Alcoholic and non-alcoholic liver disease in relation to alcohol consumption in Scotland, 1978-84. Part I: Epidemiology of liver diseases.
A common strategy in epidemiological studies linking alcohol consumption in the general population with liver cirrhosis mortality is to use non-specific cirrhosis mortality rates in which alcoholic and non-alcoholic causes of death are not distinguished. Evidence is presented from Scottish mortality data for 1979 to 1984 that the two forms of cirrhosis have quite different epidemiological profiles. Similar findings emerge from morbidity data. The two forms of disease should be distinguished in future studies in which liver cirrhosis is used as a proxy for consumption, despite the manifest shortcomings of currently available data.


When should a longer needle be used for intramuscular injection in obese patients? A combined analysis of New Zealand data.
To estimate thresholds for Body Mass Index (BMI) and arm circumference above which a longer needle is needed to ensure intramuscular (IM) delivery of a vaccine in the deltoid muscle at the site recommended by New Zealand (NZ) immunization guidelines. A combined analysis of two studies, including 442 adults, with measurements of arm circumference, BMI and skin to deltoid muscle distance (SDMD) at the NZ immunization guideline-recommended IM injection site. Receiver Operator Characteristic curves identified arm circumference and BMI cut-points that gave 100% sensitivity for SDMD thresholds. These thresholds were: SDMD of 20 mm, accounting for a minimal penetration of 5 mm into muscle with the standard needle; and 25 mm, which is the length of a standard needle for IM injection, representing the depth this can reach. Cut-point values for arm circumference, at which a longer needle would be required, were higher for males than females: 35 cm versus 30 cm for the 20 mm cut-point, and 40 cm versus 36.7 cm for the 25 mm cut-point respectively. The BMI cut-points were also higher for male than females: 24.6 kg/m2 versus 23.7 kg/m2 for the 20 mm cut-point, and 38.2 kg/m2 vs 31.6 kg/m2 for the 25 mm cut-point respectively. Arm circumference and BMI cut-points provide practical measures from which to choose a needle length that increases the chance of successful IM vaccination. Based on our data, an arm circumference of 35 cm for men and 30 cm for women should prompt selection of a longer needle to ensure intramuscular injection at the deltoid site. Thresholds for the different skin to deltoid sites proposed internationally should be determined to enable successful IM vaccination in clinical practice beyond NZ.


Hydrocarbon Synthesis via Photoenzymatic Decarboxylation of Carboxylic Acids.
A recently discovered photodecarboxylase from Chlorella variabilis NC64A ( CvFAP) bears the promise for the efficient and selective synthesis of hydrocarbons from carboxylic acids. CvFAP, however, exhibits a clear preference for long-chain fatty acids thereby limiting its broad applicability. In this contribution, we demonstrate that the decoy molecule approach enables conversion of a broad range of carboxylic acids by filling up the vacant substrate access channel of the photodecarboxylase. These results not only demonstrate a practical application of a unique, photoactivated enzyme but also pave the way to selective production of short-chain alkanes from waste carboxylic acids under mild reaction conditions.


Hypoxia and reoxygenation: a pressure for mutant p53 cell selection and tumour progression.
Recent findings indicate that in a hypoxic environment, oncogenically transformed cells with a mutant form of the tumour suppressor gene p53 may have a survival advantage over similar cells with wild-type p53. This is because the extent of hypoxia-induced apoptosis has been observed to diminish with the loss of wild-type p53 function in certain cell lines. Hypoxic conditions, common in most solid tumours, may thus provide a physiological pressure to select for cells with mutations in the p53 gene. A new model incorporating cell-specific parameters is proposed here to quantify the survival advantage of mutant or null p53 cells over their wild-type counterparts at any level of oxygen deprivation. Predictions are in good agreement with previous monolayer culture experiments comparing hypoxic survival of null and wild-type p53 cells. By extending the model we are able to investigate the effects of repeated rounds of hypoxia and reoxygenation on a mixture of wild-type and mutant or null p53 cells and determine how many rounds are required before a subpopulation of mutant or null p53 cells overtakes a given population of wild-type p53 cells.


Gathering useful opinions about the job applicant.
Getting people to talk to you about former employees' job performance can be like pulling teeth. It seems that everyone these days is afraid of saying the wrong thing and having even innocent remarks come back to haunt them. Most people say nothing. However, you can increase your chances of getting useful employment references by following a few basic guidelines. This article describes the most effective methods for conducting reference checks. It suggests who is most likely to talk with you about a former employee and how to make you approach. It provides specific questions to ask and to avoid when seeking opinions about the job applicant. This article also offers simple and easy-to-implement techniques for using reference checking to build goodwill and referrals for your practice.


Power sources for portable electronics and hybrid cars: lithium batteries and fuel cells.
The activities in progress in our laboratory for the development of batteries and fuel cells for portable electronics and hybrid car applications are reviewed and discussed. In the case of lithium batteries, the research has been mainly focused on the characterization of new electrode and electrolyte materials. Results related to disordered carbon anodes and improved, solvent-free, as well as gel-type, polymer electrolytes are particularly stressed. It is shown that the use of proper gel electrolytes, in combination with suitable electrode couples, allows the development of new types of safe, reliable, and low-cost lithium ion batteries which appear to be very promising power sources for hybrid vehicles. Some of the technologies proven to be successful in the lithium battery area are readapted for use in fuel cells. In particular, this approach has been followed for the preparation of low-cost and stable protonic membranes to be proposed as an alternative to the expensive, perfluorosulfonic membranes presently used in polymer electrolyte membrane fuel cells (PEMFCs).


5-HT1A Receptors Mediate Analgesia Induced by Emulsified Sevoflurane in Thermal Nociception but Have Little Effect on Chemical Nociception.
The study aimed to investigate the relationship between the analgesic effect of sevoflurane and 5-serotonin receptor 1A (5-HT1A R) in the spinal cords of mice. Analgesic mouse models were established by intraperitoneal injection of emulsified sevoflurane, and the influence of p-MPPF (a specific antagonist of 5-HT1A Rs) intrathecal injection on the changes in tail-flick latency in tail-withdrawal test, pain threshold in hot-plate test (HPPT), and writhing times in acetic acid-induced writhing test were recorded. Intraperitoneal injection of emulsified sevoflurane alone produced an analgesic effect (p < 0.05). p-MPPF (2, 4, and 8 μg) alone had no impact on tail-flick latency, HPPT, and writhing times in mice (p > 0.05). The 3 doses of p-MPPF reduced the tail-flick latency or HPPT. p-MPPF 8 μg can increase the writhing times (p < 0.05) in analgesic mice with sevoflurane, while p-MPPF 2 and 4 μg did not affect the writhing times. 5-HT1A Rs in the spinal cord may be an important target for the analgesic effect of sevoflurane on the thermal nociception, but it has little relation to the anti-chemical chemical nociceptive effect of sevoflurane.


Evaluation of sex dimorphism of the mandible with geometric morphometric analysis: conventional and reconstructed panoramic radiography study.
The purpose of the study was to investigate the mandible shape dimorphism between males and females both on conventional panoramic radiographs (cPR) and reconstructed panoramic radiographs obtained from cone beam computed tomography (rPR) with geometric morphometric method. Panoramic radiographs and cone beam computed tomography scans were performed on 33 males and 35 females with median age 23.0 (13.0-57.0) years old. The mandibular shape comparisons between genders were examined with Procrustes analysis, mandible shape classification analysis was made with principal component analysis and shape deformations were concluded from thin plate spline (TPS) analysis. Age had no statistically significant difference between gender (p = 0.580). For the shape of mandible on cPR and rPR, there were statistically significant differences between males and females (p = 0.002, p = 0.032, respectively). The shape variabilities of mandible on cPR for females were 0.054 and for males 0.053. The shape variabilities of mandible on rPR for females were 0.051 and for males 0.049. Both on cPR and rPR, the shape variability of the females' mandible was similar within their group, the shape variability of the males' mandible was similar within their group. In the examination of mandibular dimorphism in cPR, maximal deformations were seen in the region between the mandibular notch, posterior ramus, anterior ramus, gonion, in both sides, in TPS graphs. On the other hand, a high level of deformations was observed in all landmarks that define the mandibular shape on rPR. The mandible dimorphism can be detected in the examination performed with geometric morphometric methods on cPR and rPR. While mandible shape differences according to gender are seen most in the ramus region in cPR, differences can be detected in all landmarks in rRP.


Manhattan Vision Screening and Follow-Up Study in Vulnerable Populations: 1-Month Feasibility Results.
Purpose/Aim: In the United States, high rates of vision impairment and eye disease disproportionately impact those who lack access to eye care, specifically vulnerable populations. The objective of our study was to test instruments, implement protocols, and collect preliminary data for a larger 5-year study, which aims to improve detection of eye diseases and follow-up eye care in vulnerable populations using community health workers (CHW) and patient navigators. In the study, trained CHWs conducted vision screening and patient navigators scheduled on-site eye exams and arranged appointments for those referred to ophthalmology to improve adherence to follow-up eye care.Materials and Methods: Eligible individuals age 40-and-older were recruited from the Riverstone Senior Center in Upper Manhattan, New York City. Participants underwent on-site vision screening (visual acuity with correction, intraocular pressure measurements, and fundus photography). Individuals who failed the vision screening were scheduled with an on-site optometrist for an eye exam; those with ocular pathologies were referred to an ophthalmologist. Participants were also administered the National Eye Institute Visual Function Questionnaire-8 (NEI-VFQ-8) and Stopping Elderly Accidents, Deaths, and Injuries (STEADI) test by community health workers.Results:Participants (n = 42) were predominantly older adults, with a mean age of 70.0 ± 9.8, female (61.9%), and Hispanic (78.6%). Most individuals (78.6%, n = 33) failed vision screening. Of those who failed, 84.8% (n = 28) attended the on-site eye exam with the optometrist. Ocular diagnoses: refractive error 13/28 (46.4%), glaucoma/glaucoma suspect 9/28 (32.1%), cataract 7/28 (25.0%), retina abnormalities 6/28 (21.4%); 13 people required eyeglasses.Conclusion: This study demonstrates the feasibility of using CHWs and patient navigators for reducing barriers to vision screening and optometrist-based eye exams in vulnerable populations, ultimately improving early detection of eye disease and linking individuals to additional eye care appointments. The full five-year study aims to further examine these outcomes.


