Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma.
Patients with stiff man syndrome and breast cancer develop anti-amphiphysin I antibodies that primarily recognise the C terminus of the protein. Anti-amphiphysin I antibodies have also been identified in a few patients with paraneoplastic neurological disorders (PND) and small cell lung cancer (SCLC). The frequency of anti-amphiphysin I antibodies in patients with SCLC and PND was analysed and the epitope specificity of these antibodies was characterised. Anti-amphiphysin I antibodies were evaluated by immunohistochemistry on human and rat cerebellum and immunoblots of rat brain homogenates. Serum samples included 134 patients with PND and anti-Hu antibodies (83% had SCLC), 44 with SCLC and PND without anti-Hu-antibodies, 63 with PND and either Yo, Ri, or Tr antibodies, 146 with SCLC without PND, and 104 with non-PND. Positive serum samples were confirmed with immunoblots of recombinant human amphiphysin I and immunoreacted with five overlapping peptide fragments covering the full length of the molecule. Serum samples positive for anti-amphiphysin I antibodies included those from seven (2.9%) patients with PND and two (1.4%) with SCLC without PND. Six of the seven anti-amphiphysin I antibody positive patients with PND had SCLC (three with Hu-antibodies), and one had anti-Hu-antibodies but no detectable tumour. The PND included encephalomyelitis/sensory neuropathy (five patients), cerebellar degeneration (one), and opsoclonus (one). All anti-amphiphysin I antibodies reacted with the C terminus of amphiphysin I, but seven also recognised other fragments of the molecule. In conclusion, anti-amphiphysin I antibodies are present at low frequency in patients with SCLC irrespective of the presence of an associated PND. All anti-amphiphysin I antibody positive serum samples have in common reactivity with the C terminus of the protein.


Early warning of West Nile virus mosquito vector: climate and land use models successfully explain phenology and abundance of Culex pipiens mosquitoes in north-western Italy.
West Nile Virus (WNV) is an emerging global health threat. Transmission risk is strongly related to the abundance of mosquito vectors, typically Culex pipiens in Europe. Early-warning predictors of mosquito population dynamics would therefore help guide entomological surveillance and thereby facilitate early warnings of transmission risk. We analysed an 11-year time series (2001 to 2011) of Cx. pipiens mosquito captures from the Piedmont region of north-western Italy to determine the principal drivers of mosquito population dynamics. Linear mixed models were implemented to examine the relationship between Cx. pipiens population dynamics and environmental predictors including temperature, precipitation, Normalized Difference Water Index (NDWI) and the proximity of mosquito traps to urban areas and rice fields. Warm temperatures early in the year were associated with an earlier start to the mosquito season and increased season length, and later in the year, with decreased abundance. Early precipitation delayed the start and shortened the length of the mosquito season, but increased total abundance. Conversely, precipitation later in the year was associated with a longer season. Finally, higher NDWI early in the year was associated with an earlier start to the season and increased season length, but was not associated with abundance. Proximity to rice fields predicted higher total abundance when included in some models, but was not a significant predictor of phenology. Proximity to urban areas was not a significant predictor in any of our models. Predicted variations in start of the season and season length ranged from one to three weeks, across the measured range of variables. Predicted mosquito abundance was highly variable, with numbers in excess of 1000 per trap per year when late season temperatures were low (average 21°C) to only 150 when late season temperatures were high (average 30°C). Climate data collected early in the year, in conjunction with local land use, can be used to provide early warning of both the timing and magnitude of mosquito outbreaks. This potentially allows targeted mosquito control measures to be implemented, with implications for prevention and control of West Nile Virus and other mosquito borne diseases.


An overview of carboxymethyl derivatives of chitosan: Their use as biomaterials and drug delivery systems.
Chitin is one of the most abundant natural polymers in the world and is used for the production of chitosan by deacetylation. Chitosan is nontoxic and biodegradable and, therefore, can be used as a biomaterial and for the construction of drug delivery systems. Nevertheless, the poor solubility of chitosan in neutral or alkalinized media has restricted its applications in the pharmaceutical and biomedical fields. Chitosan can be easily carboxymethylated to improve its solubility in aqueous media while its biodegradability and biocompatibility are preserved. Carboxymethyl chitosans show improved solubility in aqueous media, which makes them an attractive alternative source for producing biomaterials and drug delivery systems as well as for designing nanotechnology-based systems. Thus, carboxymethyl chitosan-based materials have a wide applicability and good potential in the development of biomedical nanodevices and controlled release drug formulations. This review summarizes preparations and properties of hydrophilic chitosan-based materials such as nanoparticles, microparticles, tablets, and films as well as procedures related to various practical applications.


Cooperative hydration of pyruvic acid in ice.
About 3.5 +/- 0.3 water molecules are still involved in the exothermic hydration of 2-oxopropanoic acid (PA) into its monohydrate (2,2-dihydroxypropanoic acid, PAH) in ice at 230 K. This is borne out by thermodynamic analysis of the fact that QH(T) = [PAH]/[PA] becomes temperature independent below approximately 250 K (in chemically and thermally equilibrated frozen 0.1 < or = [PA]/M < or = 4.6 solutions in D2O), which requires that the enthalpy of PA hydration (DeltaHH approximately -22 kJ mol(-1)) be balanced by a multiple of the enthalpy of ice melting (DeltaHM = 6.3 kJ mol(-1)). Considering that: (1) thermograms of frozen PA solutions display a single endotherm, at the onset of ice melting, (2) the sum of the integral intensities of the 1deltaPAH and 1deltaPA methyl proton NMR resonances is nearly constant while, (3) line widths increase exponentially with decreasing temperature before diverging below approximately 230 K, we infer that PA in ice remains cooperatively hydrated within interstitial microfluids until they vitrify.


Conflict of interest policies and disclosure requirements in neurosurgical journals.
An increasing amount of funding in neurosurgery research comes from industry, which may create a conflict of interest (COI) and the potential to bias results. The reporting and handling of COIs have become difficult, particularly as explicit policies themselves and definitions thereof continue to vary between medical journals. In this study, the authors sought to evaluate the prevalence and comprehensiveness of COI policies among leading neurosurgical journals. The authors conducted a cross-sectional study of publicly available online disclosure policies in the 20 highest-ranking neurosurgical journals, as determined by Google Scholar Metrics, in July 2016. Overall, 89.5% of the highest-impact neurosurgical journals included COI policy statements. Ten (53%) journals requested declaration of nonfinancial conflicts, while 2 journals specifically set a time period for COIs. Sixteen journals required declaration from the corresponding author, 13 from all authors, 6 from reviewers, and 5 from editors. Four journals were included in the International Committee of Medical Journal Editors (ICMJE) list of publications that follow the Uniform Requirements for Manuscripts Submitted to Biomedical Journals (currently known as Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals). Five journal policies included COI declaration verification, management, or enforcement. The neurosurgery journals with more comprehensive COI policies were significantly more likely to have higher h5-indices (p = 0.003) and higher impact factors (p = 0.01). In 2016, the majority of, but not all, high-impact neurosurgical journals had publically available COI disclosure policies. Policy inclusiveness and comprehensiveness varied substantially across neurosurgical journals, but COI comprehensiveness was associated with other established markers of individual journals' favorability and influence, such as impact factor and h5-index.


The role of hypogonadism in Klinefelter syndrome.
Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be diffi cult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.


Recurrence rates at minimum 5-year follow-up: laparoscopic versus open sigmoid resection for uncomplicated diverticulitis.
The aim of the study was to compare the impact of surgical access to sigmoid resection on recurrence rates in patients with uncomplicated diverticulitis of the sigmoid (UDS) at a minimum follow-up of 5 years. Recurrence after surgery was defined as left lower quadrant pain, fever, and leucocytosis with consistent CT and enema findings on admission and at 6 weeks, respectively. Outcome measures included splenic flexure mobilization, specimen length, inflammation at proximal resection margin, and presence of teniae coli at distal resection margin. Seventy-nine patients undergoing laparoscopic sigmoid resection (LSR) were compared with 79 matched controls with open sigmoid resection (OSR) operated on at 2 institutions during the same period. Patients were well matched for age, gender, body mass index, ASA grading, and symptoms duration, but not for follow-up length (81.9 versus 86.9 months, P = 0.046). Differences in rates of splenic flexure mobilization (19 versus 41, P < 0.001), specimen length (16.1 versus 18.3 cm, P = 0.048), inflammation at proximal resection margin (21 versus 4, P < 0.001), and teniae coli at distal resection margin (4 versus 53, P < 0.001) did not show an impact on recurrence rates when comparison was made between LSR and OSR. Three LSR patients and 7 OSR patients had 1 recurrence (P = 0.19). There were no significant differences in rates of flexure mobilization, specimen length, and rates of inflammation present at proximal resection margin in 10 recurring and 145 non-recurring patients. The rate of teniae coli present at distal resection margin was significantly increased in recurring patients (7 versus 43, P = 0.03). Median time of recurrence after surgery was 29 (range 18-74) months. Two of 11 recurrences occurred after 5 years. Surgical access to sigmoid resection for UDS is unlikely to have an impact on recurrence rates provided that the oral bowel end is anastomosed to the proximal rectum rather than to the distal sigmoid.


