Genus Epidemicus: Are Notions of Entanglement Relevant to the Homeopathic Understanding of Epidemic Disease?
Patient-practitioner-remedy (PPR) entanglement postulates non-local triadic interaction between patient (Px), practitioner (Pr) and potentised medicine (Rx), resulting in the patient's journey to cure; the in-depth homeopathic interview is considered a major contributing factor in this process. Also, by modelling entelechy, a quantised gyroscopic analogue of the Vital Force (Vf) has been developed. To discover whether entanglement notions explain the mode of action of homeopathy during the treatment of epidemic diseases, when the individualising in-depth homeopathic interview is neither possible nor necessary. The current Vf wave equation applies specifically to the in-depth patient/practitioner consultation in chronic dis-ease. A generalised form of the Vf wave equation, an earlier hypothesis based on quantum field theory (QFT) and PPR entanglement were all re-investigated. The generalised Vf wave equation was found applicable in 3 main conditions: acute self-limiting, chronic and epidemic dis-ease. In the latter, a single, coherent Vf epidemic 'wave function' covering all susceptible beings could be identified, which, after practitioner intervention, disappears. Analogies were drawn between groups of atoms in a p-doped semiconductor and a collection of susceptible beings in an epidemic. Here, genus epidemicus is likened to an 'n-type dopant', which forms a 'p-n junction' with the dis-ease. Using the QFT hypothesis/metaphor, genus epidemicus acts as a 'gauge field' restoring 'global invariance' to the symmetry-broken, symptom-expressing Vf, i.e., restoring health. Entanglement hypotheses/metaphors may have application in the homeopathic therapeutic process beyond the one-to-one in-depth interview, and so are relevant to describing the mode of action of homeopathy during treatment of epidemic disease.


Laser-assisted tympanostomy.
Laser-assisted tympanostomy (LAT) was performed in 70 ears to ventilate the middle ear space without using a pressure-equalizing tube. Using a CO2 laser attached to an operating microscope with a Microslad (microscope laser adaptor device), tympanostomies of 1.0 to 3.0 mm (average, 1.6 mm) in diameter were created and remained patent for an average of 3.14 weeks. Patency time was directly related to the size of the opening. Nearly all (97.9%) of the tympanostomies healed with no noticeable scarring and no persistent perforations. Seventy-eight percent of patients at the Florida Ear & Sinus Center (FESC, Sarasota, Fla.) and 84% of patients at the Head & Neck Surgery Group (New York) showed no evidence of recurrent effusion after a minimum follow-up of 3 months. LAT appears to be a safe, cost-effective procedure which can easily be performed in an office setting when bloodless opening in the tympanic membrane is needed for either treatment or diagnosis using endoscopes.


[Binding of monoclonal antibodies to an insulin-producing rat tumor cell (RIN) after partial cell synchronization].
Murine monoclonal antibodies against pancreatic islet cell antigens were generated by somatic cell hybridization and their binding to the insulin-producing rat insulinoma cell line (RIN-5 AH) was evaluated in an indirect immunofluorescence test. An ascites dilution of 1:50 was used for immunostaining using RIN cells harvested from monolayer cultures in RPMI 1640 supplemented with 7.5% fetal calf serum (controls) or test cultures supplemented with 10 mmol/l hydroxyurea to collect the cells in G1/S phase. The five mc-ICSA tested showed a wide variety in their individual binding from 95 up to 30% but their binding was not influenced by hydroxyurea use for synchronization. The antigenic determinant recognized by the anti-glucolipid mc-ICSA 56a F3 was not present on all RIN-5 AH cells. In average, only 35% of the RIN cells showed a striking binding of the monoclonal 56a F3.


Dynamics of virus spread in the presence of fluid flow.
The dynamics of viral infection spread, whether in laboratory cultures or in naturally infected hosts, reflects a coupling of biological and physical processes that remain to be fully elucidated. Biological processes include the kinetics of virus growth in infected cells while physical processes include transport of virus progeny from infected cells, where they are produced, to susceptible cells, where they initiate new infections. Mechanistic models of infection spread have been widely developed for systems where virus growth is coupled with transport of virus particles by diffusion, but they have yet to be developed for systems where viruses move under the influence of fluid flows. Recent experimental observations of flow-enhanced infection spread in laboratory cultures motivate here the development of initial continuum and discrete virus-particle models of infection spread. The magnitude of a dimensionless group, the Damköhler number, shows how parameters that characterize particle adsorption to cells, strain rates that reflect flow profiles, and diffusivities of virus particles combine to influence the spatial pattern of infection spread.


CCL299, a Benzimidazole Derivative Induces G1 Phase Arrest and Apoptosis in Cancer Cells.
Benzimidazoles are considered potential anticancer candidates. We herein studied the anticancer activity of CCL299, 4-(1H-1,3-benzodiazol-1-yl) benzonitrile. In this in vitro study, we used ATP assays, flow cytometry, western blotting, and caspase-3/7 assays to evaluate the effects of CCL299 on cell proliferation, cell-cycle progression and apoptosis. ATP assays showed that CCL299 inhibited cell growth in the hepatoblastoma cell line HepG2 and the cervical cancer cell line HEp-2, without exhibiting cytotoxic effects on non-cancer cells and TIG-1-20 fibroblasts. Flow cytometry, western blotting, and caspase-3/7 assays revealed that CCL299 induced G1-phase cell-cycle arrest followed by apoptosis that was associated with up-regulation of p-p53 (Ser15) and p21 expression and the down-regulation of p-CDK2 (Thr160) expression. CCL299 exhibits cytotoxic activity via apoptosis in a subset of cancer cells, and should be considered as a promising anticancer candidate agent.


Detection of hepatitis C virus (HCV) RNA in normal cervical smears of HCV-seropositive patients.
The presence of hepatitis C virus (HCV) in normal cervical smears (CS) obtained from 22 HCV-seropositive and 50 HCV-seronegative patients was assessed by reverse-transcriptase-polymerase chain reaction (RT-PCR). The presence of HCV in serum was established by use of enzyme-linked immunosorbent assay, Western blot test, and RT-PCR. HCV was detected in 36.4% (n=8) of CS cells recovered from 22 HCV-seropositive patients, but not in CS samples obtained from 50 HCV-seronegative patients. Furthermore, cells from the CS of 2 seropositive/smear-positive patients and 1 seropositive/smear-negative patient were isolated; HCV RNA was detectable in the cervical lymphocytes of the 2 smear-positive patients, but not in epithelial cells or granulocytes. HCV RNA is detectable in the CS of some HCV-seropositive women. The clinical importance of these data requires further study.


Appraisal of prospective bivalve immunomarkers.
Worldwide concern over threats to natural resources and public health has led to increased efforts to monitor and assess environmental conditions. This has stimulated the need for development and application of select biological and ecological measurements, or indicators, that are responsive to environmental stress. Measures of bivalve mollusc defence activities, such as haemocyte density, phagocytic activity, locomotion and production of cytotoxic molecules; and haemolymph constituents, such as agglutinins and lysozyme, have potential as indicators and appear to be responsive to xenobiotic chemical insults in the aquatic environment. However, basic research on the relevance of these measurements in inferring resistance to disease or enhanced survival is currently insufficient, reducing their value as potential biomarkers to address environmental objectives. In addition, variation in defence activities caused by seasonal temperature and reproductive cycling, salinity changes, nutritional status, diseases and parasites, and genetic stocks is high and may limit applicability of bivalve defence-related measurements as indicators. This review examines these sources of variability and their possible implications for interpreting changes in bivalve defence activity as an indicator of stress. Examples of contaminant-induced changes in bivalve defence functions are described.


Percutaneous tracheostomy: a 6 yr prospective evaluation of the single tapered dilator technique.
The single tapered dilator (STD) percutaneous dilatational tracheostomy (PDT) technique now appears to be the single most common method of performing a tracheostomy in the critical care unit (CCU). A single-centre, prospective evaluation of all PDTs performed in an adult mixed surgical and medical CCU between November 2003 and October 2009 was done. All procedures were undertaken by critical care physicians. A proforma recorded intraoperative complications and technical difficulties encountered during the procedure; all patients were followed up for a minimum of 3 months for delayed complications. A tracheostomy was performed on 589 patients during the study period. PDT was attempted in 576 patients and successfully completed in 572. PDT was abandoned in four patients due to bleeding, with three of these subsequently undergoing surgical tracheostomy (ST). ST was performed in 17 patients. Intraoperative technical difficulties were encountered in 149 (26%) cases. Sixteen (3%) procedures were deemed as having early complications. A further four (0.7%) cases had significant late complications including two tracheo-innominate fistulae (TIF). Both TIF patients died as a result of their complications giving a mortality directly attributable to PDT of 0.35%. There were no differences with respect to the occurrence of complications according to grade of operator. PDT performed by the STD technique is a relatively safe procedure with more than 96% of procedures performed without any early or late complications. Using this technique, more than 97% of tracheostomies undertaken during the study period were performed percutaneously. Further audit at a national level is warranted to fully evaluate long-term complications after PDT.


The role of RNA interference in heterochromatic silencing.
Soon after its discovery 75 years ago, heterochromatin, a dense chromosomal material, was found to silence genes. But its importance in regulating gene expression was controversial. Long thought to be inert, heterochromatin is now known to give rise to small RNAs, which, by means of RNA interference, direct the modification of proteins and DNA in heterochromatic repeats and transposable elements. Heterochromatin has thus emerged as a key factor in epigenetic regulation of gene expression, chromosome behaviour and evolution.


The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases.
Liquid biopsies (LB) are used routinely in clinical practice in two situations for late stage non-small-cell lung cancer (NSCLC) patients, (i) at the initial diagnosis when looking for activating mutations in EGFR in the absence of analyzable tissue DNA and, (ii) during tumor progression on a tyrosine kinase inhibitor treatment to look for the resistance mutation T790M in EGFR. LB is not presently recommended in daily practice for the diagnosis of NSCLC. Areas covered: We report the diagnosis of a NSCLC in a patient with bilateral ocular metastases after detection of a deletion in exon 19 of EGFR when using plasma DNA. Without histological analysis, the origin of the primary ocular metastasis was uncertain. In this context, a LB showing an activating mutation in EGFR and circulating tumor cells positive for TTF1 led to the diagnosis of NSCLC and targeted therapy. Expert commentary: When no tumor tissue sample is available a LB can be used to diagnose for metastatic NSCLC, when a mutation in EGFR is identified. While a tissue biopsy is the gold standard approach for the diagnosis of a NSCLC and for identification of activating mutations, LB can exceptionally provide both a diagnosis of the primitive tumor and indicate appropriate therapy based on a molecular analysis.


