[Pertussis: Where do we stand 10years after the introduction of cocooning vaccination strategy in France?]
The goals of this article are to review the pertussis cocooning strategy, which has been recommended in France since 2004 to protect infants not yet vaccinated from becoming infected by vaccinating their immediate entourage, and to present room for improvement. The analysis of the literature between 2004 and 2015 shows that pertussis vaccine coverage in new parents is lower than 50% and that attempts that have already been implemented to increase it are effective. Pertussis vaccine coverage improvement requires all health actors to collaborate and be trained in informing and motivating parents to get vaccinated before, during and after pregnancy (the parents then will act as relays to their relatives); generalization in maternity wards of systematic checking of the vaccination card; extension to the midwives of the right to prescribe and administer pertussis vaccine to spouses; vaccination facilitation in maternity wards with the support of health organizations. Exchange and sharing of experiences between health care professionals are essential. Pregnancy is the ideal period to promote pertussis vaccination.


Sentinel Node Biopsy in 105 High-Risk Cutaneous SCCs of the Head and Neck: Results of a Multicenter Prospective Study.
Regional nodal metastases from cutaneous squamous cell carcinoma (cSCC) is strongly associated with a poor prognosis, but these metastases are difficult to predict clinically. Sentinel node biopsy (SNB) has been used for a wide range of malignancies to assess for regional nodal metastasis, but is not widely used for cSCC. Patients presenting with high-risk cSCC of the head and neck with clinically N0 necks were offered SNB at the time of primary cSCC excision or secondary wide local excision. Patients with positive sentinel nodes were offered completion lymph node dissection, and all the patients were followed up at regular intervals for up to 5 years. In this study, 105 lesions underwent SNB, and 10 sentinel nodes (9.5%) were positive. In an additional five patients, regional recurrence developed after a negative sentinel node, with a total subclinical nodal metastasis rate of 14.3%. Nodal metastases were significantly associated with reduced disease-specific survival. The significant predictors of metastasis were four or more high-risk features or tumors with a concurrent invasion deeper than 5 mm and PNI. For high-risk cSCC, SNB is a safe and feasible staging technique. The total number of high risk features and certain combinations of high-risk features predicted metastasis better than individual high-risk features.


How accurate is patients' anatomical knowledge: a cross-sectional, questionnaire study of six patient groups and a general public sample.
Older studies have shown that patients often do not understand the terms used by doctors and many do not even have a rudimentary understanding of anatomy. The present study was designed to investigate the levels of anatomical knowledge of different patient groups and the general public in order to see whether this has improved over time and whether patients with a specific organ pathology (e.g. liver disease) have a relatively better understanding of the location of that organ. Level of anatomical knowledge was assessed on a multiple-choice questionnaire, in a sample of 722 participants, comprising approximately 100 patients in each of 6 different diagnostic groups and 133 in the general population, using a between-groups, cross-sectional design. Comparisons of relative accuracy of anatomical knowledge between the present and earlier results, and across the clinical and general public groups were evaluated using Chi square tests. Associations with age and education were assessed with the Pearson correlation test and one-way analysis of variance, respectively. Across groups knowledge of the location of body organs was poor and has not significantly improved since an earlier equivalent study over 30 years ago (chi2 = 0.04, df = 1, ns). Diagnostic groups did not differ in their overall scores but those with liver disease and diabetes were more accurate regarding the location of their respective affected organs (chi2 = 18.10, p < 0.001, df = 1; chi2 = 10.75, p < 0.01, df = 1). Age was significantly negatively correlated (r = -0.084, p = 0.025) and education was positively correlated with anatomical knowledge (F = 12.94, p = 0.000). Although there was no overall gender difference, women were significantly better at identifying organs on female body outlines. Many patients and general public do not know the location of key body organs, even those in which their medical problem is located, which could have important consequences for doctor-patient communication. These results indicate that healthcare professionals still need to take care in providing organ specific information to patients and should not assume that patients have this information, even for those organs in which their medical problem is located.


Multisystemic Treatment of Serious Behaviour Problems in Youth: Sustainability of Effectiveness Two Years after Intake.
Multisystemic Treatment (MST) is an intensive home- and community based intervention for youths with serious behaviour problems. The aim of this study was to examine the effectiveness of MST compared to 'regular services' (RS) two years after intake to treatment. In particular, our goals were to investigate whether MST was successful at preventing placement out of home, and to examine reductions in behaviour problems in multi-informant assessments. Participants were 75 adolescents who were randomly assigned to MST or Regular Child Welfare Services (RS) at 3 sites across Norway. Data were gathered from youths, caregivers and teachers. MST was more effective than RS in reducing out of home placement and behavioural problems. The sustainability of treatment effects was evident, supporting the MST approach to the treatment of serious behavioural problems in youth. Site differences and the moderating effects of age and gender are discussed.


Driven polymer translocation in good and bad solvent: Effects of hydrodynamics and tension propagation.
We investigate the driven polymer translocation through a nanometer-scale pore in the presence and absence of hydrodynamics both in good and bad solvent. We present our results on tension propagating along the polymer segment on the cis side that is measured for the first time using our method that works also in the presence of hydrodynamics. For simulations we use stochastic rotation dynamics, also called multiparticle collision dynamics. We find that in the good solvent the tension propagates very similarly whether hydrodynamics is included or not. Only the tensed segment is by a constant factor shorter in the presence of hydrodynamics. The shorter tensed segment and the hydrodynamic interactions contribute to a smaller friction for the translocating polymer when hydrodynamics is included, which shows as smaller waiting times and a smaller exponent in the scaling of the translocation time with the polymer length. In the bad solvent hydrodynamics has a minimal effect on polymer translocation, in contrast to the good solvent, where it speeds up translocation. We find that under bad-solvent conditions tension does not spread appreciably along the polymer. Consequently, translocation time does not scale with the polymer length. By measuring the effective friction in a setup where a polymer in free solvent is pulled by a constant force at the end, we find that hydrodynamics does speed up collective polymer motion in the bad solvent even more effectively than in the good solvent. However, hydrodynamics has a negligible effect on the motion of individual monomers within the highly correlated globular conformation on the cis side and hence on the entire driven translocation under bad-solvent conditions.


Potential sources of bacteria that are isolated from contact lenses during wear.
The aim of this paper was to determine the possible contamination sources of contact lenses during wear. Potential sources of the microbiota that colonized hydrogel contact lenses during wear were examined. The microorganisms that colonize contact lenses were grown, identified, and compared to those microorganisms that colonized the lower lid margins, upper bulbar conjunctiva, hands, and contact lens cases of contact lens wearers. In addition, the incidence of contamination of the domestic water supply in the Sydney area was obtained, and this was compared to the incidence of colonization of contact lenses by microorganisms in general and gram-negative bacteria in particular. There was a wide diversity of bacteria that were isolated from each site sampled. Coagulase-negative staphylococci and Propionibacterium spp. were the most common isolates from all ocular sites examined, and constituted the normal ocular microbiota. Other bacteria, including members of the families Enterobacteriaceae and Pseudomonadaceae, were isolated infrequently from all sites, but most frequently from contact lens cases. Statistical analysis revealed that there was a correlation between the isolation of bacteria from the contact lens and the lower lid margin (p < 0.001). Analysis of this correlation revealed that this was true for the normal microbiota. A correlation was also noted between the colonization of contact lenses by gram-negative bacteria and contamination of the domestic water supply. This study has demonstrated that the likely route for the normal ocular microbiota colonizing contact lenses is via the lid margins, whereas colonization by gram-negative bacteria, including potential agents of microbial keratitis, is likely to be from the domestic water supply.


An application of multivariate statistical analysis for Query-Driven Visualization.
Driven by the ability to generate ever-larger, increasingly complex data, there is an urgent need in the scientific community for scalable analysis methods that can rapidly identify salient trends in scientific data. Query-Driven Visualization (QDV) strategies are among the small subset of techniques that can address both large and highly complex data sets. This paper extends the utility of QDV strategies with a statistics-based framework that integrates nonparametric distribution estimation techniques with a new segmentation strategy to visually identify statistically significant trends and features within the solution space of a query. In this framework, query distribution estimates help users to interactively explore their query's solution and visually identify the regions where the combined behavior of constrained variables is most important, statistically, to their inquiry. Our new segmentation strategy extends the distribution estimation analysis by visually conveying the individual importance of each variable to these regions of high statistical significance. We demonstrate the analysis benefits these two strategies provide and show how they maybe used to facilitate the refinement of constraints over variables expressed in a user's query. We apply our method to data sets from two different scientific domains to demonstrate its broad applicability.


RUNX3 levels in human hematopoietic progenitors are regulated by aging and dictate erythroid-myeloid balance.
Healthy bone marrow progenitors yield a co-ordinated balance of hematopoietic lineages. This balance shifts with aging toward enhanced granulopoiesis with diminished erythropoiesis and lymphopoiesis, changes which likely contribute to the development of bone marrow disorders in the elderly. In this study, RUNX3 was identified as a hematopoietic stem and progenitor cell factor whose levels decline with aging in humans and mice. This decline is exaggerated in hematopoietic stem and progenitor cells from subjects diagnosed with unexplained anemia of the elderly. Hematopoietic stem cells from elderly unexplained anemia patients had diminished erythroid but unaffected granulocytic colony forming potential. Knockdown studies revealed human hematopoietic stem and progenitor cells to be strongly influenced by RUNX3 levels, with modest deficiencies abrogating erythroid differentiation at multiple steps while retaining capacity for granulopoiesis. Transcriptome profiling indicated control by RUNX3 of key erythroid transcription factors, including KLF1 and GATA1 These findings thus implicate RUNX3 as a participant in hematopoietic stem and progenitor cell aging, and a key determinant of erythroid-myeloid lineage balance.