Does vancomycin have a future in the treatment of skin infections?
Despite concerns regarding efficacy and tolerability, vancomycin continues to be the standard treatment for skin and soft tissue infections (SSTIs) when β-lactam antimicrobials cannot be used. This review sought to establish the role of both old and new alternatives to vancomycin. Methods for achieving optimization of vancomycin therapy are also explored. Several meta-analyses have demonstrated poorer clinical outcomes when the vancomycin minimum inhibitory concentration approaches the breakpoint of 2 μg/ml. Higher doses should be utilized to optimize pharmacokinetics and pharmacodynamics when higher volumes of distribution occur (e.g. sepsis). Newer agents with established noninferiority to vancomycin include the oxazolidinones linezolid and tedizolid, the lipopeptide daptomycin, the anti-meticillin-resistant Staphylococcus aureus cephalosporin ceftaroline and the glycylcycline tigecycline. Linezolid is thus far the only agent that has been shown to be associated with better clinical and microbiological cure rates. Ceftaroline and tigecycline are broad-spectrum agents best reserved for polymicrobial infections (e.g. diabetic foot infections). When vancomycin is used for the treatment of SSTIs, maximizing the dose should be performed to improve efficacy. Cost is often the main limiting factor with regard to the newer agents, but their suitability for outpatient antimicrobial therapy may counteract this.


Determinants of stigma among patients with hepatitis C virus infection.
Stigma around hepatitis C virus (HCV) infection is an important and understudied barrier to HCV treatment and elimination. The determinants of HCV-related stigma, including the impacts of stage of HCV treatment (ie spontaneously cleared; diagnosed, untreated; previously treated, not cured; currently being treated; and treated, cured) and coinfection with human immunodeficiency virus (HIV), remain unknown. To address these gaps, we conducted a cross-sectional study among patients with a history of HCV infection (n = 270) at outpatient clinics in Philadelphia from July 2018 to May 2019. We evaluated stigma using the validated HCV Stigma Scale, adapted from the Berger HIV Stigma Scale. Associations among HCV-related stigma and hypothesized demographic, behavioural, and clinical risk factors were evaluated by multivariable linear regression. Most participants (95.5%) experienced HCV-related stigma. Mean stigma scores did not differ significantly between HCV-monoinfected and HIV/HCV-coinfected participants (P = .574). However, we observed significant interactions between HIV status and multiple determinants; therefore, we stratified analyses by HIV status. Among HIV/HCV-coinfected participants, previous HCV treatment without cure, female gender, Hispanic/Latinx ethnicity and some college education were significantly associated with higher HCV-stigma scores. An annual income of $10 000-$40 000 was associated with significantly lower stigma scores. No significant associations were observed among HCV-monoinfected participants. We found that most participants experienced stigma associated with HCV diagnosis. While stigma scores were similar between HCV-monoinfected and HIV/HCV-coinfected participants, the determinants associated with HCV stigma differed by HIV status. Understanding how experiences of stigma differ between HCV-monoinfected and HIV/HCV-coinfected patients may aid in the development of targeted interventions to address the HCV epidemic.


Inhibitory effect of valproic acid on the disposition of carbamazepine and carbamazepine-10,11-epoxide in the rat.
The effects of valproic acid on the disposition of carbamazepine and carbamazepine epoxide were studied in conscious rats. Each animal received a constant rate infusion of carbamazepine and an iv bolus dose of epoxide in the presence and absence of valproate. The latter was maintained within its therapeutic range by iv infusion. Carbamazepine steady state clearance was decreased by 20.2 +/- 12.7% in the presence of valproate. The formation clearance of carbamazepine epoxide, which accounts for 50% of the total clearance, was decreased on the average by 22.7%. Also, a significant increase in the level of carbamazepine epoxide formed from carbamazepine was found in the presence of valproate. This increase in metabolite level was explained by the large reduction in epoxide clearance (41.6 +/- 13.1%) observed after single doses of epoxide. Based on this finding, a separate study examined the effect of valproate on the non-renal component of the clearance of carbamazepine epoxide. The non-renal clearance of epoxide was decreased by 59.9 +/- 11.9% in the presence of valproic acid.


Inactivation of potassium current in squid axon by a variety of quaternary ammonium ions.
The characteristics of potassium channel block by a diverse group of quaternary ammonium (QA) ions was examined in squid axons. Altering the size and nature of the head and/or tail groups of the QA ions applied internally produced only quantitative differences in the potassium current block. Although their entry rate is diminished, compounds with head groups as large as 11 X 12 A are capable of occluding the channel, whereas the smallest QA ions, with head groups approximately 5 X 6 A, are not potent blockers. When one or three terminal hydrogens of the head group were replaced by hydroxyl moieties, the compound's blocking ability was diminished, suggesting that QA binding is not improved by hydrogen bonding at these positions. QA ions bound to their site within the potassium channel with 1:1 stoichiometry, and the site is perhaps 20% or more of the distance through the membrane electric field. Raising external potassium concentration did not alter the steady-state or kinetic features of the QA block of outward potassium currents; however, increasing temperature or adding Ba2+ internally increased the rate of decay of the QA-blocked currents. From the structure-function analysis of the QA ions, projections concerning both the architecture of the potassium channel's inner mouth and the significance of various chemical constituents of the ions were made. The potassium channel may now be pictured as having a wider mouth (up to 11 X 12 A) extending to the QA binding site and then narrowing quickly to the region of channel selectivity. Important alterations that improve the blocking ability of the compounds include: (a) lengthening the alkyl hydrocarbon tail group (up to 10 carbon), (b) lengthening a second hydrocarbon chain of the head group (e.g., decyldimethylphenylammonium bromide [C10DM phi]), and (c) adding a carbonyl moiety to the tail (e.g., ambutonium).


What are the implications of using individual and combined sources of routinely collected data to identify and characterise incident site-specific cancers? a concordance and validation study using linked English electronic health records data.
To describe the benefits and limitations of using individual and combinations of linked English electronic health data to identify incident cancers. Our descriptive study uses linked English Clinical Practice Research Datalink primary care; cancer registration; hospitalisation and death registration data. We implemented case definitions to identify first site-specific cancers at the 20 most common sites, based on the first ever cancer diagnosis recorded in each individual or commonly used combination of data sources between 2000 and 2014. We calculated positive predictive values and sensitivities of each definition, compared with a gold standard algorithm that used information from all linked data sets to identify first cancers. We described completeness of grade and stage information in the cancer registration data set. 165 953 gold standard cancers were identified. Positive predictive values of all case definitions were ≥80% and ≥94% for the four most common cancers (breast, lung, colorectal and prostate). Sensitivity for case definitions that used cancer registration alone or in combination was ≥92% for the four most common cancers and ≥80% across all cancer sites except bladder cancer (65% using cancer registration alone). For case definitions using linked primary care, hospitalisation and death registration data, sensitivity was ≥89% for the four most common cancers, and ≥80% for all cancer sites except kidney (69%), oral cavity (76%) and ovarian cancer (78%). When primary care or hospitalisation data were used alone, sensitivities were generally lower and diagnosis dates were delayed. Completeness of staging data in cancer registration data was high from 2012 (minimum 76.0% in 2012 and 86.4% in 2014 for the four most common cancers). Ascertainment of incident cancers was good when using cancer registration data alone or in combination with other data sets, and for the majority of cancers when using a combination of primary care, hospitalisation and death registration data.