Vibrational Raman optical activity of alpha-lactalbumin: comparison with lysozyme, and evidence for native tertiary folds in molten globule states.
Proteins in aqueous solution are now accessible to Raman optical activity (ROA) measurements, which provide an incisive new probe of secondary and tertiary structure illustrated here by a study of bovine alpha-lactalbumin. The room-temperature ROA spectrum of native bovine alpha-lactalbumin is similar to that of native hen egg-white lysozyme except for features attributable to differences in the loop regions: in particular, a positive ROA band at approximately 1338 cm-1 assigned to conformationally homogeneous loop structure, possibly with local order corresponding to 3(10)-helix, has more than double the intensity in alpha-lactalbumin compared with lysozyme. This is consistent with the two proteins having similar secondary structure but different local details in the tertiary fold. ROA measurements on alpha-lactalbumin at pH 2.0 over a range of temperatures have provided a new perspective on the molten globule state. Thus at 35 degrees C ROA reveals the presence of some secondary structure but an almost complete loss of the tertiary loop structure; whereas at 2 degrees C the ROA spectrum is almost identical with that of the native protein, which is strong evidence that virtually all of the secondary structure and the tertiary backbone fold persist, albeit within a looser framework associated with increased solvent exposure and change of environment of many of the side-chains as evidenced by an increase in noise and bandwidth of some of the ROA signals together with aromatic fluorescence and near-UV circular dichroism signals characteristic of the molten globule state. Our sample of acid alpha-lactalbumin at 2 degrees C therefore appears to be an archetypal example of Ptitsyn's "native-like" molten globule, having a fixed native-like tertiary fold but with loss of tight packing of the side-chains; whereas at 35 degrees C it is a "disordered" molten globule. At 20 degrees C the acid molten globule appears to retain highly native-like secondary structure but with most of the tertiary fold already lost. A calcium-free sample of alpha-lactalbumin at neutral pH displayed a broad cooperative transition between native and molten globule states at approximately 15 degrees C, with the latter state showing similar but somewhat degraded tertiary loop ROA signatures to the native protein. In both the acid and apo molten globule states the ROA signatures of the secondary structure and the tertiary loops showed a gradual change with temperature.


Exploring tinnitus heterogeneity.
Tinnitus experiences differ widely. A greater understanding of the core processes underlying these variations is needed. Moreover, meaningful definitions for different subgroups are required to better manage this heterogeneous population. The objective of the present research was to contribute toward the understanding of tinnitus heterogeneity by identifying factors that can predict tinnitus severity and to ascertain if distinct subgroups of tinnitus presentation can be identified. This cross-sectional study consisted of 326 adults subdivided into subgroups of those with mild tinnitus (n=32; 10%), significant tinnitus (n=99; 30%) and severe tinnitus (n=195; 60%) according to their scores from the Tinnitus Functional Index. Multiple regression was used to identify factors associated with tinnitus severity. These factors included personal traits, tinnitus-related traits, treatment modalities and clinical comorbidities. Insomnia, hearing distress, and anxiety were the best predictors of tinnitus severity (explaining 53% of the variability). These comorbidities were stronger predictors than any demographical factors (that explained 11% of the variability). Distinct subgroups based on tinnitus severity (mild, significant, and severe) and anxiety levels were evident. Those with severe tinnitus had significantly more severe comorbidities compared with the mild and significant groups. This study highlights that people with tinnitus could initially be grouped according to tinnitus severity to direct further management. Those with higher tinnitus severity should receive more immediate and intensive care. Due to the strong associations between tinnitus severity and tinnitus-related comorbidities (e.g., insomnia, hearing disability, and anxiety), tinnitus assessment and interventions should focus on these comorbidities.


Evaluation of twice-daily administration of interferon-beta for chronic hepatitis C.
To improve the efficacy of interferon (IFN) in the treatment of chronic hepatitis C, administration of IFN-beta twice per day was evaluated. Thirty-eight patients with chronic hepatitis C (26 males and 12 females, aged 25-67 years) were included. Patients were treated with a new protocol that included twice-daily treatment with IFN-beta. Three million units (MU) of IFN-beta was administered twice daily every day for 4 weeks followed by 10 MU of IFN-alpha2b, every day for 2 weeks and then three times a week for 18 weeks (total IFN-beta, 148 MU; IFN-alpha2b, 680 MU). Complete responders (CR) were defined by alanine aminotransferase levels that normalized within 6 months after completion of IFN therapy and remained normal for more than 6 months, and by serum hepatitis C virus (HCV) RNA levels that became negative as determined using the Amplicor assay. Twenty-one of 38 (55.3%) patients were CR. Nine of 21 (42.9%) patients with HCV serotype 1 were responders compared with nine of 12 (75.0%) patients with HCV serotype 2. In patients with an HCV titre greater than 1 million equivalents ml-1 (1 MEq ml-1), nine of 24 (37.5%) responded, and in patients with HCV titres less than 1 MEq ml-1, 12 of 14 (85.7%) responded. In patients with HCV serotype 1 and greater than 1 MEq ml-1 HCV RNA, four of 15 (26.7%) responded to IFN. Two-thirds (66.7%) of the patients who became negative for HCV RNA after 2 weeks of therapy responded, while 72.7% of those with positive HCV RNA after 2 weeks of therapy were non-responders. Proteinuria was frequently observed as an adverse effect of twice-daily administration of IFN-beta. The combination of twice-daily administration of IFN-beta for 4 weeks followed by IFN-alpha showed a high response rate in patients with chronic hepatitis C, but in patients with both serotype 1 and a high titre of HCV RNA, response rates were still low. Thus, the HCV RNA titre 2 weeks after starting therapy with IFN was useful for predicting the eventual response to IFN.


Falls prevention over 2 years: a randomized controlled trial in women 80 years and older.
after 1 year, a home-based programme of strength and balance retraining exercises was effective in reducing falls and injuries in women aged 80 years and older. The exercise programme had been individually prescribed by a physiotherapist during the first 2 months of a randomized controlled trial. we aimed to assess the effectiveness of the programme over 2 years. women from both the control group and the exercise group completing a 1-year trial (213 out of the original 233) were invited to continue for a further year. falls and compliance to the exercise programme were monitored for 2 years. 81 (74%) in the control group and 71 (69%) in the exercise group agreed to continue in the study. After 2 years, the rate of falls remained significantly lower in the exercise group than in the control group. The relative hazard for all falls for the exercise group was 0.69 (95% confidence interval 0.49-0.97). The relative hazard for a fall resulting in a moderate or severe injury was 0.63 (95% confidence interval 0.42-0.95). Those complying with the exercise programme at 2 years had a higher level of physical activity at baseline, were more likely to have reported falling in the year before the study and had remained more confident in the first year about not falling compared with the rest of the exercise group. falls and injuries can be reduced by an individually tailored exercise programme in the home. For those who keep exercising, the benefit continues over a 2-year period.


Hypoxia increases corneal cell expression of CFTR leading to increased Pseudomonas aeruginosa binding, internalization, and initiation of inflammation.
To investigate the effect of hypoxia-induced molecular responses of corneal epithelial cells on the surface of rabbit and human corneas and corneal cells in culture on interactions with Pseudomonas aeruginosa that may underlie increased susceptibility to keratitis. Organ cultures of rabbit and human corneal tissue, primary rabbit and human corneal cells, and transformed human corneal cells from a patient with cystic fibrosis and the same cell line corrected for expression of wild-type cystic fibrosis transmembrane conductance regulator (CFTR), the cellular receptor for P. aeruginosa, were exposed to hypoxic conditions for 24 to 72 hours. Changes in binding and internalization of P. aeruginosa were measured using cellular association and gentamicin-exclusion assays, and expression of CFTR and activation of NF-kappaB in response to hypoxia were determined by confocal laser microscopy and quantitative measurements of NF-kappaB activation. Hypoxia induced in a time- and oxygen-concentration-dependent manner increased association and internalization of clinical isolates of P. aeruginosa in all cells tested. Hypoxia increased CFTR expression and NF-kappaB nuclear translocation in rabbit and human cells with wild-type CFTR. Corneal cells lacking CFTR had reduced NF-kappaB activation in response to hypoxia. Hypoxia did not affect the increase in corneal cell CFTR levels or NF-kappaB activation after P. aeruginosa infection. Hypoxic conditions on the cornea exacerbate the binding and internalization of P. aeruginosa due to increased levels of CFTR expression and also induce basal NF-kappaB activation. Both of these responses probably exacerbate the effects of P. aeruginosa infection by allowing lower infectious doses of bacteria to induce disease and promote destructive inflammatory responses.


[What do patients in Germany expect from their total knee arthroplasty?].
Only 84 % of patients are satisfied with the operative result after total knee arthroplasty. A relevant reason is non-fulfilled preoperative expectations. Non-fulfilled preoperative expectations cannot be influenced postoperatively. So a knowledge of preoperative expectations and their influential factors is essential. The following study analyses the expectations and influential factors in patients before total knee arthroplasty in Germany. On the day before total knee replacement in 104 patients the following data were collected: school leaving level, comorbidities, articular knee function, psychological mood, health-related quality of life, and preoperative expectations. Statistical evaluation was done by factor analyses of expectations and independent variables, and correlation and regression analyses. The following 4 factors of expectations resulted from the factor analyses: (i) relief of pain, (ii) increase of range of motion of the knee, (iii) better mobility, and (iv) better integration in social activities. In general patient expectations on the effects of a total knee replacement are high. Age and better integration in social activities correlate negatively, as also do age and better mobility. Body mass index and better integration in social activities correlate positively. The following formula analyses the expectations of better integration in social life: social expectations = 116-0.991 × age. For the first time this study determines expectations and influential factors of patients who undergo a total knee replacement in Germany. By knowing the interaction of satisfaction and preoperative expectations, this knowledge is an essential condition to increase satisfaction after total knee replacement in the German population. Collecting the preoperative expectations of patients has to be an indispensable feature of the clinical practice in orthopaedic surgery.