Immunocytochemical localization of polyamines during attachment and spreading of retinal pigment epithelial and intestinal epithelial cells.
In order to form and maintain a protective barrier for photoreceptors, the retinal pigment epithelium relies on integrin signaling and related pathways to form adhesion complexes, undergo cell spreading, and establish a confluent cellular monolayer. Polyamines are multifunctional polycations that are essential for cell attachment and spreading, although their exact mechanisms of action are as yet unclear. We report new immunocytochemical evidence suggesting that in the cells of retinal pigment epithelium and also the intestinal epithelium, polyamines are present in a population of intracellular vesicles that appear transiently during initial stages of cell spreading. In newly attached cells with minimal spreading, the vesicles are seen near the nucleus, whereas in more highly spread cells, the vesicles are localized to the plasma membrane, near, but not precisely co-localized with an enzyme marker for adhesion complexes, focal adhesion kinase. We also observe pronounced nuclear staining in newly attached cells that have not spread, whereas this staining is decreased in cells that have spread. Nuclear staining has been previously reported in other cell types and has been attributed to DNA binding of polyamines, which is known to stabilize chromatin structure. We hypothesize that the appearance of polyamine vesicles near focal adhesions of cells undergoing attachment and spreading may reflect the mechanism by which polyamine pools are targeted to appropriate interaction sites necessary for the assembly of adhesion complexes. Alternatively, the vesicles could represent the mechanism by which polyamines are removed from the nucleus and possibly released from the cell.


Clinical experience with netilmicin.
From the results from over 150 clinical trials of netilmicin 3376 completed patient treatment courses have been reviewed to assess its efficacy and safety. Fourteen-hundred and twenty-three patients with 2273 infections caused by 2322 pathogens were evaluable for treatment efficacy. Favourable clinical responses were observed in 90% of the infections treated. Eighty-three per cent of the causative pathogens were eliminated from the infection sites. Netilmicin's safety was evaluated in all patients. Nephrotoxicity considered to be probably netilmicin-related occurred in 1.7% of the patients, and was possibly related in an additional 5.2%. Auditory toxicity was probably netilmicin-related in 1.6% and possibly related in 1.9% of the patients. Vestibular toxicity, probably or possibly drug-related, was observed in 0.62% of the patients. Extensive clinical trials with netilmicin have confirmed its excellent efficacy and safety profile.


Cancer-derived VEGF plays no role in malignant ascites formation in the mouse.
Vascular endothelial growth factor (VEGF) is a potent mediator of peritoneal fluid accumulation following tumor progression. This study investigated the role of VEGF secreted by cancerous cells in the formation of malignant ascites. VEGF expression was eliminated by knockdown in the pancreas cancer cell-line PancO2 using vector-based short-hairpin type RNA interference (RNAi). Malignant ascites formation in the mouse was analyzed by intraperitoneal injection of PancO2 cells expressing VEGF or with expression knockdown. The VEGF knockdown PancO2 cell was successfully established. Knockdown of VEGF did not affect cancer cell proliferation in vitro or in vivo. The volume of ascites following peritoneal expansion of the tumor in VEGF knockdown cells and control cells did not differ statistically in this in vivo study. Moreover, the VEGF concentration in the ascites did not differ statistically. Malignant ascites formation might be mediated by VEGF production in noncancerous tissues, such as stromal compartments. An anti-VEGF strategy against malignant ascites could be applied to various tumors regardless of whether they secrete VEGF.


Effect of maternal and neonatal interleukin-6 - 174 G/C polymorphism on preterm birth and neonatal morbidity.
The aim of this study was to analyze maternal and neonatal interleukin 6 (IL-6) (-174 G/C) polymorphism and to determine effect on preterm birth and neonatal morbidity. One hundred and sixty-four mothers (100 term births, 64 preterm births) and 183 newborn infants who were 100 healthy term and 83 preterm babies followed in newborn intensive care units were evaluated. PCR-RFLP was performed for IL-6 (-174 G/C) genotyping. The rate of GG genotype in mothers of term and preterm infants were 54% (n = 54/100), 75% (n = 48/64), respectively (p > .05) and the rate of GC + CC genotype was 46% (n = 46/100) and 25% (n = 16/64) in mothers giving term and preterm birth (PTB), respectively (p < .05). Additionally, the rate of GG genotype was 65% (n = 65/100) and 81.9% (n = 68/83) in term infants and preterm infants, respectively. GC + CC genotype was 35% (n = 35/100) in term infants and 18.1% (n = 15/83) in preterm infants (p < .05). The effect of IL-6 (-174) GC + CC genotype on PTB was statistically significant. The IL-6 174 G/C gene polymorphism was significantly different between mothers who were giving to term and preterm birth. The presence of polymorphism is protective against preterm birth and was not associated with neonatal outcome.


Early Stage Finding of an Immune-Enhanced Genetic Subtype of Nonsmall Cell Lung Cancer Related with T-Cell Depletion.
Molecular categorization of lung cancer in medical care is becoming increasingly important on a regular basis. One of the molecular classifications of NSCLC (early-stage NSCLC) supports that tumors of different biological varieties differ in terms of their genomes and clinical characteristics. Based on published immune cell signatures and early-stage NSCLC gene expression data including cancer genome maps, we used consensus cluster analysis to identify immune molecular subtypes associated with early-stage NSCLC expression subtypes. These subtypes were correlated with early-stage NSCLC expression subtypes. Next, applying a wide range of statistical techniques, we evaluated the link between molecular subtypes and clinical features, immunological microenvironment, and immunotherapy reactivity. Molecular subtypes were defined as a classification of cancerous cells. Multiple RNAseq cross-platform datasets of immune genes were used to identify two molecular subtypes (C1 and C2) of NSCLC, with C1 showing a more favorable prognosis than C2. The results were validated on the CSE datasets. In terms of clinical characteristics, C2 subtype samples with a worse prognosis showed a more advanced tumor stage and higher mortality. C2 showed immuno-infiltrative characteristics but had depletion of T-cells. Biological functions such as EMT were enriched on C2. A low TIDE score in C1 indicated that C1 samples could benefit from taking immunotherapy. C2 were more susceptible to standard chemotherapeutic treatments such paclitaxel, cisplatin, sorafenib, crizotinib, and erlotinib. According to our findings, early-stage NSCLC patients may benefit from receiving treatment with immune checkpoint blockade therapy.


Nepal's Health Facility Operation and Management Committees: exploring community participation and influence in the Dang district's primary care clinics.
AimTo describe community representation in Nepal's Health Facility Operation and Management Committees (HFMCs) and the degree of influence of community representatives in the HFMC decision-making processes. Community participation has been recognised as one of the key components for the successful implementation of primary health care (PHC) strategies, following the 1978 Declaration of Alma-Ata. In low- and middle-income countries (LMICs), HFMCs are now widely considered as a mechanism to increase community participation in health through community representation. There is some research examining the implementation process, impact and factors affecting the effectiveness of HFMCs. Despite the documented evidence of the importance of factors such as adequate representation, links with wider community, and decision-making power, there is limited evidence about the nature of community representation and degree of decision making within HFMCs in the PHC setting, particularly in LMICs. Qualitative interviews with 39 key informants were held to explore different aspects of community representation in HFMCs, and the influence of the HFMC on health facility decision-making processes. In addition, a facility audit at 22 facilities and review of HFMC meeting minutes at six health facilities were conducted.FindingsThere were Dalit (a marginalised caste) and Janajati (an ethnic group) representations in 77% and 100% of the committees, respectively. Likewise, there were at least two female members in each committee. However, the HFMC member selection process and decision making within the committees were influenced by powerful elites. The degree of participation through HFMCs appeared to be at the 'Manipulation' and 'Informing' stage of Arnstein's ladder of participation. In conclusion, despite representation of the community on HFMCs, the depth of participation seems low. There is a need to ensure a democratic selection process of committee members; and to expand the depth of participation.


Pineal calcification and its relationship to the fatigue of multiple sclerosis.
Fatigue is one of the most common clinical features of multiple sclerosis (MS) and is a frequent cause of disability. The pathogenesis of fatigue remains obscure. It may result from impaired propagation of action potentials in areas of demyelination. Other contributors may be mental depression, immobility, and physical disability. The fatigue of MS may be relieved by diverse pharmacological drugs such as amantadine and pemoline, but the mechanisms by which these agents act to ameliorate fatigue are unknown. Attention has been focused recently on the relationship between MS and the pineal gland and evidence has been presented to implicate the pineal gland and melatonin in the pathogenesis of the disease. To investigate this relationship further, we studied in 47 MS patients (mean age: 41.6 +/- 9.9 yrs; mean duration of illness: 13.6 +/- 12.6 yrs) the association between fatigue and incidence of pineal calcification (PC) on CT scan, which is thought to reflect past secretory activity of the gland. For comparison, we also evaluated the incidence of choroid plexus calcification (CPC) in these patients. The sample included 20 patients who experienced ongoing, debilitating fatigue during the course of the disease. 27 patients who did not complain of fatigue served as controls. The two groups were not distinguishable with respect to age, sex, age of onset, chronicity, course (relapsing-remitting vs. chronic progressive), and severity of the disease (ambulatory vs. immobile), as well as the incidence of affective illness.(ABSTRACT TRUNCATED AT 250 WORDS)


Super stereoscopy technique for comfortable and realistic 3D displays.
Two well-known problems of stereoscopic displays are the accommodation-convergence conflict and the lack of natural blur for defocused objects. We present a new technique that we name Super Stereoscopy (SS3D) to provide a convenient solution to these problems. Regular stereoscopic glasses are replaced by SS3D glasses which deliver at least two parallax images per eye through pinholes equipped with light selective filters. The pinholes generate blur-free retinal images so as to enable correct accommodation, while the delivery of multiple parallax images per eye creates an approximate blur effect for defocused objects. Experiments performed with cameras and human viewers indicate that the technique works as desired. In case two, pinholes equipped with color filters per eye are used; the technique can be used on a regular stereoscopic display by only uploading a new content, without requiring any change in display hardware, driver, or frame rate. Apart from some tolerable loss in display brightness and decrease in natural spatial resolution limit of the eye because of pinholes, the technique is quite promising for comfortable and realistic 3D vision, especially enabling the display of close objects that are not possible to display and comfortably view on regular 3DTV and cinema.