[Validation of the sentinel lymph node biopsy in breast cancer].
Assessment of our experience and validation of the sentinel lymph node biopsy technique in breast cancer stage T0-T2N0M0 surgery. Identification and biopsy of the sentinel lymph node by the radio colloid method in a consecutive series of 205 patients undergoing surgery for breast cancer stage T0-T2N0M0 between October 1998 and January 2007, initially in association with a complete axillary lymph node dissection (learning curve), later in an elective way. Prospective recording of the data and analysis with an average follow-up of 50 months (3 to 102 months). Biopsy rate of the sentinel lymph node of 90%, false negative rate of the method 2.5%, axillary recurrence rate 0%. We confirm in this series that the sentinel lymph node biopsy technique is a reliable approach in our experience for the evaluation of the axillary lymph node status in breast cancer stage T0-T2N0M0.


Intensity of official Futsal matches.
The purpose of this study was to assess the intensity of official Futsal matches, expressed in different ways. Fourteen male professional Futsal players from a First Division Brazilian team volunteered to participate in this study. Maximal oxygen uptake (VO(2)max) and the heart hate (HR) and oxygen uptake (VO(2)) correlation were determined for each player. The match intensity was estimated from the players' average HR measured during 13 National Futsal League matches. The HR measurements were obtained while the players were in the court but the values recorded while the players were sitting on the bench were not considered. In addition, these HR values were used to estimate the intensity of the effort expressed as a percentage of the maximal HR (% HRmax), percentage of VO(2)max (% VO(2)max), kilocalories per minute (kcal·min(-1)), and total caloric expenditure. The mean intensity of the matches was 86.4 ± 3.8% HRmax, 79.2 ± 9.0% VO(2)max, 18.0 ± 2.2 kcal·min(-1), and 313 ± 9.3 kcal. It was concluded that official Futsal matches have high intensity when expressed in the different ways used in this study. The information provided by this research can be used for planning the athletes' workouts, diets, and resting periods.


Network-based approach to online cursive script recognition.
The idea of combining the network of HMMs and the dynamic programming-based search is highly relevant to online handwriting recognition. The word model of HMM network can be systematically constructed by concatenating letter and ligature HMM's while sharing common ones. Character recognition in such a network can be defined as the task of best aligning a given input sequence to the best path in the network. One distinguishing feature of the approach is that letter segmentation is obtained simultaneously with recognition but no extra computation is required.


Determinants of metabolic syndrome and its prognostic implications among stroke patients in Africa: Findings from the Stroke Investigative Research and Educational Network (SIREN) study.
The prognostic implications of metabolic syndrome (METS) among African stroke patients are poorly understood. This study aimed to investigate the determinants of METS and its prognostic implications among Africans with newly diagnosed stroke in the SIREN study. We included stroke cases (adults aged >18 years with CT/MRI confirmed stroke). The validated tools comprehensively evaluated vascular, lifestyle, and psychosocial factors. We used logistic regression to estimate adjusted odds ratios (OR) with 95% CIs for the association between METS and risk factors. We also computed the prediction power of the domain of covariates in a sequential manner using the area under the receiver operating curve (ROC) curve. Among 3998 stroke subjects enrolled in the study, 76.8% had METS by at least one of the clinical definitions. Factors associated with METS were age > 50 years (OR- 1.46, CI-1.19-1.80), male gender (OR 4.06, CI- 3.28-5.03), income >100USD (OR1.42, CI-1.17-1.71), stress (OR1.46, CI-1.14-1.87), family history of diabetes mellitus (OR1.38, CI-1.06-1.78), and cardiac disease (OR1.42, CI-1.18-1.65). Stroke severity was higher among those with METS (SLS = 5.8 ± 4.3) compared with those without METS (6.2 ± 4.5) at p = 0.037. METS was associated with higher odds (aOR 1.31, CI-1.08-1.58) of one-month fatality after adjusting for stroke severity, age > 50 years, and average monthly income >100USD. METS is very common among African stroke patients and is associated with stroke severity and worse one-month fatality. Lifestyle interventions may prevent METS and attenuate its impact on stroke occurrence and outcomes.


Light-mediated activation of stromal sedoheptulose bisphosphatase.
When isolated wheat (Triticum aestivum) chloroplasts were illuminated, the activity of sedoheptulose bisphosphatase increased severalfold. The rate of activation was limited by the size of the carbon pool, and experiments with a partially purified enzyme preparation showed that the degree of reductive activation of the enzyme is governed by the concentration of its substrate.


Constitutive promoter methylation of BRCA1 and RAD51C in patients with familial ovarian cancer and early-onset sporadic breast cancer.
Genetic defects in breast cancer (BC) susceptibility genes, most importantly BRCA1 and BRCA2, account for ~40% of hereditary BC and ovarian cancer (OC). Little is known about the contribution of constitutive (soma-wide) epimutations to the remaining cases. We developed bisulfite pyrosequencing assays to screen >600 affected BRCA1/BRCA2 mutation-negative patients from the German Consortium for Hereditary Breast and Ovarian Cancer for constitutive hypermethylation of ATM, BRCA1, BRCA2, RAD51C, PTEN and TP53 in blood cells. In a second step, patients with ≥6% promoter methylation were analyzed by bisulfite plasmid sequencing to demonstrate the presence of hypermethylated alleles (epimutations), indicative of epigenetic gene silencing. Altogether we identified nine (1.4%) patients with constitutive BRCA1 and three (0.5%) with RAD51C hypermethylation. Epimutations were found in both sporadic cases, in particular in 2 (5.5%) of 37 patients with early-onset BC, and familial cases, in particular 4 (10%) of 39 patients with OC. Hypermethylation was always confined to one of the two parental alleles in a subset (12-40%) of the analyzed cells. Because epimutations occurred in cell types from different embryonal layers, they most likely originated in single cells during early somatic development. We propose that analogous to germline genetic mutations constitutive epimutations may serve as the first hit of tumor development. Because the role of constitutive epimutations in cancer development is likely to be largely underestimated, future strategies for effective testing of susceptibility to BC and OC should include an epimutation screen.


Out of Southern East Asia of the Brown Rat Revealed by Large-Scale Genome Sequencing.
The geographic origin and migration of the brown rat (Rattus norvegicus) remain subjects of considerable debate. In this study, we sequenced whole genomes of 110 wild brown rats with a diverse world-wide representation. We reveal that brown rats migrated out of southern East Asia, rather than northern Asia as formerly suggested, into the Middle East and then to Europe and Africa, thousands of years ago. Comparison of genomes from different geographical populations reveals that many genes involved in the immune system experienced positive selection in the wild brown rat.


Mechanism for the transcriptional repression by c-Myc on PDGF beta-receptor.
c-Myc plays a key role in the cell cycle dependent control of the PDGF beta-receptor mRNA. The mouse platelet-derived growth factor (PDGF) beta-receptor promoter contains a CCAAT motif, and NF-Y plays an essential role in its transcription. Coexpression of c-Myc represses PDGF beta-receptor luciferase reporter activity, and the CCAAT motif in the promoter is indispensable for this repression. Here we show that c-Myc binds NF-Y subunits, YB and YC, by immunoprecipitation from cotransfected COS-1 cells. The in vitro-translated c-Myc also binds the glutathione S-transferase (GST)-NF-YB fusion protein and GST-NF-YC, but not GST-NF-YA. The most C-terminal region of HAP domains of NF-YB and NF-YC, and the Myc homology boxes, but not the C-terminal bHLHZip domain, are indispensable for the coimmunoprecipitation, and also for the repression of PDGF beta-receptor. c-Myc binds NF-Y complex without affecting the efficiency of NF-Y binding to DNA. However, the expression of Myc represses the transcriptional activation of NF-YC when fused to the GAL4 DNA binding domain. Furthermore, this repression was seen only when Myc homology boxes are present, and NF-YC contains the c-Myc binding region.