Thoracoscopy in the management of pediatric empyema.
The surgical management of empyema consists of (1) aggressive therapy with thoracotomy and decortication or (2) conservative treatment with chest tube drainage and intravenous antibiotics. Recently, Kern and Rodgers introduced thoracoscopic debridement as an adjunct to the management of children with empyema, with promising results. Hence, the authors report their experience with thoracoscopy in the management of pediatric patients with empyema. In the last years, 10 children have undergone thoracoscopic debridement (TD) for empyema. The average age was 6.9 years (range, 2 to 16). Children underwent TD an average of 14 days (range, 8 to 16) after initial presentation and 4 days (range, 2 to 6) after admission to the authors' hospital. Indications for TD were persistent requirement of supplemental oxygen and failure of conservative medical management that consisted of antibiotics and tube thoracostomy. Three children had positive pleural fluid cultures for Streptococcus pneumoniae. In all cases, preoperative ultrasound or chest computed tomography examination showed dense pleural fluid with septation. During surgery, TD allowed for lung expansion and precise chest tube placement in all patients except one who required conversion to minithoracotomy and decortication for persistent encasement with a thick pleural peel. There were no postoperative complications related to the procedure. After TD, all children had prompt clinical improvement. The patients were weaned from supplemental oxygen by postoperative day 2, and following early chest tube removal, nine children were discharged home by postoperative day 7 (range, 3 to 10). One child required further hospitalization for underlying renal failure. In the authors' hands, TD was effective in producing prompt clinical improvement in children with empyema.(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of cyclosporin A on the expression of tissue kallikrein, kininogen, and bradykinin receptor in rat.
The tissue kallikrein-kinin system is involved in vasodilation and blood pressure regulation. In the present study, we investigated the effects of chronic cyclosporin A (CsA) administration on blood pressure and the expression of tissue kallikrein, kininogen, and bradykinin receptor in normotensive Wistar rats. Chronic administration of CsA significantly increased systolic blood pressure compared with control rats (n = 6, P < 0.01), although body weight was significantly lower than control rats (n = 6, P < 0.01). The development of hypertension was accompanied by the altered expression of kallikrein-kinin system components. Immunoreactive renal kallikrein and urinary excretion of tissue kallikrein levels were increased by chronic administration of CsA (n = 5 or 6, P < 0.05). Levels of N-tosyl-L-phenylalanine chloromethyl ketone-trypsin and kallikrein-releasable kininogens in sera increased in response to chronic CsA treatment (n = 5 or 6, P < 0.05). Chronic CsA treatment significantly increased renal kallikrein, bradykinin B2 receptor, and hepatic kininogen mRNA levels. The increased levels of tissue kallikrein-kinin system components were accompanied by significant increases in 24-h urine excretion and water intake after chronic CsA treatment (n = 5, P < 0.05). These results suggest that enhanced activity of the tissue kallikrein-kinin system may compensate for the CsA-induced vasoconstriction and hypertension.


Transport of 14C-gamma-aminobutyric acid into brain, cerebrospinal fluid and choroid plexus in neonatal and adult rats.
In general blood to brain entry of amino acids is greater in the neonatal rats compared to the adults. gamma-Aminobutyric acid (GABA), a neurotransmitter amino acid, shows limited transport across the blood-brain barrier (BBB) in the adult rat. Characteristics of GABA entry into the immature rat brain is yet to be addressed. This investigation was set to study the entry of GABA into brain of the neonatal rat compared to the adult. Using the bilateral in situ brain perfusion technique, the entry of 14C-GABA into brain, cerebrospinal fluid (CSF) and lateral ventricles choroid plexuses was studied in the adult and neonatal rats. 14C-GABA uptake into neonatal rat brain after 20 min perfusion was 0.116+/-0.014 ml g(-1), approximately twice that of the adults (P<0.01). Half saturation constant, K(m), did not change with age (P>0.05), whereas maximal transport into the brain, V(max), was reduced from 0.152 to 0.068 nmol min(-1) g(-1) showing a significant reduction with age (P<0.05). In the neonate the entry of GABA into the CSF was dominant when compared to that into the brain, this could be due to a greater diffusional component, K(d), which was detected to be high in the neonate. In conclusion, the uptake of 14C-GABA into brain of the immature rats exceeded that in the adults which is thought to be due to both greater maximal transport and greater diffusion in the neonate compared to the adult.


Plant growth and metal distribution in tissues of Prosopis juliflora-velutina grown on chromium contaminated soil in the presence of Glomus deserticola.
Arbuscular mycorrhizal fungi have been known to increase metal uptake in plants. In this study, mesquite (Prosopis juliflora-velutina) inoculated with Glomus deserticola or amended with EDTA were grown for 30 days in soil containing Cr(III) or Cr(VI) at 0, 40, 80, and 160 mg kg(-1). Total amylase activity (TAA) was monitored as a stress indicator. Element concentrations and distribution in tissue were determined using ICP-OES, electron scanning microprobe, and TEM. Inoculated Cr(VI) treated plants had 21% and 30% more Cr than uninoculated and EDTA treated roots, respectively, at 80 mg Cr kg(-1) treatment. In the case of Cr(III), EDTA produced the highest Cr accumulation in roots. TAA was higher in inoculated plants grown with Cr(III) at 80 and 160 mg kg(-1) and Cr(VI) at 40 and 160 mg kg(-1). The X-ray mapping showed higher metal concentrations in the vascular system of inoculated plants and the TEM micrographs demonstrated the presence of G. deserticola in roots.


Photosynthetic electron transport determines nitrate reductase gene expression and activity in higher plants.
The influence of photosynthetic electron flow in chloroplasts on the expression and enzyme activity of the cytosolic nitrate reductase (NR) was studied. Using light sources that predominantly excite either photosystem I (PSI) or photosystem II (PSII), we modulated photosynthetic electron transport in tobacco, Arabidopsis, and Lemna sprouts. In all instances, oxidation of components of photosynthetic electron flow by PSI light correlated with an increase in NR activity and/or transcription. This is confirmed by experiments with electron transport inhibitors 3-(3',4'-dichlorophenyl)-1,1'-dimethyl urea and 2,5-dibromo-3-methyl-6-isopropyl-p-benzoquinone. In addition, a Lemna mutant deficient in the cytochrome b(6)/f complex failed to respond to the different light sources and exhibited a constitutively high level of NR activity. These data indicate that NR is activated by the oxidized state of an electron transport component located after the plastoquinone pool. An involvement of the cytoplasmic photoreceptor phytochrome A in this light regulation could be excluded, since an Arabidopsis phytochrome A mutant exhibited a wild-type like response. The observation that NR activity in the cytoplasm and the expression of its gene in the nucleus is controlled by signals from photosynthetic electron flow adds a new facet to the intracellular cross-talk between chloroplasts and the nucleus.


Factors associated with acute and recurrent erysipelas in a young population: a retrospective of 147 cases.
erysipelas is a common infection of the superficial layer of the skin, predominantly caused by groups A β-hemolytic streptococci. It is an acute infection of the skin and frequently affects the legs. It is common in the elderly and favoured by the associated comorbidities. Its occurrence in young healthy people is rare. The present study aimed to elucidate factors associated with acute and recurrent erysipelas in a young population. We retrospectively analyzed 147 cases of erysipelas admitted to the dermatology department of the Military Hospital of Tunis, Tunisia, over 18 years, identifying factors associated with recurrence. All patients were aged less than 35 years. During the study period, 147 patients were registered with the diagnosis of erysipelas. There were 125 military soldiers and 22 non-military patients. The prevalence of erysipelas was 2.23%. The median age was 25 years. Almost 86.2% of patients were male. The main favorable factors were: obesity (9%), alcoholism (8%), chronic venous insufficiency (6.5%), chronic lymphedema (3%), leg fracture (2%), and diabetes mellitus (1%). The lesions were mostly located in the lower limbs in 94.9%. According to our multivariate analysis, there was an association between recurrence and diabetes mellitus (p=0.02), female sex (p=0.004), onychomycosis (p=0.004), and plantar dyshidrotic eczema (p<0.005). Identifying factors associated with recurrent erysipelas in a young population remains essential for proposing primary and secondary prevention measures.


The Reliability of Child-Friendly Race-Attitude Implicit Association Tests.
Implicit attitudes are evaluations that are made automatically, unconsciously, unintentionally, or without conscious and deliberative processing (Nosek et al., 2007; Gawronski and De Houwer, 2014). For the last two decades implicit measures have been developed and used to assess people's attitudes and social cognition, with the most widely used measure being the Implicit Association Test (IAT; Greenwald et al., 2003). This measure has been used extensively to assess racial biases and a number of studies have examined the reliability of the IAT when administered to adults (Cunningham et al., 2001; Gawronski, 2002; Greenwald et al., 2003; Nosek et al., 2005; Nosek and Smyth, 2007; Bar-Anan and Nosek, 2014). In recent years, the IAT has also been modified for use with children. Despite the potential of this measure to provide insight into the early emergence of implicit racial attitudes, little is known about the psychometric properties of these modified child-friendly IATs (Child-IATs). In the current research we examined the internal consistency of race-attitude Child-IATs when either reduced (Study 1) or traditional-length (Study 2) versions were administered to children (Studies 1 and 2) and adults (Study 2). We also examined the test-retest reliability of this measure with both child and adult participants (Study 2). We found that these measures demonstrate an internal consistency comparable to what has been seen in previous research with adults. In addition, the internal consistency of traditional-length Child-IATs completed in succession depended on the order in which they were completed; the first Child-IAT demonstrated higher internal consistency than the second for both children and adults (Study 2). Finally, we provide the first evidence that the test-retest reliability of the Child-IAT is comparable to what has been found previously with adults (Study 2). The implications of these findings for future research examining children's implicit social cognition are discussed.


Protective effects of cimetidine on radiation-induced micronuclei and apoptosis in human peripheral blood lymphocytes.
The radioprotective effects of cimetidine, which has been used clinically as an antagonist of H2 receptor, on radiation-induced micronuclei and apoptosis in human peripheral blood lymphocytes (PBL) prepared from healthy donors were studied. Cells were treated with cimetidine before or after X-irradiation, and then cytokinesis-blocked micronucleus assay and flow cytometry for measurement of phosphatidylserine externalization were utilized to evaluate the radiation-induced cytogenetic damage and apoptosis. The protective effect of preirradiation treatment of cimetidine on radiation-induced micronuclei was dependent on the concentration. The maximum protection rates of cimetidine (1 mM) on frequencies of micronuclei were 38.8 and 30.2% for cells treated before and after X-irradiation (5 Gy), respectively. Protective effects of pre- and post-irradiation treatment with cimetidine on radiation-induced early apoptosis and decreased activity of caspase-3 were observed. A study of electron paramagnetic resonance-spin trapping with 5,5'-dimethyl-1-N-oxide revealed that the rate constant of cimetidine with radiation-induced OH radicals is about 4.5 x 10(9) l/mol/s. Cimetidine did not significantly increase the intracellular concentration of glutathione. These results suggest that cimetidine suppresses radiation-induced micronuclei and apoptosis via OH radical scavenging and an intracellular antioxidation mechanism. Cimetidine appears to be a useful candidate for the future development of post-irradiation radioprotectors.


