Correction: The Role of Nature and Nurture for Individual Differences in Primary Emotional Systems: Evidence from a Twin Study.
[This corrects the article DOI: 10.1371/journal.pone.0151405.].


RAB14 promotes epithelial-mesenchymal transition in bladder cancer through autophagy‑dependent AKT signaling pathway.
Bladder cancer (BLCA) is the 9th most common cancer of mortality. Autophagy and epithelial to mesenchymal transition (EMT) have an essential role in cancer invasion and metastasis. However, the relationship between autophagy and EMT is still poorly understood in BLCA. Functional enrichment and pathway network analysis were carried out. Comprehensive protein-protein interactions (PPI) networks were proposed to prioritize candidate autophagy-related genes. Furthermore, an autophagy-related signature and a nomogram model were established by integrating clinical information and this signature risk score to evaluate candidate autophagy-related genes. RAB14 expression and its association with pathological information and survival were evaluated in samples from TCGA dataset. Knocking down RAB14 in T24 cells was constructed, and immunofluorescence staining, transmission electron microscopy, immunohistochemistry and western blotting and a series of functional assays were performed to evaluate the migration, invasion, EMT and autophagy abilities of BLCA cells. The autophagy-related gene RAB14 was the only candidate gene identified by three kinds of analytic approaches. RAB14 was highly upregulated in BLCA and correlated with clinical outcomes based on TCGA BLCA datasets. Knocking down RAB14 was found to inhibit EMT and autophagy in T24 cells. RAB14 levels were positively related to those of LC3B and Beclin1, two genes with critical roles in the autophagy process, and the correlation was further confirmed in clinical tissue specimens by IHC and western blot analysis. In addition, RAB14-promoted EMT, migration, and invasion in T24 cells could be partially reversed by autophagy activator, rapamycin. The effects of RAB14 on autophagy was associated with level of p-Akt, indicating that they were possibly mediated via PI3K/AKT signaling. These findings indicated that autophagy-related gene RAB14-promoted EMT, migration and invasion of bladder cancer via the Akt-associated autophagic pathway.


A mathematical expression for the human crystalline lens.
A mathematical representation of the human crystalline lens is proposed. It is expressed in a parametric form, which is confirmed when tested against five independently published MRI images. Analytical functions for capsule thickness were also developed.


A novel member of the Rhomboid family, RHBDD1, regulates BIK-mediated apoptosis.
Rhomboid family members are widely conserved and found in all three kingdoms of life. They are serine proteases and serve important regulatory functions. In the present study, a novel gene highly expressed in the testis, RHBDD1, is shown to be a new member of the Rhomboid family, participating in the cleavage of BIK, a proapoptotic member of the Bcl-2 family. The RHBDD1-involved proteolytic modification is upstream of the BIK protein degradation pathway. Mutagenesis studies show that the amino acid residues glycine142 and serine144 of RHBDD1 are crucial for its activity in cleaving BIK at a site located in the transmembrane region. Overexpression or knock-down of RHBDD1 in HEK 293T cells can reduce or enhance BIK-mediated apoptosis, respectively. The present findings suggest that, by acting as a serine protease, RHBDD1 modulates BIK-mediated apoptotic activity.


Low dose sodium valproate in the treatment of juvenile myoclonic epilepsy.
Fourteen patients with juvenile myoclonic epilepsy (JME) were treated with a single low dose of a sustained-release preparation of sodium valproate (VPA, 500 mg daily). The mean age of the onset of the low dose treatment was 19.2 years (range 14-26). Before this treatment, six patients had been treated with high dose VPA for a period of more than 2 years, three patients for 1 to 2 years, three patients less than 1 year and two patients initiated the treatment from the beginning with a low dose. The mean duration of low dose treatment is 35.6 months (range 25-59 months). (All patients are still under medication). Generalized tonic-clonic and absence seizures were controlled in all patients. Myoclonic jerks relapsed only in one patient, a young mother who was looking after her newly born baby and was deprived of sleep. No adverse reactions have been reported. We suggest that JME patients can effectively be treated with single low VPA dose (500 mg daily), while at the same time seizure precipitating factors, such as sleep deprivation and alcohol ingestion, should be avoided.


Efficacy and safety of vancomycin for the treatment of Staphylococcus aureus bacteraemia: a systematic review and meta-analysis.
To evaluate the safety and efficacy of vancomycin with the other anti-Gram-positive bacteria antibiotics in the treatment of Staphylococcus aureus bacteraemia. We searched the PubMed, MEDLINE, Embase and Cochrane Library databases until August 2022 for studies that compared vancomycin with other antibiotic regimens for treating Staphylococcus aureus bacteraemia. Clinical and microbiological responses, adverse events, relapse rate and mortality were considered. Fifteen randomized controlled trials and nine retrospective studies were included. The efficacy and safety data of vancomycin differed from those of the comparators group. After subgroup analysis, the differences came mainly from the trials compared with daptomycin. Compared to daptomycin, vancomycin showed a lower microbiological cure rate (OR = 0.58, 95% CI = 0.41∼0.82, I2 = 0%, P = 0.002) and clinical cure rate (OR = 0.53, 95% CI = 0.42∼0.68, I2 = 3%, P < 0.00001), as well as more adverse events (OR = 3.21, 95% CI = 1.43∼7.19, I2 = 59%, P = 0.005). The efficacy of vancomycin in treating Staphylococcus aureus bacteraemia is still excellent but slightly inferior in adverse events. However, this does not affect its use as a first-line drug. Daptomycin is expected to be a better antimicrobial drug.


Generation of an induced pluripotent stem cell (iPSC) line from a diabetic patient with glucagon receptor (GCGR) p.W83X mutation.
Induced pluripotent stem cell (iPSC) line, SJHi001-A, was generated from a diabetic patient carrying a heterozygous c.G248A mutation in GCGR gene that generated the p.W83X. The PBMCs from her father (no diabetes and no mutation site) were also prepared into iPSC (SJHi002-A) as a control. Both two cell lines had normal karyotype, expressed pluripotency markers and could differentiate into the three germ layers in vivo.


Differential distribution of type A and B monoamine oxidase in neuronal tissues.
Various neuronal tissues of the albino rabbit were assayed for type A and type B monoamine oxidase, using norepinephrine and 2-phenylethylamine as substrates, respectively. There was an apparent positive correlation between the sympathetic character of peripheral nerves and the presence of type A monoamine oxidase activity. Type A enzyme activity was 15 fold higher in the superior cervical ganglion than in the vagus nerve. Type B activity was more uniformly distributed.


H1 and H2 histamine receptors mediate the production of inositol phosphates but not cAMP in human breast epithelial cells.
In the present work we studied the H1 and H2 histamine receptor expression and function in HBL-100 and MCF-10A cells, derived from non-tumorigenic human breast epithelia, and in MCF-10T, the H-ras-transfected MCF-10A counterpart. The signal transduction pathways associated with these receptors, and the expression of proto-oncogenes c-fos, c-myc and c-jun at the mRNA and protein levels, were examined. Saturation analysis using intact cells, showed two binding sites for [3H]tiotidine and [3H]mepyramine. Pretreatment of purified membrane with guanosine 5'-ythiotriphosphate resulted in the loss of the low affinity component for [3H]tiotidine binding, and of the high affinity component for [3H]mepyramine. In both cases, there was no modification in the total number of sites for both ligands. Neither H1 nor H2 agonists stimulated cyclic AMP production, though this pathway is functional in these cells. On the other hand, both H1 and H2 agonists enhanced phosphoinositide turnover in a dose-dependent fashion, and this induction is pertussis toxin-insensitive. H1 and H2 agonists did not influence the expression of c-myc or c-fos mRNA, nor their encoded proteins. These results indicate that the three cell lines examined showed functional H1 and H2 histamine receptors, which are involved in the metabolic turnover of inositol phosphates but are ineffective in the modulation of the cyclic AMP response. The fact that H2 receptors have lost their ability to stimulate cyclic AMP production would imply the loss of a regulatory mechanism of cell growth.


Activation by Phoneutria nigriventer spider venom of autonomic nerve fibers in the isolated rat heart.
In the isolated rat heart, Phoneutria nigriventer spider venom (10-100 microg) produced a dose-dependent and reversible rise in left ventricular developed pressure. A low dose (10 microg) of venom induced a short-lasting, positive inotropic effect (P < 0.05) with no change in heart rate or coronary flow. At a dose of 50 microg, the venom caused significant positive inotropic and chronotropic responses associated with occasional ventricular arrhythmia, whereas coronary flow was not significantly affected within 10 min after venom administration. The highest dose of venom (100 microg) caused bradycardia, transient cardiac arrest, rhythm disturbances and an increase in end diastolic pressure followed by a reduction in coronary flow. Hearts treated with the non-selective beta-adrenoceptor antagonist propranolol (3 microM) and the selective beta1-adrenoceptor antagonist CGP-20712A (10 microM) were protected against all the cardiac actions of the venom. The selective beta2-adrenoceptor antagonist butoxamine (10 microM) slightly reduced the cardiac response to 50 microg, but not to 100 microg of venom. Butoxamine also prevented the reduction in coronary flow induced by 100 microg of venom. Hearts from reserpine-treated rats (5 mg kg(-1) day(-1), i.p., for 2 days) showed a marked decrease in all venom (< or = 100 microg)-induced cardiac responses. The muscarinic receptor antagonist atropine (1 microM) slightly potentiated the response to 50 microg of venom but had little or no effect on the responses to 100 microg of venom. The cardiac responses to venom (50-100 microg) were unaltered in hearts from rats treated with 8-methyl N-vanillyl-6-nonenamide (capsaicin; 50 mg/kg, s.c.). These findings indicate that P. nigriventer venom releases norepinephrine from cardiac sympathetic nerve endings and this may explain the observed increase in contractile force and heart rate.


Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation.
Although promising new radiation therapy techniques such as hadrontherapy are currently being evaluated in the treatment of head and neck malignancies, local control of head and neck squamous cell carcinoma (HNSCC) remains low. Here, we investigated the involvement of cancer stem-like cells (CSCs) in a radioresistant HNSCC cell line (SQ20B). Stem-like cells SQ20B/SidePopulation(SP)/CD44(+)/ALDH(high) were more resistant to both photon and carbon ion irradiation compared with non-CSCs. This was confirmed by a BrdU labeling experiment, which suggests that CSCs were able to proliferate and to induce tumorigenicity after irradiation. SQ20B/SP/CD44(+)/ALDH(high) were capable of an extended G2/M arrest phase in response to photon or carbon ion irradiation compared with non-CSCs. Moreover, our data strongly suggest that resistance of CSCs may result from an imbalance between exacerbated self-renewal and proliferative capacities and the decrease in apoptotic cell death triggering. In order to modulate these processes, two targeted pharmacological strategies were tested. Firstly, UCN-01, a checkpoint kinase (Chk1) inhibitor, induced the relapse of G2/M arrest and radiosensitization of SQ20B-CSCs. Secondly, all-trans retinoic acid (ATRA) resulted in an inhibition of ALDH activity, and induction of the differentiation and radiosensitization of SQ20B/SP/CD44(+)/ALDH(high) cells. The combination of ATRA and UCN-01 treatments with irradiation drastically decreased the surviving fraction at 2Gy of SQ20B-CSCs from 0.85 to 0.38 after photon irradiation, and from 0.45 to 0.21 in response to carbon ions. Taken together, our results suggest that the combination of UCN-01 and ATRA represent a promising pharmacological-targeted strategy that significantly sensitizes CSCs to photon or carbon ion radiation.


Left ventricular emptying dynamics in patients with asymmetric septal hypertrophy and concentric hypertrophic cardiomyopathy.
We studied the dynamics of left ventricular (LV) emptying in 8 patients with asymmetric septal hypertrophy (ASH), 6 patients with concentric hypertrophic cardiomyopathy (CHC), and 6 normal controls. Four patients with ASH had resting systolic gradients greater than 20 mmHg, all had significant post premature ventricular contraction (PVC) systolic pressure gradients. LV volume (V) was obtained by frame-by-frame analysis of cineangiograms. End-diastolic volume was similar for all groups; end-systolic volume was significantly less in ASH and CHC patients than in normals. Maximum dV/dt was similar in ASH and CHC, and significantly greater than normals. Total systolic contraction time (SCT), i.e., time from peak volume to last cine frame at minimum volume, was similar for all groups, but the time required to eject 90% of stroke volume (90%T), as a fraction of SCT, was shorter for ASH (0.52 +/- 0.07) and CHC patients (0.51 +/- 0.05) than normals (0.67 +/- 0.07) (p less than 0.05 vs myopathy groups). In the sinus beat following a PVC, however, this ratio decreased significantly in normals and CHC patients, but did not change in ASH patients. We conclude that ASH and CHC have similar exaggerated systolic LV ejection dynamics in the basal state; the failure of ASH patients with post-PVC systolic outflow gradient to reduce 90% T/SCT post PVC may reflect obstruction to LV emptying.


A family of hsp60-related proteins in pancreatic beta cells of non-obese diabetic (NOD) mice.
Eukaryotic hsp60s are plastid-specific molecular chaperones implicated in the pathogenesis of many inflammatory and autoimmune diseases. We have used immunoelectron microscopy, immunoblotting and subcellular fractionation of islet cells to determine whether analogous proteins with related function are expressed in other cellular structures and whether such hsp60-related proteins could serve as antigenic targets in autoimmune diabetes. Using a panel of monoclonal and polyclonal antibodies to human and yeast hsp60s and immunoelectron microscopy, the hsp60 antibody cross-reactive proteins were detected in secretory granules, mitochondria, synaptic-like microvesicles and microtubules of mouse pancreatic beta cells. The expression of microtubule-associated hsp60 was induced by an infiltration of islets by mononuclear cells. This novel inducible-form of hsp60-related protein was recognized as an antigen by sera from diabetic mice. Subcellular fractionation of islets indicated that the molecular size of hsp60-related proteins included 66, 62, 58, 55, 52 and 38 kDa. These results demonstrate that the pancreatic beta cells express a family of hsp60-related proteins, with members differentially expressed in distinct cellular compartments. These proteins bearing hsp60 epitopes were antigenic targets for autoimmune responses in diabetic NOD mice.


Morphological transformations and fusion of PbSe nanocrystals studied using atomistic simulations.
Molecular dynamics simulations are performed on capped and uncapped PbSe nanocrystals, employing newly developed classical interaction potentials. Here, we show that two uncapped nanocrystals fuse efficiently via direct surface attachment, even if they are initially misaligned. In sharp contrast to the general belief, interparticle dipole interactions do not play a significant role in this "oriented attachment" process. Furthermore, it is shown that presumably polar, capped PbSe{111} facets are never fully Pb- or Se-terminated.


cDNA isolation, expression analysis, and chromosomal localization of two human zinc finger genes.
On the basis of sequence similarity in the repeated zinc finger domain, we have identified and characterized two human cDNA clones (ZNF7 and ZNF8), both encoding proteins containing potential finger-like nucleic acid binding motifs. Northern blot analysis indicates that both genes are expressed as multiple transcripts and they are ubiquitously present in many human cell lines of different embryological derivation. Moreover, their expression is modulated during in vitro induced terminal differentiation of human myeloid cell line HL-60. By in situ hybridization experiments, we have localized the ZNF7 gene to chromosome 8 (region q24) and the ZNF8 gene to the terminal band of the long arm of chromosome 20 (20q13).


Influence of calcium ions on the colloidal stability of surface-modified nano zero-valent iron in the absence or presence of humic acid.
To decrease aggregation and enhance the mobility of nano zero-valent iron (NZVI) used for in-situ groundwater remediation, the surface of such NZVI must be modified using organic stabilizers, which can provide electrostatic repulsion, and steric or electrosteric stabilization. However, the stability of the nanoparticles can also be affected by groundwater components such as cations and humic acid (HA). In this study, the effect of Ca(2+) on the colloidal stability of NZVI coated with three types of stabilizers (i.e., polyacrylic acid (PAA), Tween-20 and starch) was evaluated in the absence or presence of HA. Differing stability behavior was observed for different surface-modified NZVIs. The presence of Ca(2+) exerted a slight influence on the settling of NZVI modified with PAA or Tween-20, in the absence or presence of HA. However, the presence of Ca(2+) caused significant aggregation and sedimentation for starch-modified NZVI in the absence of HA, and induced an even higher degree of aggregation and sedimentation in the presence of HA. It is presumed that, in the absence of HA, starch-modified NZVI particles undergo attachment with each other via Ca(2+) complexation with the coated starch molecules on the surface of the particles, thus enhancing the aggregation and the following sedimentation of starch-modified NZVI. However, in the presence of HA, spectroscopic analysis of the starch-modified NZVI aggregates indicated that the bridging interaction of HA with Ca(2+) was the predominant mechanism for the enhanced aggregation.


Protocol of investigation into reporting quality of RCT abstracts on COVID-19 pursuant to CONSORT (CoCo study)-a review.
In 2020, the COVID-19 pandemic developed into a global crisis, the enormity and urgency of which accelerated research activities in the field. At the same time, manuscripts describing these research projects underwent fast-track peer review procedures and were published in freely accessible formats. Although full texts about COVID-19 are currently available for free, abstracts continue to play a key role since they provide essential information and possibly a decision basis for therapies. Abstracts are particularly important in case the full texts are not free, not all reports have been published in English and in emergency situations when there is less time for comprehensive analysis of all full texts. It is therefore necessary to ensure that abstracts-as publications in miniature format-contain comprehensive and transparent information. The CONSORT statement for abstracts (CONSORT-A) offers guidelines to authors how to include all necessary information in an abstract. Prior to the COVID-19 pandemic, the quality of reporting in medical research had already been the object of debate and criticism. The current crisis makes comprehensive documentation all the more important. Abstracts of COVID-19 RCTs should therefore report the criteria listed in the CONSORT-A statement fully and verifiably. The objective of this study is to check the completeness of abstracts of all COVID-19 RTCs published to date. Based on a literature search in PubMed, Embase and the Cochrane Library, all publications up to 29 October 2020 are identified and examined in terms of the subject matter (reported results from COVID-19 studies) and their study design (RTC). Subsequently, suitable publications are examined for completeness and quality of abstracts. The CONSORT checklist for RTC abstracts serves as a basis in this procedure. The primary endpoint of the study is the percentage of correctly implemented items of the CONSORT statement for abstracts. The frequency of correct reporting of each individual item is checked in a second step. The study is expected to contribute to evaluating the reporting quality on COVID-19 studies, and specifically the completeness of abstracts of RTCs. It may thus support the assessment of current research into COVID-19. Registration was not required as the study investigated existing literature.


Local release of histamine, prostaglandin F2 alpha and thromboxane B2 into the tracheal lumen and its influence on airways reactivity.
The influence of tracheal lavage with ascaris extract (AE) on airway response to acetylcholine (ACH) and histamine (Hi) was investigated in a series of 24 dogs. AE administered to a restricted area of the trachea resulted in a release of various mediators such as Hi, prostaglandin F2 alpha (PGF2 alpha, measured as the metabolite 15-keto-13, 14-dihydro-PGF2 alpha) and thromboxane B2 (TXB2) into the tracheal lumen. This differed from H2O administration which resulted in no increased release of these mediators. The relatively small concentrations of these substances measured in arterial plasma argue for the role of these mediators on a local basis. On the other hand, tracheal lavage with allergen induced changes in airway response to ACH and Hi aerosols which was not observed after tracheal lavage with water. An interaction between this allergen-induced mediator release into the trachea and peripheral airways reactivity could be demonstrated.


Flash-cooling assisted sol-gel self-ignited synthesis of magnetic carbon dots-based heterostructure with antitumor properties.
This work addresses current direction of the nanoparticles-based systems intended for cancer therapy by developing a newly-formulated innovative chemically-engineered anti-tumor composite consisting in a magnetic, fluorescent, lipophilic, and biologically-active carbon heterostructure capable by itself or through coupling with a chemotherapeutic agent to selectively induce tumor cell death. The anti-tumor compound was synthesized through a modified sol-gel method by addition of a low-cost molecule with recently proven anti-tumor properties which was combusted and flash-cooled along with magnetic iron oxides precursors at 250 °C. The synthesized compound consisted in carbon dots, graphene and hematite nanoparticles which endowed the composite with unique simultaneous fluorescence, magnetic and anti-tumor properties. The in-vitro cytotoxicity performed on tumor cells (human osteosarcoma) and normal cells (fibroblasts) showed a selective cytotoxic effect induced after 24 h of treatment by the drug-free composite, leading to a cell death of 37%, for a composite concentration of 0.01 mg/mL per 104 tumor cells, whereas the composite loaded with an antitumor drug (mitoxantrone) boosted the cell death effect to 47% for similar exposure conditions. The method shows high potential as it boosts drug transfer within tumor cells. Different antitumor drugs already in clinical use can be used following their separate or in-cocktail controlled combustion.