3D-QSAR and molecular docking studies on derivatives of MK-0457, GSK1070916 and SNS-314 as inhibitors against Aurora B kinase.
Development of anticancer drugs targeting Aurora B, an important member of the serine/threonine kinases family, has been extensively focused on in recent years. In this work, by applying an integrated computational method, including comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA), homology modeling and molecular docking, we investigated the structural determinants of Aurora B inhibitors based on three different series of derivatives of 108 molecules. The resultant optimum 3D-QSAR models exhibited (q(2) = 0.605, r(2) (pred) = 0.826), (q(2) = 0.52, r(2) (pred) = 0.798) and (q(2) = 0.582, r(2) (pred) = 0.971) for MK-0457, GSK1070916 and SNS-314 classes, respectively, and the 3D contour maps generated from these models were analyzed individually. The contour map analysis for the MK-0457 model revealed the relative importance of steric and electrostatic effects for Aurora B inhibition, whereas, the electronegative groups with hydrogen bond donating capacity showed a great impact on the inhibitory activity for the derivatives of GSK1070916. Additionally, the predictive model of the SNS-314 class revealed the great importance of hydrophobic favorable contour, since hydrophobic favorable substituents added to this region bind to a deep and narrow hydrophobic pocket composed of residues that are hydrophobic in nature and thus enhanced the inhibitory activity. Moreover, based on the docking study, a further comparison of the binding modes was accomplished to identify a set of critical residues that play a key role in stabilizing the drug-target interactions. Overall, the high level of consistency between the 3D contour maps and the topographical features of binding sites led to our identification of several key structural requirements for more potency inhibitors. Taken together, the results will serve as a basis for future drug development of inhibitors against Aurora B kinase for various tumors.


[Lectin receptors in the breast and its tumors].
Distribution of lectin receptors of peanut, soy-bean, wheat ovary and concanavalin A was studied in normal and tumor human breast tissue. It is established, that in dysplasia and benign neoplasms there is a shift of lectin receptors from the apical or basal pole of acinar epithelium and ducts to the whole plasmolemma surface. There appears a mild affinity of the cytoplasm to the lectins. In carcinoma homogeneous staining of tumour cell cytoplasm and plasmolemma increase. The number of lectin receptors in the cells from low differentiated tumours decreases, a major part of the cells losing the ability of binding to lectins. Malignancy is associated with an increase in mosaic staining. The earliest signs of malignancy can be revealed with the peanut lectin.


Standardized vectorial representation of medical data in patient records.
In this paper standardized vectorial (quantitative) representation of medical data is suggested for use in patient records. Vectorial representations are (as sequences of numbers) language independent, precise, directly comparable, and they allow advanced evaluation, e.g. similarity calculation using well defined distance functions. It is possible to search for a patient with a certain combination of diagnostic parameters on the Web records of patients with similar parameters. The information about chosen treatments and treatment outcome at these patients can be used anonymously or pseudonymously for decision support. Because patient records from all countries can be compared, in the long run this could open systematic access to a very large wealth of clinically relevant information. Here the technical principle is described and illustrated by examples (e.g. similarity search of heart sounds). Previously published material is integrated in parts for explanation of the motivation and background.


SNX9 regulates dynamin assembly and is required for efficient clathrin-mediated endocytosis.
Dynamin, a central player in clathrin-mediated endocytosis, interacts with several functionally diverse SH3 domain-containing proteins. However, the role of these interactions with regard to dynamin function is poorly defined. We have investigated a recently identified protein partner of dynamin, SNX9, sorting nexin 9. SNX9 binds directly to both dynamin-1 and dynamin-2. Moreover by stimulating dynamin assembly, SNX9 stimulates dynamin's basal GTPase activity and potentiates assembly-stimulated GTPase activity on liposomes. In fixed cells, we observe that SNX9 partially localizes to clathrin-coated pits. Using total internal reflection fluorescence microscopy in living cells, we detect a transient burst of EGFP-SNX9 recruitment to clathrin-coated pits that occurs during the late stages of vesicle formation and coincides spatially and temporally with a burst of dynamin-mRFP fluorescence. Transferrin internalization is inhibited in HeLa cells after siRNA-mediated knockdown of SNX9. Thus, our results establish that SNX9 is required for efficient clathrin-mediated endocytosis and suggest that it functions to regulate dynamin activity.


Cervical saccular limited dorsal myeloschisis, so-called "cervical myelomeningocele": long-term follow-up of a single-center series and systematic review.
Cervical saccular limited dorsal myeloschisis (LDM), previously so-called "cervical myelomeningocele," is a rare spinal dysraphism. Although the pathogenesis of true myelomeningocele is primary neurulation failure, LDM results from a delayed abnormality during the final stages of neurulation. The aim of the study was to evaluate the outcome of these patients and to assess the correlation of outcomes with the level and type of lesion. Also, pooled data from the literature on similar lesions were systematically reviewed. A retrospective study was conducted at Children's Medical Center (CMC), Tehran, Iran. Information of patients who underwent surgery between 2004 and 2020 (i.e., the recent series) was extracted and combined with data from a previously published series from the same center that were obtained between 2000 and 2003 (CMC series). The literature was reviewed for all published cases, to be combined with the CMC series for further analyses. Twenty-two patients were included in the recent series. Combined with 16 previously published cases, 38 patients with a mean ± SD age at surgery of 11.75 ± 28.64 months were included in the CMC series. The rates of neurological deficit, hydrocephalus, and Chiari malformation type II in the CMC series were 26.32%, 39.47%, and 28.95%, respectively. The lesions were at the upper levels in 17 (44.7%) and lower cervical levels in 21 (55.3%) patients, with 31 cases (81.58%) diagnosed with stalk-type lesions and 7 cases (18.42%) with myelocystocele-type lesions. At final follow-up, 31 patients (81.57%) achieved sphincter continence, and all 36 accessible patients were ambulated, consisting of 28 (73.68%) independent and 8 (21.05%) dependent ambulation patients. The rates of Chiari malformation type II and hydrocephalus were insignificantly higher in patients with upper-level lesions, but those of neurological deficit, ambulation, and sphincter continence were not associated with level. The rates of hydrocephalus (p < 0.01), Chiari type II malformation (p < 0.01), and neurological deficit (p = 0.04) were significantly higher in the myelocystocele group. In the systematic review, 24.77% of patients had neurological deficit. Binary logistic regression showed that older age at surgery (p = 0.03) and associated spinal anomalies (p = 0.04) were significant predictors of deficits. Chiari type II malformation was significantly (p < 0.001) and hydrocephalus was marginally (p = 0.06) more common in patients with myelocystocele-type lesions. The rate of Chiari malformation type II was higher in patients with upper-level lesions (p = 0.02). Patients with cervical saccular LDM had better outcome compared with those patients with true myelomeningocele in more distal areas. According to the current series, most patients obtained ambulation and voiding continence, regardless of the level or type of lesion. Hydrocephalus, Chiari type II malformation, and neurological deficit were more common in patients with myelocystocele-type lesions.


Future Treatment Options in PBC.
Because the etiopathogenesis of PBC is incompletely defined, curative therapies have not been identified, and the focus has been on prevention of disease progression. Ursodeoxycholic acid retards progression and is likely to be combined with newer therapies in future trials. Advances in our understanding of the roles of retroviral infection and autoimmune responses of T and B cells to PBC-specific autoantigens provides rationales for studies of the safety and efficacy of antiretroviral, immunosuppressive, and immunomodulatory agents in PBC. Promising options include inhibition of (1) T-cell activation and proliferation; (2) transendothelial migration and activation of effector cells; (4) cytokine and immunoglobulin effector mechanisms; and (5) inflammation and oxidation. Depletion and immunomodulation of T and B cells may provide opportunities to thwart re-emergence of effector mechanisms. Induction of tolerance in susceptible people before onset of disease or of hyporesponsiveness in established disease is increasingly feasible, as is prevention of biliary fibrosis.


Catenibacterium mitsuokai gen. nov., sp. nov., a gram-positive anaerobic bacterium isolated from human faeces.
Six strains of Eubacterium-like strains from human faeces were characterized by biochemical tests and analysis of cell wall peptidoglycan type and 16S rRNA. They were members of the Clostridium subphylum and have a specific phylogenetic association with Lactobacillus catenaformis and Lactobacillus vitulinus. These organisms resembled L. vitulinus in possessing the same A1gamma type of murein, but they showed different fermentation end-products. On the basis of a 16S rDNA sequence divergence of greater than 8% from L. vitulinus as well as phenotypic characteristics, a new genus, Catenibacterium, with one species (Catenibacterium mitsuokai), is proposed for six strains. The type strain of C. mitsuokai is JCM 10609T.