Transfer and alignment of random single-walled carbon nanotube films by contact printing.
We present a simple method to transfer large-area random single-walled carbon nanotube (SWCNT) films grown on SiO(2) substrates onto another surface through a simple contact printing process. The transferred random SWCNT films can be assembled into highly ordered, dense regular arrays with high uniformity and reproducibility by sliding the growth substrate during the transfer process. The position of the transferred SWCNT film can be controlled by predefined patterns on the receiver substrates. The process is compatible with a variety of substrates, and even metal meshes for transmission electron microscopy (TEM) can be used as receiver substrates. Thus, suspended web-like SWCNT networks and aligned SWCNT arrays can be formed over the grids of TEM meshes, so that the structures of the transferred SWCNTs can be directly observed by TEM. This simple technique can be used to controllably transfer SWCNTs for property studies, for the fabrication of devices, or even as support films for TEM meshes.


A framework for the analysis of heterogeneity of treatment effect in patient-centered outcomes research.
Individuals vary in their response to a treatment. Understanding this heterogeneity of treatment effect is critical for evaluating how well a treatment can be expected to work for an individual or a subgroup of individuals. An overemphasis on hypothesis testing has resulted in a dichotomy of all heterogeneity of treatment effect analyses into confirmatory (hypothesis testing) and exploratory (hypothesis finding) analyses. This limited view of heterogeneity of treatment effect is inadequate for creating evidence that is useful for informing patient-centered decisions. An expanded framework for heterogeneity of treatment effect assessment is proposed. It recognizes four distinct goals of heterogeneity of treatment effect analyses: hypothesis testing, hypothesis finding, reporting subgroup effects for meta-analysis, and individual-level prediction. Accordingly, two new types of heterogeneity of treatment effect analyses are proposed: descriptive and predictive. Descriptive heterogeneity of treatment effect analyses report treatment effects for prespecified subgroups in accordance with prospectively specified analytic strategy. They need not be powered to detect heterogeneity of treatment effect. They emphasize estimation and reporting of subgroup effects rather than hypothesis testing. Sampling properties (e.g., standard error) of descriptive analysis can be characterized, thus facilitating meta-analysis of subgroup effects. Predictive heterogeneity of treatment effect analyses estimate probabilities of beneficial and adverse responses of individuals to treatments and facilitates optimal treatment decisions for different types of individuals. Procedures are also suggested to improve reliability of heterogeneity of treatment effect assessment from observational studies. Heterogeneity of treatment effect analysis should be identified as confirmatory, descriptive, exploratory, or predictive analysis. Evidence should be interpreted in a manner consistent with the analytic goal.


Cryo-EM Structure and Activator Screening of Human Tryptophan Hydroxylase 2.
Human tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in the synthesis of serotonin. Its dysfunction has been implicated in various psychiatric disorders such as depression, autism, and bipolar disorder. TPH2 is typically decreased in stability and catalytic activity in patients; thus, screening of molecules capable of binding and stabilizing the structure of TPH2 in activated conformation is desired for drug development in mental disorder treatment. Here, we solved the 3.0 Å cryo-EM structure of the TPH2 tetramer. Then, based on the structure, we conducted allosteric site prediction and small-molecule activator screening to the obtained cavity. ZINC000068568685 was successfully selected as the best candidate with highest binding affinity. To better understand the driving forces and binding stability of the complex, we performed molecular dynamics simulation, which indicates that ZINC000068568685 has great potential to stabilize the folding of the TPH2 tetramer to facilitate its activity. The research might shed light on the development of novel drugs targeting TPH2 for the treatment of psychological disorders.


Relationship between normalized adductor pollicis train-of-four ratio and manifestations of residual neuromuscular block: a study using acceleromyography during near steady-state concentrations of mivacurium.
Baseline acceleromyographic adductor pollicis train-of-four (TOF) ratio varies significantly between individuals and is often greater than unity. Thus, normalization of acceleromyography data is necessary. The relationship between normalized acceleromyographic TOF ratio, lung volumes, and clinical signs of residual neuromuscular block was studied. In 12 healthy volunteers, three steady-state levels of neuromuscular block were achieved with mivacurium infusions. TOF ratio was measured acceleromyographically at the adductor pollicis using a preload. Lung volume measurements and a series of clinical tests were made at each stable block and reconciled to the normalized TOF measures. None experienced airway obstruction or arterial oxygen desaturation, even at normalized TOF ratio less than 0.4. Functional residual capacity remained unchanged whereas vital capacity decreased linearly with decreasing TOF ratio. The ability to protrude the tongue was preserved at all times. The ability to clench the teeth was lost in one volunteer at normalized TOF ratio of 0.84 but retained in four at normalized TOF ratio less than 0.4. Four volunteers lost the ability both to raise the head more than 5 s and to swallow, with the most sensitive individual demonstrating these effects at normalized TOF ratio of 0.60. At mean normalized TOF ratio of 0.42, the mean handgrip strength was approximately 20% of baseline value. Lung vital capacity decreased linearly with decreasing TOF ratio. Responses to clinical tests of muscle function varied to a large extent among individuals at comparable TOF ratios. None of the volunteers had significant clinical effects of neuromuscular block at normalized acceleromyographic TOF ratio greater than 0.90.


Management of Phantom Limb Pain through Thalamotomy of the Centro-Median Nucleus.
Phantom limb syndrome is defined as the perception of intense pain or other sensations that are secondary to a neural lesion in a limb that does not exist. It can be treated using pharmacological and surgical interventions. Most medications are prescribed to improve patients' lives; however, the response rate is low. In this case report, we present a case of phantom limb syndrome in a 42-year-old female with a history of transradial amputation of the left thoracic limb due to an accidental compression one year before. The patient underwent placement of a deep brain stimulator at the ventral posteromedial nucleus (VPM) on the right side and removal secondary to loss of battery. The patient continued to have a burning pain throughout the limb with a sensation of still having the limb, which was subsequently diagnosed as phantom limb syndrome. After a thorough discussion with the patient, a right stereotactic centro-median thalamotomy was offered. An immediate response was reported with a reduction in pain severity on the visual analogue scale (VAS) from a value of 9-10 preoperative to a value of 2 postoperative, with no postoperative complications. Although phantom limb pain is one of the most difficult to treat conditions, centro-median thalamotomy may provide an effective stereotactic treatment procedure with adequate outcomes.


Oligodendrocyte lineage and the motor neuron connection.
One of the more surprising recent discoveries in glial biology has been that oligodendrocytes (OLs) originate from very restricted regions of the embryonic neural tube. This was surprising because myelinating OLs are widespread in the mature central nervous system, so there was no reason to suspect that their precursors should be restricted. What we now know about early OL development suggests that they might have as much (or more) in common with ventral neurons-specifically motor neurons (MNs)-as with other types of glia. This has implications for the way we think about glial development, function, and evolution. In this article we review the evidence for a shared MN-OL lineage and debate whether this is the only lineage that generates OLs. We decide in favour of a single embryonic lineage with regional variations along the anterior-posterior neuraxis.


Emergence of linezolid-resistance in vancomycin-resistant Enterococcus faecium ST117 associated with increased linezolid-consumption.
We aim to describe the epidemiological, clinical and microbiological characteristics of the linezolid- and vancomycin- resistant Enterococcus faecium (LVRE) in a tertiary care hospital in Germany. We conducted a retrospective analysis of 196 LVRE cases observed from 1st January 2012 to 31th December 2018. Patients' medical charts were reviewed and available LVRE (n = 102) were subjected to whole-genome-sequencing. Antibiotic consumption was measured in defined daily dose (DDD)/100 bed-days (BD). The prevalence of LVRE isolates among VRE was 6.3 % in 2018. Most patients had an onco-hematological disease (134/196, 68.4 %). From 2012-2018 an increase of +356.7 % of linezolid defined daily dose/100 bed-days was observed. In 71.4 % (90/126, 70 missing values) of the patients, linezolid was prescribed in the previous 6 months. The median exposure to linezolid was 15 days (Interquartile, IQR 9-23). 42/196 (21.4 %) patients had an LVRE-related infection with an overall 30-day mortality rate of 33 %. In 121/196 (61.7 %) patients, linezolid-susceptible VREfm were isolated before LVRE, suggesting secondary acquisition of linezolid resistance. Genetic analysis revealed that most isolates belonged to ST117 (64/102 available isolates, 62.7 %). The G2576T 23S rDNA mutation was identified as the most common resistance mechanism (96/102, 94.1 %). poxtA was identified in two isolates, while cfr, and optrA were not detected. Incidence of LVRE related to 23S rDNA mutations is rising and probably associated with antibiotic consumption. Restrictions in the use of linezolid may be needed in order to retain therapeutic options in VRE.


pH-induced reversible dissociation of tetrameric duck lens delta-crystallin.
Animal lenses constitute many soluble proteins, which play a prominent role in eyes' light transparency. delta2-Crystallin, one of the major taxon-specific crystallins in duck lens, is a tetrameric protein consisting of four identical subunits, which contain endogenous argininosuccinate lyase activity. Under a neutral pH environment in this work, the protein was cross-linked with glutaraldehyde as tetrameric and dimeric forms with tetramer as the major form. Under acidic conditions, the protein was time-dependently dissociated into monomers with amino acid residues of pKa values 6.29+/-0.45 and 7.17+/-0.49 being involved in the monomer-monomer interactions and 6.20+/-0.10 and 8.88+/-0.07 in the dimer-dimer interactions. Duck lens delta2-crystallin thus possesses a double dimer structure (alpha2)2 with stronger monomer-monomer interactions than the dimer-dimer interactions. The acidic protein solution's reneutralization caused rapid reassociation of monomers into dimers and tetramers. The tetramer-dimer-monomer dissociation-reassociation thus is a pH-dependent freely interconvertible process.