Endoscopic deployment of multiple JOSTENT SelfX is effective and safe in treatment of malignant hilar biliary strictures.
For the treatment of unresectable biliary tract carcinoma with hilar biliary stricture, antitumor therapy and biliary stenting should be addressed in terms of prolonged survival with a good quality of life. However, the endoscopic management of malignant hilar biliary strictures is difficult even for an expert endoscopist. We evaluated the efficacy and safety of the endoscopic deployment of multiple JOSTENT SelfX units in patients with hilar biliary strictures treated with or without chemotherapy. Between November 2003 and December 2006, endoscopic deployment of multiple JOSTENT SelfX units in hilar biliary strictures by using a partial stent-in-stent procedure was performed on 41 consecutive patients with primary cholangiocarcinoma (n = 34) and gallbladder carcinoma (n = 7) at a gastroenterologic center of Okayama University Hospital. Thirty-three patients were treated with gemcitabine (n = 25) or S-1 (n = 8). Metallic stent deployment was successfully accomplished in all cases via only endoscopic procedures. During the follow-up period (mean, 210 days), mean patency time was 150 days, and metallic stent obstruction occurred in 15 cases (37%). Although a repeat intervention was required in all metallic stent obstructed cases, the deployment of the second metallic or plastic stent was completed successfully. The remaining 26 cases (63%) required no interventions. The median overall survival period was only 235 days. However, that of the patients receiving chemotherapy was 392 days. Endoscopic partial stent-in-stent deployment with multiple JOSTENT SelfX prostheses is effective and safe for the treatment of malignant hilar biliary stricture even in patients receiving chemotherapy.


Growth performance, serum biochemistry and meat quality traits of Jumbo quails fed with mopane worm (Imbrasia belina) meal-containing diets.
Alternative protein sources such as mopane worm (Imbrasia belina) meal (MWM) are essential for sustainable poultry production. To date, no studies have attempted to investigate the effect of replacing soybean products with MWM in Jumbo quail diets. Thus, this study was designed to investigate the optimum inclusion level of MWM in place of soybean products on feed intake, physiological and meat quality responses of Jumbo quails. A total of 384 two-week-old mixed-gender quails (71.2 ± 5.40 g live-weight) were allotted to four isoproteic and isocaloric dietary treatments formulated by replacing soybean products with MWM at 0 (MWM0), 50 (MWM5), 100 (MWM10), and 150 (MWM15) g/kg. Neither linear nor quadratic effects (P > 0.05) were observed for feed intake, physiological responses, carcass traits and internal organs except for large intestines, which linearly decreased (P < 0.05) with MWM levels. There were significant quadratic trends for meat redness (a*), yellowness (b*) and chroma values in response to MWM levels. No dietary influences (P > 0.05) were observed on feed intake, physiological responses, internal organ weights, and carcass and meat quality parameters, except on b*, chroma and shear force. Diets MWM5 and MWM10 promoted higher (P < 0.05) b* and chroma values than MWM0. Whereas diet MWM5 promoted the highest (P < 0.05) shear force (2.39 N) than diets MWM0 and MWM10. We concluded that MWM has the potential to replace soybean products in quail diets without compromising their performance, health and meat quality. An optimum MWM inclusion level could not be determined suggesting that higher levels of MWM should be further investigated.


Burden of respiratory syncytial virus infection in older and high-risk adults: a systematic review and meta-analysis of the evidence from developed countries.
Respiratory syncytial virus (RSV) significantly impacts the health of older and high-risk adults (those with comorbidities). We aimed to synthesise the evidence on RSV disease burden and RSV-related healthcare utilisation in both populations. We searched Embase and MEDLINE for papers published between 2000 and 2019 reporting the burden and clinical presentation of symptomatic RSV infection and the associated healthcare utilisation in developed countries in adults aged ≥60 years or at high risk. We calculated pooled estimates using random-effects inverse variance-weighted meta-analysis. 103 out of 3429 articles met the inclusion criteria. Among older adults, RSV caused 4.66% (95% CI 3.34-6.48%) of symptomatic respiratory infections in annual studies and 7.80% (95% CI 5.77-10.45%) in seasonal studies; RSV-related case fatality proportion (CFP) was 8.18% (95% CI 5.54-11.94%). Among high-risk adults, RSV caused 7.03% (95% CI 5.18-9.48%) of symptomatic respiratory infections in annual studies, and 7.69% (95% CI 6.23-9.46%) in seasonal studies; CFP was 9.88% (95% CI 6.66-14.43%). Data paucity impaired the calculation of estimates on population incidence, clinical presentation, severe outcomes and healthcare-related utilisation. Older and high-risk adults frequently experience symptomatic RSV infection, with appreciable mortality; however, detailed data are lacking. Increased surveillance and research are needed to quantify population-based disease burden and facilitate RSV treatments and vaccine development.


Effects of postoperative adjuvant chemotherapy and palliative chemotherapy on the gut microbiome in colorectal cancer.
The gut microbiome changes are related to the colorectal cancer (CRC). Chemotherapy is one of the main treatment methods for CRC. To explore the effect of chemotherapy on the gut bacteria and fungi in CRC. Total of 11 advanced CRC patients treated with the FOLFIRI regimen, 15 postoperative CRC patients treated with the XELOX regimen, and corresponding CRC patients without surgery and chemotherapy were recruited. The 16S ribosomal RNA and ITS sequences were sequenced, and bioinformatics analysis was executed to screen for the distinctive gut microbiome. The abundances of Veillonella, Humicola, Tremellomycetes and Malassezia were increased in postoperative CRC patients treated with the XELOX regimen. The abundances of Faecalibacterium, Clostridiales, phascolarctobacterium, Humicola and Rhodotorula were decreased, and the abundances of Candida, Magnusiomyces, Tremellomycetes, Dipodascaceae, Saccharomycetales, Malassezia and Lentinula were increased in advanced CRC patients treated with the FOLFIRI regimen. The abundances of Humicola, Rhodotorula, and Magnusiomyces were decreased, and the abundances of Candida, Tremellomycetes, Dipodascaceae, Saccharomycetales, Malassezia and Lentinula were increased in advanced CRC patients treated with the FOLFIRI regimen combined with cetuximab compared with those treated with the FOLFIRI regimen alone. The community structure of gut bacteria and fungi changes in chemotherapy on CRCs.


The ubiquitin-binding protein MdRAD23D1 mediates drought response by regulating degradation of the proline-rich protein MdPRP6 in apple (Malus domestica).
RAD23 (RADIATION SENSITIVE23) proteins are a group of UBL-UBA (ubiquitin-like-ubiquitin-associated) proteins that shuttle ubiquitylated proteins to the 26S proteasome for breakdown. Drought stress is a major environmental constraint that limits plant growth and production, but whether RAD23 proteins are involved in this process is unclear. Here, we demonstrated that a shuttle protein, MdRAD23D1, mediated drought response in apple plants (Malus domestica). MdRAD23D1 levels increased under drought stress, and its suppression resulted in decreased stress tolerance in apple plants. Through in vitro and in vivo assays, we demonstrated that MdRAD23D1 interacted with a proline-rich protein MdPRP6, resulting in the degradation of MdPRP6 by the 26S proteasome. And MdRAD23D1 accelerated the degradation of MdPRP6 under drought stress. Suppression of MdPRP6 resulted in enhanced drought tolerance in apple plants, mainly because the free proline accumulation is changed. And the free proline is also involved in MdRAD23D1-mediated drought response. Taken together, these findings demonstrated that MdRAD23D1 and MdPRP6 oppositely regulated drought response. MdRAD23D1 levels increased under drought, accelerating the degradation of MdPRP6. MdPRP6 negatively regulated drought response, probably by regulating proline accumulation. Thus, "MdRAD23D1-MdPRP6" conferred drought stress tolerance in apple plants.


Relevance of antibiotics in the treatment of brain abscesses. Report of a case with eight simultaneous brain abscesses treated and cured medically.
A case of eight simultaneous brain abscesses in the right cerebral hemisphere, treated medically after puncture of two of them, is reported. Antibiotics and hypertonic mannitol and, after seven days, dexamethasone were sufficient to cure these lesions. CT scan was of primary importance to follow the evolution under treatment. To get the best efficiency from antibiotics, identification of the microorganism and assessment of its resistance to antibiotics are necessary. It is suggested that in certain conditions medical therapy might be sufficient to treat cerebral abscess, after simple puncture to isolate the infecting agent. Corticosteroids should be avoided in the acute phase because they prevent antibiotics from penetrating the abscesses.


Emotional difficulties, coping strategies, and help-seeking patterns among Czech perinatal women.
To understand both, women´s perception of emotional difficulties in perinatal period and their related coping strategies. Further, we mapped and analysed help-seeking patterns utilized by these women to overcome their emotional difficulties. This study serve as an important piece of information for women-centred innovations in perinatal mental health care in Czechia, and more broadly in the region of Central and Eastern Europe. A qualitative study with an exploratory and descriptive approach using thematic analysis. Online survey consisting of open-ended questions mapping women´s perception of emotional difficulties in perinatal period and their related coping strategies and help-seeking patterns. Two hundred women self-reporting emotional difficulties in perinatal period, from whom 108 (54 %) stated that they had sought professional help with their emotional difficulties. Two themes were identified in the analysis of women´s perception of emotional difficulties including Experience of symptoms of mental disorders, and Mother-child relationship. Three themes were identified in the analysis of women´s coping with these difficulties (Personal resources, External resources, and No coping strategy used). Four themes were identified in the analysis of help seeking patterns utilized by study participants (Mental health specialists, Physicians of the first line of contact, Midwifes, and Peer consultants). Emotional difficulties of perinatal women stemmed in both, general symptoms of mental disorders and specific concerns connected to mother-child relationship. Therefore, the perinatal mental health services should cover both topics, preferably by a multidisciplinary team. Women search information about perinatal mental health, so thus, easy to reach valid resources are needed. Finally, Czech perinatal women experiencing emotional difficulties utilize various help-seeking patterns. Some of them naturalistically utilize integrated stepped care even when it is not systematically established.