Targeting geranylgeranylation reduces adrenal gland tumor burden in a murine model of prostate cancer metastasis.
The isoprenoid biosynthetic pathway (IBP) is critical for providing substrates for the post-translational modification of proteins key in regulating malignant cell properties, including proliferation, invasion, and migration. Inhibitors of the IBP, including statins and nitrogenous bisphosphonates, are used clinically for the treatment of hypercholesterolemia and bone disease respectively. The statins work predominantly in the liver, while the nitrogenous bisphosphonates are highly sequestered to bone. Inhibition of the entire IBP is limited by organ specificity and side effects resulting from depletion of all isoprenoids. We have developed a novel compound, disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]-17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which selectively targets geranylgeranyl diphosphate synthase, reducing post-translational protein geranylgeranylation. Intracardiac injection of luciferase-expressing human-derived 22Rv1 PCa cells into SCID mice resulted in tumor development in bone (100 %), adrenal glands (72 %), mesentery (22 %), liver (17 %), and the thoracic cavity (6 %). Three weeks after tumor inoculation, daily subcutaneous (SQ) injections of 1.5 mg/kg GGOHBP or the vehicle were given for one month. Dissected tumors revealed a reduction in adrenal gland tumors corresponding to a 54 % (P < 0.005) reduction in total adrenal gland tumor weight of the treated mice as compared to vehicle-treated controls. Western blot analysis of the harvested tissues showed a reduction in Rap1A geranylgeranylation in adrenal glands and mesenteric tumors of the treated mice while non-tumorous tissues and control mice showed no Rap1A alteration. Our findings detail a novel bisphosphonate compound capable of preferentially altering the IBP in tumor-burdened adrenal glands of a murine model of PCa metastasis.


Health status profiles in community-dwelling elderly using self-reported health indicators: a latent class analysis.
Latent class analysis (LCA), a statistical method for identifying latent classes within a population using multiple indicators, has been used to study the heterogeneity of health among the elderly. We aim to identify health status profiles of older adults using LCA and examine the socio-demographic characteristics associated with each profile. A community health survey of residents ≥60 years was conducted in Marine Parade, Singapore. We performed LCA on seven health indicators (number of chronic conditions, activities of daily living (ADL) dependency, pain, depression, cognition, social isolation, and frequency of socialising) to identify distinct classes of health status profiles. Multivariable logistic regression was conducted to examine the socio-demographic characteristics associated with each profile. Of the 2,444 elderly interviewed, we identified two health status profiles: "Health at risk" (n = 465, 19.0 %), and "Relatively healthy" (n = 1,979, 81.0 %). The "Health at risk" profile was characterised by high probabilities of 3+ chronic conditions (λ = 0.63), at least one basic/instrumental ADL dependency (λ = 0.56), moderate/extreme pain (λ = 0.55), cognitive impairment (λ = 0.29), depressive symptoms (λ = 0.29), social isolation (λ = 0.27), and infrequent socialisation (λ = 0.61). Individuals who were older (65-74, 75-84, and 85+ years), females, of non-Chinese ethnicity (Indian, Malay, and Others), had primary and lower education, and were unemployed/not employed were more likely to be "Health at risk". Using LCA, we identified two distinct health status profiles which accounted for the heterogeneity of the elderly population. Selected socio-demographic characteristics were associated with different profiles and provide implications for the structuring of future public health interventions targeting the older population.


Browsing preference and ecological carrying capacity of sambar deer (Cervus unicolor brookei) on secondary vegetation in forest plantation.
The browsing preference and ecological carrying capacity (ECC) of sambar deer (Cervus unicolor brookei) in acacia plantations for management and conservation of the ecosystem were investigated at Sabal Forest Reserve in Sarawak, Malaysia. The identification of the species browsed by the sambar deer was based on an observation of the plant parts consumed. ECC estimation was based on body weight (BW) and the physiological stages of animals browsed in six fenced 4-ha paddocks. Sambar deer were found foraging on only 29 out of 42 species of secondary vegetation in the acacia plantation. The remaining species are too high for the deer to reach. Planted species, Shorea macrophylla are not palatable to the deer. This augurs well for the integration of sambar deer into shorea plantations. The most frequently exploited plants were Ficus spp. Sambar deer preferred woody species more than non-woody species and they are browser animals. By producing metabolizable energy of 19,000 to 27,000 MJ/ha, the ECC was five head/ha to 5.25 head/ha. Given its contribution to the conservation of wildlife and its capacity to sustain the ecosystem, the sambar deer integrated farming system offers a promising strategy for the future of tropical forestry management.


Borrelia burgdorferi and the causative agent of human granulocytic ehrlichiosis in deer ticks, Delaware.
During the 1998 hunting season in Delaware, 1,480 ticks were collected from 252 white- tailed deer; 98% were Ixodes scapularis, a significant increase from the 85% reported in 1988. Ticks were tested for Borrelia burgdorferi and the causative agent of human granulocytic ehrlichiosis. Infection rates remained stable in New Castle and Kent counties, but increased from <1% to 8% in sussex county.


Development and preliminary psychometric properties of a well-being index for medical students.
Psychological distress is common among medical students but manifests in a variety of forms. Currently, no brief, practical tool exists to simultaneously evaluate these domains of distress among medical students. The authors describe the development of a subject-reported assessment (Medical Student Well-Being Index, MSWBI) intended to screen for medical student distress across a variety of domains and examine its preliminary psychometric properties. Relevant domains of distress were identified, items generated, and a screening instrument formed using a process of literature review, nominal group technique, input from deans and medical students, and correlation analysis from previously administered assessments. Eleven experts judged the clarity, relevance, and representativeness of the items. A Content Validity Index (CVI) was calculated. Interrater agreement was assessed using pair-wise percent agreement adjusted for chance agreement. Data from 2248 medical students who completed the MSWBI along with validated full-length instruments assessing domains of interest was used to calculate reliability and explore internal structure validity. Burnout (emotional exhaustion and depersonalization), depression, mental quality of life (QOL), physical QOL, stress, and fatigue were domains identified for inclusion in the MSWBI. Six of 7 items received item CVI-relevance and CVI-representativeness of >or=0.82. Overall scale CVI-relevance and CVI-representativeness was 0.94 and 0.91. Overall pair-wise percent agreement between raters was >or=85% for clarity, relevance, and representativeness. Cronbach's alpha was 0.68. Item by item percent pair-wise agreements and Phi were low, suggesting little overlap between items. The majority of MSWBI items had a >or=74% sensitivity and specificity for detecting distress within the intended domain. The results of this study provide evidence of reliability and content-related validity of the MSWBI. Further research is needed to assess remaining psychometric properties and establish scores for which intervention is warranted.


[The minimally invasive surgical access to the thyroid and parathyroid glands through the oral cavitiy].
The use of minimally invasive surgical access and technologies allows the substantial improvement in rates of the postoperative rehabilitation, shorten the hospital stay and improve the cosmtic result of the operation. The thorough topographic description of the transoral access to the thyroid and parathyroid glands is highlighted in the article. The construction of the original wound expander is depicted. The operative technique of the hemythyroidectomy is expamled.


Theoretical design and mechanistic study of the metal-free reduction of CO2 to CO.
A strategy for the reduction of CO2 to CO by or catalyzed by metal-free silylboranes has been proposed with the aid of density functional theory (DFT) computations. We showed that one oxygen atom of CO2 can be abstracted by silylboranes without catalysts or by diboranes in the presence of silylborane catalysts with surprisingly low free-energy barriers so that the reaction can be realized under mild experimental conditions. To achieve this, the reduction mechanism of CO2 by a hierarchy of silylboranes (R1)2BSi(R2)3 was systematically investigated. Several rules of thumb were obtained to guide the design of silylboranes with high activity toward CO2 reduction. After considering many factors, such as side reactions, the stability of the silylboranes, and the solvent effect, two silylboranes, (PFP)2BSi(CH2F)3 and Me2BSi(CH2F)3, suitable for the reduction of CO2 under mild experimental conditions were designed. The overall free-energy barriers for the reduction of CO2 by the two silylboranes are just 26.1-27.0 kcal mol-1 and 28.1-28.9 kcal mol-1, respectively, at 298.15 K in solution. We further showed that CO2 can be reduced to CO by diborane Me2BBMe2 using Me2BSi(CH2F)3 as the catalyst. The overall free-energy barrier for this catalytic reaction is just 30.6-30.7 kcal mol-1 at 298.15 K in solution.


Marek's Disease Virus Virulence Genes Encode Circular RNAs.
Circular RNAs (circRNAs) are a recently rediscovered class of functional noncoding RNAs that are involved in gene regulation and cancer development. Next-generation sequencing approaches identified circRNA fragments and sequences underlying circularization events in virus-induced cancers. In the present study, we performed viral circRNA expression analysis and full-length sequencing in infections with Marek's disease virus (MDV), which serves as a model for herpesvirus-induced tumorigenesis. We established inverse PCRs to identify and characterize circRNA expression from the repeat regions of the MDV genome during viral replication, latency, and reactivation. We identified a large variety of viral circRNAs through precise mapping of full-length circular transcripts and detected matching sequences with several viral genes. Hot spots of circRNA expression included the transcriptional unit of the major viral oncogene encoding the Meq protein and the latency-associated transcripts (LATs). Moreover, we performed genome-wide bioinformatic analyses to extract back-splice junctions from lymphoma-derived samples. Using this strategy, we found that circRNAs were abundantly expressed in vivo from the same key virulence genes. Strikingly, the observed back-splice junctions do not follow a unique canonical pattern, compatible with the U2-dependent splicing machinery. Numerous noncanonical junctions were observed in viral circRNA sequences characterized from in vitro and in vivo infections. Given the importance of the genes involved in the transcription of these circRNAs, our study contributes to our understanding and complexity of this deadly pathogen. IMPORTANCE Circular RNAs (circRNAs) were rediscovered in recent years both in physiological and pathological contexts, such as in cancer. Viral circRNAs are encoded by at least two human herpesviruses, the Epstein Barr virus and the Kaposi's Sarcoma-associated herpesvirus, both associated with the development of lymphoma. Marek's disease virus (MDV) is a well-established animal model to study virus-induced lymphoma but circRNA expression has not been reported for MDV yet. Our study provided the first evidence of viral circRNAs that were expressed at key steps of the MDV lifecycle using genome-wide analyses of circRNAs. These circRNAs were primarily found in transcriptional units that corresponded to the major MDV virulence factors. In addition, we established a bioinformatics pipeline that offers a new tool to identify circular RNAs in other herpesviruses. This study on the circRNAs provided important insights into major MDV virulence genes and herpesviruses-mediated gene dysregulation.