Diagnosis of dementia in individuals with intellectual disability.
The foremost impediment to progress in the understanding and treatment of dementia in adults with intellectual disability is the lack of standardized criteria and diagnostic procedures. Standardized criteria for the diagnosis of dementia in individuals with intellectual disability are proposed, and their application is discussed. In addition, procedures for determining whether or not criteria are met in individual cases are outlined. It is the intention of the authors, who were participants of an International Colloquium on Alzheimer Disease and Mental Retardation, that these criteria be appropriate for use by both clinicians and researchers. Their use will improve communication among clinicians and researchers, and will allow researchers to test hypotheses concerning discrepancies in findings among research groups (e.g. dementia prevalence ranges and age of onset).


Robust estimation of encouragement-design intervention effects transported across sites.
We develop robust targeted maximum likelihood estimators (TMLE) for transporting intervention effects from one population to another. Specifically, we develop TMLE estimators for three transported estimands: intent-to-treat average treatment effect (ATE) and complier ATE, which are relevant for encouragement-design interventions and instrumental variable analyses, and the ATE of the exposure on the outcome, which is applicable to any randomized or observational study. We demonstrate finite sample performance of these TMLE estimators using simulation, including in the presence of practical violations of the positivity assumption. We then apply these methods to the Moving to Opportunity trial, a multi-site, encouragement-design intervention in which families in public housing were randomized to receive housing vouchers and logistical support to move to low-poverty neighborhoods. This application sheds light on whether effect differences across sites can be explained by differences in population composition.


The sorafenib plus nutlin-3 combination promotes synergistic cytotoxicity in acute myeloid leukemic cells irrespectively of FLT3 and p53 status.
Both the multi-kinase inhibitor sorafenib and the small molecule inhibitor of the MDM2/p53 interaction, nutlin-3, used alone, have shown promising anti-leukemic activity in acute myeloid leukemia cells. Thus, in this study we investigated the effect of the combination of sorafenib plus nutlin-3 in acute myeloid leukemia. Primary acute myeloid leukemia blasts (n=13) and FLT3(wild-type)/p53(wild-type) (OCI-AML3), FLT3(mutated)/p53(wild-type) (MOLM), FLT3(mutated)/p53(mutated) (MV4-11), FLT3(wild-type)/p53(deleted) (HL60) or FLT3(wild-type)/p53(mutated) (NB4) acute myeloid cell lines were exposed to sorafenib, used alone or in association with nutlin-3 at a 1:1 ratio, in a range of clinically achievable concentrations (1-10 μM). Induction of apoptosis and autophagy was evaluated by transmission electron microscopy and by specific flow cytometry analyses. The levels of Mcl-1, p53 and Bak proteins were analyzed by western blotting. Knock-down of Bax and Bak gene expression was performed in transfection experiments with specific short interfering RNA. The sorafenib+nutlin-3 drug combination exhibits synergistic cytotoxicity in primary acute myeloid leukemia blasts and in acute myeloid leukemia cell lines with maximal cytotoxicity in FLT3(mutated) MV4-11 and MOLM, followed by the FLT3(wild-type) OCI-AML3, HL60 and NB4 cell lines. The cytotoxic activity of sorafenib+nutlin-3 was characterized by an increase of both apoptosis and autophagy. Moreover, Bax and Bak showed prominent roles in mediating the decrease of cell viability in response to the drug combination in p53(wild-type) OCI-AML3 and p53(deleted) HL-60 cells, respectively, as demonstrated in transfection experiments performed with specific short interfering RNA. Our data demonstrate that acute myeloid leukemia cells show a variable but overall good susceptibility to the innovative therapeutic combination of sorafenib+nutlin-3, which differentially involves the pro-apoptotic Bcl-2 family members Bax and Bak in p53(wild-type) and p53(deleted) cells.


Three-Dimensional Otic Neuronal Progenitor Spheroids Derived from Human Embryonic Stem Cells.
Stem cell-replacement therapies have been proposed as a potential tool to treat sensorineural hearing loss by aiding the regeneration of spiral ganglion neurons (SGNs) in the inner ear. However, transplantation procedures have yet to be explored thoroughly to ensure proper cell differentiation and optimal transplant procedures. We hypothesized that the aggregation of human embryonic stem cell (hESC)-derived otic neuronal progenitor (ONP) cells into a multicellular form would improve their function and their survival in vivo post-transplantation. We generated hESC-derived ONP spheroids-an aggregate form conducive to differentiation, transplantation, and prolonged cell survival-to optimize conditions for their transplantation. Our findings indicate that these cell spheroids maintain the molecular and functional characteristics similar to those of ONP cells, which are upstream in the SGN lineage. Moreover, our phenotypical, electrophysiological, and mechanical data suggest an optimal spheroid transplantation point after 7 days of in vitro three-dimensional (3D) culture. We have also developed a feasible transplantation protocol for these spheroids using a micropipette aided by a digital microinjection system. In summary, the present work demonstrates that the transplantation of ONP cells in spheroid form into the inner ear through micropipette 7 days after seeding for 3D spheroid culture is an expedient and viable method for stem cell replacement therapies in the inner ear.


Proteomic analysis of differentially expressed proteins in kidneys of brain dead rabbits.
A large number of previous clinical studies have reported a delayed graft function for brain dead donors, when compared with living relatives or cadaveric organ transplantations. However, there is no accurate method for the quality evaluation of kidneys from brain‑dead donors. In the present study, two‑dimensional gel electrophoresis and MALDI‑TOF MS‑based comparative proteomic analysis were conducted to profile the differentially‑expressed proteins between brain death and the control group renal tissues. A total of 40 age‑ and sex‑matched rabbits were randomly divided into donation following brain death (DBD) and control groups. Following the induction of brain death via intracranial progressive pressure, the renal function and the morphological alterations were measured 2, 6 and 8 h afterwards. The differentially expressed proteins were detected from renal histological evidence at 6 h following brain death. Although 904±19 protein spots in control groups and 916±25 in DBD groups were identified in the two‑dimensional gel electrophoresis, >2‑fold alterations were identified by MALDI‑TOF MS and searched by NCBI database. The authors successfully acquired five downregulated proteins, these were: Prohibitin (isoform CRA_b), beta-1,3‑N-acetylgalactosaminyltransferase 1, Annexin A5, superoxide dismutase (mitochondrial) and cytochrome b‑c1 complex subunit 1 (mitochondrial precursor). Conversely, the other five upregulated proteins were: PRP38 pre‑mRNA processing factor 38 (yeast) domain containing A, calcineurin subunit B type 1, V‑type proton ATPase subunit G 1, NADH dehydrogenase [ubiquinone] 1 beta subcomplex subunit 10 and peroxiredoxin‑3 (mitochondrial). Immunohistochemical results revealed that the expressions of prohibitin (PHB) were gradually increased in a time‑dependent manner. The results indicated that there were alterations in levels of several proteins in the kidneys of those with brain death, even if the primary function and the morphological changes were not obvious. PHB may therefore be a novel biomarker for primary quality evaluation of kidneys from brain‑dead donors.


High-grade medullary thyroid carcinoma with papillary-like nuclear features: A report of five cases.
Medullary thyroid carcinoma (MTC) with papillary-like nuclear features has not been previously described. Here, we aimed to describe the unique features of MTC and examine their prognostic value as markers of high-grade MTC. Of the 110 MTC patients reviewed, a total of five (4.5%) who exhibited MTC with papillary-like nuclear features based on observations from cytological preparations were included in this study. Papillary-like nuclear features were defined as exhibiting all of the following characteristics: ground-glass chromatin pattern, grooves, indented membrane, and lobulation. The patients included four females and one male, with a median age of 70 years. Calcitonin-doubling times for patients 1 and 3 were 0.8 and 0.34 years, respectively. Cytologically, patients 4 and 5 displayed a Ki-67 labeling index of 5.1% and necrotic cells, respectively. All three histologically evaluated patients exhibited papillary-like nuclear features and a Ki-67 labeling index of >5.0%. Patients 1 and 3 had mitotic counts of ≥5 per 2 mm2 . The MTC in all five patients was classified as high-grade. Moreover, patient 1 harbored a RET mutation (M918T), while RET (R912W), BRAF (V600E), and CTNNB1 (S33F, T41I) mutations were present in patient 2. Our work suggests that papillary-like nuclear features in MTC may be associated with high-grade tumors. These findings may be cytologically indicative of high-grade tumors other than necrosis or mitosis.


Moral development of chinese students in Hong Kong.
The Defining Issues Test (DIT) of moral judgment by Rest was administered to 242 Chinese secondary school and university students in Hong Kong. Metric unfolding analysis on the stage scores of different groups of both sexes and various educational levels revealed that the moral development of the Chinese students were in agreement with Kohlberg's major distinctions of preconventional, conventional and postconventional levels. The sequence of stage development within the same level (e.g., between stages 5 and 6), however, was sometimes ambiguous. Results also showed that older university students were morally more mature than the younger secondary school students in their P%, D, and stages 5 and 6 scores. The applicability of DIT in the Chinese culture and the universality of Kohlberg's 6-stage model were generally supported.


Socioeconomic trajectories across the life course and health outcomes in midlife: evidence for the accumulation hypothesis?
Recent research in social epidemiology has established the importance of considering the accumulation of advantage and disadvantage across the life course when examining adult health outcomes. This paper examines (1) accumulation across trichotomous categories of socioeconomic position (SEP), and (2) accumulation in analysis stratified by adult SEP. Data are from the Whitehall II study. Each participant was categorized as having high (0), intermediate (1), or low (2) SEP at three time points in the life course, leading to 27 socioeconomic trajectories. These trajectories were summarized to yield a scale ranging from 0 (high SEP at all three time points) to 6 (low SEP at all three time points). Logistic regression was used to examine odds of incident coronary heart disease (CHD), poor mental and physical functioning, and minor psychiatric disorder. There was a graded linear relationship between accumulation of socioeconomic exposure and health. Men with a score of 6 had increased odds of CHD (2.53, 95% CI: 1.3, 5.1), poor physical functioning (2.19, 95% CI: 1.4, 4.1), and poor mental functioning (2.60, 95% CI: 1.4, 4.9) compared with men with a score of 0. In women there was an accumulation effect for CHD and physical functioning. No cumulative effect of SEP on minor psychiatric disorder was observed. The effects of accumulation were weaker in analyses stratified by adult SEP, with early deprivation followed by high adult SEP particularly detrimental for CHD. The health effects of socioeconomic disadvantage accumulate over the life course. In addition to accumulation effects, analysis stratified by adult SEP also provided support for the critical period and the pathway model.


Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer's and Parkinson's Diseases.
Alzheimer's Disease (AD) and Parkinson's Disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors. Ovid Medline and PubMed databases were used to perform an ordered search of the peerreviewed research literature described in this review. This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD. We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding neuroinflammatory mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.


Risk Score Elaboration for Stroke in Cardiac Surgery.
Stroke is a complication that causes considerable morbidity and mortality during the heart surgery postoperative period (incidence: 1.3 to 5%; mortality: 13 to 41%). Models for assessing the risk of stroke after heart surgery have been proposed, but most of them do not evaluate postoperative morbidity. The aim of this study was to develop a risk score for postoperative stroke in patients who undergo heart surgery with cardiopulmonary bypass. A cohort study was conducted with data from 4,862 patients who underwent surgery from 1996 to 2016. Logistic regression was used to assess relationships between risk factors and stroke. Data from 3,258 patients were used to construct the model. The model's performance was then validated using data from the remainder of the patients (n=1,604). The model's accuracy was tested using the area under the receiver operating characteristic (ROC) curve. The prevalence of stroke during the postoperative period was 3% (n=149); 59% of the patients who exhibited this outcome were male, 51% were aged ≥ 66 years, and 31.5% of the patients died. The variables that remained as independent predictors of the outcome after multivariate analysis were advanced age, urgent/emergency surgery, peripheral arterial occlusive disease, history of cerebrovascular disease, and cardiopulmonary bypass time ≥ 110 minutes. The area under the ROC curve was 0.71 (95% confidence interval 0.66 - 0.75). We were able to develop a risk score for stroke after heart surgery. This score classifies patients as low, medium, high, or very high risk of a surgery-related stroke.


[Current principles of diagnosis and treatment of chronic lymphocytic B-cell leukemia].
Chronic lymphocytic leukaemia is the most frequent form of malignant hematological diseases in the Western countries, it comprises 30-40% of all the leukaemias and it manifests itself between 60-65 years of age. Clinical features are caused in 93% of the cases by the accumulation and proliferation of immunologically incompetent, anergic, long lived, CD5 positive B-lymphocytes, expressing monoclonal IgM or IgD immunglobulin, in the bone marrow, the peripheral blood, the lymphoid and in other organs. In the etiology genetic basis is highly supposed, whereas affect of toxic agents and radiation exposure can be neglected. The prognosis of patients is variable and is determined by the clinical stage and the proliferative activity of the disease. Treatment is indicated in intermediate and high-risk clinical stages only with signs of disease activation on the basis of individual patient's risk. As first line treatment, Chlorambucil is indicated in high doses. Results achieved by combined chemotherapy are generally not superior compared to high-dose Chlorambucil treatment. For patients who developed resistance to alkilating agents purin analogues are recommended. Out of them the most favorable results had been accumulated with Fludarabine as second line treatment. For minority of the cases hemopoetic stem cell transplantation as the only curative therapeutic measure is being introduced in an increasing number. This review gives an account of the recent advances in the diagnosis and therapy of the disease.


Flux of catecholamines through chromaffin vesicles in cultured bovine adrenal medullary cells.
Primary cultures of bovine adrenal medullary chromaffin cells were pulse-labeled with [3H]dopamine or [3H]norepinephrine and examined for radioactive and total catecholamine contents by high performance liquid chromatography after additional incubations of 15 min to 10 days. [3H]Dopamine was rapidly taken up by chromaffin vesicles in situ and converted to norepinephrine with a half-time of approximately 6 h. [3H] Norepinephrine taken up by the cells was metabolized in three phases. 1) During its brief transit through the cytoplasm, 20 to 35% of this amine was converted to [3H]epinephrine. 2) Following vesicular accumulation, 65 to 70% of the remaining [3H]norepinephrine was methylated to form [3H]epinephrine with a half-time of approximately 30 h, corresponding to the rate of vesicular catecholamine loss from reserpine-treated cells. 3) The residual [3H]norepinephrine decreased with a half-time of 5 days, probably representing loss from norepinephrine-storing cells. [3H]Epinephrine formed endogenously had a half-life in the cultures of approximately 15 days. These data suggest that leakage of norepinephrine from chromaffin vesicles into the cytoplasm limits the rate of dopamine conversion to epinephrine in the adrenal medulla. The kinetic data indicate that approximately 18% of the endogenous norepinephrine and 73% of the endogenous dopamine are present in epinephrine cells.


A randomized, open-label clinical trial to evaluate immunogenicity and safety of an indigenously developed DTwP-Hib tetravalent combination vaccine (Easyfour®-TT) with Quadrovax® in Indian infants.
An open-label, randomized, multi-center trial was conducted to compare the immunogenicity and safety of an indigenously developed tetravalent DTwP-Hib vaccine, Easyfour®-TT with a commercially available vaccine, Quadrovax®. A total of 244 infants in good health, aged 6-10 weeks, were randomized in a 1:1 allocation to receive three doses of the test or comparator vaccine. Immunogenicity of the vaccines was determined by measuring the baseline and post-vaccination antibody response against the vaccine antigens; safety was evaluated in terms of local and systemic reactions (solicited and unsolicited) reported during the trial. Similar levels of seroprotection/seroresponse were achieved, 4 weeks after receiving 3 doses of Easyfour®-TT and Quadrovax®, and the antibody response of Easyfour®-TT was found non-inferior to Quadrovax®, against all four vaccine antigens. Both vaccines were well tolerated and had similar reactogenicity profiles, with a significantly lower occurrence of local (redness at injection site) and systemic reactions (irritability post-vaccination) with Easyfour®-TT vaccine as compared to Quadrovax® (p < 0.05). All adverse events resolved completely with no sequelae. All through the study, only one serious adverse event was observed that completely resolved upon treatment and was deemed unrelated to the vaccine administered. This study demonstrated that Easyfour®-TT vaccine was safe and immunogenic. CTRI/2014/12/005326 (registered with the Clinical Trial Registry of India (CTRI)).


The use of ceramic-on-ceramic bearings in isolated revision of the acetabular component.
The practice of removing a well-fixed cementless femoral component is associated with high morbidity. Ceramic bearing couples are low wearing and their use minimises the risk of subsequent further revision due to the production of wear debris. A total of 165 revision hip replacements were performed, in which a polyethylene-lined acetabular component was revised to a new acetabular component with a ceramic liner, while retaining the well-fixed femoral component. A titanium sleeve was placed over the used femoral trunnion, to which a ceramic head was added. There were 100 alumina and 65 Delta bearing couples inserted. The mean Harris hip score improved significantly from 71.3 (9.0 to 100.0) pre-operatively to 91.0 (41.0 to 100.0) at a mean follow up of 4.8 years (2.1 to 12.5) (p < 0.001). No patients reported squeaking of the hip. There were two fractures of the ceramic head, both in alumina bearings. No liners were seen to fracture. No fractures were observed in components made of Delta ceramic. At 8.3 years post-operatively the survival with any cause of failure as the endpoint was 96.6% (95% confidence interval (CI) 85.7 to 99.3) for the acetabular component and 94.0% (95% CI 82.1 to 98.4) for the femoral component. The technique of revising the acetabular component in the presence of a well-fixed femoral component with a ceramic head placed on a titanium sleeve over the used trunnion is a useful adjunct in revision hip practice. The use of Delta ceramic is recommended.


Should chest compressions be considered an aerosol-generating procedure? A literature review in response to recent guidelines on personal protective equipment for patients with suspected COVID-19.
There is disagreement between international guidelines on the level of personal protective equipment (PPE) required for chest compressions for patients with suspected COVID-19. This discrepancy centres on whether they are considered to be an aerosol-generating procedure (AGP), thus requiring airborne protection to prevent transmission to healthcare workers (HCWs). The need to don higher-level PPE has to be weighed against the resulting delay to emergency treatment.We performed a literature search on this topic which found eight relevant studies. All were observational with low patient numbers and multiple confounding factors, but describe cases of acute respiratory infection transmission during chest compressions. One systematic review concluded that chest compressions were not an AGP. Two simulated studies (released as preprints) potentially demonstrate aerosol generation. Given that there is evidence for infection transmission during chest compressions, we conclude that a precautionary approach with appropriate PPE is necessary to protect HCW from contracting a potentially fatal infection.


High-efficiency cleaning technology and lifespan prediction for the ceramic membrane treating secondary treated effluent.
Chemical cleaning is one of the key technical means to control membrane fouling, restore membrane flux and ensure the stable operation of membrane systems. In the experiment, the six most representative chemical cleaning agents for ceramic membranes, such as sulfuric acid (H2SO4), sodium hydroxide (NaOH), sodium hypochlorite (NaClO), ethylenediaminetetraacetic acid disodium salt (EDTA-Na2), sodium dodecyl sulfate (SDS) and nonylphenol polyoxyethylene ether (OP-10), were used as research objects. The cleaning effect of the two-step combined cleaning of chemical cleaning agents on the fouled membrane was systematically investigated. Results showed that the order of the chemical cleaning agent had a significant effect on the cleaning effect. The best chemical cleaning program was determined to be NaClO first and then SDS: the fouled ceramic membrane was soaked in NaClO solution at 0.15% for 2.5 h and further soaked in SDS solution at five times its own critical micelle concentration for 2.5 h. The predicted long-term lifespan of the ceramic membranes was 4.91 years. Scanning electron microscopy-energy spectrum analysis showed that the surface roughness of the cleaned ceramic membrane was slightly higher than that of the new membrane. The contact angle was slightly lower than that of the new membrane.


