties from the periodic table using convolutional neural networks.
In recent years, convolutional neural networks (CNNs) have achieved great success in image recognition and shown powerful feature extraction ability. Here we show that CNNs can learn the inner structure and chemical information in the periodic table. Using the periodic table as representation, and full-Heusler compounds in the Open Quantum Materials Database (OQMD) as training and test samples, a multi-task CNN was trained to output the lattice parameter and enthalpy of formation simultaneously. The mean prediction errors were within DFT precision, and the results were much better than those obtained using only Mendeleev numbers or a random-element-positioning table, indicating that the two-dimensional inner structure of the periodic table was learned by the CNN as useful chemical information. Transfer learning was then utilized by fine-tuning the weights previously initialized on the OQMD training set. Using compounds with formula X2YZ in the Inorganic Crystal Structure Database (ICSD) as a second training set, the stability of full-Heusler compounds was predicted by using the fine-tuned CNN, and tungsten containing compounds were identified as rarely reported but potentially stable compounds.


Recognizing Unmet Need in the Era of Targeted Therapy for CLL/SLL: "What's Past Is Prologue" (Shakespeare).
The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.


Macroevolution of life-history traits in passerine birds: adaptation and phylogenetic inertia.
We used a recent passerine phylogeny and comparative method to evaluate the macroevolution of body and egg mass, incubation and fledging periods, time to independence and time with parents of the main passerine lineages. We hypothesised that passerine reproductive traits are affected by adaptation to both past and present environmental factors and phenotypic attributes such as body mass. Our results suggest that the evolution of body and egg mass, time to independence, incubation and fledging times are affected by strong phylogenetic inertia and that these breeding traits are all affected by body mass. Time with parents, where major lineages exhibit their own fixed optima and body mass does not have an effect, and clutch size which is affected by body mass and additionally by climate regimes, do not exhibit any phylogenetic inertia.


On the Determination of Kappa Distribution Functions from Space Plasma Observations.
The velocities of space plasma particles, often follow kappa distribution functions. The kappa index, which labels and governs these distributions, is an important parameter in understanding the plasma dynamics. Space science missions often carry plasma instruments on board which observe the plasma particles and construct their velocity distribution functions. A proper analysis of the velocity distribution functions derives the plasma bulk parameters, such as the plasma density, speed, temperature, and kappa index. Commonly, the plasma bulk density, velocity, and temperature are determined from the velocity moments of the observed distribution function. Interestingly, recent studies demonstrated the calculation of the kappa index from the speed (kinetic energy) moments of the distribution function. Such a novel calculation could be very useful in future analyses and applications. This study examines the accuracy of the specific method using synthetic plasma proton observations by a typical electrostatic analyzer. We analyze the modeled observations in order to derive the plasma bulk parameters, which we compare with the parameters we used to model the observations in the first place. Through this comparison, we quantify the systematic and statistical errors in the derived moments, and we discuss their possible sources.


Safety of food served in Mid-Day Meal program: An in-depth study in upper primary schools of Kolkata.
The Mid-Day Meal (MDM) program is the world's biggest supplementary school lunch program and is being implemented all over India for primary and upper primary school students. To continue a healthy program, personal hygiene of food handlers and beneficiaries should be well maintained. This study aims at examining the status of food safety measures including personal hygiene of food handlers and beneficiaries of MDM. An institution-based observational study with cross-sectional design was conducted in upper primary schools (government, government-aided school) in Kolkata over a period of 2 years from November 2016 to October 2018. A sample of 52 schools from a total of 515 schools were then selected by simple random sampling. Analyses were conducted using SPSS software (SPSS Inc., released 2007 SPSS for Windows, version 16.0). Among 52 schools, 53.8% were government-aided schools and 46.2% were government schools. There were significant differences in cleaning practice by cook-cum-helper (CCH) (χ2 = 4.4, df = 1, P = 0.036), personal hygiene of CCH (χ2 = 19.01, df = 1, P = 0.000) and beneficiaries (χ2 = 9.3, df = 1, P = 0.002), practice during serving (χ2 = 4.4, df = 1, P = 0.036), and use and storage of oils and condiments in MDM (χ2 = 27.7, df = 1, P = 0.000) between government and government-aided schools. School authority should be concerned about maintaining proper hygiene. Adequate facilities and training program must be arranged for CCH to provide a healthy meal.