Antigens expressed on NIH 3T3 cells following transformation with DNA from human pancreatic tumor.
This report documents that the pancreatic adenocarcinoma cell line, HPAF, contains oncogene activity detected by transformation of NIH 3T3 cells through transfection with HPAF DNA. The HPAF transfected NIH 3T3 cells do not contain oncogenes homologous with c-H-ras, c-K-ras, c-N-ras, v-fms, c-myb, c-sis, v-fgr, c-mos, c-myc, c-fos, v-fes, v-src, v-erb A, v-erb B, c-N-myc, v-raf, or v-abl, other than the endogenous mouse genes. The transfectants do express proteins detected by two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis which were not found in nontransfected NIH 3T3 cells. Monoclonal antibodies raised against the transfectants recognize proteins not found in untransfected NIH 3T3 cells that are antigenically identical to proteins found in the HPAF cells. These antigens are also detected on six other human pancreatic adenocarcinoma cell lines but show a much more restricted distribution on lymphoblastoid, melanoma, prostatic carcinoma, and normal skin fibroblast cell lines.


The mysterious appearance of enterococci in filled root canals.
In this narrative review, the potential reasons for the high occurrence of enterococci in filled root canals are explored. The pulpless root canal appears to be a habitat for these bacteria, particularly for Enterococcus faecalis. However, re-surveying the literature in caries research, it can be concluded that, contrary to earlier belief, enterococci are rare if ever found at the advancing front of dentinal lesions. The same is the case for true primary endodontic infections, but some uncertainty remains, because the coronal seal and the history of teeth harbouring enterococci have rarely been accurately investigated. Furthermore, from longitudinal studies with a known infection at the initiation of treatment, which was carried out under controlled asepsis, it is questionable whether enterococci are as difficult to eliminate from the canal system as is commonly held. A more likely explanation for the high occurrence of enterococci in filled root canals is that they enter after treatment, but from which source? The intriguing finding in this context is that enterococci do not appear to be colonizers of the oral cavity. They are merely transient oral bacteria, unless there is a predilection site such as the unsealed necrotic or filled root canal. The origin of this infection is most likely food. Using the example of enterococci in filled root canals, this paper highlights the possible importance of transient microorganisms in the oral cavity and changes in a microenvironment that can create favourable conditions for infection.


The effect of therapeutic exercise in the prevention of lymphoedema secondary to breast cancer: a systematic review.
One of the most frequent complications of breast cancer treatment is lymphoedema (LE), with lymphadenectomy and radiotherapy being the main triggers of this pathology in developed countries. The aim of the study was to determine the efficacy of therapeutic exercise in the prevention of upper limb (UL) lymphoedema evaluated through cirtometry, volumetry, or bioimpedance spectroscopy (BIS) in women after breast cancer removal surgery. The Pubmed, PEDro, and Cochrane databases were consulted up to May 2020, including randomised clinical trials (RCTs) on therapeutic physical exercise as a possible preventive measure against breast cancer-related lymphoedema (BCRL). The studies were requested to have participants with UL lymphoedema and a control group. A total of 304 articles were found, of which 9 were included (stand-alone studies). A therapeutic exercise program (strength and/or aerobic training) in women who had been surgically intervened for breast cancer may prevent lymphedema, compared to a regular care. A therapeutic exercise program (strength and/or aerobic training) in women operated on for breast cancer contributes to reducing the number of cases that could obtain a greater difference in volume in their upper limbs, compared to a regular care program. However, further research is necessary to affirm that therapeutic physical exercise prevents BCRL.


Suppressor of cytokine signaling 1 DNA administration inhibits inflammatory and pathogenic responses in autoimmune myocarditis.
Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4(+) T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.


Accounting for the Presence of Molecular Clusters in Modeling and Interpreting Nucleation and Growth.
The effect of molecular cluster formation on the estimation of kinetic parameters for primary nucleation and growth in different systems has been studied using computationally generated data and three sets of experimental data in the literature. It is shown that the formation of molecular clusters decreases the concentration of monomers and hence the thermodynamic driving force for crystallization, which consequently affects the crystallization kinetics. For a system exhibiting a strong tendency to form molecular clusters, accounting for cluster formation in a kinetic model is critical to interpret kinetic data accurately, for instance, to estimate the specific surface energy γ from a set of primary nucleation rates. On the contrary, for a system with negligible cluster formation, a consideration of cluster formation does not affect parameter estimation outcomes. Moreover, it is demonstrated that using a growth kinetic model that accounts for cluster formation allows the estimation of γ from typical growth kinetic data (i.e., de-supersaturation profiles of seeded batch crystallization), which is a novel method of estimating γ developed in this work. The applicability of the novel method to different systems is proven by showing that the estimated values of γ are closely comparable to the actual values used for generating the kinetic data or the corresponding estimates reported in the literature.


The regulation of natural anticoagulant pathways.
Vascular endothelium plays an active role in preventing blood clot formation in vivo. One mechanism by which prevention is achieved involves a cell surface thrombin-binding protein, thrombomodulin, which converts thrombin into a protein C activator. Activated protein C then functions as an anticoagulant by inactivating two regulatory proteins of the coagulation system, factors Va and VIIIa. The physiological relevance of the protein C anticoagulant pathway is demonstrated by the identification of homozygous protein C--deficient infants with severe thrombotic complications. Recent studies suggest that this pathway provides a link between inflammation and coagulation.


Foodborne outbreaks in northern Portugal, 2002.
In October 2001, foodborne outbreaks (FBO) were included in the Portuguese alert and response surveillance system. Accordingly, the northern regional health authority (Delegado Regional de Saude do Norte--DRSN) began a surveillance programme of foodborne outbreaks. This report is a brief description of data generated from this programme in 2002. For each foodborne outbreak the local health authority (Delegado de Saude Concelhio--DSC) produced a written report. Fifty-nine percent of the 27 FBOs studied by DSCs during 2002 were reported within 72 hours after the date of onset. Five hundred and seventy seven people became ill, 9.6% of the patients were admitted to hospital, and no deaths were reported. The aetiological agent was identified from patients in 63% of FBOs, and in food items in 18.5% of the situations. Salmonella enterica was responsible for 73.7% of the outbreaks in which the agent was laboratory confirmed. Meals implicated in the outbreak were mainly prepared in restaurants and private homes (75.0% of FBO). Inadequate processing, preparing or handling of foods were the contributing factors more often reported by the DSC. We believe that epidemiological surveillance and control of FBO must be reinforced in Portugal as part of a wider strategy to promote food safety.


Pharmacokinetics and pharmacodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys.
The pharmacokinetics (PK) of SB-240563 have been investigated after i.v. and s.c. administration to cynomolgus monkeys. Approximately linear PK was observed following i.v. administration over a 6000-fold dose range (0.05-300 mg/kg). After i.v. dosing, SB-240563 concentration declined in a biexponential manner with a mean terminal half-life of 13 +/- 2 days. The plasma clearance and volume of distribution at steady state were approximately 0.2 ml/h/kg and 70 ml/kg, respectively. Following s.c. administration, SB-240563 was completely absorbed into the systemic circulation. Because interleukin-5 is known to stimulate production, activation, and maturation of eosinophils, eosinophil counts were measured to assess pharmacologic activity of SB-240563. The maximal response (81-96% decrease in eosinophil count relative to baseline) following a single s.c. administration occurred at 3 weeks postdosing. Suppression of eosinophil count also was observed following multiple monthly administrations of SB-240563 to monkeys. The pharmacokinetic/pharmacodynamic relationship was generally well described with an indirect pharmacologic response model with an estimated IC(50) value of 1.43 microg/ml. The combination of a low IC(50) value for reduction of circulating eosinophils and a long terminal half-life suggests the possibility of an infrequent dosing regimen for SB-240563 for treatment of diseases associated with increased eosinophil function such as asthma.


Photoperiod differentially regulates clock genes' expression in the suprachiasmatic nucleus of Syrian hamster.
The suprachiasmatic nuclei (SCN) contain the master circadian pacemaker in mammals. Generation and maintenance of circadian oscillations involve clock genes which interact to form transcriptional/translational loops and constitute the molecular basis of the clock. There is some evidence that the SCN clock can integrate variations in day length, i.e. photoperiod. However, the effects of photoperiod on clock-gene expression remain largely unknown. We here report the expression pattern of Period (Per) 1, Per2, Per3, Cryptochrome (Cry) 1, Cry2, Bmal1 and Clock genes in the SCN of Syrian hamsters when kept under long (LP) and short (SP) photoperiods. Our data show that photoperiod differentially affects the expression of all clock genes studied. Among the components of the negative limb of the feedback loop, Per1, Per2, Per3, Cry2 but not Cry1 genes show a shortened duration of their peak expression under SP compared with LP. Moreover, mRNA expression of Per1, Per3 and Cry1 are phase advanced in SP compared with LP. Per3 shows an mRNA peak of higher amplitude under SP conditions whereas Per1 and Per2 peak amplitudes are unaffected by photoperiod changes. Bmal1 expression is phase advanced without a change of duration in SP compared with LP. Furthermore, the expression of Clock is rhythmic under SP whereas no rhythm is observed under LP. These results, which provide further evidence that the core clock mechanisms of the SCN integrate photoperiod, are discussed in the context of the existing molecular model.


Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo.
Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. We explored integrin expression in patients with IBD by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanised mouse model in dextran sodium sulfate-treated immunodeficient mice. High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. T cell receptor stimulation and transforming growth factor β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from patients with IBD under vedolizumab therapy. AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD.


Association between labor union presence and return to work after occupational injury or illness: A nationally representative longitudinal study in South Korea.
This study sought to examine the association between labor union presence and return to work after occupational injury or illness (RTW) among workers in South Korea. We analyzed the first (2018) and second (2019) wave data from the Panel Study of Workers' Compensation Insurance in South Korea. The cohort consisted of 3,294 workers who had suffered occupational injury or illness and completed their convalescence by 2017. We examined whether RTW was associated with the presence of labor unions in the workplace at the time of the occupational injury or illness occurred. Compared to workers without labor unions, those with labor unions were more likely to report RTW (prevalence ratio: 1.35, 95% confidence interval: 1.20-1.51) after adjusting for potential confounders, including employment status, duration of convalescence, and severity of injury or illness. This study found that labor union presence was associated with RTW among workers who suffered occupational injury or illness in South Korea.