Guiding Principles for the Clinical Use and Selection of Microcatheters in Complex Coronary Interventions.
The use of microcatheters as a coronary interventional tool for a therapeutic approach to complex coronary interventions like bifurcation lesions, ostial location, tortuous anatomy, angled takeoffs, coronary calcification, and chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is growing among cardiologists across the country. During the treatment of such complex lesions, microcatheters play an essential part of the tool kit with both single-lumen and double-lumen microcatheters (DLMs) having their specific niche areas. The selection of microcatheters involves a detailed understanding of the microcatheter specification, lesion anatomy, lesion location, vessel tortuosity and trajectory, and crossing techniques. The selection of appropriate crossing techniques with different microcatheters increases success rates of PCI, reduces procedural time and contrast use, and lowers the radiation. However, the use of microcatheters and their technicalities have not yet fully realized by many operators and their true scope has not been fully explored. This article discusses and summarizes the thoughts and key opinions of experts in this field.


Acute abdominal pain: value of non-contrast enhanced ultra-low-dose multi-detector row CT as a substitute for abdominal radiographs.
The aim of this study was to evaluate a non-enhanced ultra-low-dose (ULD) abdominal-pelvic multi-detector row computerized tomography (MDCT) to assess patients with acute abdominal pain who would otherwise undergo three-view abdominal X-ray series. Institutional review board approval was obtained with waiver of informed consent. This study was Health Insurance Portability and Accountability Act-compliant. One hundred and sixty-three patients (mean age, 51 years; range, 19-82 years, M/F = 110:53) who underwent ULD MDCT were included in the study. Two subspecialty radiologists independently reviewed the images for abnormal findings and image quality parameters. The effective radiation dose was calculated for each patient and compared to standard-dose computed tomography (CT) scans of 50 matched controls. Findings were confirmed by reviewing the patients' medical records, and statistical analysis was performed. ULD MDCT showed a high sensitivity (100%), specificity (98.5%), and positive predictive value (91.7%) for detection of free air, stones, and intestinal obstruction. For other sources of abdominal pain, the overall sensitivity, specificity, and positive predictive value were 86%, 96%, and 95%, respectively. Mean effective radiation dose from this study was 2.10 mSv (range of 0.67 to 6.64 mSv) with a 78% mean dose reduction compared to standard-dose CT. There was good inter-observer agreement (=0.4 to 0.81). ULD abdominal-pelvic MDCT provides rapid and reasonably accurate diagnostic information in patients with acute abdominal pain at a very low radiation dose.


Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets.
This study aimed to identify the underlying genetic mutation in patients with hypophosphatemic rickets (HR). Genomic DNA was analysed for mutations in PHEX, FGF23 and CLCN5 by polymerase chain reaction (PCR) followed by denaturing high-performance liquid chromatography (dHPLC). Bi-directional sequencing was performed in samples with deviating chromatographic profiles. DMP1 and SLC34A3 were sequenced, only. In addition, a multiplex ligation-dependent probe amplification (MLPA) analysis was performed to detect larger deletions/duplications in PHEX or FGF23. Familial cases accounted for 12 probands while 12 cases were sporadic. In 20 probands, mutations were detected in PHEX of which 12 were novel, and one novel frameshift mutation was found in DMP1. Three PHEX mutations were identified by the MLPA analysis only; that is, two large deletions and one duplication. No mutations were identified in FGF23, SLC34A3 or CLCN5. By the methods used, a disease causing mutation was identified in 83% of the familial and 92% of the sporadic cases, thereby in 88% of the tested probands. Genetic analysis performed in HR patients by PCR, dHPLC, sequencing and in addition by MLPA analysis revealed a high identification rate of gene mutations causing HR, including 12 novel PHEX and one novel DMP1 mutation.


[Programms of community psychiatry].
Three main resources in all Health Care Programs are classified into three groups: The Psychiatric Hospital. It is a strictly hierarchical organization, where decisions are made at the top of the pyramid, and authority flows down administrative channels. Tasks are clearly defined, and so are responsibilities. The Therapeutic Community. It is a non-hierarchical group, with the goal of re-socializing disturbed individuals. It stresses group and individual responsibilities, aiming at learning new patterns of interaction. All members, patients and personnel alike, are equal members sharing full responsibilities, including decisions concerning the group and/or the individuals. Joining the group, leaving it, or dismissing a member, are all joint decisions. The underlying theory assumes therapeutic potentialities for a group with those special requirements, and for each of its members, regardless of its roles. The Programs of Community Psychiatry. All resources of large population groups are oriented and origanized into comprehensive community programs. All physical facilities are co-ordinated into a network. Personnel is recruited, whenever possible, using the human resources within the same community. All actions, at all scales, are organically co-ordinated in order to maximize benefits and minimize efforts and expenses. All three systems collide substantially, because of their radically different conceptions, grounds and operating requirements. Their many conflicts are analyzed in detail, assessing their consequences on the efficacity of services. A general conclusion is drawn on the valuable data emerging from the application of different systems simultaneously, allowing for future further evaluations. The author stresses that all three systems must be analyzed within a much broader socio-economical framework, and taking into account additional difficulties emerging from: a) great social distance between patient and therapeutic team, impeding exchanges; b) politically unstable climate for officials in charge of mental health policies; c) lack of psychological and technical fitness and heterogeneity of training affecting most mental health workers and agents.


Real-time expert systems interfaces, cognitive processes, and task performance: an empirical assessment.
In this experiment we investigated the effect of different real-time expert system interfaces on operators' cognitive processes and performance. The results supported the principle that a real-time expert system's interface should focus operators' attention on where it is required most. However following this principle resulted in unanticipated consequences. In particular, it led to inferior performance for less critical, yet important cases requiring operators' attention. For such cases operators performed better with an interface that let them select where they wanted to focus their attention. Having a rule generation capability improved performance with all interfaces but did so less than hypothesized. In all cases performance with different interfaces and a rule generation capability was explained by the effect of the interfaces on cognitive process measures.


Carpal tunnel syndrome: a frequent, invalidating, long-term complication of chronic hemodialysis.
Among 100 patients treated by chronic hemodialysis, 12 developed a carpal tunnel syndrome (CTS). After surgery, improvement was dramatic with regression of pain and paresthesiae within a few hours. Recovery of motor and sensory deficits was longer (2-3 weeks). No relationship could be established between CTS and the type of nephropathy, severity of polyneuritis, Ca and PO4 metabolism, the presence of vascular access and efficacy of dialysis. The bilaterality of the lesions in 7 patients suggests general pathogenic mechanisms superimposed to the presence of the vascular access. While only 3 out of 65 patients treated for less than 4 years complained about CTS, 9 out of 35 treated for more than 4 years were symptomatic.


Protein-coding cis-natural antisense transcripts have high and broad expression in Arabidopsis.
Pairs of genes within eukaryotic genomes are often located on opposite DNA strands such that transcription generates cis-natural sense antisense transcripts (cis-NATs). This orientation of genes has been associated with the biogenesis of splice variants and natural antisense small RNAs. Here, in an analysis of currently available data, we report that within Arabidopsis (Arabidopsis thaliana), protein-coding cis-NATs are also characterized by high abundance, high coexpression, and broad expression. Our results suggest that a permissive chromatin environment may have led to the proximity of these genes. Compared with other genes, cis-NAT-encoding genes have enriched low-nucleosome-density regions, high levels of histone H3 lysine-9 acetylation, and low levels of H3 lysine-27 trimethylation. Promoters associated with broadly expressed genes are preferentially found in the 5' regulatory sequences of cis-NAT-encoding genes. Our results further suggest that natural antisense small RNA production from cis-NATs is limited. Small RNAs sequenced from natural antisense small RNA biogenesis mutants including dcl1, dcl2, dcl3, and rdr6 map to cis-NATs as frequently as small RNAs sequenced from wild-type plants. Future work will investigate if the positive transcriptional regulation of overlapping protein-coding genes contributes to the prevalence of these genes within other eukaryotic genomes.


Arthropod-Microbiota Integration: Its Importance for Ecosystem Conservation.
Recent reports indicate that the health of our planet is getting worse and that genuine transformative changes are pressing. So far, efforts to ameliorate Earth's ecosystem crises have been insufficient, as these often depart from current knowledge of the underlying ecological processes. Nowadays, biodiversity loss and the alterations in biogeochemical cycles are reaching thresholds that put the survival of our species at risk. Biological interactions are fundamental for achieving biological conservation and restoration of ecological processes, especially those that contribute to nutrient cycles. Microorganism are recognized as key players in ecological interactions and nutrient cycling, both free-living and in symbiotic associations with multicellular organisms. This latter assemblage work as a functional ecological unit called "holobiont." Here, we review the emergent ecosystem properties derived from holobionts, with special emphasis on detritivorous terrestrial arthropods and their symbiotic microorganisms. We revisit their relevance in the cycling of recalcitrant organic compounds (e.g., lignin and cellulose). Finally, based on the interconnection between biodiversity and nutrient cycling, we propose that a multicellular organism and its associates constitute an Ecosystem Holobiont (EH). This EH is the functional unit characterized by carrying out key ecosystem processes. We emphasize that in order to meet the challenge to restore the health of our planet it is critical to reduce anthropic pressures that may threaten not only individual entities (known as "bionts") but also the stability of the associations that give rise to EH and their ecological functions.


Neonatal evaluation by nurses in a neonatal special care unit.
The value of a nursing questionnaire in the evaluation of preterm infants during their stay in the neonatal special care unit was studied. The questions were related to feeding, crying, sleeping, motoric process, tremor and stress, state control, position, sensory capabilities and parental attitudes. In general, questions were answered in 95%, but the questions related to sensory capabilities were only answered in 30%. Evaluation by the nurses of feeding, crying, motoric process, tremor and parental attitudes correlated well with observational data and with the results of a neurological examination. It was concluded that evaluation by the nurses using a questionnaire can be of value in neonatal units, especially when detailed observations or a systematic neurological examination are not feasible.