Estimating fish orientation from broadband, limited-angle, multiview, acoustic reflections.
This article demonstrates that multiview, broadband (635-935 kHz), nearly monostatic, acoustic reflections recorded from lateral views of juvenile fish can be used to infer animal orientation. Calibrated acoustic data were recorded from live fish in a laboratory, while orientation was measured simultaneously via optical images. Using eight animals, two-dimensional data sets of target strength as a function of frequency and orientation were obtained. Fish length, lateral thickness, and dorsoventral thickness ranged from 24 to 48 mm, 3 to 7 mm and 10 to 20 mm, respectively. Preliminary estimates of orientation were computed from the direction of the gradient of the local autocorrelation function in the target strength image. These local estimates were then median-filtered over the full system bandwidth (but still limited-angle) to improve accuracy. Angular estimates were then corrected for systematic bias via a simple, one-dimensional model that approximated the animals' reflection by that of a bar target. Taken over all orientations, the average absolute error in orientation estimation is 5.6° to 17°, dependent on the data set. Results indicate, for most sets of views, reasonable estimates of lateral orientation can be obtained from broadband, multiview data over a set of limited angular reflections.


Maternal recall of distant pregnancy events.
Women themselves are often the most convenient source of information regarding their pregnancy and birth outcomes such as prematurity. However, the ability of mothers to recall birth information and the accuracy of information they do recall has rarely been assessed. This study used a mail survey of women who delivered either term or preterm infants in Rochester, Minnesota, between 1980 and 1985. Maternal reports of circumstances and outcome of delivery were compared to data abstracted from the medical records. Maternal ability to recall and report events varied from 99.5% for smoking during pregnancy to 85% for infant's gestational age at birth. Agreement between medical record and maternal report was very high for perinatal events such as delivery by cesarean section, preexisting diabetes, and smoking. Percent negative agreement was quite high when comparing information on rare events such as placental abruption. Recall of gestational age was better for women delivering preterm infants but uncommon in all women. Maternal reports of perinatal events in which they directly participated such as cesarean section can be accurately and reliably reported 10 to 15 years after the birth. Gestational age is reported less accurately and with different rates of recall for mothers with term and preterm deliveries.


Antibiotic inhibition of protease production by Pseudomonas aeruginosa.
The effects of tetracycline, chloramphenicol and polymyxin B on growth and protease production by Pseudomonas aeruginosa were studied. Tetracycline inhibited protease production at concentrations much lower than those required to cause growth inhibition; the effect was not due to inhibition of protease activity by the antibiotic. In contrast, chloramphenicol and polymyxin B inhibted protease production in direct proportion to the inhibition of growth. Lysozyme-release experiments with washed tetracycline-treated cells indicated that the protease did not accumulate intracellularly. The protease-inhibiting effect of tetracycline might have therapeutic significance if it were found to occur in vivo.


Analysis of SRrp86-regulated alternative splicing: control of c-Jun and IκBβ activity.
Previous work led to the hypothesis that SRrp86, a related member of the SR protein superfamily, can interact with and modulate the activity of other SR proteins. Here, we sought to test this hypothesis by examining the effect of changing SRrp86 concentrations on overall alternative splicing patterns. SpliceArrays were used to examine 9,854 splicing events in wild-type cells, cells overexpressing SRrp86, and cells treated with siRNAs to knockdown SRrp86. From among the 500 splicing events exhibiting altered splicing under these conditions, the splicing of c-Jun and IκBβ were validated as being regulated by SRrp86 resulting in altered regulation of their downstream targets. In both cases, functionally distinct isoforms were generated that demonstrate the role SRrp86 plays in controlling alternative splicing.