Cell death and apoptosis in osteoarthritic cartilage.
Osteoarthritis (OA) is the most common chronic joint disease in the elderly population, causing significant pain and disability. Because the cardinal feature of OA is a progressive loss of articular cartilage, a great portion of the research endeavour into the pathogenesis of OA has been focused on the regulation of matrix synthesis and degradation. The phenotypic stability and survival of the chondrocytes are essential for the maintenance of a proper cartilage matrix. This has lead to the long-standing assumption that cell death is a central feature in OA cartilage degeneration. The important role of apoptosis in OA has been demonstrated in in vitro and in vivo models. However, it should be noted that the relative contribution of apoptotic cell death in the pathogenesis of OA is still difficult to assess because of the chronic nature of the disease process. Therefore, the apoptosis of chondrocytes seems to be a potential target for therapeutic interventions in OA. The death receptor, mitochondrial and endoplasmic reticulum pathways are the major cellular pathways of apoptosis. Of all these elements involved in the apoptosis of chondrocytes, caspase inhibition has been studied with the most detail. Other molecules with the capacity to modulate mitochondria function, phosphatase (PP-1A/B) activity and pro-apoptosis stimuli (NO, prostaglandins, cytokines, ROS) could be excellent targets to block apoptosis of chondrocytes. Finally, the regulation of the natural inhibitors of apoptosis (c-FLIP, BAR, ARC and HC-gp39) could complement the other strategies to reduce cartilage degradation.


Future Economics of Liver Transplantation: A 20-Year Cost Modeling Forecast and the Prospect of Bioengineering Autologous Liver Grafts.
During the past 20 years liver transplantation has become the definitive treatment for most severe types of liver failure and hepatocellular carcinoma, in both children and adults. In the U.S., roughly 16,000 individuals are on the liver transplant waiting list. Only 38% of them will receive a transplant due to the organ shortage. This paper explores another option: bioengineering an autologous liver graft. We developed a 20-year model projecting future demand for liver transplants, along with costs based on current technology. We compared these cost projections against projected costs to bioengineer autologous liver grafts. The model was divided into: 1) the epidemiology model forecasting the number of wait-listed patients, operated patients and postoperative patients; and 2) the treatment model forecasting costs (pre-transplant-related costs; transplant (admission)-related costs; and 10-year post-transplant-related costs) during the simulation period. The patient population was categorized using the Model for End-Stage Liver Disease score. The number of patients on the waiting list was projected to increase 23% over 20 years while the weighted average treatment costs in the pre-liver transplantation phase were forecast to increase 83% in Year 20. Projected demand for livers will increase 10% in 10 years and 23% in 20 years. Total costs of liver transplantation are forecast to increase 33% in 10 years and 81% in 20 years. By comparison, the projected cost to bioengineer autologous liver grafts is $9.7M based on current catalog prices for iPS-derived liver cells. The model projects a persistent increase in need and cost of donor livers over the next 20 years that's constrained by a limited supply of donor livers. The number of patients who die while on the waiting list will reflect this ever-growing disparity. Currently, bioengineering autologous liver grafts is cost prohibitive. However, costs will decline rapidly with the introduction of new manufacturing strategies and economies of scale.


Endurance swimming activates trout lipoprotein lipase: plasma lipids as a fuel for muscle.
Fish endurance swimming is primarily powered by lipids supplied to red muscle by the circulation, but the mechanism of delivery remains unknown. By analogy to mammals, previous studies have focused on non-esterified fatty acids (NEFA bound to albumin), but lipoproteins have not been considered as an energy shuttle to working muscles. The effects of exercise on fish lipoprotein lipase (LPL) have never been investigated. We hypothesized that LPL and circulating lipoproteins would be modified by prolonged swimming. Because LPL is naturally bound to the endothelium, we have used heparin to release the enzyme in the circulation and to characterize reserve capacity for lipoprotein catabolism. The effects of exercise (4 days at 1.5 body lengths s(-1) in a swim tunnel) were measured for red muscle LPL, post-heparin plasma LPL, and lipoprotein concentration/composition. Red muscle LPL activity increased from 18+/-5 (rest) to 49+/- 9 nmol fatty acids min(-1) g(-1) (swimming). In resting fish, heparin administration caused a 27-fold increase in plasma LPL activity that reached a maximum of 1.32+/- 0.67 micromol fatty acids min(-1) ml(-1) plasma. This heparin-induced response of plasma LPL was not different between resting controls and exercised fish. Heparin or prolonged swimming had no effect on the concentration/composition of lipoproteins that contain 92% of the energy in total plasma lipids. We conclude that (1) red muscle LPL is strongly activated by endurance swimming, (2) rainbow trout have a high reserve capacity for hydrolyzing lipoproteins, and (3) future studies should aim to measure lipoprotein flux because their concentration does not reflect changes in flux. These novel characteristics of fish LPL imply that lipoproteins are used as a metabolic shuttle between fat reserves and working muscles, a strategy exploiting an abundant source of energy in rainbow trout.


Involvement of C-Terminal Histidines in Soybean PM1 Protein Oligomerization and Cu2+ Binding.
Late embryogenesis abundant (LEA) proteins are widely distributed among plant species, where they contribute to abiotic stress tolerance. LEA proteins can be classified into seven groups according to conserved sequence motifs. The PM1 protein from soybean, which belongs to the Pfam LEA_1 group, has been shown previously to be at least partially natively unfolded, to bind metal ions and potentially to stabilize proteins and membranes. Here, we investigated the role of the PM1 C-terminal domain and in particular the multiple histidine residues in this half of the protein. We constructed recombinant plasmids expressing full-length PM1 and two truncated forms, PM1-N and PM1-C, which represent the N- and C-terminal halves of the protein, respectively. Immunoblotting and cross-linking experiments showed that full-length PM1 forms oligomers and high molecular weight (HMW) complexes in vitro and in vivo, while PM1-C, but not PM1-N, also formed oligomers and HMW complexes in vitro. When the histidine residues in PM1 and PM1-C were chemically modified, oligomerization was abolished, suggesting that histidines play a key role in this process. Furthermore, we demonstrated that high Cu2+ concentrations promote oligomerization and induce PM1 and PM1-C to form HMW complexes. Therefore, we speculate that PM1 proteins not only maintain ion homeostasis in the cytoplasm, but also potentially stabilize and protect other proteins during abiotic stress by forming a large, oligomeric molecular shield around biological targets.


Triple phase boundary photovoltammetry: resolving rhodamine B reactivity in 4-(3-phenylpropyl)-pyridine microdroplets.
Rhodamine B base is employed as a photoactive redox system in a liquid | liquid | electrode triple phase boundary electrochemical experiment. Microdroplets of the water-immiscible 3-(4-phenylpropyl)-pyridine (PPP) containing rhodamine B are deposited onto a basal plane pyrolytic graphite electrode surface which is then immersed into an aqueous solution containing 0.5 M phosphate buffer solution (pH 12). In cyclic voltammetry experiments, it is shown that dark reduction of rhodamine B to leuco-rhodamine B in PPP occurs in two steps--both one electron processes--and the re-oxidation occurs in a single two-electron process. Voltammetric signals are consistent with Na(+) transfer (for the first reduction step) and proton transfer (for the second reduction step) coupled to the electron transfer. A proton-driven disproportionation reaction (with k(dis)=3 mol(-1) dm(3) s(-1) at pH 12) is observed for the one-electron reduced intermediate. In the presence of light, a new photocatalysed oxidation process for the two-electron conversion of leuco-rhodamine B to rhodamine B is observed. Photoexcitation of rhodamine B is shown to trigger an effective photo-comproportionation mechanism. Quantitative insights into the dark and photomechanisms are obtained by comparison of rhodamine B and rhodamine B octadecylester and by applying an approximate numerical simulation procedure based on DigiSim.


Potential therapeutic role of Tridham in human hepatocellular carcinoma cell line through induction of p53 independent apoptosis.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths reported worldwide. The incidence is higher in Asia and Africa, where there is greater endemic prevalence of hepatitis B and C. The devastating outcome of cancer can be minimized only by the use of potent therapeutic agents. Tridham (TD) has been acknowledged since olden days for its wide spectrum of biological properties and was used by traditional practitioners of Siddha and other indigenous systems of medicine. The present study aims at investigating the mechanistic action of TD by assessing the antiproliferative and pro-apoptotic effects on human hepatocellular carcinoma cell line (Huh7). Cell viability and apoptosis assay using MTT analysis and trypan blue staining, DAPI staining, DNA fragmentation, cell cycle analysis, mitochondrial membrane potential, real-time reverse transcription-polymerase chain reaction, western blotting and immunofluorescence staining were determined in Huh7 cells. Viability studies of TD treated Huh7 cells showed an inhibition in cell growth in time and dose dependent manner. Chromatin condensation, DNA fragmentation and apoptotic bodies, which are structural changes characteristic of apoptosis, were found following TD treatment of Huh7 cells. DAPI staining and agarose gel electrophoresis confirmed the induction of apoptosis by TD. Cell cycle analysis of Huh7 cells treated with TD exhibited a marked accumulation of cells in the sub-G1 phase of the cell cycle in a dose dependent manner. Immunofluorescent staining for Ki-67 showed a higher level of expression in untreated cells as compared to TD treated cells. We observed a significant loss in the mitochondrial membrane potential and the release of cytochrome c into the cytosol in TD treated cells. Down regulation of Bcl-2, up regulation of Bax and Bad as well as activation of caspases-3 and 9 were also observed. The p53 gene expression was found to be unaltered in TD treated cells. These results suggest that TD induces apoptosis of Huh7 cells through activation of Bax and triggered caspase cascade, independent of p53 function. This study throws light on the mechanistic action of TD in triggering apoptosis in Huh 7 cells.