The European 2030 climate and energy package: do domestic strategy adaptations precede EU policy change?
The European Union's 2030 climate and energy package introduced fundamental changes compared to its 2020 predecessor. These changes included a stronger focus on the internal market and an increased emphasis on technology-neutral decarbonization while simultaneously de-emphasizing the renewables target. This article investigates whether changes in domestic policy strategies of leading member states in European climate policy preceded the observed changes in EU policy. Disaggregating strategic change into changes in different elements (goals, objectives, instrumental logic), allows us to go beyond analyzing the relative prioritization of different goals, and to analyze how policy requirements for reaching those goals were dynamically redefined over time. To this end, we introduce a new method, which based on insights from social network analysis, enables us to systematically trace those strategic chances. We find that shifts in national strategies of the investigated member states preceded the shift in EU policy. In particular, countries reframed their understanding of supply security, and pushed for the internal electricity market also as a security measure to balance fluctuating renewables. Hence, the increasing focus on markets and market integration in the European 2030 package echoed the increasingly central role of the internal market for electricity supply security in national strategies. These findings also highlight that countries dynamically redefined their goals relative to the different phases of the energy transition.


Relative resistance of Brazil strain trypomastigote forms of Trypanosoma cruzi to in vitro antibody-dependent complement-mediated lysis.
Various assay conditions were employed in experiments examining the susceptibility of trypomastigote forms of the Brazil strain of Trypanosoma cruzi to antibody-dependent complement-mediated lysis. To identify optimal assay conditions, both guinea pig serum and normal human serum were used as complement sources, and fibroblast-derived or blood-form trypomastigotes were either coincubated with immune sera and complement together, or the parasites were first precoated with antibodies and then were incubated in complement. Under conditions promoting maximal lysis by antibodies and complement, 60-90% of the trypomastigote forms were not lysed. These results indicate that trypomastigotes of certain isolates of T. cruzi, such as the Brazil strain, may possess an escape mechanism by which they evade complement-mediated lysis.


Impact of SRY-Box Transcription Factor 11 Gene Polymorphisms on Oral Cancer Risk and Clinicopathologic Characteristics.
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 "TC + CC" variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047-1.674; p= 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics.


Consequences of childhood reading difficulties and behaviour problems for educational achievement and employment in early adulthood.
Reading difficulties (RDs) and behaviour problems (BPs) are two common childhood problems that have a high degree of stability and often negatively affect well-being in both the short and longer terms. The study aimed to shed light on the unique and joint consequences of these two childhood problems for educational and occupational outcomes in early adulthood. Data were drawn from a life-course longitudinal study of psychosocial development, the Australian Temperament Project. Parent and teacher reports and a standard reading test were used to define four groups of children at 7-8 years: RDs only; BPs only; both problems; and neither problem. These groups were followed forward to ascertain educational attainment and employment status at 19-20 and 23-24 years. Each childhood problem was a unique risk for poorer educational and occupational outcomes, with co-occurring problems significantly increasing the risk of poorer educational outcomes. Further analyses revealed that the effects of childhood BPs on occupational status were mediated by secondary school non-completion, but childhood RDs were not. The findings point to the importance of screening and early intervention to prevent or minimize the development of these two childhood problems, as well as continuing to support vulnerable children to increase their likelihood of secondary school completion.


Determination of nicotine concentrations in human milk.
A total of 34 samples of human milk from 15 donors was analyzed for nicotine content, using a new method of sample preparation and subsequent quantification by gas chromatography. Nicotine was not found in the six samples of milk from non-smokers. The 28 samples from smokers contained an average of 91 parts per billion (ppb) nicotine (ranging from less than 20 ppb to 512 ppb). While no adverse effects to the infant due to nicotine in human milk have been documented, this method of analysis will allow systematic monitoring of nicotine concentrations in the milk of lactating women. These results should not be used to deter breast-feeding; rather, they offer another reason for mothers to reduce or cease smoking.


A Systematic Review and Meta-analysis of the Factors Associated With Nonadherence and Discontinuation of Statins Among People Aged ≥65 Years.
Older individuals (aged ≥65 years) are commonly prescribed statins but may experience a range of barriers in adhering to therapy. The factors associated with poor statin adherence and/or discontinuation among this population have not been comprehensively reviewed. We conducted a systematic review to identify English articles published through December 12, 2016 that reported factors associated with nonadherence and/or discontinuation of statins among older persons. Data were pooled via random-effects meta-analysis techniques. Forty-five articles reporting data from more than 1.8 million older statin users from 13 countries were included. The factors associated with increased statin nonadherence were black/non-white race (odds ratio [OR] 1.66, 95% confidence interval [CI] 1.39-1.98), female gender (OR 1.08, 95% CI 1.03-1.13), current smoker (OR 1.12, 95% CI 1.03-1.21), higher copayments (OR 1.38, 95% CI 1.25-1.52), new user (OR 1.58, 95% CI 1.21-2.07), lower number of concurrent cardiovascular medications (OR 1.08, 95% CI 1.06-1.09), primary prevention (OR 1.49, 95% CI 1.40-1.59), having respiratory disorders (OR 1.17, 95% CI 1.12-1.23) or depression (OR 1.11, 95% CI 1.06-1.16), and not having renal disease (OR 1.09, 95% CI 1.04-1.14). The factors associated with increased statin discontinuation were lower income status (OR 1.20, 95% CI 1.06-1.36), current smoker (OR 1.14, 95% CI 1.06-1.23), higher copayment (OR 1.61, 95% CI 1.53-1.70), higher number of medications (OR 1.04, 95% CI 1.01-1.06), presence of dementia (OR 1.18, 95% CI 1.02-1.36), cancer (OR 1.22, 95% CI 1.11-1.33) or respiratory disorders (OR 1.19, 95% CI 1.05-1.34), primary prevention (OR 1.66, 95% CI 1.24-2.22), and not having hypertension (OR 1.13, 95% CI 1.07-1.20) or diabetes (OR 1.09, 95% CI 1.04-1.15). Interventions that target potentially modifiable factors including financial and social barriers, patients' perceptions about disease risk as well as polypharmacy may improve statin use in the older population.


Prenatal IV Cocaine: Alterations in Auditory Information Processing.
One clue regarding the basis of cocaine-induced deficits in attentional processing is provided by the clinical findings of changes in the infants' startle response; observations buttressed by neurophysiological evidence of alterations in brainstem transmission time. Using the IV route of administration and doses that mimic the peak arterial levels of cocaine use in humans, the present study examined the effects of prenatal cocaine on auditory information processing via tests of the auditory startle response (ASR), habituation, and prepulse inhibition (PPI) in the offspring. Nulliparous Long-Evans female rats, implanted with an IV access port prior to breeding, were administered saline, 0.5, 1.0, or 3.0 mg/kg/injection of cocaine HCL (COC) from gestation day (GD) 8-20 (1×/day-GD8-14, 2×/day-GD15-20). COC had no significant effects on maternal/litter parameters or growth of the offspring. At 18-20 days of age, one male and one female, randomly selected from each litter displayed an increased ASR (>30% for males at 1.0 mg/kg and >30% for females at 3.0 mg/kg). When reassessed in adulthood (D90-100), a linear dose-response increase was noted on response amplitude. At both test ages, within-session habituation was retarded by prenatal cocaine treatment. Testing the females in diestrus vs. estrus did not alter the results. Prenatal cocaine altered the PPI response function across interstimulus interval and induced significant sex-dependent changes in response latency. Idazoxan, an α(2)-adrenergic receptor antagonist, significantly enhanced the ASR, but less enhancement was noted with increasing doses of prenatal cocaine. Thus, in utero exposure to cocaine, when delivered via a protocol designed to capture prominent features of recreational usage, causes persistent, if not permanent, alterations in auditory information processing, and suggests dysfunction of the central noradrenergic circuitry modulating, if not mediating, these responses.


Understanding Beta-Lactam-Induced Lysis at the Single-Cell Level.
Mechanical rupture, or lysis, of the cytoplasmic membrane is a common cell death pathway in bacteria occurring in response to β-lactam antibiotics. A better understanding of the cellular design principles governing the susceptibility and response of individual cells to lysis could indicate methods of potentiating β-lactam antibiotics and clarify relevant aspects of cellular physiology. Here, we take a single-cell approach to bacterial cell lysis to examine three cellular features-turgor pressure, mechanosensitive channels, and cell shape changes-that are expected to modulate lysis. We develop a mechanical model of bacterial cell lysis and experimentally analyze the dynamics of lysis in hundreds of single Escherichia coli cells. We find that turgor pressure is the only factor, of these three cellular features, which robustly modulates lysis. We show that mechanosensitive channels do not modulate lysis due to insufficiently fast solute outflow, and that cell shape changes result in more severe cellular lesions but do not influence the dynamics of lysis. These results inform a single-cell view of bacterial cell lysis and underscore approaches of combatting antibiotic tolerance to β-lactams aimed at targeting cellular turgor.


Percutaneous injury, blood exposure, and adherence to standard precautions: are hospital-based health care providers still at risk?
To examine factors associated with blood exposure and percutaneous injury among health care workers, we assessed occupational risk factors, compliance with standard precautions, frequency of exposure, and reporting in a stratified random sample of 5123 physicians, nurses, and medical technologists working in Iowa community hospitals. Of these, 3223 (63%) participated. Mean rates of hand washing (32%-54%), avoiding needle recapping (29%-70%), and underreporting sharps injuries (22%-62%; overall, 32%) varied by occupation (P<.01). Logistic regression was used to estimate the adjusted odds of percutaneous injury (aOR(injury)), which increased 2%-3% for each sharp handled in a typical week. The overall aOR(injury) for never recapping needles was 0.74 (95% CI, 0.60-0.91). Any recent blood contact, a measure of consistent use of barrier precautions, had an overall aOR(injury) of 1.57 (95% CI, 1.32-1.86); among physicians, the aOR(injury) was 2.18 (95% CI, 1.34-3.54). Adherence to standard precautions was found to be suboptimal. Underreporting was found to be common. Percutaneous injury and mucocutaneous blood exposure are related to frequency of sharps handling and inversely related to routine standard-precaution compliance. New strategies for preventing exposures, training, and monitoring adherence are needed.


[Dental pulp diseases of the deciduous teeth. II. Clinical classification].
Clinical and pathomorphological studies of various pulpal affections in 55 deciduous molars from children aged between 2.5 and 8 years call in question the clinical appropriateness of the current classification of pulpal affections that makes use of the pathohistological nomenclautre. In this paper, a classification is suggested that is based on clinical symptoms and allows for current methods of therapy.