[Anamnestic factors in at-risk SID children with peculiar breathing pattern].
436 out of about 9000 infants who were born between April 1987 and November 1990 in Jena were selected by means of a risk score for a polygraphy monitoring. This score contains anamnestic factors of the mother and the infant which are characteristic of an enhanced risk for the sudden infant death syndrome (SIDS). We performed a day-time polysomnography (ECG, heart rate, respiration, EEG, EOG, EMG) with a sleep duration of at least one hour. 23 of the infants investigated demonstrated abnormal breathing patterns (increased mean apnea duration, apneas longer than 15 s, apneas with bradycardia) and were treated with aminophylline to prevent a possible SIDS event. Now we investigated the statistical relation between 26 anamnestic factors of our risk score and the need for treatment. In univariate statistical comparisons treated infants differed from untreated infants concerning the occurrence of intraventricular haemorrhages (IVH), the gestational age (GA) (preterm of fullterm) and the occurrence of hyperbilirubinemia (HB) in their anamnesis. In a multivariate analysis with all 26 factors the birth weight was the third important factor beside IVH and GA, but only factor IVH was statistically significant. A cluster analysis of the variables with respect to the separation of the two groups of infants indicates that the variables IVH, GA and HB strongly correlate. In the light of these results we can underline that abnormal breathing patterns can be expected especially in infants with IVH, short GA and low birth weight.


Oxygen transfer in animal cell culture medium.
Both k(L)a and k(L) measurements were carried out by an unsteady state technique at impeller speeds ranging from 1.6 to 5.8 s(-1) in a mechanically agitated animal cell culture vessel of working volume 1.5 L. Checks were made that the time constant of the oxygen electrode was negligible compared to the time for aeration and that the oxygen electrode reading was not a function of agitator speed in the range employed. The k(L) values by surface aeration of (1.18-3.54) x 10(-5) m/s and k(L)a values by sparged aeration of (2.8-8.5) x 10(-4) s(-1) were found. The former are in reasonable agreement with published experimental values and the latter in accord with values estimated from published correlations based on agitator power input and aeration rate. The fluids used were water, basal medium, and basal medium supplemented with 5% (v/v) foetal calf serum; for each of these, k(L) and k(L)a values were similar. However, the addition of silicone antifoam (6 PPM) reduced the k(L)a value by ca. 50%.


Do natural disasters cause an excessive fear of heights? Evidence from the Wenchuan earthquake.
This paper uses the 2008 Wenchuan earthquake in China to examine if the occurrence of a natural disaster can cause an excessive fear of living in upper floors. We rely on potential variations in earthquake risk perceptions by floor level to assess whether the pricing of apartments in lower versus upper floors is consistent with a disproportionate fear of heights. We use a unique transaction dataset for new apartment units in the affected area. We find that the relative price of low to high floor units, particularly units located in the first and second floor, considerably increased for several months after the earthquake and then returned back to the levels observed prior to the tremor. This temporal increase in relative prices is in line with a higher risk perception and fear, triggered after the earthquake, of living in upper floors, which gradually dissipated over time. The results are robust to alternative model estimations.


Detection of syphilitic hearing loss.
Syphilis can cause sensorineural hearing loss that is potentially treatable. To determine the incidence of positive serological findings in patients with sensorineural hearing loss, the rapid plasma reagin card test (RPRCT) and the FTA-ABS test were performed in a study group composed of patients with sensorineural hearing loss of obscure origin. Of the 306 patients with sensorineural hearing loss, 20 (6.5%) demonstrated a positive FTA-ABS as compared with two of 100 (2%) of the control group. Considerable variation was found in the rate of the false-negative and the biological false-positive RPRCT as performed by our hospital and state laboratories when compared with the results of the FTA-ABS test. Syphilis should be considered in any patient with sensorineural hearing loss of obscure origin, despite a negative history for syphilis. The FTA-ABS is the preferred test to exclude hearing loss of syphilitic origin.


Naxibacter varians sp. nov. and Naxibacter haematophilus sp. nov., and emended description of the genus Naxibacter.
Six Gram-negative, rod-shaped, non-spore-forming bacteria isolated from clinical specimens and water samples were investigated for their taxonomic allocation. On the basis of 16S rRNA gene sequence similarities, these strains (CCUG 35299(T), CCUG 24677A, CCUG 48018, CCUG 49054, CCUG 48700A and CCUG 38318(T)) were shown to belong to the Betaproteobacteria, closely related to Naxibacter alkalitolerans (97.9-98.8 % sequence similarity to the type strain). Chemotaxonomic data (major ubiquinone Q-8; major polyamines hydroxyputrescine and putrescine; major polar lipids phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol; major fatty acids C(16 : 1)omega7c and C(16 : 0), with 3-OH C(10 : 0) and 2-OH C(12 : 0) as hydroxylated fatty acids) supported the affiliation of the isolates to the genus Naxibacter. The results of DNA-DNA hybridization and physiological and biochemical tests allowed both genotypic and phenotypic differentiation of the isolates from the described Naxibacter species. Isolates CCUG 35299(T), CCUG 24677A, CCUG 48018, CCUG 49054 and CCUG 48700A were closely related on the basis of DNA-DNA reassociation experiments and therefore represent a single novel species, for which the name Naxibacter varians sp. nov. is proposed, with the type strain CCUG 35299(T) (=CCM 7478(T)). Strain CCUG 38318(T) represents a second novel Naxibacter species, for which we propose the name Naxibacter haematophilus sp. nov. (type strain CCUG 38318(T) =CCM 7480(T)).