[From inquiry to interactive communication].
Three functions of communication are distinguishable in the practice of dentists: the function directly related to the treatment, the function related to 'informed consent' and the preventive function. For these three functions different communication-models are applicable: communication as transfer-of-information, communication as persuasion and communication as interaction. It is argued that the interaction model of communication is the most promising model nowadays.


Tear dynamics and corneal confocal microscopy of subjects with mild self-reported office dry eye.
To investigate changes in tear dynamics and corneal microstructure in mild self-reported office dry eye. Prospective laboratory investigation. Twenty healthy office workers, 20 office workers with mild self-reported dry eye, and 20 office workers with moderate to severe dry eye as determined by the Ocular Surface Disease Index (OSDI). Real-time anterior segment optical coherence tomography was used to obtain upper (UTMV), lower (LTMV), tear meniscus volumes. The total tear meniscus volume (TTMV) was the sum of the UTMV and LTMV. This was followed by measurement of noninvasive tear breakup time (NITBUT), fluorescein tear breakup time (FTBUT), fluorescein staining, Schirmer I test, and in vivo confocal microscopy of cornea. Upper tear meniscus volume, LTMV, TTMV, NITBUT, fluorescein tear FTBUT, fluorescein staining, Schirmer I test, and in vivo confocal microscopy of cornea. There were no significant differences in UTMV and LTMV between the control and mild self-reported dry eye groups (P>0.05). These values in the moderate to severe dry eye group were significantly lower than those in the control and mild dry eye groups (P<0.01). Both mild and moderate to severe office dry eye groups had decreased NITBUT (P<0.05 each) and FTBUT (P<0.01 each) compared with controls. On the basis of receiver operating characteristic curves, the cutoff value for abnormal FTBUT was 3.3 seconds, yielding good diagnostic accuracy with a sensitivity of 0.75 and specificity of 0.80. For NITBUT, when the cutoff time was 9.7 seconds, the sensitivity was 0.90 and specificity was 0.50. The moderate to severe office dry eye group had decreased Schirmer I test values and increased subbasal nerve tortuosity compared with the mild office dry eye and control groups (P<0.05 each). Both the mild dry eye and moderate to severe dry eye groups had decreased cell densities in superficial, intermediate, and basal epithelial layers compared with the controls (P<0.05 each). Although the quantity of tears in patients with mild self-reported office dry eye was not decreased, ocular surface damage was present.


Immunological control of a murine gammaherpesvirus independent of CD8+ T cells.
Adult thymectomized C57 BL/6J mice were depleted of T cell subsets by MAb treatment either prior to, or after, respiratory challenge with murine gammaherpesvirus-68. Protection against acute infection was maintained when either the CD4+ or the CD8+ T cell population was greatly diminished, whereas the concurrent removal of both T cell subsets proved invariably fatal. The same depletions had little effect on mice with established infection. The results indicate firstly that both CD4+ and CD8+ T cells play a significant part in dealing with the acute infection, and secondly that virus-specific antibody contributes to controlling persistent infection with this gammaherpesvirus.


The Fried frailty criteria as inclusion criteria for a randomized controlled trial: personal experience and literature review.
among current operational definitions of frailty, the criteria proposed by Fried and colleagues have attracted great scientific interest. However, these criteria have usually been applied in epidemiological and only rarely in interventional studies. the present paper aims at testing the applicability of the Fried frailty criteria in the context of the recruitment process of a randomized controlled trial in prefrail older persons, and it discusses the respective scientific literature. recruitment was promoted by newspaper articles as well as by targeted mail to customers of a local health insurance company and to recently treated patients of a geriatric day clinic. Furthermore, presentations were given in assisted living facilities. Potential candidates were screened for prefrailty, i.e. to see whether they met 1 or 2 of the Fried criteria (weight loss, handgrip strength, gait speed, exhaustion, physical activity). a total of 298 people were screened. Among them 181 were not frail, 116 were prefrail and 1 was diagnosed as frail. The most prevalent criterion was exhaustion (24% of those screened). The second most prevalent criterion was low handgrip strength (20%). Low gait speed (8%), low physical activity (2%) and weight loss (2%) had a lower prevalence. According to the Geriatric Depression Scale, 14% of those who met the criterion 'exhaustion' were depressed. With regard to the Minnesota Leisure Time Physical Activity Questionnaire, used for the evaluation of 'physical activity', only 3 activities among the 18 selected by Fried were applicable to our cohort. under the study conditions, good applicability of the Fried criteria was observed. Nevertheless, further refinement may be expedient in several criteria, especially exhaustion and physical activity, to enhance clinical usefulness. It may be helpful to adapt the cutoffs when applying the criteria to a European population.


The clinical usefulness of routine stacked multiplanar reconstruction in helical abdominal computed tomography.
The authors evaluate the usefulness of stacked multiplanar reconstructions in routine, thick-section abdominal computed tomography. Twenty-five routine, thick-section contrast abdominal CTs performed with equivalent technique were reformatted by multiplanar reconstructions in sagittal and coronal planes sequentially from side-to-side and front-to-back. The image sets were submitted, first axial images only followed by axial plus multiplanar reconstructions (MPRs), to 5 separate physician readers including 2 radiologists and 3 nonradiologists. These readers graded the visualization of a variety of normal and up to 5 pathologic lesions per patient on a scale of 1 to 5 (5 = best). The addition of sagittal and coronal multiplanar reconstructions significantly improved the visualization of all normal anatomic structures (mean axial only, 3.8; mean axial plus MPR, 4.1; P < 0.0001). In addition, most pathologic lesions were statistically better visualized with the addition of multiplanar reconstructions (mean axial images only, 3.9; mean axial plus MPR, 4.1; P < 0.0001). All five readers found improved visualization in nearly every category with the addition of the multiplanar reconstructions. However, in only 7% of cases, did a reviewer find new diagnostic information with the addition of MPR images. Stacked multiplanar reconstructions of routine, thick-section abdominal CT has clinical value in both the display of normal anatomic and pathologic lesions. Further studies, however, are required to confirm these findings before it is commonly used.


Clock genes, melanopsins, melatonin, and dopamine key enzymes and their modulation by light and glutamate in chicken embryonic retinal cells.
The avian circadian system is composed of the retina, the mammalian homolog region of the suprachiasmatic nucleus (SNC), and the pineal gland. The retina, itself, displays many rhythmic physiological events, such as movements of photoreceptor cells, opsin expression, retinal reisomerization, and melatonin and dopamine production and secretion. Altogether, these rhythmic events are coordinated to predict environmental changes in light conditions during the day, optimizing retina function. The authors investigated the expression pattern of the melanopsin genes Opn4x and Opn4m, the clock genes Clock and Per2, and the genes for the key enzymes N-Acetyltransferase and Tyrosine Hidroxylase in chicken embryo dispersed retinal cells. Primary cultures of chicken retina from 8-day-old embryos were kept in constant dark (DD), in 12-h light/12-h dark (12L:12D), in 12L:12D followed by DD, or in DD in the absence or presence of 100 µM glutamate for 12 h. Total RNA was extracted throughout a 24-h span, every 3 h starting at zeitgeber time 0 (ZT0) of the 6th day, and submitted to reverse transcriptase-polymerase chain reaction (RT-PCR) followed by quantitative PCR (qPCR) for mRNA quantification. The data showed no rhythmic pattern of transcription for any gene in cells kept in DD. However under a light-dark cycle, Clock, Per2, Opn4m, N-Acetyltransferase, and Tyrosine Hydroxylase exhibited rhythmic patterns of transcription. In DD, 100 µM glutamate was able to induce rhythmic expression of Clock, strongly inhibited the expression of Tyrosine Hydroxylase, and, only at some ZTs, of Opn4x and Opn4m. The neurotransmitter had no effect on Per2 and N-Acetyltransferase transcription. The authors confirmed the expression of the protein OPN4x by immunocytochemistry. These results suggest that chicken embryonic retinal cells contain a functional circadian clock, whose synchronization requires light-dark cycle or glutamate stimuli.


External Validation of Proposed American Heart Association Algorithm for Cardiovascular Screening Before Kidney Transplantation.
Screening for cardiovascular disease is currently recommended before kidney transplantation. The present study aimed to validate the proposed algorithm by the American Heart Association (AHA-2022) considering cardiovascular findings and outcomes in kidney transplant candidates, and to compare AHA-2022 with the previous recommendation (AHA-2012). We applied the 2 screening algorithms to an observational cohort of kidney transplant candidates (n=529) who were already extensively screened for coronary heart disease by referral to cardiac computed tomography between 2014 and 2019. The cohort was divided into 3 groups as per the AHA-2022 algorithm, or into 2 groups as per AHA-2012. Outcomes were degree of coronary heart disease, revascularization rate following screening, major adverse cardiovascular events, and all-cause death. Using the AHA-2022 algorithm, 69 (13%) patients were recommended for cardiology referral, 315 (60%) for cardiac screening, and 145 (27%) no further screening. More patients were recommended cardiology referral or screening compared with the AHA-2012 (73% versus 53%; P<0.0001). Patients recommended cardiology referral or cardiac screening had a higher risk of major adverse cardiovascular events (hazard ratio [HR], 5.5 [95% CI, 2.8-10.8]; and HR, 2.1 [95% CI, 1.2-3.9]) and all-cause death (HR, 12.0 [95% [CI, 4.6-31.4]; and HR, 5.3 [95% CI, 2.1-13.3]) compared with patients recommended no further screening, and were more often revascularized following initial screening (20% versus 7% versus 0.7%; P<0.001). The AHA-2022 algorithm allocates more patients for cardiac referral and screening compared with AHA-2012. Furthermore, the AHA-2022 algorithm effectively discriminates between kidney transplant candidates at high, intermediate, and low risk with respect to major adverse cardiovascular events and all-cause death.