Vaccinating for Whom? Distinguishing between Self-Protective, Paternalistic, Altruistic and Indirect Vaccination.
Preventive vaccination can protect not just vaccinated individuals, but also others, which is often a central point in discussions about vaccination. To date, there has been no systematic study of self- and other-directed motives behind vaccination. This article has two major goals: first, to examine and distinguish between self- and other-directed motives behind vaccination, especially with regard to vaccinating for the sake of third parties, and second, to explore some ways in which this approach can help to clarify and guide vaccination debates and policy. I propose conceiving of vaccination in terms of three basic elements: the vaccination decision-maker, the vaccine recipient and the primary beneficiary. I develop a taxonomy based on the relations between these elements to distinguish four kinds of vaccination: self-protective, paternalistic, altruistic and indirect. I finally discuss the case of human papillomavirus vaccine regulation for men and women to show how each kind of vaccination is associated with and raises specific ethical questions.


Assessing heterogeneity in the relationship between wheat yield and Fusarium head blight intensity using random-coefficient mixed models.
Seventy-seven studies reporting Fusarium head blight disease index (Y; mean percentage of diseased spikelets per spike) and wheat yield (W; MT/ha) were analyzed to determine the relationship between W and Y, and to assess the degree of variation for the relationship among studies. A linear random-coefficient model-comprising a population-average intercept and slope, a random residual term, and random effects of study on the intercept and slope (best linear unbiased predictors; BLUPs)-was successfully fitted to the data using maximum likelihood. From the predicted random effects, study-specific intercepts and slopes were obtained, and both population-average and subject-specific predictions of yield were determined. The estimated population-average intercept (expected yield when disease symptoms were not present) was 4.10 MT/ha, and the population-average slope was 0.038 MT/ha per unit increase of disease index. Wheat class had a significant effect on the intercept but not on the slope, with soft-red winter wheat having, on average, 0.85 MT/ha higher yield than spring wheat. Based on the estimates of the among-study variances, there was high variation in the effects of study on the intercept, but substantially lower variation in the effects of study on the slope. Thus, although one cannot predict with accuracy the actual wheat yield in a field or plot based on disease index using population-average results, one can predict with accuracy the decline in yield at a given level of disease index using the population-average slope. Through the modeling results, predicted relative yield (as a percentage of yield when disease is not present) can be determined, as well as predicted disease index at which a prespecified level of yield (or yield loss) is expected to occur. The predicted reduction in yield on a percentage scale was greater for spring than for soft-red winter wheat, on average, because of the lower estimated intercept in absolute units for spring wheat.


The zebrafish transcriptome during early development.
The transition from fertilized egg to embryo is accompanied by a multitude of changes in gene expression, and the transcriptional events that underlie these processes have not yet been fully characterized. In this study RNA-Seq is used to compare the transcription profiles of four early developmental stages in zebrafish (Danio rerio) on a global scale. An average of 79 M total reads were detected from the different stages. Out of the total number of reads 65% - 73% reads were successfully mapped and 36% - 44% out of those were uniquely mapped. The total number of detected unique gene transcripts was 11187, of which 10096 were present at 1-cell stage. The largest number of common transcripts was observed between 1-cell stage and 16-cell stage. An enrichment of gene transcripts with molecular functions of DNA binding, protein folding and processing as well as metal ion binding was observed with progression of development. The sequence data (accession number ERP000635) is available at the European Nucleotide Archive. Clustering of expression profiles shows that a majority of the detected gene transcripts are present at steady levels, and thus a minority of the gene transcripts clusters as increasing or decreasing in expression over the four investigated developmental stages. The three earliest developmental stages were similar when comparing highly expressed genes, whereas the 50% epiboly stage differed from the other three stages in the identity of highly expressed genes, number of uniquely expressed genes and enrichment of GO molecular functions. Taken together, these observations indicate a major transition in gene regulation and transcriptional activity taking place between the 512-cell and 50% epiboly stages, in accordance with previous studies.


Analysis of cell-free DNA in maternal blood in screening for fetal aneuploidies: updated meta-analysis.
To review clinical validation or implementation studies of maternal blood cell-free (cf) DNA analysis and define the performance of screening for fetal trisomies 21, 18 and 13 and sex chromosome aneuploidies. Searches of PubMed, EMBASE and The Cochrane Library were performed to identify all peer-reviewed articles on cfDNA testing in screening for aneuploidies between January 2011, when the first such study was published, and 4 January 2015. In total, 37 relevant studies were identified and these were used for the meta-analysis on the performance of cfDNA testing in screening for aneuploidies. These studies reported cfDNA results in relation to fetal karyotype from invasive testing or clinical outcome. Weighted pooled detection rates (DR) and false-positive rates (FPR) in singleton pregnancies were 99.2% (95% CI, 98.5-99.6%) and 0.09% (95% CI, 0.05-0.14%), respectively, for trisomy 21, 96.3% (95% CI, 94.3-97.9%) and 0.13% (95% CI, 0.07-0.20) for trisomy 18, 91.0% (95% CI, 85.0-95.6%) and 0.13% (95% CI, 0.05-0.26%) for trisomy 13, 90.3% (95% CI, 85.7-94.2%) and 0.23% (95% CI, 0.14-0.34%) for monosomy X and 93.0% (95% CI, 85.8-97.8%) and 0.14% (95% CI, 0.06-0.24%) for sex chromosome aneuploidies other than monosomy X. For twin pregnancies, the DR for trisomy 21 was 93.7% (95% CI, 83.6-99.2%) and the FPR was 0.23% (95% CI, 0.00-0.92%). Screening for trisomy 21 by analysis of cfDNA in maternal blood is superior to that of all other traditional methods of screening, with higher DR and lower FPR. The performance of screening for trisomies 18 and 13 and sex chromosome aneuploidies is considerably worse than that for trisomy 21.


Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD.
Autosomal dominant polycystic kidney disease (ADPKD), caused by mutation in PKD1 or PKD2, is usually an adult-onset disorder but can rarely manifest as a neonatal disease within a family characterized by otherwise typical ADPKD. Coinheritance of a hypomorphic PKD1 allele in trans with an inactivating PKD1 allele is one mechanism that can cause early onset ADPKD. Here, we describe two pedigrees without a history of cystic kidney disease that each contain two patients with onset of massive PKD in utero. The presentations were typical of autosomal recessive PKD (ARPKD) but they were not linked to the known ARPKD gene, PKHD1. Mutation analysis of the ADPKD genes provided strong evidence that both families inherited, in trans, two incompletely penetrant PKD1 alleles. These patients illustrate that PKD1 mutations can manifest as a phenocopy of ARPKD with respect to renal involvement and highlight the perils of linkage-based diagnostics in ARPKD without positive PKHD1 mutation data. Furthermore, the phenotypic overlap between ARPKD and these patients resulting from incomplete penetrant PKD1 alleles support a common pathogenesis for these diseases.


In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent.
One of the cardinal pathologic features of Alzheimer's disease (AD) is the formation of senile, or amyloid, plaques. Transgenic mice have been developed that express one or more of the genes responsible for familial AD in humans. Doubly transgenic mice develop "human-like" plaques, providing a mechanism to study amyloid plaque biology in a controlled manner. Imaging of labeled plaques has been accomplished with other modalities, but only MRI has sufficient spatial and contrast resolution to visualize individual plaques noninvasively. Methods to optimize visualization of plaques in vivo in transgenic mice at 9.4 T using a spin echo sequence based on adiabatic pulses are described. Preliminary results indicate that a spin echo acquisition more accurately reflects plaque size, while a T2* weighted gradient echo sequence reflects plaque iron content, not plaque size. In vivo MRI-ex vivo MRI-in vitro histologic correlations are provided. Histologically verified plaques as small as 50 microm in diameter were visualized in living animals. To our knowledge this work represents the first demonstration of noninvasive in vivo visualization of individual AD plaques without the use of a contrast agent.