Association of obesity susceptibility gene variants with metabolic syndrome and related traits in 1,443 Czech adolescents.
Genome-wide association studies have revealed several gene variants associated with obesity; however, only a few studies have further investigated their association with metabolic syndrome. We performed a study of eleven variants in/near genes TMEM18, SH2B1, KCTD15, PCSK1, BDNF, SEC16B, MC4R, and FTO in Czech adolescents and analysed their association with obesity, metabolic syndrome and related traits. Genotyping was performed in 1,443 adolescents aged 13.0-17.9 years. Anthropometric parameters, biochemical parameters and blood pressure were assessed. Metabolic syndrome was defined according to the International Diabetes Federation. The FTO rs9939609 variant was associated with overweight/obesity (OR 1.40, 95% CI 1.21-1.63, P < 0.001). The minor allele of TMEM18 rs7561317 was related to underweight (OR 1.78, 95% CI 1.14-2.79, P = 0.015). BDNF rs925946 and MC4R rs17782313 were associated with metabolic syndrome (OR 1.53, 95% CI 1.14-2.04, P = 0.005; 1.51, 95% CI 1.12-2.04, P = 0.009). The PCSK1 rs6235 variant was negatively related to increased blood glucose (OR 0.69, 95% CI 0.49-0.97, P = 0.040). In conclusion, the FTO variant was associated with overweight/obesity in Czech adolescents. Moreover, MC4R and BDNF variants increased the risk of metabolic syndrome, probably through their effect on abdominal obesity. The PCSK1 variant may have a protective role in the development of type 2 diabetes.


Math Error Types and Correlates in Adolescents with and without Attention Deficit Hyperactivity Disorder.
Objective: The aim of this study was to examine the types of errors made by youth with and without a parent-reported diagnosis of attention deficit and hyperactivity disorder (ADHD) on a math fluency task and investigate the association between error types and youths' performance on measures of processing speed and working memory. Method: Participants included 30 adolescents with ADHD and 39 typically developing peers between 14 and 17 years old matched in age and IQ. All youth completed standardized measures of math calculation and fluency as well as two tests of working memory and processing speed. Math fluency error patterns were examined. Results: Adolescents with ADHD showed less proficient math fluency despite having similar math calculation scores as their peers. Group differences were also observed in error types with youth with ADHD making more switch errors than their peers. Conclusion: This research has important clinical applications for the assessment and intervention on math ability in students with ADHD.


Accuracy of acute-phase proteins in identifying lethargic and anorectic cats with increased serum feline pancreatic lipase immunoreactivity.
The mainstay of laboratory diagnostics of feline pancreatitis (FP) is measuring serum feline pancreatic lipase immunoreactivity (fPLI). Thus far, several studies have investigated the relationship between acute-phase proteins (APPs) and the presence and severity of FP. Although changes in serum amyloid A (SAA) concentration have been linked with FP, its diagnostic accuracy remains unknown. We aimed to determine the accuracy of selected APPs in identifying cats with a high risk of FP based on increased fPLI. Serum fPLI was measured in cats (n = 52) that were presented to veterinary clinics with signs of lethargy and anorexia. The cats were divided into two groups (fPLI ≤3.5 μg/L; n = 27 and fPLI >3.5 μg/L, n = 25), corresponding to low and high risks of FP. Serum albumin, globulin, haptoglobin (Hp), and SAA concentrations, as well as the albumin-to-globulin ratio (A/G) and SAA-to-albumin (SAA/A) ratios, were determined and compared between groups. The accuracy of these measurements was examined using a multivariable logistic regression model and receiver operator characteristic (ROC) curve analysis. SAA concentrations and SAA/A ratios were significantly (P = .026 and P = .022) higher in cats with increased fPLI, with the area under ROC curve (AUROC) of 68.1% (CI 95%: 53.4%, 82.9%) and 68.6% (CI 95%: 54.0%, 83.2%), respectively. The logistic regression model combining SAA and A/G had AUROC of 75.2% (CI 95%: 62.0%, 88.4%) for identifying cats with increased fPLI. SAA as a sole analyte or combined with A/G had low to moderate accuracy in identifying anorexic, lethargic cats with increased fPLI. Serum albumin, globulin, and Hp concentrations had no discriminatory potential in these cats.


[Effect of sodium difluoroacetate on retinal lactate levels in diabetic rats].
Our experiments were carried out in normal and streptozotocin-diabetic rats. The effects of sodium difluoroacetate (DFA) at the dose of 40 mg/kg daily were studied on the blood and retinal lactate levels; these effects were compared to those of an identical dose of sodium dichloroacetate (DCA) which is the most known among the pyruvate dehydrogenase activators. DFA and DCA were administered orally by oesophageal tube during 5 months. At these doses, neither DFA nor DCA significantly modified the blood and retinal lactate levels in the normal animals. The blood and retina lactate levels of the non treated diabetic rats were much higher than those of the normal rats; the treatment by DFA and DCA significantly decreased the blood and retina lactate levels in diabetic rats.


Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs).
Diet as a key factor in determining genomic stability is more important than previously imagined because we now know that it impacts on all relevant pathways, namely exposure to dietary carcinogens, activation/detoxification of carcinogens, DNA repair, DNA synthesis and apoptosis. Current recommended dietary allowances for vitamins and minerals are based largely on the prevention of diseases of deficiency such as scurvy in the case of vitamin C. Because diseases of development, degenerative disease and aging itself are partly caused by damage to DNA it seems logical that we should focus better our attention on defining optimal requirements of key minerals and vitamins for preventing damage to both nuclear and mitochondrial DNA. To date, our knowledge on optimal micronutrient levels for genomic stability is scanty and disorganised. However, there is already sufficient evidence to suggest that marginal deficiencies in folate, vitamin B12, niacin and zinc impact significantly on spontaneous chromosome damage rate. The recent data for folate and vitamin B12 in humans with respect to micronucleus formation in blood and epithelial cells provide compelling evidence of the important role of these micronutrients in maintenance of genome integrity and the need to revise current RDAs for these micronutrients based on minimisation of DNA damage. Appropriately designed in vitro studies and in vivo placebo controlled trials with dose responses using a complementary array of DNA damage biomarkers are required to define recommended dietary allowances for genomic stability. Furthermore these studies would have to be targeted to individuals with common genetic polymorphisms that alter the bioavailability of specific micronutrients and the affinity of specific key enzymes involved in DNA metabolism for their micronutrient co-factor. That there is a need for an international collaborative effort to establish RDAs for genomic stability is self-evident.


Bacterial and fungal microleakage of AH26 and AH Plus root canal sealers.
To evaluate the penetration of Candida albicans alone and a combination of bacteria through root canals filled with gutta-percha and one or other root canal sealers, AH26 and AH Plus. Eighty teeth were randomly divided into two groups of 40 teeth each and obturated with gutta-percha using either AH26 or AH Plus sealer. A further 10 teeth served as negative controls and 10 as positive controls. The external surface of each root, except the apical 2 mm, was covered with two layers of nail varnish. The teeth were inserted into Eppendorf plastic tubes and suspended in glass bottles containing sterile Schaedler broth. Streptococcus mutans, Streptococcus mitis, Prevotella melaninogenica and Lactobacillus acidophilus were placed in the access cavities of 20 teeth filled with AH26 and 20 with AH Plus. Candida albicans was placed in the access cavities of the other teeth. The culture medium with microorganisms was changed every 7 days. Every 72 h bacterial or fungal growth in the broth was tested up to a period of 90 days. Leakage in the experimental teeth occurred between 14 and 87 days. Leakage was present in 47% of all samples. From the samples with AH26, 45% leaked bacteria and 60% leaked fungi; whilst from the samples with AH Plus, 50% leaked bacteria and 55% fungi. There was no statistically significant difference in penetration of bacteria and fungi between the sealers. In this in vitro study, gutta-percha and the sealers AH26 and AH Plus allowed leakage of bacteria and fungi.


Position Paper on the Value of Extended Adjuvant Therapy with Neratinib for Early HER2+/HR+ Breast Cancer.
In August 2018, neratinib - an oral, irreversible pan-HER-tyrosine-kinase inhibitor - was approved by the European Commission for the extended adjuvant treatment of adult patients with early-stage, hormone receptor-positive (HR+), HER2 overexpressed/amplified (HER2+) breast cancer who completed trastuzumab-based adjuvant therapy within the last year. Despite recent improvements in long-term outcome, there is still an unmet need to further reduce the risk of recurrence, especially in patients with poor response to neoadjuvant treatment. National and international guidelines included recommendations for using neratinib. Based on the health technology assessment for neratinib, the Federal Joint Committee (G-BA) in Germany has granted an added benefit for neratinib compared with the standard "watch and wait" strategies. Inclusion in the Reimbursement Code, however, was rejected by the Austrian social insurance companies in July 2020, and neratinib is now in the "No Box" for individual head physician reimbursement. We analysed the value of extended adjuvant therapy with neratinib in early HER2+/HR+ breast cancer based on current data and made recommendations for the evidence-based and economical use of neratinib in Austria. In particular, prognostic factors associated with an increased risk of recurrence following standard therapy are considered. Extended adjuvant therapy should be offered primarily to nodal-positive patients at surgery. For nodal-negative patients, neratinib therapy may be considered in case of large and/or inflammatory primary tumours (T3-4) without pathological complete response after neoadjuvant therapy. For all other patients, neratinib may be considered depending on additional risk factors on an individual basis that should be evaluated by interdisciplinary tumour conferences.


HAND1 and HAND2 are expressed in the adult-rodent heart and are modulated during cardiac hypertrophy.
The HAND basic Helix-Loop-Helix (bHLH) transcription factors are essential for normal cardiac and extraembryonic development. Although highly evolutionarily conserved genes, HAND cardiac expression patterns differ across species. Mouse expression of HAND1 and HAND2 was reported absent in the adult heart. Human HAND genes are expressed in the adult heart and HAND1 expression is downregulated in cardiomyopathies. As rodent and human expression profiles are inconsistent, we re-examined expression of HAND1 and HAND2 in adult-rodent hearts. HAND1 and HAND2 are expressed in adult-rodent hearts and HAND2 is expressed in the atria. Induction of cardiac hypertrophy shows modulation of HAND expression, corresponding with observations in human cardiomyopathy. The downregulation of HAND expression observed in rodent hypertrophy and human cardiomyopathy may reflect a permissive role allowing, cardiomyocytes to reinitiate the fetal gene program and initiate the adaptive physiological changes that allow the heart to compensate (hypertrophy) for the increase in afterload.


New frontiers for ovarian cancer risk evaluation: proteomics and contrast-enhanced ultrasound.
The grim ovarian cancer statistics are attributed to the fact that most women typically present with widespread disease at the time of initial diagnosis. Our current diagnostic tools, such as pelvic examination and standard ultrasound, are inadequate to detect early-stage epithelial ovarian cancer. In recent years there has been an explosion of important advances in biomedical engineering, proteomic technologies, and computational analyses that has led to the identification of hundreds of previously unknown proteins unique to the pathophysiology of ovarian cancer, some of which are currently under clinical validation. At present, no one biomarker exists with 100% specificity and sensitivity for the accurate detection of early-stage epithelial ovarian cancer. As the search for a panel of biomarkers detecting cancer, let alone early-stage disease, progresses, diagnostic imaging will continue to play a critical role to confirm or refute these biomarker assays. Interestingly, recent studies using contrast-enhanced ultrasound have shown potential as an early-detection tool by detecting the aberrant vascularity required for tumor growth before the development of a mass. Thus, we propose that the use of proteomic-based biomarker discovery and contrast-enhanced ultrasound may serve as a promising combination to help accurately identify early-stage epithelial ovarian cancer to improve women's health care.