A locus on chromosome 1 promotes susceptibility of experimental autoimmune myocarditis and lymphocyte cell death.
We previously identified by linkage analysis a region on chromosome 1 (Eam1) that confers susceptibility to experimental autoimmune myocarditis (EAM). To evaluate the role of Eam1, we created a congenic mouse strain, carrying the susceptible Eam1 locus of A.SW on the resistant B10.S background (B10.A-Eam1 congenic) and analyzed three outcomes: 1) the incidence and severity of EAM, 2) the susceptibility of lymph node cells (LNCs) to Cy-enhanced cell death, and 3) susceptibility of lymphocytes to antigen-induced cell death. Incidence of myocarditis in B10.A-Eam1 congenic mice was comparable to A.SW mice, confirming that Eam1 plays an important role in disease development. Caspase 3, 8 and 9 activation in LNCs following Cy treatment and in CD4(+) T cells after immunization with myosin/CFA was significantly lower in A.SW than B10.S mice whereas B10.A-Eam1 congenic mice exhibited an intermediate phenotype. Our results show that Eam1 reduces lymphocyte apoptosis and increases susceptibility to EAM.


Erratum to: New spectrofluorimetric methods for determination of melatonin in the presence of N-{2-[1-({3-[2-(acetylamino)ethyl]-5-methoxy-1H-indol-2-yl}methyl)-5-methoxy-1H-indol-3-yl]-ethyl}acetamide: a contaminant in commercial melatonin preparations.
[This corrects the article DOI: 10.1186/1752-153X-6-36.].


Low-symptomatic skeletal muscle disease in patients with a cardiac disease - Diagnostic approach in skeletal muscle laminopathies.
Mild skeletal muscle symptoms might be accompanied with severe cardiac disease, sometimes indicating a serious inherited disorder. Very often it is a cardiologist who refers a patient with cardiomyopathy and/or cardiac arrhythmia and discrete muscle disease for neurological consultation, which helps to establish a proper diagnosis. Here we present three families in which a diagnosis of skeletal muscle laminopathy was made after careful examination of the members, who presented with cardiac arrhythmia and/or heart failure and a mild skeletal muscle disease, which together with positive family history allowed to direct the molecular diagnostics and then provide appropriate treatment and counseling.


High-mobility group box 1 exacerbates CCl₄-induced acute liver injury in mice.
High-mobility group box 1 (HMGB1) is a nuclear factor that can also serve as an imflammatory mediator once released into extracellular milieu. Therefore, HMGB1 has been recognized to play a pivotal role in inflammatory diseases such as sepsis, acute lung injury, ischemia reperfusion injury and type 1 diabetes. Nevertheless, its impact on carbon tetrachloride (CCl4)-induced hepatic injury is yet to be elucidated. In the present report, we demonstrated evidence indicating that high levels of HMGB1 were not only present in the necrotic area of liver but also in the serum after CCl4 challenge. In line with these observations, administration of exogenous recombinant HMGB1 exacerbated CCl4-induced hepatic injury, while HMGB1 blocking antibody provided protection for mice against CCl4-induced acute liver injury as evidenced by the decrease of serum transaminase and reduction of hepatic tissues necrosis. Mechanistic studies revealed that blockade of HMGB1 attenuated CCl4-induced MDA accumulation along with improved SOD and GSH activity. Treatment of mice with HMGB1 neutralizing antibody also significantly inhibited the production of proinflammatory mediators TNF-α and IL-6 along with attenuated HMGB1 expression and its extracellular release. Together, our data suggest an essential role for HMGB1 in CCl4-induced acute liver injury, while HMGB1 neutralizing antibody could be served as an effective regimen for preventing CCl4-induced acute liver injury.


Essential role of autophagy in fucoxanthin-induced cytotoxicity to human epithelial cervical cancer HeLa cells.
To investigate the effects and the molecular mechanisms of fucoxanthin, a major carotenoid found in edible seaweed, on HeLa cells. The cytotoxicity of fucoxanthin was evaluated using MTT assay. Cell cycle and apoptosis were evaluated using flow cytometric analysis. Autophagy was detected with acridine orange staining and transient transfection of the GFP-LC3 plasmid into the cells. Protein expression was detected with Western blotting. Treatment of HeLa cells with fucoxanthin (10-80 μmol/L) for 48 h caused dose-dependent cytotoxicity with an IC50 value of 55.1±7.6 μmol/L. Fucoxanthin (10, 20, and 40 μmol/L) dose-dependently induced G0/G1 arrest, but did not change the apoptosis of HeLa cells. The same concentrations of fucoxanthin dose-dependently increased the protein expression of LC3 II (the autophagosome marker) and Beclin 1 (the initiation factor for autophagosome formation) in HeLa cells. Moreover, fucoxanthin dose-dependently decreased the levels of phosphorylated Akt and its downstream proteins p53, p70S6K, and mTOR, and increases the expression of PTEN in HeLa cells. Pretreatment of HeLa cells with 3-methyladenine (5 mmol/L) blocked the cytotoxic effect of fucoxanthin as well as fucoxanthin-induced autophagy. Fucoxanthin exerts autophagy-dependent cytotoxic effect in HeLa cells via inhibition of Akt/mTOR signaling pathway.


Space-time analysis of ovarian cancer mortality rates by age groups in spanish provinces (1989-2015).
Ovarian cancer is a silent and largely asymptomatic cancer, leading to late diagnosis and worse prognosis. The late-stage detection and low survival rates, makes the study of the space-time evolution of ovarian cancer particularly relevant. In addition, research of this cancer in small areas (like provinces or counties) is still scarce. The study presented here covers all ovarian cancer deaths for women over 50 years of age in the provinces of Spain during the period 1989-2015. Spatio-temporal models have been fitted to smooth ovarian cancer mortality rates in age groups [50,60), [60,70), [70,80), and [80,+), borrowing information from spatial and temporal neighbours. Model fitting and inference has been carried out using the Integrated Nested Laplace Approximation (INLA) technique. Large differences in ovarian cancer mortality among the age groups have been found, with higher mortality rates in the older age groups. Striking differences are observed between northern and southern Spain. The global temporal trends (by age group) reveal that the evolution of ovarian cancer over the whole of Spain has remained nearly constant since the early 2000s. Differences in ovarian cancer mortality exist among the Spanish provinces, years, and age groups. As the exact causes of ovarian cancer remain unknown, spatio-temporal analyses by age groups are essential to discover inequalities in ovarian cancer mortality. Women over 60 years of age should be the focus of follow-up studies as the mortality rates remain constant since 2002. High-mortality provinces should also be monitored to look for specific risk factors.


Vancomycin-associated retinal hemorrhages in pediatric age group: A case report.
To report a case of possible post-lensectomy vancomycin-induced retinal hemorrhages in a 9-month-old infant to raise awareness of this rare postoperative complication in the pediatric age group. A retinal vascular occlusion-like findings were noted bilaterally after sequential uneventful parsplicata lensectomy in a 9-month-old infant during the very early postoperative follow-up (1-2 days). The case was recorded with no remarkable intraoperative events and received intraoperative vancomycin 20μg/ml in irrigating solution (a routine endophthalmitis prophylactic protocol). Vancomycin-associated hemorrhagic occlusive retinal vasculitis (HORV) is a rare reported postoperative complication of intraocular prophylactic vancomycin injection. Although all documented cases were reported in elderly patients aged 50 years and above, all presented with almost common findings of occlusive retinal vasculitis. To the best of author's knowledge, this is the first reported case of presumed HORV in pediatric age group. The author finds this of utmost importance to demonstrate the case to expand awareness of this possible complication in the pediatric age group as well.


A blueprint for advancing genetics-based cancer therapy.
In the era of next-generation sequencing, there are significant challenges to harnessing cancer genome information to develop novel therapies. Key research thrusts in both academia and industry will speed this transition, and lessons learned for cancer will more broadly shape the process for genetic contributions to the therapy of disease more broadly.


Teaching medical informatics: teaching on the seams of disciplines, cultures, traditions.
This paper reviews different concepts of medical informatics and identifies two families of approaches to education in it: a "specialist" approach, whereby medical informatics is taught as a specialization track for established disciplines like medicine, computer science, nursing, engineering, etc., and a "generalistic" approach, whereby it is taught as an integrated discipline incorporating essential traits of the aforementioned disciplines. The pros and cons of these approaches are outlined. The need to accommodate specific requirements of education is emphasized and these are identified, together with an outline of particular challenges that we are facing.


Performing an intestinal stoma with placement of an Artificial Sphincter® Intestinal Valve (VITEA): A case report.
Intestinal stomas are created for distinct clinical conditions. They may involve the small bowel (ileostomy) or the large bowel (colostomy), depending on the objective or site of the stoma. Intestinal stomas may be temporary or permanent; they cause loss control of intestinal transit due to the absence of a sphincter that regulates its exit, provoking a continuous passage of fecal matter through the stoma. Within the environment of the ostomized patients, there are several important complications involving their quality of life. The Intestinal Valve Type Artificial Sphincter (VITEA) device is placed in a patient diagnosed with cervical cancer, who has a vaginal-rectum fistula that requires a definitive colostomy. Intestinal stomas have been validated for over a century. We present the case with a similar complication rate to those described after performing a stoma with conventional open technique in terms of quality of life and cost-benefit ratio. The proportion of complications and the quality of life found in the ostomized patient with the VITEA* device is acceptable, and also eliminates the colostomy bags, providing the function of an artificial sphincter by everting the mucosa on the same device. No complications were found during the follow-up. The results from this proposal will allow to evaluate the safety and efficacy profile associated with a stomal bags.


Treatment of advanced carcinoma of the prostate (stage D) with infusion of cis-diamminedichloroplatinum (II NSC 119875): a pilot study.
A study was done on 21 patients who had advanced carcinoma of the prostate (stage D) treated with 1 mg./kg. cis-diamminedichloroplatinum per week for 6 weeks. The infusions were then spaced every 3 weeks thereafter. One patient had never been treated previously and 20 patients were failures of previous therapy with estrogens and/or radiotherapy and/or chemotherapy. A partial objective clinical remission was seen in 9 of the 21 patients (43 per cent). This response lasted from 3 to 14 months, with an average of 5.8 months. The responses were evidenced by a 50 per cent or more decrease of lesions in the liver (2 patients), recalcification of a bone lytic lesion (1 patient), disappearance of positive lymph nodes in the neck (2 patients), disappearance of pleural effusion (1 patient), disappearance of lymphatic block of lower extremities (2 patients) and disappearance of lung metastases and ureteral obstruction (1 patient). Six patients (28.5 per cent) had a complete disappearance of the bone pain and became ambulatory and asymptomatic, 2 patients (9.5 per cent) with bony metastases remained asymptomatic and apparently stable and 4 patients did not respond to treatment and showed progression. Cis-diamminedichloroplatinum seems to be the most effective drug available to date for the treatment of advanced carcinoma of the prostate.