Early and late direct costs in a Southern African antiretroviral treatment programme: a retrospective cohort analysis.
There is a paucity of data on the health care costs of antiretroviral therapy (ART) programmes in Africa. Our objectives were to describe the direct heath care costs and establish the cost drivers over time in an HIV managed care programme in Southern Africa. We analysed the direct costs of treating HIV-infected adults enrolled in the managed care programme from 3 years before starting non-nucleoside reverse transcriptase inhibitor-based ART up to 5 years afterwards. The CD4 cell count criterion for starting ART was <350 cells/microl. We explored associations between variables and mean total costs over time using a generalised linear model with a log-link function and a gamma distribution. Our cohort consisted of 10,735 patients (59.4% women) with 594,497 mo of follow up data (50.9% of months on ART). Median baseline CD4+ cell count and viral load were 125 cells/microl and 5.16 log(10) copies/ml respectively. There was a peak in costs in the period around ART initiation (from 4 mo before until 4 mo after starting ART) driven largely by hospitalisation, following which costs plateaued for 5 years. The variables associated with changes in mean total costs varied with time. Key early associations with higher costs were low baseline CD4+ cell count, high baseline HIV viral load, and shorter duration in HIV care prior to starting ART; whilst later associations with higher costs were lower ART adherence, switching to protease inhibitor-based ART, and starting ART at an older age. Drivers of mean total costs changed considerably over time. Starting ART at higher CD4 counts or longer pre-ART care should reduce early costs. Monitoring ART adherence and interventions to improve it should reduce later costs. Cost models of ART should take into account these time-dependent cost drivers, and include costs before starting ART. Please see later in the article for the Editors' Summary.


Quantifying population preferences around vaccination against severe but rare diseases: A conjoint analysis among French university students, 2016.
Several concepts are available to explain vaccine decision making by individual and inter-individual factors, including risk perception, social conformism and altruism. However, only a few studies have quantified the weight of these determinants in vaccine acceptance. Using a conjoint analysis tool, we aimed at eliciting preferences in a student population regarding vaccination against a rare, severe and rapidly evolving hypothetical disease, similar to meningococcal serogroup C meningitis or measles. During March-May 2016, we conducted an emailing survey among university students aged 18-24years (N=775) in Rennes, France. Participants were asked to decide for or against immediate vaccination in 24 hypothetical scenarios, containing various levels of four attributes: epidemic situation, adverse events, information on vaccination coverage, and potential for indirect protection. Data were analysed using random effect estimator logit models. Participants accepted on average 52% of scenarios and all attributes significantly impacted vaccination acceptance. The highest positive effects were seen with an epidemic situation (OR 3.81, 95%-CI 3.46-4.19), 90% coverage in the community (3.64, 3.15-4.20) and potential for disease elimination from the community (2.87, 2.53-3.26). Information on "insufficient coverage" was dissuasive (vs. none of friends vaccinated: 0.65, 0.56-0.75). Controversy had a significantly greater negative effect than a confirmed risk of severe adverse events (OR 0.05 vs. 0.22). In models including participant characteristics, preference weights were unchanged, while trust in health authorities and vaccination perceptions strongly influenced acceptance themselves. The greatest significant variation of preference weights between subgroups was observed with controversy among students using alternative medicine daily (OR 0.28) and among students relying on scientific vaccine information (OR 0.02). Among young adults, potential for indirect protection and factual information on coverage in the community and potential side effects positively impact theoretical vaccine acceptance. Conjoint analyses should be conducted to understand vaccine hesitancy in specific vaccination programs.