Formulation approaches to pediatric oral drug delivery: benefits and limitations of current platforms.
Most conventional drug delivery systems are not acceptable for pediatric patients as they differ in their developmental status and dosing requirements from other subsets of the population. Technology platforms are required to aid the development of age-appropriate medicines to maximize patient acceptability while maintaining safety, efficacy, accessibility and affordability. The current approaches and novel developments in the field of age-appropriate drug delivery for pediatric patients are critically discussed including patient-centric formulations, administration devices and packaging systems. Despite the incentives provided by recent regulatory modifications and the efforts of formulation scientists, there is still a need for implementation of pharmaceutical technologies that enable the manufacture of licensed age-appropriate formulations. Harmonization of endeavors from regulators, industry and academia by sharing learning associated with data obtained from pediatric investigation plans, product development pathways and scientific projects would be the way forward to speed up bench-to-market age appropriate formulation development. A collaborative approach will benefit not only pediatrics, but other patient populations such as geriatrics would also benefit from an accelerated patient-centric approach to drug delivery.


Consumption of 100% Tart Cherry Juice Reduces Serum Urate in Overweight and Obese Adults.
Gout is a frequently occurring, complex rheumatologic form of inflammatory arthritis caused by the accumulation of serum uric acid (sUA) and deposition of uric acid crystals in the joints and tissues of the body. Hyperuricemia is also a significant independent risk factor for all-cause and cardiovascular morbidity and mortality and is associated with hypertension, diabetes, obesity, and osteoarthritis. However, patient adherence to prescribed urate-lowering therapies ranges from 20% to 70%, suggesting that other additional strategies, such as dietary intervention with specific, efficacious foods or beverages, may be necessary to mitigate the risk of arthritis, as well as other comorbidities. Tart cherry juice (TCJ) has been used for decades by some for gout based largely on anecdotal evidence of its efficacy and its antioxidant and anti-inflammatory properties. We designed this study to test the effect of TCJ on uricemia, lipidemia, glycemia, and inflammation in at-risk overweight and obese humans with a specific hypothesis that TCJ consumption would reduce sUA concentrations. In this randomized, placebo-controlled crossover study, we recruited overweight and obese participants with body mass index (BMI) >25.0 kg/m2 (n = 26, 18 women/8 men, 41 ±11 y; BMI 31.3 ± 6.0; 12 obese, 14 overweight) to consume 240 mL/d (8 oz/d) of either TCJ or placebo beverage, for 4 wk each with a 4-wk intervening washout period followed by 4 wk of the alternate beverage. TCJ significantly reduced sUA concentration by 19.2% (P < 0.05) and reduced by 19.4% (P = 0.09) and 6.3% (P = 0.08) proinflammatory high-sensitivity C-reactive protein and monocyte chemoattractant protein-1, respectively. The participants in this study displayed risk ratios indicating increased cardiovascular disease risk and insulin resistance but no differences in the pre- and postintervention groups of either placebo or TCJ groups. Collectively, the data suggest that 100% TCJ reduces sUA concentrations, mitigating hyperuricemia associated with gouty arthritis. This trial was registered at clinicaltrials.gov as NCT03636529.


Assessing the impact of human trampling on vegetation: a systematic review and meta-analysis of experimental evidence.
Vegetation trampling resulting from recreation can adversely impact natural habitats, leading to the loss of vegetation and the degradation of plant communities. A considerable primary literature exists on this topic, therefore it is important to assess whether this accumulated evidence can be used to reach general conclusions concerning vegetation vulnerability to inform conservation management decisions. Experimental trampling studies on a global scale were retrieved using a systematic review methodology and synthesised using random effects meta-analysis. The relationships between vegetation recovery and each of initial vegetation resistance, trampling intensity, time for recovery, Raunkiaer life-form (perennating bud position), and habitat were tested using random effects multiple meta-regressions and subgroup analyses. The systematic search yielded 304 studies; of these, nine reported relevant randomized controlled experiments, providing 188 vegetation recovery effect sizes for analysis. The synthesis indicated there was significant heterogeneity in the impact of trampling on vegetation recovery. This was related to resistance and recovery time, and the interactions of these variables with Raunkiaer life-form, but was not strongly dependent on the intensity of the trampling experienced. The available evidence suggests that vegetation dominated by hemicryptophytes and geophytes recovers from trampling to a greater extent than vegetation dominated by other life-forms. Variation in effect within the chamaephyte, hemicryptophyte and geophyte life-form sub-groups was also explained by the initial resistance of vegetation to trampling, but not by trampling intensity. Intrinsic properties of plant communities appear to be the most important factors determining the response of vegetation to trampling disturbance. Specifically, the dominant Raunkiaer life-form of a plant community accounts for more variation in the resilience of communities to trampling than the intensity of the trampling experienced, suggesting that simple assessments based on this trait could guide decisions concerning sustainable access to natural areas. Methodological and reporting limitations must be overcome before more disparate types of evidence can be synthesised; this would enable more reliable extrapolation to non-study situations, and a more comprehensive understanding of how assessments of intrinsic plant traits can be used to underpin conservation management decisions concerning access.


Palbociclib has antitumour effects on Pten-deficient endometrial neoplasias.
PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1-CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD-332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen-inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten-deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D-CDK4/6 activity in their development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Errors in laparoscopic surgery.
Laparoscopic surgery is the most significant advancement in the field of surgery over the past 15 years. This minimal access approach has been widely embraced and adopted to many common operations. Demonstrated benefits include decreased post-operative pain, shorter lengths of in-patient hospitalization, increased patient acceptance, and a more rapid return to gainful employment. With its ever-growing popularity, it has become fertile ground for civil litigation, ranking along with birth injuries and failure to diagnose cancer. A brief synopsis of the history of its evolution is presented along with general and specific comments concerning potential errors as they relate to specific common operations which are commonly done utilizing this technique.


[Diagnosis, procedures and conservative therapy of a bronchial rupture after intubation with double-lumen tube].
Bronchial rupture is a rare but severe complication of intubation with a double-lumen tube. Cardinal symptoms are mediastinal and subcutaneous emphysema as well as pneumothorax. Larger injuries result in an air leak and the endtidal carbon dioxide decreases. The gas exchange may worsen drastically when mucosal prolapse or bronchial haemorrhagia lead to bronchial occlusion. Mediastinitis or sepsis can be the sequel of the opened mediastinum. If bronchial injury is suspected probably fibreoptic bronchoscopy is indicated. We report on a case of bronchial rupture due to overinflation of the endobronchial cuff or movement of the inflated cuff when repositioning the patient. The conservative therapy was successful in spite of the fact that surgical intervention is recommended in the literature following bronchial rupture. To avoid tracheobronchial injuries an adequate tubus size must be selected. The more flexible polyvinylchloride (PVC) tubes without a carinal hook should be preferred to the Carlens tube. An atraumatic intubation is promoted by leaving the stylet inside after the tip of the tube has passed the vocal cords. To identify the minimum occlusive pressure of the endobronchial cuff for lung isolation different methods are described and should be used. The cuff has to be deflated when the patient is repositioned and when one-lung-ventilation is not required. Tumours of the tracheobronchial tree and weakness of the bronchial wall caused by steroid hormone therapy or COPD may increase the risk of tracheobronchial laceration.


[Stereologic analysis of vacuolization of the T-system of frog muscle fibers, detected using confocal fluorescence microscopy].
The confocal fluorescence microscopy has been used for quantitative evaluation of the T-system reversible vacuoles produced by efflux of 80-120 mM glycerol from frog skeletal muscle fibers. The fibers were stained by membrane probe RH414 and by water-soluble dye fluorescein dextran that marks the vacuolar lumen. Using morphometrical and stereological methods the volume and surface densities of vacuoles were measured on single optical sections and Z-series during a 30 min glycerol efflux. Various methods of measurements (three-dimensional reconstruction of vacuoles, computer morphometry, point counting method) applied to the same Z-series provide similar results. The vacuolar membranes stained by RH414 look like bright rings 0.3-0.4 micron in width. It is concluded that the real position of vacuolar membrane corresponds to the middle of the vacuolar envelope. The measurements of the external dimensions of the envelope overestimate the stereological parameters up to 50%. The volume density of vacuoles reaches 10% within 20-30 min of glycerol efflux. It means that the volume of the T-system may increase by 25-30 times compared to the control value (0.3-0.4%). The surface density of vacuoles during reversible vacuolation is equal to 0.20-0.35 micron-1 and does not exceed the surface density of normal T-system. The sufficiency of membrane material for the T-system reversible vacuolation is discussed in addition to the role of geometrical factor in this phenomenon.