Crystallization of Mordenite Platelets using Cooperative Organic Structure-Directing Agents.
Organic structure-directing agents (OSDAs) are exploited in the crystallization of microporous materials to tailor the physicochemical properties of the resulting zeolite for applications ranging from separations to catalysis. The rational design of these OSDAs often entails the identification of molecules with a geometry that is commensurate with the channels and cages of the target zeolite structure. Syntheses tend to employ only a single OSDA, but there are a few examples where two or more organics operate synergistically to yield a desired product. Using a combination of state-of-the-art characterization techniques and molecular modeling, we show that the coupling of N,N,N-trimethyl-1,1-adamantammonium and 1,2-hexanediol, each yielding distinct zeolites when used alone, results in the cooperative direction of a third structure, HOU-4, with the mordenite framework type (MOR). Rietveld refinement using synchrotron X-ray diffraction data reveals the spatial arrangement of the organics in the HOU-4 crystals, with amines located in the large channels and alcohols oriented in the side pockets lining the one-dimensional pores. These results are in excellent agreement with molecular dynamics calculations, which predict similar spatial distributions of organics with an energetically favorable packing density that agrees with experimental measurements of OSDA loading, as well as with solid-state two-dimensional 27Al{29Si}, 27Al{1H}, and 13C{1H} NMR correlation spectra, which establish the proximities and interactions of occluded OSDAs. A combination of high-resolution transmission electron microscopy and atomic force microscopy is used to quantify the size of the HOU-4 crystals, which exhibit a platelike morphology, and to index the crystal facets. Our findings reveal that the combined OSDAs work in tandem to produce ultrathin, nonfaulted HOU-4 crystals that exhibit improved catalytic activity for cumene cracking in comparison to mordenite crystals prepared via conventional syntheses. This novel demonstration of cooperativity highlights the potential possibilities for expanding the use of dual structure-directing agents in zeolite synthesis.


Effects of compression on orientation of ligands in fluorescent complexes between hydroxyapatite with amino acids and their optical properties.
This study aims to reveal the effects of pressure during cold isostatic pressing (CIP) on the microstructure and optical properties of fluorescent HAp complexes. Although the microsturucture-dependent properties of fluorescent HAp complexes have been reported to improve the antibacterial properties of photocatalyst coating layers, the mechanism behind the changes in the fluorescence properties of highly compressed HAp complexes has not yet been unveiled. CIP was successfully used to fabricate fluorescent HAp - amino acid complexes, and their fluorescence intensities increased with increasing fabrication pressure. Peak wavelength of fluorescence emitted by the HAp - amino acid complexes exhibited yellow to red shift. Although the thickness of the amino acid layer was saturated in higher pressure cases, the concentration of amino acids increased proportionally with pressure, which suggests changes in the packing structures of the ligands in the HAp- amino acid complexes. Polarized Raman spectroscopy measurements clearly detected ligands normally arranged to the HAp layer under high pressure fabrication conditions, which can provide the tightly packed ligand structure in the HAp- amino acid complexes. These tightly packed ligand structure in the HAp- amino acid complexes could emit stronger fluorescence owing to the increased density of complexations. This newly found pressure dependency in the optical properties of HAp-amino acid complexes is beneficial for developing biocompatible fluorescence materials or enhancement agents for antibacterial coating layers.


Peroxide-Induced Damage to Plasminogen Molecules.
Plasminogen is a zymogenic form of plasmin, an enzyme that plays a fundamental role in the dissolution of fibrin clots as well as in many other physiological processes. For the first time, by the method of gas chromatography-mass spectrometry, post-translational modifications in the primary structure of plasminogen treated with physiologically relevant amounts of hydrogen peroxide were identified. It was found that methionine and tryptophan residues located in different structural regions of plasminogen served as targets of the oxidant. Plasminogen oxidation caused a dose-dependent effect in decreasing the fibrinogenolytic activity of plasmin evidenced by the formation of fibrinogen degradation products. The possible antioxidant role of methionines in the oxidative modification of plasminogen is discussed.


Preliminary Investigation of Microbiome and Dietary Differences in Patients with Phenylketonuria on Enzyme Substitution Therapy Compared to Traditional Therapies.
Phenylketonuria (PKU) is an inborn error of metabolism that impairs the function of the enzyme phenylalanine hydroxylase. Historical treatment includes limiting dietary phenylalanine (Phe) consumption while supplementing with medical food; however, this treatment has been associated with complications, such as nutritional deficiencies and disruptions in the gut microbiota. The study aim was to compare dietary and gut microbiome differences between adult patients on a traditional PKU diet with those receiving the enzyme substitution therapy Palynziq on a liberalized diet while controlling blood Phe levels to <600 μmol/L (to convert to mg/dL divide by 60.5). A cross-sectional study was conducted comparing patients on a traditional Phe-restricted diet with patients receiving Palynziq eating a liberalized diet. Six patients eating a traditional Phe-restricted diet with medical food and 6 patients on Palynziq eating a liberalized diet without medical food intake for more than 3 years were selected from the University of Kentucky Metabolic Clinic from August to December 2019. Nutrient intake from 3-day diet records and fecal microbiome taxonomic abundances were analyzed. Mann-Whitney U tests were used for dietary data analysis. Differential abundance analysis for microbiome taxa and pathway data was done using DESeq2 analysis. Dietary data showed patients receiving Palynziq consumed a lower percent of kilocalories from total protein and lower amounts of most micronutrients, but consumed greater amounts of intact protein and cholesterol (P < .05). Microbiome data revealed a greater abundance of the phylum Verrucomicrobia and genus Lachnobacterium in the Traditional group and a greater abundance of the genus Prevotella in the Palynziq group (P < .05). Pathway analysis depicted greater enrichment in carotenoid and amino acid metabolism pathways in the Traditional group (P < .05). Protein (% kcal), dietary fiber (g), fat (% kcal), linolenic acid (% Dietary Reference Intakes), and age were correlated with the underlying microbial community structure for both groups combined. Patients with PKU treated with Palynziq on a liberalized diet manifest significant differences in diet composition compared with those treated with traditional Phe-restricted diets. Several of these dietary differences may affect the microbiome architecture.


Altered gene expression in human leukemia K562 cells selected for resistance to etoposide.
Sublines of K562 human leukemia cells were selected for resistance (30- to 80-fold) to etoposide by continuous exposure to 0.5 microM VP-16. Two etoposide-resistant cell lines, K/VP.5 and K/VP.5-1, showed a 5-fold reduction in levels of topoisomerase II alpha protein compared with K562 cells. Northern analysis indicated a 2.5-fold reduction in topoisomerase II alpha mRNA in etoposide-resistant cell lines, due in part to a 1.7-fold decrease in topoisomerase II mRNA stability with no change in transcription rate. Immunoblotting assays of electrophoresed cell lysates from VP-16-treated cells revealed less drug-induced covalent topoisomerase II/DNA adducts in resistant than in sensitive cells, suggesting a functional alteration in resistant cell topoisomerase II. Recent reports of specific topoisomerase II DNA binding sites near the promoter sites of growth response genes and alterations of gene expression in cells treated with topoisomerase II inhibitory drugs led to experiments to determine if the apparent functional alterations of topoisomerase II were accompanied by changes in the regulation of these genes. Therefore, the expression of several growth response genes was compared by northern analysis in parental K562 and both VP-16-resistant cell lines. Basal levels of c-myc were comparable for all three cell lines, but levels of c-jun and c-fos were elevated 2- to 4-fold in VP-16-resistant cell lines. Increased levels of c-fos and c-jun were not a result of altered rates of transcription, as determined by nuclear run-off assays. Exposure of both sensitive and resistant cells to 200 microM VP-16 for 5 hr resulted in no further changes in topoisomerase II mRNA levels but caused an additional 2- to 3-fold elevation in the level of c-jun mRNA, indicating that altered basal levels of this gene were not due to deregulation of this gene. Acquired VP-16 resistance in K/VP.5 and K/VP.5-1 cells was accompanied by reduced levels and altered activities of DNA topoisomerase II as well as changes affecting the expression of genes important for growth and differentiation.


Product Failures in Respirators and Consumables: Analysis of Field Safety Notices of 2005-2013 Publicized by the Federal Institute for Drugs and Medical Devices in Germany.
The current European system governed by the three EC directives 93/42/EEC (Medical Device Directive), 98/79/EC (In-Vitro Diagnostic Directive) and 90/385/EEC (Active Implantable Medical Device Directive) regulates marketing and post-market surveillance of medical devices in the European Economic Area (EEA). In cases of incidents raising the field safety corrective actions (FSCA), manufacturers have to inform the responsible Competent Authority (CA; in Germany this is the Federal Institute for Drugs and Medical Devices, BfArM) and the public by field safety notices (FSN). In this study we analyzed FSN of respirators and consumables directly required for their function, whereas devices for anesthesia and gas delivery were excluded. FSCA and FSN of 2005-2013 publicized by BfArM for the included products were analyzed with respect to the MEDDEV 2.12-1 rev. 8. In total, 60 FSCA were publicized. German and English FSN were found in 59/53 cases, respectively. FSN were clearly characterized as FSN in 44/38 cases and declaration of the type of action in 45/44 cases, respectively. Product names were provided in all cases. Lot numbers or other information for product characterization were available in 7/7 and 43/40 cases, respectively. Detailed information regarding FSCA and product malfunction was found in all cases. Information on product related risks with previous use of affected devices was provided in 42/38 cases. In 53/53 cases manufacturers provided information to mitigate product related risks. Requests to pass FSN to persons needing awareness in the organization were found in 27/24 cases. Contact data were provided in 53/48 cases, respectively. Confirmation that a CA was informed was found in 28/26 cases and in 19/15 cases a customer confirmation was included. The identified risks were: total loss of function (19/16), short circuit (1/1) and burn (3/3), and inhalation of foreign particles (1/1) which might cause severe risk to patients and users. The most frequent FSCA were product modifications and customer information. The data suggest that there is an annually increasing number of FSCA on devices included in our study. Most FSN fulfill the criteria of MEDDEV 2.12-1 rev. 8. However, there are differences between German and English FSN, e.g., regarding the distribution to persons needing awareness, missing statement that a CA was informed, and missing customer confirmation. Due to the importance of FSN for reduction of product related risks in FSCA, the type and content of FSN should be further improved.