Transformed malignant lymphoma from Lennert's lesion is a CD4+ T cell lymphoma: an immunohistochemical study.
We describe a case of Lennert's lesion terminating in T cell non-Hodgkin's lymphoma (NHL). A 53-year-old woman showed inguinal lymphadenopathy. This was histologically interpreted as toxoplasmic lymphadenitis. However, Lennert's lesion was diagnosed in subsequent biopsies. Because additional lymphadenopathy and constitutional symptoms were absent, anti-neoplastic therapy was not given. During the five and a half years after the initial biopsy, generalized lymphadenopathy and constitutional symptoms developed. Histological examination of the cervical lymph node disclosed NHL, diffuse, large cell type. Transformed lymphoma cells were confirmed to be of peripheral T cell origin with a helper/inducer phenotype. We speculate that some cases of Lennert's lesion have a potentiality of spontaneous transformation into high grade malignant lymphoma associated with disappearance of epithelioid histiocytes.


Optimal estimation of hearing-aid compression parameters.
A new procedure for measuring the attack and release time constants of a hearing-aid compression circuit is presented in this paper. The procedure is based on a mathematical model of the response of a compression system to sudden increments or decrements in the amplitude of a sinusoidal excitation. The parameters of the model, which include the attack and release time constants, are fitted to the measured hearing-aid test-signal response using a minimum mean-squared error criterion. A computer simulation of a compression hearing aid is used to illustrate the behavior of the compression amplifier and to assess the accuracy of the estimated attack and release time constants.


Effects of prognostic factors and treatment on survival in advanced non-small cell lung cancer.
In this study, 304 stage III-B and IV non-small cell lung cancer (NSCLC) cases diagnosed and followed up in our hospital between January 2000 and December 2002 are retrospectively analysed. The effects of demographic, clinical, laboratory findings and different therapeutic modalities on survival were investigated. Of the cases, 31 (10.2%) were women, 273 (89.8%) were men and mean age was 60.59 +/- 10.73. Analysis by the Kaplan-Meier method revealed that median survival was 6.0 +/- 0.5 (95% CI: 5.1-6.9) months and 12 and 24-month survival rates were 25.27 +/- 2.99% and 11.48 +/- 2.77% respectively. By univariate analysis of 33 parameters, 12 of them were found to be effective on survival and this relationship was statistically significant (p< 0.05). These parameters indicating poor prognosis were age > 70, ECOG performance score > 1, dyspnea, peripheral lymphadenomegaly (LAM), mediastinal invasion, pleural effusion, distant metastasis, elevated serum LDH, CA 19.9, CA-125 values, not receiving curative radiotherapy (RT) (> 50 Gy) or chemotherapy (CT). A multivariate analysis by Cox regression method revealed that advanced age, mediastinal invasion and metastatic disease were not independent prognostic factors on survival whereas ECOG performance score > 1 (p= 0.000), absence of CT (p= 0.000) and curative RT (p= 0.018), dyspnea (p= 0.035), peripheral LAM (p= 0.022) and pleural effusion (p= 0.043) were independent prognostic factors on survival.


Metabolic measurement techniques to assess bone fracture healing: a preliminary study.
The purpose of this study was to project the effectiveness of using positron emission tomography for evaluation of fracture healing using the analogous method of liquid scintillation. A reproducible comminuted fracture model in rabbit femurs was stabilized with external fixation. Thirty-nine rabbits were divided into four groups: Group A had slight distraction, Group B had shortening, Group C had a bone defect, and Group D was the sham control group. At 2 and 4 weeks after fracture, the femurs had liquid scintillation measurements using 2-[14C]-deoxyglucose (2DG C-14). Glucose uptake was significantly elevated in the experimental limb relative to the contralateral control femurs at both times. The distraction group showed a significant decrease in uptake from 2-4 weeks. There was a high correlation between the liquid scintillation measurements and the radiographic fracture healing scores, with higher levels of 2DG C-14 uptake corresponding to lower levels of fracture healing calcification. The high correlation found between 2DG C-14 uptake and radiographic scores suggests that positron emission tomography used in conjunction with a glucose-based radiopharmaceutical such as 2-[18F]fluoro-2-deoxyglucose can monitor the fracture healing process effectively.


Highly symmetric networks derived from cubane-related octametallic complexes of a new oxyanion of carbon, C4O7(4-), each molecule attached to eight neighbors by 24 equivalent hydrogen bonds.
Aqueous reaction mixtures containing dihydroxyfumaric acid, M2+ (M = Zn, Co, Fe, and Mg) and acetate ion at room temperature give crystals, suitable for single-crystal X-ray diffraction studies, of composition [(MII)8(C4O7)4(H2O)12].24H2O, in which the C4O74- component is the alkoxide-tricarboxylate tetra-anionic species -OC(CO2-)3, a new oxyanion of carbon. All four compounds crystallize in the body-centered space group I3m with cell dimensions a approximately 15.0 A. Discrete electrically neutral [(MII)8(C4O7)4(H2O)12] molecules are present, with a cubane-like core consisting of four trigonal prismatic metal centers and four mu3-alkoxo bridges from separate -OC(CO2-)3 ligands. The octametallic molecule is highly symmetrical, with four fac tri-aqua octahedral metal centers tetrahedrally appended to the central cubane-based [(MII)8(C4O7)4 ]8- unit. The molecules assemble in the crystal in a body-centered cubic fashion, each being attached to its eight neighbors by 24 equivalent hydrogen bonds-an extreme example of self-complementarity.


Large primary kinetic isotope effects in the abstraction of hydrogen from organic compounds by a fluorinated radical in water.
Isotope effects have been measured for the abstraction of hydrogen from a series of organic substrates by the perfluoro radical, Na+ -O3SCF2CF2OCF2CF2*, in water. Both primary and secondary deuterium isotope effects were measured, with the primary isotope effects ranging in value from 4.5 for isopropanol to 19.6 for acetic acid. The values for the alpha- and beta-secondary deuterium isotope effects were 1.06 and 1.035, respectively. It was concluded that tunneling contributes significantly to the production of the observed, large primary kinetic isotope effects in these C-H abstraction reactions.


Absence of need for amniocentesis in patients with elevated levels of maternal serum alpha-fetoprotein and normal ultrasonographic examinations.
Recent improvements in the accuracy of sonographic diagnosis of neural-tube and ventral-wall defects have raised a question about the wisdom of routinely offering amniocentesis to women who have elevated levels of maternal serum alpha-fetoprotein with a structurally normal fetus as determined by ultrasonography. We reviewed the ultrasound findings in 51 consecutive fetuses with spina bifida, encephalocele, gastroschisis, or omphalocele that were delivered or aborted at a single hospital, to estimate the sensitivity of ultrasonography for these diagnoses. In all cases, the mothers had undergone prenatal sonography at one facility between 16 and 24 weeks after the last menstrual period. We used these data to calculate the probability of an affected fetus in a women with a given level of maternal serum alpha-fetoprotein and a normal sonogram. These four types of anomalies were correctly identified in all 51 cases, yielding a sensitivity of 100 percent (95 percent confidence interval, 94 to 100 percent). Using the lower limit of this confidence interval, we calculated that the probability of an affected fetus ranges from 0.01 to 0.15 percent for maternal serum alpha-fetoprotein levels ranging from 2.0 to 3.5 times the median, respectively. This level of risk is less than the reported risk of abortion due to amniocentesis and may lead some women with elevated levels of alpha-fetoprotein to decide not to proceed with amniocentesis.


Effectiveness of milnacipran for the treatment of chronic pain in the orofacial region.
The effect of milnacipran for the treatment of chronic pain in the orofacial region, including burning mouth syndrome (BMS) and atypical odontalgia (AO), was assessed while accounting for the influence of concurrent depressive symptoms on the pain-relieving effect. Milnacipran was administered for 12 weeks to 36 patients with chronic pain in the orofacial region (3 men and 29 women, aged between 22 and 76 years with a mean age of 59 years). Of those patients, 22 and 10 patients had BMS and AO, respectively. The initial dose of milnacipran was 15 mg a day, and the dose was raised up to 100 mg a day. Pain was assessed using the visual analog scale, and symptoms of depression were evaluated using the Hamilton Depression Rating Scale at baseline and at weeks 1, 2, 4, 6, 8, 10, and 12 of the study treatment. Data from 32 patients who completed the study were included in the analysis. The visual analog scale score significantly decreased after the 12-week treatment, and it showed a similar time course of decline irrespective of concurrent depressive symptoms during the 12 weeks. Treatment with milnacipran resulted in a significant improvement of chronic pain in the orofacial region irrespective of concurrent symptoms of depression. The present results suggested that milnacipran may be an effective agent for treatment of such disorders.


[Pathogenesis of endothelial dysfunction in cerebral atherosclerosis and their correction].
The authors review the studies on oxidative stress in the pathogenesis of cerebrovascular diseases (CVD) and highlight a contribution of endothelial dysfunction to the CVD development. Own experience of using divasa in patients of old and very old age with chronic CVD comorbid to cerebral atherosclerosis is described.


Feasibility and scalability of a fitness tracker study: Results from a longitudinal analysis of persons with multiple sclerosis.
Consumer-grade fitness trackers offer exciting opportunities to study persons with chronic diseases in greater detail and in their daily-life environment. However, attempts to bring fitness tracker measurement campaigns from tightly controlled clinical environments to home settings are often challenged by deteriorating study compliance or by organizational and resource limitations. By revisiting the study design and patient-reported experiences of a partly remote study with fitness trackers (BarKA-MS study), we aimed to qualitatively explore the relationship between overall study compliance and scalability. On that account, we aimed to derive lessons learned on strengths, weaknesses, and technical challenges for the conduct of future studies. The two-phased BarKA-MS study employed Fitbit Inspire HR and electronic surveys to monitor physical activity in 45 people with multiple sclerosis in a rehabilitation setting and in their natural surroundings at home for up to 8 weeks. We examined and quantified the recruitment and compliance in terms of questionnaire completion and device wear time. Furthermore, we qualitatively evaluated experiences with devices according to participants' survey-collected reports. Finally, we reviewed the BarKA-MS study conduct characteristics for its scalability according to the Intervention Scalability Assessment Tool checklist. Weekly electronic surveys completion reached 96%. On average, the Fitbit data revealed 99% and 97% valid wear days at the rehabilitation clinic and in the home setting, respectively. Positive experiences with the device were predominant: only 17% of the feedbacks had a negative connotation, mostly pertaining to perceived measurement inaccuracies. Twenty-five major topics and study characteristics relating to compliance were identified. They broadly fell into the three categories: "effectiveness of support measures", "recruitment and compliance barriers", and "technical challenges". The scalability assessment revealed that the highly individualized support measures, which contributed greatly to the high study compliance, may face substantial scalability challenges due to the strong human involvement and limited potential for standardization. The personal interactions and highly individualized participant support positively influenced study compliance and retention. But the major human involvement in these support actions will pose scalability challenges due to resource limitations. Study conductors should anticipate this potential compliance-scalability trade-off already in the design phase.