Metabolic Signature of Pluripotent Stem Cells.
Pluripotent stem cells (PSCs), with the capacity to self-renew and differentiate into all other cell types, are of benefit in regenerative medicine applications. Tightly controlled gene expression networks and epigenetic factors regulate these properties. In this study, we aim to evaluate the metabolic signature of pluripotency under 2i and R2i culture conditions versus serum condition. In this experimental study, we investigated bioinformatics analysis of the shotgun proteomics data for cells grown under 2i, R2i, and serum culture conditions. The findings were validated by cell cycle analysis and gene expressions of the cells with flow cytometry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. Expressions of 163 proteins increased in 2i-grown cells and 181 proteins increased in R2i-grown cells versus serum, which were mostly involved in glycolysis signaling pathway, oxidation-reduction, metabolic processes, amino acid and lipid metabolism. Flow cytometry analysis showed significant accumulation of cells in S phase for 2i (70%) and R2i (61%) grown cells. This study showed that under 2i and R2i conditions, glycolysis was highlighted for energy production and used to maintain high levels of glycolytic intermediates to support cell proliferation. Cells grown under 2i and R2i conditions showed rapid cell cycling in comparison with the cells grown under serum conditions.


Phase I study of metformin in combination with carboplatin/paclitaxel chemotherapy in patients with advanced epithelial ovarian cancer.
Background Metformin use is associated with reduced cancer risk in epidemiological studies and has preclinical anti-cancer activity in ovarian cancer models. The primary objective of this phase I study was to determine the recommended phase II dose (RP2D) of metformin in combination with carboplatin/paclitaxel in patients with ovarian cancer. Secondary objectives were to describe safety and pharmacokinetics. Methods In this single-center trial the RP2D of metformin in combination with carboplatin area under the concentration-time curve (AUC) 6 and paclitaxel 175 mg/m2 every 3 weeks (q3w) in patients with advanced epithelial ovarian cancer was determined using a 3 + 3 escalation rule at three fixed dose levels: 500 mg three times daily (tds), 850 mg tds and 1000 mg tds. Metformin was commenced on day 3 of cycle 1 and continued until 3 weeks after the last chemotherapy administration. The RP2D was defined as the dose level at which 0 of 3 or ≤ 1 of 6 evaluable subjects experienced a metformin-related dose-limiting toxicity (DLT). Safety was assessed according to CTCAE v4.0. Plasma and serum samples for pharmacokinetic (PK) analyses were collected during treatment cycles 1 and 2. Results Fifteen patients with epithelial ovarian cancer and an indication for neo-adjuvant (n = 5) or palliative (n = 10) treatment were included. No DLTs were observed. Three patients discontinued study treatment during cycle 1 for other reasons than DLT. Six patients were treated at the RP2D of metformin 1000 mg tds. The most frequent low-grade toxicities were anemia, hypomagnesemia and diarrhea. Grade 3 adverse events (AEs) occurred in ten patients, most common were leucopenia (n = 4), thrombocytopenia (n = 3) and increased GGT (n = 3). There were no grade 4 AEs. Metformin increased the platinum (Pt) AUC (Δ22%, p = 0.013) and decreased the Pt clearance (Δ-28%, p = 0.013). Metformin plasma levels were all within the therapeutic range for diabetic patients (0.1-4 mg/L). Conclusion The RP2D of metformin in combination with carboplatin and paclitaxel in advanced ovarian cancer is 1000 mg tds. This is higher than the RP2D reported for combination with targeted agents. A potential PK interaction of metformin with carboplatin was identified.


Protein homeostasis as a therapeutic target for diseases of protein conformation.
Protein misfolding and aggregation are widely implicated in an increasing number of human diseases providing for new therapeutic opportunities targeting protein homeostasis (proteostasis). The cellular response to proteotoxicity is highly regulated by stress signaling pathways, molecular chaperones, transport and clearance machineries that function as a proteostasis network (PN) to protect the stability and functional properties of the proteome. Consequently, the PN is essential at the cellular and organismal level for development and lifespan. However, when challenged during aging, stress, and disease, the folding and clearance machineries can become compromised leading to both gain-of-function and loss-of-function proteinopathies. Here, we assess the role of small molecules that activate the heat shock response, the unfolded protein response, and clearance mechanisms to increase PN capacity and protect cellular proteostasis against proteotoxicity. We propose that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated with the variety of protein conformational diseases.


Pre-lysosomal divergence of alpha 2-macroglobulin and transferrin: a kinetic study using a monoclonal antibody against a lysosomal membrane glycoprotein (LAMP-1).
We have used electron microscopic immunocytochemistry to compare the distribution of LAMP-1, a marker for lysosomal membranes, with the intracellular localization of alpha 2-macroglobulin (alpha 2-M) and transferrin at various time points after their endocytosis into cultured NIH 3T3 cells. The purposes of this study were (a) to determine how soon endocytic ligands reach lysosomal organelles, (b) to examine whether the intermediate endocytic vesicles gained lysosomal markers gradually or in a precipitous, discrete event, and (c) to examine the relationship, if any, between the pathway of recycling ligands and lysosomes. At early time points (0-5 min) after initiation of endocytosis, most structures containing alpha 2-M labeled with colloidal gold (receptosomes) were not labeled by anti-LAMP-1 detected using ferritin bridge or peroxidase immunocytochemistry. At late time points (greater than or equal to 15 min), the structures containing alpha 2-M (lysosomes) were strongly labeled by anti-LAMP-1. In contrast, transferrin that was directly labeled with ferritin was mostly located in LAMP-1-negative structures at all time points studied. The proportion of alpha 2-M-gold containing vesicles strongly labeled for LAMP-1 roughly paralleled the proportion of alpha 2-M-gold-containing structures positive for cytochemically detectable acid phosphatase. Our data indicate that ligands such as transferrin that are internalized through coated pits and receptosomes, but not delivered to lysosomes, do not traverse a lysosomal organelle compartment as marked by LAMP-1 content. Ligands such as alpha 2-M that are destined for lysosomal delivery reach a LAMP-1-positive organelle compartment only after they traverse LAMP-1-negative, non-lysosomal vesicles previously described as receptosomes.


Tangzhiqing decoction attenuates cognitive dysfunction of mice with type 2 diabetes by regulating AMPK/mTOR autophagy signaling pathway.
Tangzhiqing decoction (TZQD) is an effective prescription developed by Jiangsu Province Hospital of Chinese Medicine for the treatment of diabetes mellitus (DM) and its complications, which has a clear cerebral protective effect on mice with diabetic cognitive dysfunction, but its specific mechanism has not been well elucidated. This study aims to verify the protection of TZQD on cognitive function in mice with type 2 diabetes mellitus (T2DM) and explore the possible underlying mechanisms. Six active ingredients in TZQD were detected using high-performance liquid chromatography analysis. In vivo experiments, the protection of TZQD on cognitive function and hippocampal neurons in type 2 diabetes mice was verified to obtain the optimal intervention dose of TZQD. TZQD and 3-methyladenine (3 MA) respectively or jointly intervened in mice with T2DM for 12 weeks, followed by detecting the cognitive difference, hippocampus cornu ammonis 1 (CA1) region injury, and hippocampal neuronal apoptosis in each group. Simultaneously, the investigation of autophagosome formation and organelle impairment in hippocampal neurons, along with the examination of AMPK/mTOR pathway proteins and autophagy-related proteins, was conducted to elucidate the potential mechanisms, through which TZQD modulates autophagy and enhances cognitive function. In vitro experiments, TZQD-containing serum and AMPK inhibitor Compound C (CC) were used to intervene in mouse hippocampal neuron HT22 cells under high glucose environment, further clarifying the regulatory role of TZQD on the AMPK/mTOR pathway and its impact on HT22 cell apoptosis and autophagy. In vivo experiment results showed that TZQD had an obvious hypoglycemic effect. Different doses of TZQD could improve cognitive function and hippocampus damage in diabetes mice, with the middle dose of TZQD showing the best effect. TZQD increased the swimming speed of diabetes mice, improved their spatial recognition and memory ability, and reduced hippocampal neuronal apoptosis, Nissl body injury, and p-tau217 protein deposition. In addition, through transmission electron microscopy (TEM), immunofluorescence, and Western blot (WB) detection, TZQD significantly improved the organelle damage of hippocampal neurons in diabetes mice, promoted the formation of autophagy lysosomes, increased the expression of autophagy-related proteins like Beclin 1, LC3II/LC3I, LAMP1, and LAMP2, reduced the level of P62 and promoted autophagy flow, which, however, were all significantly weakened by 3 MA. Meanwhile, TZQD regulated the expressions of AMPK/mTOR pathway proteins. In vitro experimental study results showed that TZQD can regulate the expression ratio of p-AMPK/AMPK alpha 1 and p-mTOR/mTOR in HT22 cells under high glucose conditions and improved the morphology and vitality of HT22 cells. By employing techniques such as monodansylcadaverine (MDC) staining, Lysosomal red fluorescent probe staining, and Annexin V-FITC/PI double staining, the investigation revealed that TZQD administration resulted in enhanced autophagosome formation, preservation of a lysosomal acidic milieu, and consequent mitigation of HT22 cell apoptosis under high glucose conditions. TZQD can regulate the AMPK/mTOR pathway to activate autophagy to attenuate hippocampal neuronal apoptosis, thereby protecting cognitive function in diabetic mice.