News of TNM and its use for classification of gastric cancer.
Tumor classification is associated with two inherent problems: (1) to find a compromise between the simplicity needed for a wide application by the medical community and sufficient differentiation and specification required for the presently high differentiation in treatment options and for detailed analysis of treatment results; and (2) to achieve an agreement between the stability necessary for data collection over long periods and the needed continuous inclusion of new proposals that arise by advances in diagnostic and therapeutic methods and the increasing knowledge of prognostic factors. The aim of this report is to inform on the changes and expansions of the international classification of gastric carcinoma during the last few years, to refer to new developments, to point out the relations between established classifications and molecular biology, and to show the future trend in tumor classification.


Prognostic Significance of Pre- to Postoperative Dynamics of the Prognostic Nutritional Index for Patients with Renal Cell Carcinoma Who Underwent Radical Nephrectomy.
This study aimed to examine the prognostic role of Prognostic Nutritional Index (PNI) dynamics in the pre- and postoperative periods for patients with renal cell carcinoma (RCC) who undergo radical nephrectomy (RN). The study analyzed 324 patients with RCC who underwent RN. The overall population was classified into four groups according to four types of pre- to postoperative PNI dynamics as follows: group 1 (low → low PNI), group 2 (low → high PNI), group 3 (high → low PNI), and group 4 (high → high PNI). The level of PNI was calculated using the following formula: 10 × serum albumin level (g/dL) + 0.005 × absolute lymphocyte counts in blood (/mm3). The primary end point was cancer-specific survival (CSS), and the secondary end point was overall survival (OS). The patients with higher pre- and postoperative PNI (>45) had better survival outcomes than those with lower pre- and postoperative PNI (≤45). Notably, the patients in group 4 showed the best CSS and OS rates, whereas the patients in group 1 had the worst survival outcomes. Furthermore, PNI dynamics were identified as an independent predictor of CSS and OS outcomes, in addition to pre- and postoperative PNI, tumor size, and pathologic T (pT) stage. The patients with localized RCC (≤pT2) showed significant differences in both CSS and OS estimates, whereas the patients with advanced pT stage (≥pT3) demonstrated a difference only in OS outcomes, according to PNI dynamics. This study is the first to provide the independent prognostic importance of dynamics of nutritional status for patients with RCC.


[Effect of peptide geroprotectors on the navigation system learning and caspase-3 in brain structures in rats of different age].
The study of the effects of peptide geroprotectors cortexin and pinealon on the system of caspase-3 in the brain structures and training of rats of different ages was held. Regional changes in activity and the content of caspase-3 in the cerebral cortex and brainstem of young and old rats under the influence of peptides were identified. It is suggested that the functional state of caspase-3 in the brain is one of the reasons that determines the animals' ability to learn. Pinealon has prevalent positive effect on learning of both young and old animals in the Morris labyrinth compared to cortexin.


Affinity chromatography on hydroxyalkyl methacrylate gels. II. Isolation of thiol-containing protein and peptide using mercurial derivatives of gels.
Absorption properties of hydroxyalkyl methacrylate gels containing various amounts of mercuri derivatives of p-acetaminophenoxyethyl methacrylates (Hg-APEMA) and methacrylanilide (Hg-MAA) were investigated by means of a reduced Ellman's agent (5,5'-dithiobis-2-nitrobenzoic acid) and papain. The optimum gel was used for the affinity chromatography of SH-protease from beans and for the isolation of a peptide with a free sulphhydryl group from the chymotryptic hydrolyzate of serum albumin.


Comparison of the minimal model and the hyperglycemic clamp for measuring insulin sensitivity and acute insulin response to glucose.
Glucose clamp techniques are established methods for assessment of insulin sensitivity and secretion. The minimal model technique (MMT) has been proposed as an alternative approach to the hyperinsulinemic-euglycemic clamp technique for determination of an insulin sensitivity index (ISI), but has not been directly compared with the hyperglycemic clamp for measurement of ISI or insulin secretion. To address this issue, the present study was undertaken to compare determinations of ISI and the acute insulin response to glucose (AIRg) obtained using the MMT with similar measures obtained from a hyperglycemic clamp. Measures for ISI and AIRg obtained from MMT analysis of a tolbutamide-modified frequently sampled intravenous glucose tolerance test (FSIGT) were compared with similar measures obtained from a 3-hour hyperglycemic clamp performed at a plasma glucose level of 10 mmol/L (180 mg/dL). Paired comparisons were performed in 14 women with normal glucose tolerance. Significant positive correlation coefficients were obtained for both ISI (r = .88, P < .001) and AIRg (r = .75, P < .005) between the MMT and clamp studies. We conclude that indices for ISI and AIRg obtained with the MMT are highly correlated with those obtained using the hyperglycemic clamp. The MMT is a valid alternative to the hyperglycemic clamp for assessing insulin sensitivity and AIRg.


[Minimal-invasive tissue sampling at the bovine udder].
In some cases, classical diagnostic procedures of bovine mastitis, including adspectation, palpation, and examination of milk samples, are of limited reliability, such that histological examination of udder tissue would be a useful addition. The study aimed to identify localizations for tissue sampling and to validate the biopsy technique. In the present study, sonographic examinations on bovine udders (n = 16) were performed, to identify ideal localizations for tissue sampling, which were tested in slaughterhouse organs (n = 10) and verified in udders of lactating cows (n = 16). Ideal localizations for tissue sampling, avoiding puncturing of blood vessels, were sonographically identified in the area of the udder cistern. Tissue sampling in lactating cows proved to be free of complications in 73 % of cases and all tissue specimens obtained were suitable for histology. Tissue sampling by biopsy for microbiological and histopathological examinations supplements common procedures in the diagnostics of mastitis in the dairy cow and, if performed in the area of the udder cistern, can be conducted without sonographical control under field conditions.


Association of PD-L1 tumor proportion score ≥20% with early resistance to osimertinib in patients with EGFR-mutated NSCLC.
The relationship between epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance, including osimertinib, and programmed cell death-ligand 1 (PD-L1) expression status in EGFR-mutated non-small cell lung carcinoma (NSCLC) remains unclear. We retrospectively analyzed 64 patients with unresectable advanced or metastatic NSCLC carrying EGFR exon 19 deletions (ex19del) or EGFR exon 21 L858R substitutions (L858R) who received osimertinib as the first-line treatment. We compared progression-free survival (PFS) between eligible patients with PD-L1 tumor proportion scores (TPS) ≥20% and PD-L1 TPS <20% using the Kaplan-Meier survival plots with a log-rank test. Multivariate analysis was performed to examine the poor prognostic factors of PFS. The PD-L1 TPS ≥20% group included 22 cases (median [range] age: 70.5 [33-86] years; 10 women [45.5%]; 11 current or ex-smokers [50%]); ECOG performance status (PS) of 0-1/2/3/4 was noted in 16/4/1/1 patients, respectively. The PD-L1 TPS <20% group included 42 patients (median [range] age 73 [43-88] years; 29 women [69%]; 12 current or ex-smokers [28.6%]); ECOG PS of 0-1/2/3/4 was noted in 33/6/3/0 cases, respectively. The median PFS was 9.1 and 28.1 months in the PD-L1 TPS ≥20% and PD-L1 TPS <20% groups, respectively (log-rank p = 0.013). Multivariate analysis revealed that PD-L1 TPS ≥20% was associated with PFS (hazard ratio: 2.35, 95% confidence interval: 1.09-5.08, p = 0.030). PD-L1 TPS ≥20% in patients with EGFR-mutated NSCLC may be associated with early resistance to osimertinib.


Is the relationship between child abuse and suicide attempts mediated by nonsuicidal self-injury and pain tolerance?
Although there is evidence for an association of child abuse with lifetime suicidal behaviour, the underlying mechanisms remain unclear. In recent research, we found this relationship to be indirect and mediated by capability for suicide (CS). Emotional and sexual abuse were directly associated with CS. Based on the Interpersonal Psychological Theory of Suicide, the result for emotional abuse was surprising and raised the question for a missing link in this association. Consequently, this study examines nonsuicidal self-injury (NSSI) as an additional mediator (M1 ) between child abuse (X), pain tolerance (M2 ), and suicide attempts (Y). We included 308 psychiatric inpatients (M = 36.9 years, 53% female) with either an acute suicidal crisis (n = 146) or a recent suicide attempt (n = 157). For the assessment, we used the Childhood Trauma Screener (CTS), the German version of the self-injurious thoughts and behaviours interview (SITBI-G), the German Capability for Suicide Questionnaire (GCSQ), and a pressure algometer for measuring pain tolerance objectively. Serial mediator analyses were applied. All types of abuse showed relationships with NSSI, which itself was connected to suicidal behaviour in almost all models, whereas pain tolerance did not show the expected relations. The results suggest that NSSI is an important predictor for suicide attempts and should be considered in suicide risk assessment. Future research should address this topic in prospective studies with a more comprehensive assessment of child abuse. In summary, this study once again highlights the serious effects of child abuse and in particular the mediating role of NSSI.


The Nature of Posttraumatic Growth in Adult Survivors of Child Sexual Abuse.
Potential negative sequelae for survivors of child sexual abuse is well documented. However, growing evidence suggests that some individuals who actively cope with traumatic events can progress from a negative trajectory toward positive psychological change, often termed posttraumatic growth. Current posttraumatic growth theories may be of limited applicability to developmental considerations involved in child sexual abuse. This explorative study examines posttraumatic growth among adult female survivors of child sexual abuse. In-depth interviews were conducted with six participants who believed they had grown through coping with their abuse. Data was analyzed using interpretative phenomenological analysis. Three superordinate and nine subordinate themes were identified and explored. Some participants reported experiencing growth and distress simultaneously. Theoretical and clinical implications are examined in relation to the study's findings.


Racial And Ethnic Inequalities In COVID-19 Mortality Within Carceral Settings: An Analysis Of Texas Prisons.
The COVID-19 pandemic has taken a heightened toll on people incarcerated in prisons in the United States, with those incarcerated experiencing a higher rate of infection and mortality than the US population more generally. What is less well known is the degree to which COVID-19 outcomes differ among incarcerated populations, especially by race and ethnicity, where significant differences have been found among the US population as a whole. This knowledge gap is, in part, due to a lack of reporting of COVID-19 outcomes by race and ethnicity by most state prison systems. To shed light on this topic, we analyzed mortality patterns of the population incarcerated in Texas state prison facilities during both the year before (beginning April 1, 2019) and the first year of (beginning April 1, 2020) the COVID-19 pandemic. We used a unique data set of roster information from the Texas Department of Criminal Justice and medical examiner records. COVID-19 mortality was 1.61 and 2.12 times higher for Black and Hispanic populations, respectively, when compared with the White population in Texas prisons. Strategies for COVID-19 mitigation in carceral settings, such as vaccination and decarceration, should include an equity component to minimize disparities.