Genital Abnormalities, Hormonal Contraception, and Human Immunodeficiency Virus Transmission Risk in Rwandan Serodifferent Couples.
We explored the role of genital abnormalities and hormonal contraception in human immunodeficiency virus (HIV) transmission among heterosexual serodifferent couples in Rwanda. From 2002 to 2011, HIV-serodifferent couples who were not using antiretroviral treatment were followed up, and sociodemographic and clinical data were collected, family planning provided, and HIV-negative partners retested. Couples were assessed for genital ulcers; nonulcerative genital sexually transmitted infection (STIs), including gonorrhea, chlamydia, and trichomoniasis; and non-STI vaginal infections, including bacterial vaginosis and candida. Multivariable models evaluated associations between covariates and HIV transmission genetically linked to the index partner. Among 877 couples in which the man was HIV positive, 37 linked transmissions occurred. Factors associated with women's HIV acquisition included genital ulceration in the female partner (adjusted hazard ratio, 14.1) and nonulcerative STI in the male partner (8.6). Among 955 couples in which the woman was HIV positive, 46 linked transmissions occurred. Factors associated with HIV acquisition in men included nonulcerative STI in the female partner (adjusted hazard ratio, 4.4), non-STI vaginal dysbiosis (7.1), and genital ulceration in the male partner (2.6). Hormonal contraception use was not associated with HIV transmission or acquisition. Our findings underscore the need for integrating HIV services with care for genital abnormalities. Barriers (eg, cost of training, demand creation, advocacy, and client education; provider time; and clinic space) to joint HIV/STI testing need to be considered and addressed.


Efficient and sequence-independent replication of DNA containing a third base pair establishes a functional six-letter genetic alphabet.
The natural four-letter genetic alphabet, comprised of just two base pairs (dA-dT and dG-dC), is conserved throughout all life, and its expansion by the development of a third, unnatural base pair has emerged as a central goal of chemical and synthetic biology. We recently developed a class of candidate unnatural base pairs, exemplified by the pair formed between d5SICS and dNaM. Here, we examine the PCR amplification of DNA containing one or more d5SICS-dNaM pairs in a wide variety of sequence contexts. Under standard conditions, we show that this DNA may be amplified with high efficiency and greater than 99.9% fidelity. To more rigorously explore potential sequence effects, we used deep sequencing to characterize a library of templates containing the unnatural base pair as a function of amplification. We found that the unnatural base pair is efficiently replicated with high fidelity in virtually all sequence contexts. The results show that, for PCR and PCR-based applications, d5SICS-dNaM is functionally equivalent to a natural base pair, and when combined with dA-dT and dG-dC, it provides a fully functional six-letter genetic alphabet.


Impact of Race and Ethnicity on Use and Outcomes of Septal Reduction Therapies for Obstructive Hypertrophic Cardiomyopathy.
Background Information on impact of race and ethnicity on use and early outcomes of septal reduction therapies (SRTs) for obstructive hypertrophic obstructive cardiomyopathy are limited. Methods and Results Using the National Inpatient Sample from January 2012 through December 2019, we identified all adult admissions with a primary diagnosis of obstructive hypertrophic cardiomyopathy and those undergoing SRT. Predictors of receiving SRT and outcomes including in-hospital mortality, complications, and resource use were evaluated in racial and ethnic groups. Among a total of 18 895 adult admissions with obstructive hypertrophic cardiomyopathy, SRT was performed in 7255 (38.4%) admissions. Septal myectomy was performed in 4930 (26.1%), while alcohol septal ablation was performed in 2325 (12.3%). In adjusted analysis, Black patient (versus White patient adjusted odds ratio, 0.65 [95% CI, 0.57-0.73]; P<0.001) and Hispanic patient admissions (versus White adjusted odds ratio, 0.78 [95% CI, 0.66-0.92]; P=0.003) were less likely to receive SRT. Among admissions undergoing SRT, in-hospital mortality was significantly higher for Hispanic (adjusted odds ratio, 3.38 [95% CI, 1.81-6.30], P<0.001) and other racial and ethnic groups (adjusted odds ratio 2.02 [95% CI, 1.00-4.11]; P=0.05) compared with White patient admissions, whereas Black patient admissions had comparable mortality. Black, Hispanic, and other ethnic group patients had higher rates of SRT complications and more frequent dismissals to acute care facilities. Conclusions Among obstructive hypertrophic cardiomyopathy hospitalizations, minoritized racial groups were less likely to receive SRT. Importantly, hospitalizations of Hispanic and other ethnic patients undergoing SRT had significantly higher in-hospital mortality and complication rates. Further studies with granular echocardiographic information to assess indications for SRT are needed to better understand these differences.


Biotyping of Serratia marcescens and its use in epidemiological studies.
A Serratia marcescens biotyping system using eight carbon sources (benzoate, DL-carnitine, m-erythritol, 3-hydroxybenzoate, 4-hydroxybenzoate, lactose, D-quinate, and trigonelline), a tetrathionate reduction test, production of prodigiosin, and horse blood hemolysis was derived from a recent numerical taxonomic study (Grimont et al., J. Gen. Microbiol. 98:39-66, 1977). A total of 98.6% of 2,210 isolates from various sources could be assigned to 1 of 19 biotypes. Distribution and spread of 1,088 S. marcescens isolates throughout 13 clinical departments of Pellegrin Hospital (Bordeaux, France) were studied from 1968 through 1975. Except for one that colonized the intestinal tract of newborns, the six pigmented biotypes were seldom isolated. Each of the 13 nonpigmented biotypes showed a particular pattern of distribution and spread. The usefulness of S. marcescens biotyping was shown by relating several isolates recovered from patients and their inanimate environment and by pointing out the possible existence of infections or colonizations by two unrelated biotypes. S. marcescens strains isolated from the natural environment (water) are usually pigmented, and their biotypes are uncommon in hospitals. Biotyping can, therefore, be of help in epidemiological and ecological surveys.


Laryngeal mask airway vs endotracheal tube to facilitate bedside percutaneous tracheostomy in critically ill patients: a prospective comparative study.
Inadvertent puncture of endotracheal tube (ETT) cuff and accidental tracheal extubation are the potential life threatening complications during percutaneous dilatational tracheostomy (PDT). As an alternative to ETT, the laryngeal mask airway (LMA) has been used sporadically but no large study is available on its use. To study the use of LMA during PDT on controlled ventilation in critically sick patients and compare its advantages and disadvantages in relation to ETT. This prospective, randomised, comparative study was conducted in intensive care unit of a super-speciality, tertiary care hospital. The bedside PDT was performed in 60 critically ill patients using Ciaglia's kit. The patients received controlled ventilation of lungs either through ETT or LMA. The feasibility of the procedure and complications were compared in two groups. In LMA group, 33% of patients suffered with potentially catastrophic complications, e.g., loss of airway, inadequate ventilation of lungs leading to significant hypoxia, gastric distension and regurgitation. In ETT group there were 6.6% incidence of ETT impalement, 6.6% cuff puncture and 3.3% accidental tracheal extubation. Despite the technical difficulties (cuff puncture, etc.) the ETT technique was basically safe, whereas despite of the theoretical advantages the LMA technique rendered some patients at considerable risks of hypoxia and gastric regurgitation-aspiration. The LMA does not provide safe patent airway to facilitate bedside PDT in critically sick population on controlled ventilation. The ETT is safer for controlled ventilation and should be continued to secure the airway for this purpose until a better alternative is available.


Serum insulin and lipid profile in normal pregnant and pregnancy-induced hypertensive women from North India.
High serum insulin and lipoproteins have been reported in pregnancy-induced hypertension. Little is known about the insulin and lipoprotein profile in Indian women. To address this question we compared serum insulin and lipoproteins of women with pregnancy induced hypertension (PIH) and normotensive pregnant women. The serum insulin, triglycerides, total cholesterol and HDL cholesterol of 104 women with PIH were compared with 99 control women. Hypertensive women had significantly higher insulin (53.94 +/- 29.58 versus 37.69 +/- 17.39 pmol/L, p=0.0004) and triglyceride (3.27 +/- 1.2 versus 2.66 +/- 0.6, p=0.0001). There was no significant difference in total cholesterol and HDL cholesterol levels. Insulin levels had a positive correlation with systolic blood pressure (r=0.64) and diastolic blood pressure (r=0.55) in women with PIH. These differences persisted even after adjusting for possible confounding variables such as age, body mass index and the period of gestation. We conclude that elevated serum insulin values or insulin resistance may contribute to the pathogenesis of PIH in Indian women.


Isobolographic analysis of propofol-thiopental hypnotic interaction in surgical patients.
Drugs acting via the same mechanism interact additively, whereas a supraadditive effect can result from an interaction of drugs with different mechanisms of action. Hypnotic midazolam-propofol and midazolam-thiopental interactions are supraadditive. In contrast to midazolam, the mechanisms of actions of propofol and thiopental are quite similar. The aim of this study was to test the hypothesis that similarity in the mechanisms of action of propofol and thiopental results in the additive hypnotic interaction. We studied the hypnotic effects of thiopental, propofol, and their combinations in 150 unpremedicated patients in a randomized, double-blind fashion. The ability to open eyes on command was used as an end point. Dose-response curves for the drugs given separately and in combinations at three different dose ratios between the drugs were determined by using a probit procedure, and the 50% effective dose values were compared by using isobolographic and algebraic (fractional) analysis. The hypnotic propofol-thiopental combination was additive with all dose ratios between components of the combination. The absence of propofol-thiopental synergy, as demonstrated with midazolam-thiopental or propofol-midazolam combinations, suggests that the mechanisms underlying the hypnotic effects of propofol and thiopental, in contrast to the above combinations with midazolam, are very similar and could be identical. The propofol-thiopental hypnotic interaction is additive.


The mononuclear phagocyte system in hepatocellular carcinoma.
The mononuclear phagocyte system (MPS) consists of monocytes, dendritic cells and macrophages, which play vital roles in innate immune defense against cancer. Hepatocellular carcinoma (HCC) is a complex disease that is affected or initiated by many factors, including chronic hepatitis B virus infection, hepatitis C virus infection, metabolic disorders or alcohol consumption. Liver function, tumor stage and the performance status of patients affect HCC clinical outcomes. Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments. Cytokines derived from the innate immune response can regulate T-cell differentiation, thereby shaping adaptive immunity, which is associated with the prognosis of HCC. Therefore, it is important to elucidate the function of the MPS in the progression of HCC. In this review, we outline the impact of HCC on the MPS. We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.