Exploring barriers and facilitators to women's intention and behavior to seek treatment for distressing sexual problems.
Many women experience distressing problems with sexual functioning, most commonly in the form of low sexual desire or arousal, difficulties reaching orgasm, or genito-pelvic pain with sexual activity. Although effective treatments are available, more than half of the women who experience distressing sexual problems do not seek professional help. Understanding help-seeking patterns, experiences with treatment providers, and barriers to treatment is crucial to address this underutilization. Examining the role of personal characteristics, sexual problem symptoms, and cognitive factors in explaining the intention to seek treatment can help identify individuals who are most reluctant to seek help. Psychological online interventions are a promising resource to increase the availability of effective treatments. Knowledge about the predictors of women's intention to use internet-delivered treatments, as well as information about personal preferences regarding their scope, can help tailor them to women's needs. To address these research questions, cross-sectional data of 800 women (Mage = 30.49, range = 18-73) were analyzed. While many women considered clinical psychologists to be the most qualified treatment providers, gynecologists were cited as the most likely first point of contact. Among women not utilizing any treatments, many reported a preference for dealing with a sexual problem on their own as a reason not to seek help. Higher help-seeking intention was related to living in a larger city, experiencing higher sexual distress, experiencing pain or difficulties with vaginal penetration, higher self-stigma. and lower sexual assertiveness. Women who were convinced of the effectiveness of psychological online interventions and who appreciated the benefits of anonymity indicated that they were more likely to use them. Understanding what factors influence women's decisions about whether or not to seek professional help for distressing sexual problems is key to reducing the underutilization of available resources and developing treatments that meet their needs and preferences.


Roles of G-protein-coupled receptor signaling in cancer biology and gene transcription.
G-protein-coupled receptors (GPCRs) are ubiquitous mediators of signal transduction across mammalian cell membranes. Among other roles, GPCRs are known to regulate cellular motility, growth and differentiation, and gene transcription, three factors central to the biology of cancer. Because GPCRs are tractable drug targets, mechanisms by which receptors and their associated proteins impact cellular transformation and metastasis might lead to novel cancer therapies. Recent work has elucidated mechanisms explaining correlations between cancer progression and the expression of GPCRs, such as a protease-activated receptor (PAR1), and G-proteins, such as Galpha(12/13). Of special interest, the discovery of novel nuclear roles for heterotrimeric G-proteins expands the direct impact of G-protein signaling on processes fundamental to the pathology of cancer.


Studies of a common idiotype PR4 in autoimmune rheumatic disease.
A new common idiotype, designated PR4, is described. This idiotype was originally identified on a human hybridoma-derived monoclonal antibody from a patient with leprosy, which binds the major Mycobacterium leprae-derived antigen, phenolic glycolipid-1, poly(ADP)-ribose, DNA, and poly(dT). The PR4 idiotype was found in patients with systemic lupus erythematosus (SLE) (70%), rheumatoid arthritis (40%), and Sjögren's syndrome (15%). It was not, however, found in the spouses of the SLE patients or (unlike other lupus idiotypes) in their healthy first-degree relatives. Although no correlation between PR4 idiotype levels and disease activity in SLE was found, a subset of rheumatoid arthritis patients with high levels of the idiotype was identified.


The performance and assessment of hospital trauma teams.
The purpose of the trauma team is to provide advanced simultaneous care from relevant specialists to the seriously injured trauma patient. When functioning well, the outcome of the trauma team performance should be greater than the sum of its parts. Trauma teams have been shown to reduce the time taken for resuscitation, as well as time to CT scan, to emergency department discharge and to the operating room. These benefits are demonstrated by improved survival rates, particularly for the most severely injured patients, both within and outside of dedicated trauma centres. In order to ensure the best possible performance of the team, the leadership skills of the trauma team leader are essential and their non-technical skills have been shown to be particularly important. Team performance can be enhanced through a process of audit and assessment of the workings of the team and the evidence currently available suggests that this is best facilitated through the process of video review of the trauma resuscitation. The use of human patient simulators to train and assess trauma teams is becoming more commonplace and this technique offers a safe environment for the future education of trauma team staff. Trauma teams are a key component of most programmes which set out to improve trauma care. This article reviews the background of trauma teams, the evidence for benefit and potential techniques of performance assessment. The review was written after a PubMed, Ovid, Athens, Cochrane and guideline literature review of English language articles on trauma teams and their performance and hand searching of references from the relevant searched articles.


RGD liposome-protamine-siRNA (LPR) nanoparticles targeting PAX3-FOXO1 for alveolar rhabdomyosarcoma therapy.
Alveolar rhabdomyosarcoma (ARMS) are aggressive soft tissue tumors harboring specific fusion transcripts, notably PAX3-FOXO1 (P3F). Current therapy concepts result in unsatisfactory survival rates making the search for innovative approaches necessary: targeting PAX3-FOXO1 could be a promising strategy. In this study, we developed integrin receptor-targeted Lipid-Protamine-siRNA (LPR) nanoparticles using the RGD peptide and validated target specificity as well as their post-silencing effects. We demonstrate that RGD-LPRs are specific to ARMS in vitro and in vivo. Loaded with siRNA directed against the breakpoint of P3F, these particles efficiently down regulated the fusion transcript and inhibited cell proliferation, but did not induce substantial apoptosis. In a xenograft ARMS model, LPR nanoparticles targeting P3F showed statistically significant tumor growth delay as well as inhibition of tumor initiation when injected in parallel with the tumor cells. These findings suggest that RGD-LPR targeting P3F are promising to be highly effective in the setting of minimal residual disease for ARMS.


Visceroptosis and the Ehlers-Danlos Syndrome.
The case of a patient with visceroptosis and Ehlers-Danlos syndrome hypermobility type (RDS-HT) is reported here. The literature on this unusual but probably under-recognized complication is reviewed.


Higher exercise intensity delays postexercise recovery of impedance-derived cardiac sympathetic activity.
Systolic time intervals (STIs) provide noninvasive insights into cardiac sympathetic neural activity (cSNA). As the effect of exercise intensity on postexercise STI recovery is unclear, this study investigated the STI recovery profile after different exercise intensities. Eleven healthy males cycled for 8 min at 3 separate intensities: LOW (40%-45%), MOD (75%-80%), and HIGH (90%-95%) of heart-rate (HR) reserve. Bio-impedance cardiography was used to assess STIs - primarily pre-ejection period (PEP; inversely correlated with cSNA), as well as left ventricular ejection time (LVET) and PEP:LVET - during 10 min seated recovery immediately postexercise. Heart-rate variability (HRV), i.e., natural-logarithm of root mean square of successive differences (Ln-RMSSD), was calculated as an index of cardiac parasympathetic neural activity (cPNA). Higher preceding exercise intensity elicited a slower recovery of HR and Ln-RMSSD (p < 0.001), and these measures did not return to baseline by 10 min following any intensity (p ≤ 0.009). Recovery of STIs was also slower following higher intensity exercise (p ≤ 0.002). By 30 s postexercise, higher preceding intensity resulted in a lower PEP (98 ± 14 ms, 75 ± 6 ms, 66 ± 5 ms for LOW, MOD, and HIGH, respectively, p < 0.001). PEP recovered to baseline (143 ± 11 ms) by 5 min following LOW (139 ± 13 ms, p = 0.590) and by 10 min following MOD (145 ± 17 ms, p = 0.602), but was still suppressed at 10 min following HIGH (123 ± 21 ms, p = 0.012). Higher preceding exercise intensity attenuated the recovery of indices for cSNA (from STIs) and cPNA (from HRV) in a graded dose-response fashion. While exercise intensity must be considered, acute recovery may be a valuable period during which to concurrently monitor these noninvasive indices, to identify potentially abnormal cardiac autonomic responses.


Blood cytokine and complement levels in patients with sepsis.
We measured serum levels of endotoxin, cytokines, and eicosanoids and investigated their relationship to serum complement levels in patients with sepsis. Serum endotoxin (Et) levels (5.3 +/- 2.4 pg/ml) were within the normal range, but levels of tumor necrosis factor-alpha (TNF-alpha, 114 +/- 104.94 pg/ml), interleukin 6 (IL-6, 86.7 +/- 50.9 pg/ml), interleukin 8 (IL-8, 86.8 +/- 49.7 pg/ml), type-II phospholipase A2 (type II PLA2, 211.3 +/- 193.9 ng/ml), leukotriene B4 (LTB4, 88.7 +/- 27.2 pg/ml), thromboxane B2 (TXB2, 58.7 +/- 50.9 pg/ml) and 6-keto-prostaglandin F1 alpha (PGF1 alpha, 21.0 +/- 11.0 pg/ml) levels were above normal. Levels of C3a (1088.4 +/- 83.8.7 ng/ml) and C4a (1951.5 +/- 1697.8 ng/ml) were also above normal; C3 (66.0 +/- 25.6 mg/dl) and C4 (23.6 +/- 5.3 mg/dl) were within the normal range, and C5a was lower than the detectable limit in all but one of the subjects. Serum TNF-alpha was significantly correlated with C3a (p < 0.001). Serum IL-6 had a significant negative correlation with C3 (p = 0.002) and C4 (p = 0.010). Type II PLA2 was significantly correlated with C3a (p < 0.001). There were no significant correlations between serum Et or IL-8 and serum C3, C4, C3a or C4a. Our findings suggest that increased levels of TNF-alpha, IL-6, and Type II PLA/ in patients with sepsis contribute to activation of the complement system.