Trans-anal total mesorectal excision in low rectal cancers: Preliminary oncological results of a comparative study.
The management of lower rectal cancers is a therapeutic challenge both from the oncological and functional viewpoints. The aim of this study is to assess the oncological results and postoperative morbidity after transanal total mesorectal excision (TaTME) for low rectal cancer. In this monocentric retrospective study, we compared the quality of carcinologic resection and the morbidity-mortality between a group of 20 patients undergoing TaTME and 21 patients treated by abdomino-perineal resection (APR) between 2016 to 2019. More patients had a positive circumferential resection margin (CRM) (≤1mm) in the APR group (47.6% vs. 5%; P<0.0036). The difference in the rates of grades I-II and III-IV complications (Clavien-Dindo classification) between the two groups was not statistically significant (50% vs. 57.1% and 5% vs. 9.5% in TaTME and APR, respectively; P=0.7579, P=1.00). The median follow-up was longer in the TaTME group (20 months vs. 11 months; P=0.58). The local recurrence rate did not differ between the two groups (5% vs. 4.8%; P=1.00) CONCLUSION: TaTME provides a reliable total mesorectal resection with an acceptable CRM. However, like any new technique, it requires experience and the learning curve is long.


Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease.
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = -8.349, 95%CI (-9.266, -7.265), Diosmtrin Log IC50 = -8.419, 95%CI (-8.889, -7.950), Log IC50 = -8.349, 95%CI (-9.266, -7.265), Methyl rosmarinate Log IC50 = -8.415, 95%CI (-8.751, -8.085), Kaempferol Log IC50 = -8.297, 95%CI (-9.001, -7.615), Quercetin Log IC50 = -8.864, 95%CI (-9.107, -8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.


Analgesics/Anti-Inflammatory Drugs Preferred Following Implant Placement: A Retrospective Study.
In dentistry, pain is a rather inevitable perception that often plagues both the care provider and receiver. Pain, which was described by Rene Descartes in the sixteenth century, has been defined as an unpleasant sensory and emotional experience associated with tissue damage or described in terms of such damage. Various dental procedures also provoke a perception of anxiety that culminates with pain and exaggerates the perception of pain. Hence, adequate pain control and assurance are of utmost importance during and following implant surgery. The aim of the present study was to assess the analgesics and anti-inflammatory drugs preferred following implant placement and also to find an association between gender, age, and various analgesics/anti-inflammatories prescribed following implant surgery. Retrospective data collection was conducted from June 2019 to March 2020 among 200 patients who underwent implant surgery, based on records management system software to analyze the most commonly prescribed analgesics/anti-inflammatory drugs following implant surgery. Among 200 patients the frequency distribution showed that 87% of the patients were prescribed with combination of Aceclofenac (100 mg), Paracetamol (325 mg), and Serratiopeptidase (15 mg), 10% of the patients were prescribed with Paracetamol (650 mg), whereas 3% of the patients were prescribed with Piroxicam (20 mg). The present study showed that combination of Aceclofenac, Paracetamol, and Serratiopeptidase was the commonly prescribed analgesic/anti-inflammatory drug for postoperative pain management following implant placement. Also there was no significant association between gender vs. various analgesics/anti-inflammatory drugs prescribed following implant placement.


Effects of diazepam, citalopram, methadone and naloxone on PCP-induced stereotyped behaviour and social isolation in the rat social interaction test.
Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. In the social interaction test PCP induces stereotyped behaviour and social isolation in rats, and these behaviours can be inhibited by antipsychotic drugs. In order to further evaluate the predictive validity of this model of schizophrenia the anxiolytic diazepam (0.02-17.5 micromol/kg; 0.005-5.0 mg/kg), the antidepressant citalopram (0.62-19.8 micromol/kg; 0.3-4.0 mg/kg), the opioid agonist methadone (0.36-5.8 micromol/kg; 0.13-2.0 mg/kg) and the opioid antagonist naloxone (0.34-22.0 micromol/kg; 0.13-8.0 mg/kg) were tested as examples of drugs without antipsychotic activity. The experiments demonstrated that these compounds did not specifically inhibit the behavioural effects of PCP. So far only antipsychotic drugs have been able to specifically inhibit the PCP-induced behaviours.


Nuclear magnetic resonance titration curves of histidine ring protons. Human metmyoglobin and the effects of azide on human, horse, and sperm whale metmyoglobins.
Four titrating histidine ring C2 and C4 proton resonances are observed in 220 MHz proton NMR spectra of human metmyoglobin as a function of pH. Values of ionization constants determined from the NMR titration data using an equation describing a simple proton association-dissociation equilibrium are curves (1) 6.6, (2) 7.0, (3) 5.8, and (4) 7.4. Four histidine residues have also been found to be solvent-accessible in human metmyoglobin by carboxymethylation studies (Harris, C.M., and Hill, R.L. (1969) J. Biol. Chem. 244, 2195-2203). Two of the titration curves (3 and 4) deviate significantly from the chemical shift values normally observed for histidine C2 proton resonances. Curve 3, with a low pKa, is shifted downfield at high values of pH and also exhibits a second minor inflection with a pKa value of 8.8. On the other hand, the high pKa curve, 4, is shifted upfield at all values of pH. The characteristics of the NMR titration curves with the lowest and highest pKa values (3 and4) are very similar to curves observed previously with sperm whale and horse metmyoglobins (Cohen, J.S., Hagenmaier, H., Pollard, H., and Schechter, A.N. (1972) J. Mol. Biol. 71, 513-519). These results indicate that the histidine residues from which these curves are derived have unusual and characteristic environments in this series of homologous proteins. The NMR spectra of all three metmyoglobins are changed extensively as a result of azide ion binding, indicating conformational changes affecting the environments of several imidazole side chains. The presence of azide ion causes a selective downfield chemical shift for the low pKa curve and a selective upfield chemical shift for the high pKa curve in all three proteins. Azide also abolishes the second inflection seen in the low pKa curve at high pH. In addition to these effects, the presence of azide ion permits the observation of two additional titrating proton resonances for all three metmyoglobins. Increasing the azide to protein ratio at several fixed values of pH yields results which show that a slow exchange process is occurring with each of the metmyoglobins. In the azide titration studies the maximum changes in the NMR spectra occurred at approximately equimolar concentrations. The NMR results for these proteins in the absence and presence of azide ion are related to x-ray crystallographic studies of sperm whale metmyoglobin and the known alkylation properties of the histidine residues. Tentative assignments of the titrating resonances observed are suggested.


Erratum: An Investigation into the efficacy of nursing curriculum on elderly health problems via Delphi's method.
[This corrects the article on p. 2300 in vol. 8, PMID: 31463246.].


Polymorphisms in the promoter region of RANTES in Han Chinese and their relationship with systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease afflicting more than 600,000 individuals in China. RANTES (regulated on activation, normal T cell expressed and secreted, 17q11.2-q12) is a member of the proinflammatory cytokine family known as "chemokines". It plays an important role in the attraction and recruitment of lymphocytes, monocytes and eosinophils to sites of inflammation. A total of 146 SLE patients and 159 random healthy volunteer individuals in Han Chinese patients were enrolled in this study. Genotypes of RANTES -403 locus and -28 locus were observed to be different in all racial groups. The frequency of individuals who possessed G allele at -28 locus among SLE patients was not significantly different from that among normal controls. A total of seven compound genotypes at -403 locus and -28 locus were observed in this study. The frequency of this compound genotype (-403 G/G, -28 C/C) was different between the two groups. The distribution of genotypes and alleles at RANTES-403 locus was observed to be significantly different between renal damaged group and no renal damaged group (P<0.05), while there was no significant difference in distribution of genotypes and alleles at RANTES-28 locus between the two groups. These results suggest that (a) two genetic polymorphisms in the RANTES promoter do not correlate with SLE as individual polymorphisms. (b) interaction of the polymorphisms at two loci probably exerts a risk effect against SLE and (c) polymorphism at RANTES-403 locus is probably related with renal damage.


Structure, redox, pKa, spin. A golden tetrad for understanding metalloenzyme energetics and reaction pathways.
After a review of the current status of density functional theory (DFT) for spin-polarized and spin-coupled systems, we focus on the resting states and intermediates of redox-active metalloenzymes and electron transfer proteins, showing how comparisons of DFT-calculated spectroscopic parameters with experiment and evaluation of related energies and geometries provide important information. The topics we examine include (1) models for the active-site structure of methane monooxygenase intermediate Q and ribonucleotide reductase intermediate X; (2) the coupling of electron transfer to proton transfer in manganese superoxide dismutase, with implications for reaction kinetics; (3) redox, pK(a), and electronic structure issues in the Rieske iron-sulfur protein, including their connection to coupled electron/proton transfer, and an analysis of how partial electron delocalization strongly alters the electron paramagnetic resonance spectrum; (4) the connection between protein-induced structural distortion and the electronic structure of oxidized high-potential 4Fe4S proteins with implications for cluster reactivity; (5) an analysis of cluster assembly and central-atom insertion into the FeMo cofactor center of nitrogenase based on DFT structural and redox potential calculations.


Regulatory functions of soluble auxin-binding proteins.
Since the effects of auxin on plant tissues are complex, the mode of action of auxin at the molecular level may not depend on a single mechanism. There may be a mechanism by which the interaction of auxin with receptors localized in the cytoplasmic membranes activates certain enzymes which are necessary to generate the putative second messengers. On the other hand, soluble auxin-binding proteins have been isolated from a variety of plant tissues. Some of these proteins have a high affinity for auxins and the binding is auxin specific, reversible, and saturable, characteristics which suggest that these proteins may be auxin receptors. Although these criteria are often used to distinguish real receptors from nonfunctional binding proteins, it is necessary to clarify the biological function of the binding proteins to classify them as putative receptors. The reported results on the function of soluble auxin-binding proteins demonstrate that, in the transcription system composed of isolated nuclei, auxin interacts with soluble auxin-binding proteins and stimulates the expression of specific genes. Thus, one of the mechanisms of action of auxin may involve a direct interaction with a soluble receptor protein, such that the resultant auxin-receptor complex, possibly together with other protein factors, can subsequently recognize the promoter region of specific gene(s) and interact with RNA polymerase II to cause a transcription of the gene(s).