Availability and Utilization of World Health Organization Recommended Priority Life-Saving Medicines for Under Five-Year-Old Children in Gondar Town, Ethiopia: A Cross-Sectional Study.
Globally, more than eight million under-five children die every year because of diseases that could be treated or prevented with drug therapy. Thus, this study aimed to evaluate the utilization and availability of the World Health Organization (WHO) suggested priority life-saving medicines for under-five-year-old children in Gondar town. Institutional-based cross-sectional survey was conducted from March 2020 to May 2020 in public health centers of Gondar town. Data entry and validation were performed in EpiData 3.1 and exported to SPSS version 20 for descriptive analysis like frequency, percentage, mean, standard deviation, and median. The availability of zinc phosphate and oral rehydration salt for the diarrheal cases was 57.14% and 85.71%, respectively. The availabilities of amoxicillin dispersible tablet and gentamicin injection for the treatments of pneumonia cases were 71.43% and 42.85%, respectively, and the availability of paracetamol tablet was high (85.71%). The availabilities of artemether/lumefantrine tablet and artesunate rectal were ranged between fairly high (57.1%) to very low (28.5%), respectively, and the availabilities of zidovudine/lamivudine/nevirapine-based antiretroviral regimen was 100%, a utilization for this regimen was high (96.29%). Two (3.70%) of the surveyed cases were utilized lopinavir/ritonavir-based regimen. The utilization of priority medicines was low for pain management and pneumonia which was 18.5% and 48.18%, respectively. The study concluded that medicine was not consistently available throughout public health centers in Gondar town. Thus, this finding suggests the integration of WHO-recommended life-saving priority medicines into the essential drug management systems and health unit logistics to raise their utilization and availability.


How rainfall, relative humidity and temperature influence volatile emissions from apple trees in situ.
Headspace volatiles from apple-bearing twigs were collected in the field with a Radiello sampler during three different diurnal periods over the complete fruit growing season. Analyses by thermal desorption-GC-MS identified a total of 62 compounds in changing quantities, including the terpenoids alpha-pinene, camphene, beta-pinene, limonene, beta-caryophyllene and (E,E)-alpha-farnesene, the aldehydes (E)-2-hexenal, benzaldehyde and nonanal, and the alcohol (Z)-3-hexen-1-ol. The variations in emission of these plant odours were statistically related to temperature, humidity and rainfall in the field. Remarkably, rainfall had a significant positive influence on changes in volatile release during all three diurnal periods, and further factors of significance were temperature and relative humidity around noon, relative humidity in the late afternoon, and temperature and relative humidity during the night. Rainfall was associated consistently with an increase in the late afternoon in terpene and aldehyde volatiles with a known repellent effect on the codling moth, one of the key pests of apple fruit. During the summer of 2003, a season characterized by below-average rainfall, some postulated effects of drought on trees were tested by establishing correlations with rainfall. Emissions of the wood terpenes alpha-pinene, beta-pinene and limonene were negatively correlated with rainfall. Another monoterpene, camphene, was only detected in this summer but not in the previous years, and its emissions were negatively correlated with rainfall, further supporting the theory that drought can result in higher formation of secondary metabolites. Finally, the two green leaf volatiles (E)-2-hexenal and (Z)-3-hexen-1-ol were negatively correlated with rainfall, coinciding well with the expectation that water deficit stress increases activity of lipoxygenase. To our knowledge, this work represents the first empirical study concerning the influence of abiotic factors on volatile emissions from apple trees in situ.


Internal pallidum and substantia nigra control different parts of the mesopontine reticular formation in primate.
The locomotor area has recently emerged as a target for deep brain stimulation to lessen gait disturbances in advanced parkinsonian patients. An important step in choosing this target is to define anatomical limits of its 2 components, the pedunculopontine nucleus and the cuneiform nucleus, their connections with the basal ganglia, and their output descending pathway. Based on the hypothesis that pedunculopontine nucleus controls locomotion whereas cuneiform nucleus controls axial posture, we analyzed whether both nuclei receive inputs from the internal pallidum and substantia nigra using anterograde and retrograde tract tracing in monkeys. We also examined whether these nuclei convey descending projections to the reticulospinal pathway. Pallidal terminals were densely distributed and restricted to the pedunculopontine nucleus, whereas nigral terminals were diffusely observed in the whole extent of both the pedunculopontine nucleus and the cuneiform nucleus. Moreover, nigral terminals formed symmetric synapses with pedunculopontine nucleus and cuneiform nucleus dendrites. Retrograde tracing experiments confirmed these results because labeled cell bodies were observed in both the internal pallidum and substantia nigra after pedunculopontine nucleus injection, but only in the substantia nigra after cuneiform nucleus injection. Furthermore, anterograde tracing experiments revealed that the pedunculopontine nucleus and cuneiform nucleus project to large portions of the pontomedullary reticular formation. This is the first anatomical evidence that the internal pallidum and the substantia nigra control different parts of the brain stem and can modulate the descending reticulospinal pathway in primates. These findings support the functional hypothesis that the nigro-cuneiform nucleus pathway could control axial posture whereas the pallido-pedunculopontine nucleus pathway could modulate locomotion.


Low Frequency of Early Complications With Dual-mobility Acetabular Cups in Cementless Primary THA.
Dislocation complicates 1% to 5% of primary total hip arthroplasties (THAs). As a result, some surgeons consider dual-mobility articulations, which are usually used in the revision setting to decrease the likelihood of dislocation, as an option for primary THA. However, few studies have evaluated their use in this setting. (1) What is the cup survivorship when the dual-mobility articulation is used in the setting of primary THA? (2) What are the clinical outcomes with this approach? (3) What are the radiographic outcomes? (4) What are the complications of dual-mobility articulations in primary THA? Between 2011 and 2013, the five participating surgeons performed 495 cementless primary THAs. During that time, one of the five surgeons used dual-mobility articulations for all THAs, and the other four used it whenever the acetabular cup size was 52 mm or greater to enable a 28-mm head. Of the 495 patients, 453 (92%) were performed using this device. Smaller patients were treated with a standard THA. Of the 453 patients, a total of 43 patients (10%) were lost to followup before the 2-year minimum. The resulting 410 patients who were included in the analysis (164 men, 246 women) had a mean age of 64 years (SD, 12 years). The mean followup was 3 years (SD, 0.7 years). We performed Kaplan-Meier analyses to assess survivorship to aseptic failure and all-cause acetabular component survivorship. Clinical outcomes were evaluated using the Harris hip score (HHS); radiographs were assessed for cup migration, progressive radiolucencies, and positional changes of the components; and any surgery-related complications were recorded. The survivorship to aseptic failure and all-cause acetabular component survivorship was 99.8% (failures, n = 1) (95% confidence interval [CI], 4.517-4.547) and 99.3% (failures, aseptic, n = 1; septic, n = 2) (95% CI, 4.494-4.543); one hip had trunnion notching caused by impingement of a malpositioned cup, which was treated with revision of the cup and stem; and two patients had periprosthetic infections that were treated with two-stage revisions. There were no dislocations. Patients had a mean HHS of 94 (SD, 6) at final followup. On radiographic evaluation, no progressive radiolucencies or positional changes of the components were identified. Surgical complications included one traumatic avulsion of the abductors, one traumatic avulsion of the greater trochanter, which was repaired without revision of any of the components, and one loose femoral stem, which required revision of the femoral component only. Dual-mobility cups in primary THA yield seemingly comparable survivorship and complications to conventional THA bearings at short-term followup. Because serious complications have occasionally been reported with the use of these bearings, larger, longer term, comparative-and ideally, randomized-trials will be needed to establish the superiority of one approach over the other. Until or unless such studies show the superiority of dual-mobility designs for primary THA, we recommend that in the setting of uncomplicated primary THA, dual-mobility articulations be used only in centers that track their results carefully or in research protocols. Level IV, therapeutic study.


Loss of superficial femoral artery relaxation following ischemia-reperfusion.
Acute ischemia followed by reperfusion in skeletal muscle is associated with tissue edema and necrosis. The purpose of this study was to demonstrate superficial femoral artery endothelial injury following complete ischemia with reperfusion. New Zealand white rabbits underwent total devascularization of one hindlimb for 3 hr followed by 0, 1, and 2 hr of reperfusion. Control rabbits underwent a sham operation. Superficial femoral artery rings were then studied for acetylcholine induced relaxation in vitro. The response to acetylcholine was measured as percentage relaxation at three incremental doses (1 x 10(-7) , 3 x 10(-7) and 5 x 10(-7) M). The ischemia-only (26.30 +/- 7.07, 62.63 +/- 8.64, 88.08 +/- 5.25%) and the 1-hr reperfusion group (19.35 +/- 12.99, 39.24 +/- 15.78, 62.01 +/- 14.03%) showed no significant difference (P > or = 0.05, Student's t test) in relaxation as compared to the control group (13.73 +/- 2.11, 47.88 +/- 7.23, 72.44 +/- 9.00%). The 2-hr reperfusion group (6.10 +/- 1.02, 15.33 +/- 2.56, 34.67 +/- 6.31%), however, had a significant loss of relaxation at all three doses of acetylcholine compared to that seen in the control group (P < or = 0.05, Student's t test). In this model of complete ischemia, superficial femoral artery rings lose their ability to relax in response to acetylcholine following 3 hr of ischemia and 2 hr of reperfusion, demonstrating endothelial injury. However, immediately after 3 hr of ischemia or ischemia followed by only 1 hr of reperfusion, superficial femoral artery rings did not lose their ability to relax in response to acetylcholine. This study identifies a window of opportunity for therapeutic intervention after ischemia and prior to endothelial injury from reperfusion.


Figure Correction: Using Social Media to Help Understand Patient-Reported Health Outcomes of Post-COVID-19 Condition: Natural Language Processing Approach.
[This corrects the article DOI: 10.2196/45767.].