Influence of hepatitis B virus (HBV) genotype on the clinical course of disease in patients coinfected with HBV and hepatitis delta virus.
We evaluated the influence of hepatitis B virus (HBV) genotype on the course of disease in patients coinfected with HBV and hepatitis delta virus (HDV). We evaluated HBV genotypes in 190 patients, 140 of whom had chronic HBV monoinfection and 50 of whom had chronic HBV-HDV coinfection. Real-time polymerase chain reactions for the amplification of HBV DNA and HDV RNA were developed, and we compared the patient groups with respect to HBV genotype, viral load, alanine aminotransferase (ALT) and bilirubin levels, and disease severity. Coinfected patients had higher ALT and bilirubin levels as well as a higher prevalence of liver cirrhosis and liver carcinoma. ALT levels were higher among individuals coinfected with HDV and HBV genotype F than among individuals infected only with HBV genotype F. Among HDV-HBV-coinfected patients, HDV load was lower among those infected with HBV genotype A than among those infected with HBV genotype D or genotype F. Liver inflammation and HDV load are influenced by HBV genotype in individuals coinfected with HBV and HDV.


Effect of aging on gastric mucosal defense mechanisms: ROS, apoptosis, angiogenesis, and sensory neurons.
Aging changes in the stomach lead to a decreased capacity for tissue repair in response to gastric acid. The aim of this study was to determine the mechanism associated with the increased susceptibility to injury of aging mucosa including reactive oxygen species (5), apoptosis, angiogenesis, and sensory neuron activity. Fischer 344 rats at four different ages (6, 31, 74 wk, and 2 yr of age) were studied. The connective tissue indicators [salt-soluble collagen and sulfated glycosaminoglycan (sGAG)], lipid hydroperoxide (LPO), myeloperoxidase (MPO), and hexosamine were assessed. We also evaluated the expression of early growth response-1 (Egr-1), phosphatase and tension homologue deleted on chromosome 10 (PTEN), caspase-9 (index of apoptosis), VEGF (index of angiogenesis), calcitonin gene-related peptide (CGRP, index of sensory neurons), and neuronal nitric oxide synthase (nNOS). The histological connective tissue area in the lower part of rat gastric mucosa increased with aging, with increase of salt-soluble collagen and sGAG. LPO and MPO in old rats were significantly greater than in the young rats, whereas hexosamine was significantly reduced. The old gastric mucosa had increased expression of Egr-1, PTEN, and caspase-9, whereas the VEGF, CGRP, and nNOS expression were significantly reduced. These results indicate that the lower part of rat gastric mucosa was found to be replaced by connective tissue with accumulation of oxidative products with aging. In addition, impairment of apoptosis, angiogenesis, and sensory neuron activity via the activation of Egr-1 and PTEN might increase the susceptibility of gastric mucosa to injury during aging.


[Stereotactic hypofractionated radiotherapy of non-hepatic abdominal tumors].
The clinical experiences of 12 patients with non-hepatic abdominal tumors who underwent stereotactic hypofractionated radiotherapy are presented. Ten lesions were metastatic, one was a primary pancreatic cancer, and the remaining one was irradiated postoperatively for a positive margin of extrahepatic bile duct cancer. In one patient, single fractional stereotactic radiotherapy was employed, while the remaining 11 patients were treated with 3 fractions. Gross tumor volume of the 10 ranged from 2 cc to 32 cc (mean: 11 cc), and the minimal dose enclosing 95% of the planning target volume (D95) was between 28.6 Gy and 35 Gy. The minimal number of portals was 6. In 8 patients, radiotherapy was performed under respiratory gating. Mean follow-up time was 10 months (5-51 months). Local regrowth was seen in 9 months in only 1 of the 12 tumors, and the patient died of the disease. Four patients died because of tumor growth in other sites. The remaining 7 patients are alive without disease. As for morbidity, NCI-CTC grade 3 gastritis was seen in one patient, grade 2 gastritis in 2 patients, and grade 2 duodenitis in one patient. These patients all improved with non-surgical therapy. Stereotactic hypofractionated radiotherapy is effective for the treatment of selected non-hepatic abdominal tumors. However, the optimal radiation dose for tumor control and the tolerance dose of the gastrointestinal tract in hypofractionated irradiation must be studied further.


Parotid gland dose reduction in the hippocampus avoidance whole-brain radiotherapy using helical tomotherapy.
The present study aimed to reduce the parotid gland dose in the hippocampus avoidance with whole-brain radiotherapy (HA-WBRT) using the helical tomotherapy (HT). Ten patients who had previously undergone WBRT were randomly selected and enrolled in this study. During the treatment planning, two different techniques to the jaw were applied for each patient, namely, 1.0 cm fixed jaw and 2.5 cm dynamic jaw. To efficiently reduce the dose in the bilateral parotid glands, directional block (DB) mode was set. The DB is a function of a treatment planning system for the dose reduction in organs at risk. The standard HA-WBRT plan which did not reduce the parotid gland dose was also designed to compare the plan quality. Compared with the standard HA-WBRT plan, the parotid gland dose could be reduced by approximately 70% without extending the delivery time by adding the parotid gland on the DB mode to the dose constraint. In addition, the differences in dosimetric parameters observed between the plans employing the 1.0 cm fixed jaw and 2.5 cm dynamic jaw were almost negligible. Moreover, delivery time in the 2.5 cm dynamic jaw could be greatly reduced by 60% compared with that in the 1.0 cm fixed jaw.


A long acting nanoformulated lamivudine ProTide.
A long acting (LA) hydrophobic and lipophilic lamivudine (3TC) was created as a phosphoramidate pronucleotide (designated M23TC). M23TC improved intracellular delivery of active triphosphate metabolites and enhanced antiretroviral and pharmacokinetic (PK) profiles over the native drug. A single treatment of human monocyte derived macrophages (MDM) with nanoformulated M23TC (NM23TC) improved drug uptake, retention, intracellular 3TC triphosphates and antiretroviral activities in MDM and CD4+ T cells. PK tests of NM23TC administered to Sprague Dawley rats demonstrated sustained prodrug and drug triphosphate levels in blood and tissues for 30 days. The development of NM23TC remains a substantive step forward in producing LA slow effective release antiretrovirals for future clinical translation.


Plasma LH, FSH and testosterone concentrations in adult rams which were homozygous carriers or non-carriers of the Booroola fecundity gene.
No gene-specific differences were found with respect to LH or testosterone pulsatile secretion (over 12 h), or in 12 hourly mean FSH concentrations in adult Booroola FF and ++ rams. Also, no differences between genotypes in the LH response to an injection of testosterone propionate, the FSH response to an infusion of bovine follicular fluid, or the testosterone response to injections of PMSG were noted. However, during the phase of seasonal testicular development, mean testosterone pulse amplitude (over 12 h) and the FSH response to 25 micrograms GnRH were higher in FF than in ++ rams (P less than 0.05); there were also significant effects of sire (P less than 0.05 in FF genotype only) and litter size (P less than 0.05) on testosterone pulse amplitude and GnRH-stimulated FSH release, respectively. During the breeding season, mean LH, but not FSH, concentrations were higher in FF than in ++ rams, after an injection of 0.5 micrograms GnRH; LH release was not affected by sire or litter size (P greater than 0.05). Long-term studies revealed that the FF rams were born in significantly larger litters, they weighed significantly less than ++ rams (P less than 0.05), and that bodyweight was significantly correlated (P less than 0.05) with litter size. There were no differences in testis size, and testis size was not significantly correlated with bodyweight. There was a strong tendency (P = 0.056) for overall mean FSH concentrations, measured weekly for 9 months, to be highest more often in FF than in ++ rams.(ABSTRACT TRUNCATED AT 250 WORDS)


Anticancer activity of betulinic acid on MCF-7 tumors in nude mice.
Breast cancer is a major public health problem and the low effectiveness of conventional therapies to achieve long-term survival results in increased mortality associated with advanced breast cancers. Betulinic acid (BA) is a pentacyclic triterpene which can be isolated from number of plants grown in the tropics. It exhibits cytotoxic activity against variety of cancer cell lines. In the present study, the in vitro cytotoxic activity and in vivo antitumor activity of BA was evaluated in athymic nude mice bearing MCF-7 breast adenocarcinoma xenografts. In vitro cytotoxic activity of BA on MCF-7 cells was studied using the MTT assay and BA was cytotoxic towards MCF-7 cells with IC50 value of 13.5 microg/mL. The antitumor activity of BA was studied at concentrations of 50 and 100 mg/kg body weight in mice injected with MCF-7 cells. BA treatment delayed tumor formation and statistically significant reduction (P < 0.0001) of 52 and 77% in the tumor size at concentrations of 50 and 100 mg, respectively was observed. Histopathological analysis of tumors revealed decreased angiogenesis, proliferation and invasion in BA treated animals. This is one of the first studies demonstrating the in vivo antitumor activity of BA on MCF-7 breast cancer tumors in nude mice. The antitumor effect of BA can further be enhanced by use of combination therapy and novel drug delivery systems, thus making it a promising candidate for management of breast cancer patients.


[The role of silent hepatic insufficiency in pathogenesis of postoperative biliary peritonitis].
The results of clinico-morphologic and biochemical investigations of the liver were conducted in 58 patients, in whom postoperative biliary peritonitis (PBP) was revealed. There was established, that in the basement of hepatic insufficiency formation in PBP lie the hepatocytes damage and severe portal toxaemia, caused by damaging effect of the middle mass peptides and the lipids peroxidal oxidation products.