Control of sweating during the human menstrual cycle.
Thermoregulatory responses were studied in seven women during two separate experimental protocols in the follicular (F, days 4-7) phase and during the luteal (L, days 19-22) phase of the menstrual cycle. Continuous measurements of esophageal temperature (Tes), mean skin temperature (Tsk), oxygen uptake and forearm sweating (ms) were made during all experiments. Protocol I involved both passive heat exposure (3 h) and cycle exercise at approximately 80% VO2 peak during which the environmental chamber was controlled at Ta = 50.0 degrees C, rh = 14% (Pw = 1.7 kPa). In protocol II subjects were tested during thirty-five minutes of exercise at approximately 85% VO2 peak at Ta = 35 degrees C and rh = 25% (Pw = 1.4 kPa). The normal L increase in resting Tes (approximately 0.3 degrees C) occurred in all seven subjects. Tsk was higher during L than F in all experiments conducted at 50 degrees C. During exercise and passive heat exposure, the Tes threshold for sweating was higher in L, with no change in the thermosensitivity (slope) of ms to Tes between menstrual cycle phases. This rightward or upward shift in Tes threshold for initiation of sweating averaged 0.5 degrees C for all experiments. The data indicate the luteal phase modulation in the control of sweating in healthy women is also apparent during severe exercise and/or heat stress.


Simultaneous nitrification-denitrification by phosphate accumulating microorganisms.
Nitrogen and phosphorous are important inorganic water pollutants that pose a major threat to the environment and health of both humans and animals. The physical and chemical ways to remove these pollutants from water and soil are expensive and harsh, so biological removal becomes the method of choice to alleviate the problem without any side effects. The identification of microorganisms capable of simultaneous heterotrophic nitrification and aerobic denitrification has greatly simplified the sequestration of nitrogen from ammonium (NH4+) into dinitrogen (N2). Further, the discovery of phosphorous accumulating organisms offers greater economic benefits because these organisms can favourably and simultaneously remove both nitrogen and phosphorous from wastewaters hence reducing the nutrient burden. The stability of the system and removal efficiency of inorganic pollutants can be enhanced by the use of immobilized organisms. However, limited work has been done so far in this direction and there is a need to further the efforts towards refining process efficiency by testing low-cost substrates and diverse microbial populations for the total eradication of these contaminants from wastewaters.


Evaluation of a panel of molecular markers for the diagnosis of malignant serous effusions.
Our main goal was to evaluate a panel of molecular markers for the detection of cancer cells in serous effusions and to determine their value as an adjunctive reverse transcription-PCR (RT-PCR) test to cytologic examination. One hundred fourteen serous effusions from 71 patients with tumors and 43 patients with benign diseases were subjected to RT-PCR for expression of carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (Ep-CAM), E-cadherin, mammaglobin, mucin 1 (MUC1) isoforms MUC1/REP, MUC1/Y, and MUC1/Z, calretinin, and Wilms' tumor 1 susceptibility gene. CEA, Ep-CAM, E-cadherin, and mammaglobin were specifically expressed in malignant effusions. The sensitivity of RT-PCR in cytologically negative malignant effusions was 63.1% combining CEA and Ep-CAM (with 100% specificity) and reached 78.9% adding MUC1/Y or MUC1/Z (with 93% specificity). In the whole population of effusions, the combination of cytology with RT-PCR of CEA and Ep-CAM yielded a 90.1% sensitivity, a specificity and a positive predictive value of 100%, and a 86% negative predictive value for malignancy. Adding MUC1/Y or MUC1/Z to the panel, the sensitivity was 94.5% with 93% specificity, 95.7% PPV, and 90.9% negative predictive value. Moreover, CEA and mammaglobin were specifically expressed in epithelial malignancies, and mammaglobin was mainly expressed in effusions from breast carcinoma (97.3% of specificity). A combination of cytology and RT-PCR analysis of CEA and Ep-CAM significantly improved the detection sensitivity of tumor cells in serous effusions. RT-PCR analysis of CEA, Ep-CAM, and mammaglobin in serous effusions could be a beneficial adjunct to cytology for the diagnosis of malignancy.


Recovery of infective Schistosoma mansoni schistosomula from liquid nitrogen: a step towards storage of a live schistosomiasis vaccine.
Successful recovery of infective schistosomula of Schistosoma mansoni following storage at -196 degrees C is reported. The technique involves a two-step cooling procedure--slow cooling (0.65 degrees C min-1) to an intermediate temperature of -28 degrees C, followed by rapid cooling into liquid nitrogen (10,000 degrees C min-1). Rewarming (10,000 degrees C min-1) and rapid dilution to remove the cryoprotectant (17.5% methanol) yielded motile organisms some of which developed to adult worms in mice after intramuscular injection. The percentage of schistosomula developing to adult worms was small (0.44%), but is a significant step towards storage of trematode larvae and of a live attenuated vaccine for schistosomiasis.


Factorial design provides evidence to guide practice of anaesthesia.
Many scientific articles are written merely to get something published, neglecting the clinician who would like the medical literature to guide their practice. Evidence-based medicine is expected to help in clinical decision-making. Systematic reviews of the literature followed by a meta-analysis of randomized, controlled trials (RCT) have claimed to represent the highest strength of evidence. However, the results published in meta-analyses have not always been confirmed in subsequent large RCTs. An analysis of 12 large RCTs and 19 meta-analyses addressing the same questions found that the outcomes of these large RCTs were not predicted accurately 35% of the time by previously published meta-analyses. Therefore, meta-analyses of several small RCTs do not obviate the need for large, multicentre RCTs, which can still be considered as a gold standard for the development of clinical guidelines or practice plans. Moreover, large RCTs using a factorial design can be highly efficient because they can answer several clinical questions at the same time and offer the only systematic approach to investigate an interaction of combinations in multimodal approaches.


Repurposing of antiangiogenic agents for treatment of vascular anomalies.
Vascular anomalies (VA) are developmental anomalies of veins, arteries, lymphatics or capillaries thought to be caused by mutations in genes that drive angiogenesis. Treatments targeting these genes are limited. We review the literature for conventional medications and products from traditional medicine cultures that have been found to have antiangiogenic activity. Fewer than 50 drugs with credible human activity in VA were identified and include β blockers, monoclonal antibodies, microtubule inhibitors, multi-kinase inhibitors, PIK3CA- and RAS-MAPK pathway inhibitors, and thalidomides. Other drug categories of potential interest are ACE-inhibitors, antifungals, antimalarials, MMP9-inhibitors, and over-the-counter compounds used in Eastern traditional medicine. Low toxicity for some offers the possibility of combined use with known effective agents. In addition to already familiar drugs, others with antiangiogenic capabilities already in use in children or adults may deserve further attention for repurposing for VA.


Atorvastatin prevents Angiotensin II induced myocardial hypertrophy in vitro via CCAAT/enhancer-binding protein β.
Previous evidences suggested that atorvastatin not only reduced blood lipids but also reduced myocardial hypertrophy and remodeling. And it was reported that C/EBPβ (CCAAT/enhancer-binding protein β) played a pivotal role both in the physiologic and pathological cardiac hypertrophy. However, it has not been reported before whether this signaling pathway of C/EBPβ participates in protective effect of atorvastatin for hypertrophy cardiomyocytes. In present study, We found that overexpression of C/EBPβ significantly abrogated the effect of atorvastatin on increasing Bcl-2/Bax and PGC-1α while the early and late apoptosis rate increased and mitochondrial membrane potential (MMP) was reduced. In conclusion, we further identified the protective effect of atorvastatin on hypertrophic cardiomyocytes induced by Angiotensin II by rescuing the MMP and inhibiting apoptosis, which might be at least partly attributed to down-regulation of C/EBPβ. And C/EBPβ might be a new target to rescue mitochondrion function and apoptosis in pathological cardiac hypertrophy.


Delayed surgical management of a traumatic aortic arch injury.
We report successful management of a blunt traumatic injury to the aortic arch with intentionally delayed surgical repair. The aorta was repaired after the stabilization of other, potentially fatal, traumatic injuries.


RNAseq analysis of olfactory neuroepithelium cytological samples in individuals with Down syndrome compared to euploid controls: a pilot study.
Down syndrome is a common genetic disorder caused by partial or complete triplication of chromosome 21. This syndrome shows an overall and progressive impairment of olfactory function, detected early in adulthood. The olfactory neuronal cells are located in the nasal olfactory mucosa and represent the first sensory neurons of the olfactory pathway. Herein, we applied the olfactory swabbing procedure to allow a gentle collection of olfactory epithelial cells in seven individuals with Down syndrome and in ten euploid controls. The aim of this research was to investigate the peripheral gene expression pattern in olfactory epithelial cells through RNAseq analysis. Validated tests (Sniffin' Sticks Extended test) were used to assess olfactory function. Olfactory scores were correlated with RNAseq results and cognitive scores (Vineland II and Leiter scales). All Down syndrome individuals showed both olfactory deficit and intellectual disability. Down syndrome individuals and euploid controls exhibited clear expression differences in genes located in and outside the chromosome 21. In addition, a significant correlation was found between olfactory test scores and gene expression, while a non-significant correlation emerged between olfactory and cognitive scores. This first preliminary step gives new insights into the Down syndrome olfactory system research, starting from the olfactory neuroepithelium, the first cellular step on the olfactory way.


Characterization and expression of a CD40 homolog gene in Japanese flounder Paralichthys olivaceus.
A CD40 homolog cDNA encoding 300 amino acid residues was isolated from a Japanese flounder leukocyte cDNA library. The amino acid sequence identities of Japanese flounder CD40 and previously reported CD40s of cow, human, mouse, and chicken range from 32 to 35%. The positions of cysteine residues, CD40 ligand binding amino acid residues, and four cysteine-rich domains are well conserved in Japanese flounder CD40. The Japanese flounder CD40 gene is composed of nine exons and eight intervening introns spread over 6 kb. The nucleotide sequence of the 5'-flanking region of this gene revealed the presence of several regulatory regions, including a TATA-like box, AP-1-, CEBPB-, IRF-1-, LYF-1-, NF-kappaBp-, SP-1-, and Stat-1-like motifs. In healthy fish, reverse transcriptase-polymerase chain reaction (RT-PCR) detected constitutive expression of CD40 in all tested tissues (leukocytes, kidney, spleen, liver, intestine, brain, gill, and skin). The mRNA of CD40 was predominantly expressed in several tissues that contained lymphocytes (leukocytes, kidney, spleen, intestine, and gill). Expression of the Japanese flounder CD40 molecule was induced in peripheral blood leukocytes from 1 to 6 h following Con A (50 microg/ml)/phorbol myristate acetate (PMA) (0.35 microg/ml) stimulation, with a peak at 1 h after stimulation, and increased at 1, 3, and 6 h after induction by lipopolysaccharide (LPS) (500 microg/ml) compared with the control.