Single Nucleus RNA-sequencing Reveals Altered Intercellular Communication and Dendritic Cell Activation in Nonobstructive Hypertrophic Cardiomyopathy.
End stage, nonobstructive hypertrophic cardiomyopathy (HCM) is an intractable condition with no disease-specific therapies. To gain insights into the pathogenesis of nonobstructive HCM, we performed single nucleus RNA-sequencing (snRNA-seq) on human HCM hearts explanted at the time of cardiac transplantation and organ donor hearts serving as controls. Differential gene expression analysis revealed 64 differentially expressed genes linked to specific cell types and molecular functions. Analysis of ligand-receptor pair gene expression to delineate potential intercellular communication revealed significant reductions in expressed ligand-receptor pairs likely affecting the extracellular matrix, growth factor binding, peptidase regulator activity, platelet-derived growth factor binding and protease binding in the HCM tissue. Changes in Integrin-β1 receptor expression were responsible for many observed changes related to extracellular matrix interactions, by increasing in dendritic, smooth muscle and pericyte cells while decreasing in endothelial and fibroblast cells, suggesting potential mechanisms for fibrosis and microvascular disease in HCM and a potential role for dendritic cells. In contrast, there was an increase in ligand-receptor pair expression associated with adenylate cyclase binding, calcium channel molecular functions, channel inhibitor activity, ion channel inhibitor activity, phosphatase activator activity, protein kinase activator activity and titin binding, suggesting important shifts in various signaling cascades in nonobstructive, end stage HCM.


Psychotropic drug use in a cohort of workers 4 years after an industrial disaster in France.
Two years after the 2001 Toulouse industrial disaster, a longitudinal study was set up to evaluate the impact of the disaster. The current substudy examines the medium-term impact (5 years) the incident had on the mental health of 3,004 participants. As part of the monitoring, data relating to the psychotropic drug use of 2,494 participants were collected from administrative databases 4 years after the disaster. Use of psychotropics was higher among women for anxiolytics (10.4% for men and 15.0% for women), hypnotics (10.5% and 17.0%), and antidepressants (7.6% and 11.2%). Exposure to the disaster, especially proximity to the exposure, was significantly associated with the use of antidepressants in men, OR = 3.22, 95% CI[1.57, 6.61]. This was also the case for other exposure factors (saw dead or injury, injured, home damage, death or injury loved one, psychological disorders, exposure toxic fumes): range of OR 1.75 to 2.52 in men, 1.48 to 1.62 in women. In conclusion, this study highlights the medium-term psychological impact of an industrial disaster on psychotropic drug use and the potential for using medical records data as a means for tracking postdisaster mental health.


Fine mapping and resequencing of the PARK16 locus in Parkinson's disease.
The PARK16 locus, spanning five genes on chromosome 1, was among the first genetic regions to show genome-wide association in Parkinson's disease (PD). Subsequent investigations have found variability in PARK16 top-hits and association patterns across populations, and the implicated genes and mechanisms are currently unclear. In the present study, we aimed to explore the contribution of PARK16 variability to PD risk in a Scandinavian population. We genotyped 17 single-nucleotide polymorphisms in a case-control sample set of 2570 individuals from Norway and Sweden to fine map the locus. Targeted resequencing of the full coding regions of SLC45A3, NUCKS1, RAB7L1, SLC41A1 and PM20D1 was performed in DNA pools from a subset of 387 patient samples. We find evidence for an association with PD for rs1775143 as well as a haplotype located around the 5' region of RAB7L1, implicating variants which are not in high linkage disequilibrium with the strongest signal from a recent large meta-analysis in Caucasians. We also provide suggestive support for epistasis between RAB7L1 and LRRK2 as previously hypothesized by others. Comparing our results with previous work, allelic heterogeneity at PARK16 appears likely, and further studies are warranted to disentangle the complex patterns of association and pinpoint the functionally relevant variants.


Using the Venous Pectoral Branch from the Thoracoacromial System as a Lifeboat in Autologous Breast Reconstruction.
The most common recipient vessels for autologous free flap breast reconstruction are the internal mammary vessels. At times, there are problems with the exposed internal mammary vein (IMV) that require other options such as using the contralateral IMV, superior rib resection to access proximal IMV, retrograde IMV use, and thoracodorsal vein access with or without a vein graft. This case demonstrates using the pectoral branch of the thoracoacromial venous system without a vein graft as a lifeboat option when the IMV is not suitable for anastomosis. C.W. was a 65-year-old female who underwent right-sided mastectomy with placement of a tissue expander. After adjuvant radiation therapy, C.W. underwent deep inferior epigastric perforator free flap breast reconstruction. During exposure of the internal mammary artery and IMV, an iatrogenic venotomy occurred that precluded the use of this vessel as a reliable recipient. The deep inferior epigastric perforator flap pedicle was then dissected proximal to isolate the artery and vein, and the vein was successfully anastomosed to the venous pectoral branch of the thoracoacromial system. The postoperative course was uneventful and patient was discharged home on postoperative day 4. Using the venous pectoral branch of the thoracoacromial is a safe and valuable option that can be considered in difficult situations when the IMV is not a suitable option.


Evaluation of Sweetener Synergy in Humans by Isobole Analyses.
The chemical senses and pharmaceuticals fundamentally depend on similar biological processes, but novel molecule discovery has classically been approached from vastly different vantage points. From the perspective of ingredient and flavor companies, there are countless ingredients that act via largely unknown mechanisms, whereas the pharmaceutical industry has numerous mechanisms in search of novel compounds. Mixtures of agonists can result in synergistic (superadditive) responses, which can be quantified via isobole analysis, a well-proven clinical approach in pharmacology. For the food and beverage industries, bulk (caloric) sweeteners like sugars are a key ingredient in sweetened foods and beverages, but consumers also desire products with fewer calories, which has led to the development of sweet enhancers and sweetener blends intended to achieve synergy or superadditivity. Synergistic mixtures are highly attractive targets commercially as they enable lower usage levels and enhanced efficacy. Although the psychophysical literature contains numerous prior reports of sweetener synergy, others have also noted that classical additive models fail to account for nonlinear dose-response functions. To address this shortcoming, here we systematically apply the isobole method from pharmacology to quantify the presence or absence of psychophysical synergy for binary pairs of sweeteners in a series of 15 separate experiments, each with ~100 adult volunteers (total n = 1576). Generally, these data support the hypothesis that structurally similar sweeteners acting as agonists will not synergize, whereas structurally dissimilar sweeteners binding to overlapping or distal sites can act as allosteric agonists or agonist-antagonists, respectively.


Thymic neuroendocrine tumors: a SEER database analysis of 160 patients.
Thymic neuroendocrine tumors (NETs) are uncommon but malignant tumors of the thymus gland that are usually associated with systemic symptoms due to hypersecretion of biogenic amines from metastatic lesions. Due to the limited number of studies in the literature, very little is known about progress or trends made in the treatment and survival of patients with thymic NET. We reviewed 160 patients diagnosed with thymic NET in the SEER database to evaluate patient demographics and their clinical course. Specifically, we evaluated the role of surgery and adjuvant radiation in the SEER cohort. We also performed univariable and multivariate Cox proportional hazard modeling of standard prognostic factors. According to our results, thymic NETs afflict males and whites primarily. As expected, advanced stage correlates with poorer long-term survival (P = 0.009) and those patients who undergo surgery do better than their counterpart (P = 0.005). We did not observe any survival benefit for radiation delivered as a part of primary therapy. Univariable and multivariate analyses demonstrated that tumor stage (P = 0.009), grade (P = 0.002), surgical resection (P = 0.005), and tumor size (P = 0.02) correlated with overall survival. Our study demonstrates that surgery continues to be the mainstay of treatment, and that there is a need to define a staging system for thymic NETs that can perhaps allow clinicians to formulate better therapeutic strategies for such patients.


Computed Tomography Findings for Diagnosing Follicular Thyroid Neoplasms.
Since no diagnostic method has been established to distinguish follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA), surgery has been the only way to reach a diagnosis of follicular neoplasm. Here we investigated the computed tomography (CT) features of follicular neoplasms, toward the goal of being able to identify specific CT features allowing the preoperative differentiation of FTC from FTA. We retrospectively analyzed the cases of 205 patients who underwent preoperative CT of the neck and were histopathologically diagnosed with FTC (n=31) or FTA (n=174) after surgery between January 2002 and June 2016 at several hospitals in Japan. In each of these 205 cases, non-enhanced and contrast-enhanced CT images were obtained, and we analyzed the CT features. On univariate analysis, inhomogeneous features of tumor lesions on contrast-enhanced CT were more frequently observed in FTC than in FTA (p=0.0032). A multivariate analysis identified inhomogeneous features of tumor lesions on contrast-enhanced CT images as an independent variable indicative of FTC (p=0.0023). CT thus offers diagnostic assistance in distinguishing FTC from FTA.


Deficiency of the adhesive protein complex lymphocyte function antigen 1, complement receptor type 3, glycoprotein p150,95 in a girl with recurrent bacterial infections. Effects on phagocytic cells and lymphocyte functions.
A patient presenting delayed umbilical cord detachment, severe recurrent bacterial infections, and inability to form pus exhibited a profound defect in the expression of alpha- and beta-chains of the receptor for the C3bi fragment of C3 (CR3), lymphocyte function antigen 1 (LFA-1) molecule, and the p150,95 molecule found on neutrophils, monocytes, and lymphocyte membranes. This was shown by immunofluorescence studies using specific monoclonal antibodies, rosette formation with C3bi-coated erythrocytes, and immunoprecipitation for the LFA-1 complex. These membrane defects were responsible for abnormal phagocytic cell functions including adherence to nylon wool, cell movement, phagocytosis, and opsonized particle-induced oxidative response and for defective natural killer cell activity. In addition, lymphocyte function deficiencies previously unobserved in this disease were found. Cytolytic T lymphocyte activity was profoundly reduced; alpha- and gamma-interferon production were impaired. Finally, there was no antibody production to vaccinal antigens whereas the antibody responses to polysaccharides and to cytomegalovirus were found to be normal. The cytotoxic T cell deficiency could be expected from previous blocking experiments of this function with monoclonal antibodies to LFA-1 and is probably related to an extremely severe deficiency in LFA-1 expression in this patient. Anomalies in interferon and in antibody production suggest additional role(s) of the LFA-1 complex in monocyte/T lymphocyte/B lymphocyte cell interactions that have not yet been envisaged.