A European Observational Study to Evaluate the Safety and the Effectiveness of Safinamide in Routine Clinical Practice: The SYNAPSES Trial.
Safinamide modulates both dopaminergic and glutamatergic systems with positive effects on motor and non-motor symptoms of Parkinson's disease (PD). The drug utilization study SYNAPSES was designed to investigate the use of safinamide in routine clinical practice, as recommended by the European Medicines Agency. To describe the occurrence of adverse events in PD patients treated with safinamide in real-life conditions. The SYNAPSES trial is an observational, European, multicenter, retrospective-prospective cohort study. Patients were followed up to 12 months with analyses performed in the overall population and in patients aged >75 years, with relevant comorbidities and with psychiatric conditions. Of the 1610 patients included, 82.4% were evaluable after 12 months with 25.1% of patients >75 years, 70.8% with relevant comorbidities and 42.4% with psychiatric conditions. During observation 45.8% patients experienced adverse events, 27.7% patients had adverse drug reactions and 9.2% patients had serious adverse events. The adverse events were those already described in the patients' information leaflet. The majority were mild or moderate and completely resolved and no differences were detected between the subgroup of patients. Clinically significant improvements were seen in the UPDRS motor score and in the UPDRS total score in ≥40% of patients, according to the criteria developed by Shulman et al.Conclusion:The SYNAPSES study confirms the good safety profile of safinamide even in special groups of patients. Motor complications and motor scores improved with clinically significant results in the UPDRS scale maintained in the long-term.


Structure-function analysis of human cytochrome P450 3A4 using 7-alkoxycoumarins as active-site probes.
The oxidation of a series of seven alkyl ethers of 7-hydroxycoumarin by cytochrome P450 3A4 (CYP3A4) has been studied to probe the active site of the enzyme. TLC of the reaction mixture showed formation of metabolites other than 7-hydroxycoumarin. The separation and characterization of the different metabolites of the C4 to C7 compounds were achieved using a combination of TLC, HPLC, and gas chromatography-electron impact mass spectra. Among the 7-alkoxycoumarins, 7-hexoxycoumarin was found to be the most suitable candidate for investigating the active site of cytochrome CYP3A4, due to the well-separated metabolite peaks on TLC and HPLC. 7-hexoxycoumarin was found to produce three side-chain hydroxylated products besides 7-hydroxycoumarin: 7-(5-hydroxyhexoxy)coumarin, 7-(4-hydroxyhexoxy)coumarin, and 7-(3-hydroxycoumarin). The substitution of residues from substrate recognition sites -1, -4, -5, and -6 of CYP3A4 showed a strong influence on the product profile of 7-hexoxycoumarin, the most prominent effects observed with mutants at residues 119, 301, 305, 370, 373, and 479. The docking of 7-hexoxycoumarin into a molecular model of CYP3A4 also confirmed the presence of these residues within 5 A of the substrate. A comparative study of cytochrome P450 2B1 showed that the active-site mutants F206L, T302V, V363A, and S478G but not V363L exhibited a dramatic decrease in total 7-hexoxycoumarin hydroxylation. The study suggests that although the electronic nature of the substrate is important, enzymatic constraints significantly contribute to CYP3A4 selectivity.


Covering the costs of care in neonatal intensive care units.
The continued rise of health care costs, despite private and governmental control efforts, has sustained cost containment as a central issue for health care researchers and policy makers. In keeping with these concerns, the Florida Health Care Cost Containment Board conducted a study of neonatal intensive care units (NICUs) in Florida to ascertain the costs, charges, and net revenues associated with NICU services in individual hospitals, to document cost shifting and cross-subsidization as a means of financing NICU care for indigent populations, and to assess the fiscal impact of NICUs in state-sponsored vs non-state-sponsored Regional Perinatal Intensive Care Center hospitals providing NICU care. Hospitals in the state-sponsored program reported a loss of approximately $16.5 million in contrast to the non-state-sponsored hospitals, which reported a gain of $1 million. Payment being generated by private-pay patients amounted to almost 60% of total revenues but constituted less than one third of the costs in state-sponsored hospitals, indicating a high level of cost shifting. Government support of state-sponsored NICUs, while substantial, has been insufficient; increasing constraints on this funding source would likely worsen the deficit and increase the necessity of cost shifting.


Complications of intraarterial urokinase-lys-plasminogen infusion therapy in arterial ischemia of lower limbs.
Thirty-five patients with peripheral arterial occlusions were treated by intraarterial infusion of low-dose urokinase associated with bolus of lys-plasminogen. Thrombolysis was achieved in 26 cases (74%), but only 10 patients (28.5%) experienced sustained improvement. Complications of thrombolysis occurred in 11 patients: Five patients developed groin hematoma, five had distal emboli, and one experienced macroscopic hematuria. Catheter-related thrombosis was observed in 14 patients (40%) despite intravenous heparin. Nine patients suffered from recurrent thrombosis and three from proximal emboli. A patient died from catheter-related infection. Limited fibrinolysis could increase pericatheter thrombosis, and further work will be necessary to assess the local risk of intraarterial thrombolysis.


Involvement of eicosanoids and surfactant protein D in extrinsic allergic alveolitis.
The pathophysiology of extrinsic allergic alveolitis (EAA) involves oxidative lung damage as well as interstitial and alveolar inflammation. Macrophages and mast cells are inflammatory components of EAA that produce both leukotrienes (LTs) and prostaglandin D2 (PGD2). In addition, PGD2 is also produced by the free-radical-catalysed peroxidation of arachidonic acid during oxidative stress. Urinary 8-iso prostaglandin F2alpha (8-isoPGF2alpha) and serum surfactant protein D (SP-D) are considered appropriate biomarkers of oxidative stress and interstitial lung disease activity, respectively. The present study aimed to assess the association of these biomarkers with the pathophysiology of EAA. Two cases of acute EAA caused by the inhalation of fungi spores were reported. Eight asthmatic patients and six healthy control subjects were also enrolled in the current study. The serum SP-D and urinary eicosanoid (LTE4, PGD2 metabolite (9alpha,11betaPGF2), 8-isoPGF2alpha) concentrations markedly increased during the acute exacerbation phase. These concentrations decreased following corticosteroid therapy in the EAA patients. There was a significant correlation between serum SP-D and urinary 9alpha,11betaPGF2 concentrations in the EAA patients. In conclusion, although the present study proposes that serum surfactant protein-D and urinary eicosanoids are new biomarkers involved in the various immunological responses in extrinsic allergic alveolitis, further large-scale studies are needed to investigate the role of these compounds, not just as biomarkers, but also as biological potentiators of extrinsic allergic alveolitis.


Psychological implications of vitreous opacities - A systematic review.
Given that depression and anxiety can be comorbid to several treatable eye diseases, it is paramount to understand whether vitreous opacities are also associated with increased risk of well-being and mental health problems. The current systematic review summarises research examining psychological implications of vitreous opacities in adult patients. PubMed, Cochrane library, EMBASE, Global Health, Web of Science, EBSCO, and Science Direct were systematically searched for all articles published up to May 5th 2021. Inclusion criteria included studies that have assessed outcomes related to patients' mental health; well-being; quality of life; coping with the disease; studies exploring patients' experiences/perceptions/cognitions of illness and/or medical treatments related to vitreous opacities. 5 studies were included in this review, with a total of 139 patients [278 eyes] assessed. Patients' age ranged from 32 to 78 years old. Compared with healthy controls, patients with vitreous opacities showed significantly higher levels of symptoms of depression, perceived stress, state anxiety, and trait anxiety. Studies also suggested that patients are more likely to show low vision-related quality of life, and social functioning. Studies also suggested a significant positive effect of medical treatments [e.g. pars plana victretomy] on patients' symptoms of depression and anxiety and on patients' vision-related quality of life. The topic of psychological implications of vitreous opacities is still relatively new in the literature with very preliminary evidence of mental health problems and reduced quality of life associated with this condition.


Most consumed foods in Brazil: evolution between 2008-2009 and 2017-2018.
To describe the evolution of food consumption by the Brazilian population in 2008-2009 to 2017-2018. Data from the National Dietary Surveys of 2008-2009 and 2017-2018 were used. Both surveys estimated food consumption of two non-consecutive days of individuals aged 10 years or older. The first survey collected consumption data from 34,003 individuals through food records; the second, obtained data from 46,164 individuals, through 24-hour recalls. The twenty most frequently reported food groups in the two surveys were identified. The probability of consumption of each food group in the two surveys was estimated according to sex, age and income. This study presents the foods that had a change in the frequency of consumption of 5% or higher between the two surveys. The probability of consumption was corrected for intra-individual variability using the method developed by the National Cancer Institute. Rice, beans, coffee, bread, vegetables and beef remained the staple Brazilian diet, ranking as the six most consumed items in both surveys. Ultra-processed foods such as sweet/stuffed cookies, savory cookies, processed meats and carbonated drinks also remained among the 20 most consumed foods. Trend analyses showed, regardless of gender, age and income range, a decrease in the consumption of rice, beans, beef, bread, fruit, milk and dairy, processed meats and carbonated drinks, and an increase in the consumption of sandwiches. The Brazilian diet is still characterized by consumption of traditional foods, such as rice and beans, and by high frequency of consumption of ultra-processed foods, such as cookies and carbonated drinks. However, between the years of 2008-2009 and 20172018, there was a decrease in the consumption of rice, beans, beef, bread, fruit, milk and dairy, processed meats and carbonated drinks, but an increase in the consumption of sandwiches. The results show a decrease in quality in the Brazilian diet.


Endometriosis and Pelvic Pain for the Gastroenterologist.
Endometriosis, affecting 5-10% of reproductive-age women, is a common contributor to dysmenorrhea and chronic pelvic pain. Diagnosis requires laparoscopic tissue biopsy, but careful pelvic examination, and/or imaging with either ultrasound or MRI, may identify patients who should receive empiric first-line therapy. The presence of dyschezia, particularly with cyclical exacerbation, should raise suspicion for bowel or rectovaginal septum involvement, and a greater need for surgical management. Treatment of dysmenorrhea includes hormonal suppression of the menstrual cycle, and/or analgesics; more severe cases with strong pain and disability may require earlier surgical intervention to excise disease while preserving fertility desires.


Mental distress in the Danish general population.
To present data on mental distress in the Danish general population using recently validated Hopkins symptom checklist (SCL) subscales and compare with data from other countries. To evaluate associations between mental distress and biopsychosocial factors. Questionnaires were sent to a gender- and age-stratified random sample comprising 2040 Danes. Mean SCL subscale scores were calculated. Cases were defined in accordance with the traditional criteria, and Danish and US raw score cut-offs were compared. A multiple regression model was developed to describe associations between biopsychosocial factors and SCL scores. The response rate was 58%. The Danish mean scores were significantly higher than reported for a US non-patient sample, and Danish raw score cut-offs for caseness were higher. The Danish scores were closer to Nordic mean scores. Age, gender, social status, somatic disorder and traumatic life events in the past year in work life as well as personal life were significantly associated with the level of mental distress. SCL scores were compared with scores on the Major Depression Inventory. The SCL mean scores of the Danish general population were relatively high, but similar to data from the Nordic countries. Consequently, interpretation of the Danish SCL requires Danish norms and Danish cut-off scores for caseness.


[Survey of occupational health practices of foreign-owned companies].
We conducted a survey to clarify the present state of the occupational health practices (OHPs) of foreign-owned companies (FOCs) in Japan. The results reveal more strategic OHPs of FOCs located in Japan as local subsidiaries. Furthermore, the results should contribute to smoother global development of OHPs for international corporations with headquarters (HQs) in Japan. A total of 1,220 FOCs in Japan with at least 50 employees that are listed in Gaishikeikigyo-Soran (Overview of FOCs) 2009 published by Toyo Keizai, Inc. were targeted in our survey. A questionnaire with items concerning the (1) present situation of global and local OHP standards, (2) relationships with overseas HQ, and (3) impressions regarding daily OHPs was sent to a high-ranking person engaged in OHPs at each FOC. We ask about renkei-kan (sense of cooperation with overseas HQ), a positive Japanese word, in order to evaluate preferable relationships between FOCs and their HQs. There were 123 valid responses. Of these, only 50 had indicated the implementation of global standards (GS). Of the OHPs that were mentioned in GS, responses mainly included risk management for occupational diseases. With respect to local standards (LS), responses indicated that individual approaches toward each worker were an area of particular focus. Satisfaction with staff numbers and budget was high, although HQ involvement in staff numbers and budget control was low. Furthermore, 71.5% of respondents had low renkei-kan. We also found correlations among: renkei-kan, GS availability, frequency of reporting to overseas superiors, audit interval, and understanding of OHP organization at HQs. We found FOCs established OHPs independently of HQs and that they were satisfied with the present situation. On the other hand, there are many respondents who do not have positive feelings, renkei-kan, toward their relationships with HQs. OHP staff of FOCs can enhance renkei-kan by making use of GS, identifying key HQ personnel, and implementing understanding for them and their organization through daily reports and regular audits.


[Surgical treatment of Ménière's disease by sacculotomy, cochleo-sacculotomy and transtympanic aerators].
Sixty-two patients suffering from severe Ménière's disease with invalidating vertigo attacks were treated between 1976 and 1987 by three minoir surgical procedures: sacculotomy (19), cochleo-sacculotomy (15) or a transtympanic ventilation tube (28). The results were assessed after the second post-operative year according to the criteria of the American Academy of Otolaryngology (1985). The overall success rate for vertigo control was 79% with sacculotomy, 80 with cochleo-sacculotomy and 82% with transtympanic ventilation tubes. Severe permanent hearing-losses occurred in 20% after sacculotomy and cochleo-sacculotomy. Drop-attacks were not improved. These three surgical procedures give similar results with respect to vertigo control without any vital risk. The precise mechanisme of action in these procedures is not yet well understood.


Characterization of T2-Low and T2-High Asthma Phenotypes in Real-Life.
Asthma is a heterogeneous and complex condition characterized by chronic airway inflammation, which may be clinically stratified into three main phenotypes: type 2 (T2) low, T2-high allergic, and T2-high non-allergic asthma. This real-world study investigated whether phenotyping patients with asthma using non-invasive parameters could be feasible to characterize the T2-low and T2-high asthma phenotypes in clinical practice. This cross-sectional observational study involved asthmatic outpatients (n = 503) referring to the Severe Asthma Centre of the San Luigi Gonzaga University Hospital. Participants were stratified according to the patterns of T2 inflammation and atopic sensitization. Among outpatients, 98 (19.5%) patients had T2-low asthma, 127 (25.2%) T2-high non-allergic, and 278 (55.3%) had T2-high allergic phenotype. In comparison to T2-low, allergic patients were younger (OR 0.945, p < 0.001) and thinner (OR 0.913, p < 0.001), had lower smoke exposure (OR 0.975, p < 0.001) and RV/TLC% (OR 0.950, p < 0.001), higher prevalence of asthma severity grade 5 (OR 2.236, p < 0.05), more frequent rhinitis (OR 3.491, p < 0.001) and chronic rhinosinusitis with (OR 2.650, p < 0.001) or without (OR 1.919, p < 0.05) nasal polyps, but less common arterial hypertension (OR 0.331, p < 0.001). T2-high non-allergic patients had intermediate characteristics. Non-invasive phenotyping of asthmatic patients is possible in clinical practice. Identifying characteristics in the three main asthma phenotypes could pave the way for further investigations on useful biomarkers for precision medicine.


Analysis of protein composition of red wine in comparison with rosé and white wines by electrophoresis and high-pressure liquid chromatography-mass spectrometry (HPLC-MS).
Wine proteins not only influence wine stability but are also being discussed as potential allergens. Proteins from red, rosé, and white wines were enriched by dialysis and lyophilization followed by separation by SDS-PAGE. Significant differences were detected in the protein compositions of the analyzed wine varieties, and the major protein bands were identified by mass spectrometry after in-gel digestion with trypsin. In German Portugieser red wine, a total of 121 tryptic peptides were identified, which were attributed to 12 grape proteins and 6 proteins derived from yeast. Among the identified constituents are several proteins considered to influence wine stability and previously described potential grape allergens. The pathogenesis-related proteins represent the main proteins in all of the wines, but only some red wines show a band with a molecular mass of 12 kDa, identified as a lipid transfer protein (LTP). The occurrence and distribution of LTP depend on the wine variety.


Direct detection of aptamer-thrombin binding via surface-enhanced Raman spectroscopy.
In this study, we exploit the sensitivity offered by surface-enhanced Raman scattering (SERS) for the direct detection of thrombin using the thrombin-binding aptamer (TBA) as molecular receptor. The technique utilizes immobilized silver nanoparticles that are functionalized with thiolated thrombin-specific binding aptamer, a 15-mer (5'-GGTTGGTGTGGTTGG-3') quadruplex forming oligonucleotide. In addition to the Raman vibrational bands corresponding to the aptamer and blocking agent, new peaks (mainly at 1140, 1540, and 1635 cm(-1)) that are characteristic of the protein are observed upon binding of thrombin. These spectral changes are not observed when the aptamer-nanoparticle assembly is exposed to a nonbinding protein such as bovine serum albumin (BSA). This methodology could be further used for the development of label-free biosensors for direct detection of proteins and other molecules of interest for which aptamers are available.


Oxidative protein folding in the secretory pathway and redox signaling across compartments and cells.
The endoplasmic reticulum (ER) is central for many essential cellular activities, such as folding, assembly and quality control of secretory and membrane proteins, disulfide bond formation, glycosylation, lipid biosynthesis, Ca(2+) storage and signaling. In addition, this multifunctional organelle integrates many adaptive and/or maladaptive signaling cues reporting on metabolism, proteostasis, Ca(2+) and redox homeostasis. We are beginning to understand how these functions and pathways are integrated with one another to regulate homeostasis at cell, tissue and organism levels. The mechanisms underlying the introduction of the proper set of disulfide bonds into secretory proteins (oxidative folding) are strictly related to redox homeostasis, ER stress sensing and signaling and provide a good example of the integration systems operative in the early secretory compartment.


Comparative Transcriptomics Analyses across Species, Organs, and Developmental Stages Reveal Functionally Constrained lncRNAs.
The functionality of long noncoding RNAs (lncRNAs) is disputed. In general, lncRNAs are under weak selective pressures, suggesting that the majority of lncRNAs may be nonfunctional. However, although some surveys showed negligible phenotypic effects upon lncRNA perturbation, key biological roles were demonstrated for individual lncRNAs. Most lncRNAs with proven functions were implicated in gene expression regulation, in pathways related to cellular pluripotency, differentiation, and organ morphogenesis, suggesting that functional lncRNAs may be more abundant in embryonic development, rather than in adult organs. To test this hypothesis, we perform a multidimensional comparative transcriptomics analysis, across five developmental time points (two embryonic stages, newborn, adult, and aged individuals), four organs (brain, kidney, liver, and testes), and three species (mouse, rat, and chicken). We find that, overwhelmingly, lncRNAs are preferentially expressed in adult and aged testes, consistent with the presence of permissive transcription during spermatogenesis. LncRNAs are often differentially expressed among developmental stages and are less abundant in embryos and newborns compared with adult individuals, in agreement with a requirement for tighter expression control and less tolerance for noisy transcription early in development. For differentially expressed lncRNAs, we find that the patterns of expression variation among developmental stages are generally conserved between mouse and rat. Moreover, lncRNAs expressed above noise levels in somatic organs and during development show higher evolutionary conservation, in particular, at their promoter regions. Thus, we show that functionally constrained lncRNA loci are enriched in developing organs, and we suggest that many of these loci may function in an RNA-independent manner.


Molecular complexity and gene expression controlling cell turnover during a digestive cycle of carnivorous sponge Lycopodina hypogea.
Lycopodina hypogea is a carnivorous sponge that tolerates laboratory husbandry very well. During a digestion cycle, performed without any digestive cavity, this species undergoes spectacular morphological changes leading to a total regression of long filaments that ensure the capture of prey and their reformation at the end of the cycle. This phenomenon is a unique opportunity to analyze the molecular and cellular determinants that ensure digestion in the sister group of all other metazoans. Using differential transcriptomic analysis coupled with cell biology studies of proliferation, differentiation, and programmed cell deaths (i.e., autophagy and the destructive/constructive function of apoptosis), we demonstrate that the molecular and cellular actors that ensure digestive homeostasis in a sister group of all remaining animals are similar in variety and complexity to those controlling tissue homeostasis in higher vertebrates. During a digestion cycle, most of these actors are finely tuned in a coordinated manner. Our data benefits from complementary approaches coupling in silico and cell biology studies and demonstrate that the nutritive function is provided by the coordination of molecular network that impacts the cells turnover in the entire organism.


[Job retention and health issues: an example of personalized assistance in northern France].
"Santé Emploi Info Service" (Health and Employment Information Service) is a regional information service aimed at providing support and assistance to people who are struggling to perform their job effectively or to return to work as a result of a health problem. Through personalized assistance and follow-up, the service aims to help individuals to avoid professional exclusion, to provide accessible information, and to encourage networking between healthcare professionals and services specializing in job retention and vocational rehabilitation. In total, 1,392 calls have been received since the service opened in 2006, with most calls dealing with employment, income and legal matters and a range of psychological counseling issues. More than half of the proposed solutions have proved successful. The regional service (a unique initiative in France) is supported by Lille Regional Hospital and helps individuals suffering from health problems to overcome obstacles to job retention and vocational rehabilitation. The service also provides specifically-tailored information about legal procedures relating to professional integration and vocational rehabilitation.