One health behavior or many health-related behaviors?
Of the many existing health models, models of health behavior are considered optimal for research and application as they focus on concrete forms of behavior that support, maintain, or undermine one's health, and they accentuate the individual as the initiator of this behavior. Research in this area follows a broad range of concrete partial manifestations of health behavior. Is it necessary to differentiate between various types of health behavior or could these partial manifestations be combined under one common scale? Data acquisition tool: Health-Related Behavior Scale (HRBS, 42 items). Data processing methods: principal component analysis (the internal structure of HRBS), confirmatory factor analysis (the latent factor structure of four tested models). Sample: N=1,664 adult respondents. The HRBS described ten areas of health-related behavior (ten extracted factors). All tested models of latent structure showed almost identical mathematical and statistical values of the model. Health-related behavior includes a set of partial behaviors (behavior related to nutrition, addictive substances, movement, and physical exercises). An unambiguous latent factor structure has not been revealed. An open question remains whether there is one latent factor behind all health-related behaviors or whether there are multiple latent factors. The use of one or the other model should be deduced from the underlying theory and research objectives. To find a reliable model of health behavior, it is necessary to include moderators and mediators such as personality, attitude, or economic status.


Exogenous Ca2+ priming can improve peanut photosynthetic carbon fixation and pod yield under early sowing scenarios in the field.
Harnessing cold-resilient and calcium-enriched peanut production technology are crucial for high-yielding peanut cultivation in high-latitude areas. However, there is limited field data about how exogenous calcium (Ca2+) application would improve peanut growth resilience during exposure to chilling stress at early sowing (ES). To help address this problem, a two-year field study was conducted to assess the effects of exogenous foliar Ca2+ application on photosynthetic carbon fixation and pod yield in peanuts under different sowing scenarios. We measured plant growth indexes, leaf photosynthetic gas exchange, photosystems activities, and yield in peanuts. It was indicated that ES chilling stress at the peanut seedling stage led to the reduction of Pn, gs, Tr, Ls, WUE, respectively, and the excessive accumulation of non-structural carbohydrates in leaves, which eventually induced a chilling-dependent feedback inhibition of photosynthesis due mainly to weaken growth/sink demand. While exogenous Ca2+ foliar application improved the export of nonstructural carbohydrates, and photosynthetic capacity, meanwhile activated cyclic electron flow, thereby enhancing growth and biomass accumulation in peanut seedlings undergoing ES chilling stress. Furthermore, ES combined with exogenous Ca2+ application can significantly enhance plant chilling resistance and peanut yield ultimately in the field. In summary, the above results demonstrated that exogenous foliar Ca2+ application restored the ES-linked feedback inhibition of photosynthesis, enhancing the growth/sink demand and the yield of peanuts.


Serological survey of avian H5N2-subtype influenza virus infections in human populations.
To investigate the distribution of antibodies against H5N2 influenza virus in humans living in Ibaraki prefecture, Japan, 266 single serum samples were collected to perform serological tests. Results were compared to investigate the relationship between positive results and several factors. The number of positive serum neutralization antibody titers (> or = 40) against avian influenza virus A/H5N2 was significantly greater (P < 0.05) among poultry workers, in comparison to a Japanese healthy population. The geometric mean titers of serum neutralization antibody against A/H5N2 were significantly higher (P < 0.05) among Ibaraki inhabitants and poultry workers (P < 0.0001) when compared to a Japanese healthy population. Seropositivity against A/H5N2 virus was significantly (P < 0.05) associated with age (> or = 50 years old) in poultry workers. These results suggest that seropositivity against H5N2 virus in Ibaraki specimens is significantly higher than those of a Japanese healthy population and that the surveillance of avian influenza viruses is very important to evaluate the invasion or emergence of new pandemic influenza viruses from species other than humans.


The pragmatist's guide to comparative effectiveness research.
Following an acrimonious health care reform debate involving charges of "death panels," in 2010, Congress explicitly forbade the use of cost-effectiveness analysis in government programs of the Patient Protection and Affordable Care Act. In this context, comparative effectiveness research emerged as an alternative strategy to understand better what works in health care. Put simply, comparative effectiveness research compares the efficacy of two or more diagnostic tests, treatments, or health care delivery methods without any explicit consideration of costs. To economists, the omission of costs from an assessment might seem nonsensical, but we argue that comparative effectiveness research still holds promise. First, it sidesteps one problem facing cost-effectiveness analysis--the widespread political resistance to the idea of using prices in health care. Second, there is little or no evidence on comparative effectiveness for a vast array of treatments: for example, we don't know whether proton-beam therapy, a very expensive treatment for prostate cancer (which requires building a cyclotron and a facility the size of a football field) offers any advantage over conventional approaches. Most drug studies compare new drugs to placebos, rather than "head-to-head" with other drugs on the market, leaving a vacuum as to which drug works best. Finally, the comparative effectiveness research can prove a useful first step even in the absence of cost information if it provides key estimates of treatment effects. After all, such effects are typically expensive to determine and require years or even decades of data. Costs are much easier to measure, and can be appended at a later date as financial Armageddon draws closer.


Substrate dependence of angiotensin I-converting enzyme inhibition: captopril displays a partial selectivity for inhibition of N-acetyl-seryl-aspartyl-lysyl-proline hydrolysis compared with that of angiotensin I.
Angiotensin I-converting enzyme (ACE) is composed of two highly similar domains (referred to here as the N and C domains) that play a central role in blood pressure regulation; ACE inhibitors are widely used in the treatment of hypertension. However, the negative regulator of hematopoiesis, N-acetyl-seryl-aspartyl-lysyl-prolyl (AcSDKP), is a specific substrate of the N domain-active site; thus, in addition to the cardiovascular function of ACE, the enzyme may be involved in hematopoietic stem cell regulation, raising the interest of designing N domain-specific ACE inhibitors. We analyzed the inhibition of angiotensin I and AcSDKP hydrolysis as well as that of three synthetic ACE substrates by wild-type ACE and the N and C domains by using a range of specific ACE inhibitors. We demonstrate that captopril, lisinopril, and fosinoprilat are potent inhibitors of AcSDKP hydrolysis by wild-type ACE, with K(i) values in the subnanomolar range. However, of the inhibitors tested, captopril is the only compound able to differentiate to some degree between AcSDKP and angiotensin I inhibition of hydrolysis by wild-type ACE: the K(i) value with AcSDKP as substrate was 16-fold lower than that with angiotensin I as substrate. This raises the possibility of using captopril to enhance plasma AcSDKP levels with the aim of normal hematopoeitic stem cell protection during chemotherapy and a limited effect on the cardiovascular function of ACE.


The biology of the platelet with special reference to inflammation, wound healing and immunity.
While platelets have long been known to be essential for maintaining hemostasis in the vasculature, their role in tissue repair, inflammation and innate and adaptive immunity is a more recent science. The ability of platelets to attach to the vessel wall, form aggregates and promote fibrin formation, key elements of blood clotting, has been said to both favor and dampen inflammation, to fight infection and to assure an adequate immune response. To fulfill their different roles platelets often synchronize with leukocytes and cells of the immune system. But just as the molecular pathways of platelets in preventing blood loss can lead to arterial thrombosis and stroke if occurring in an uncontrolled manner, the failure to control inflammation can lead to sepsis and inadequate platelet function and can aggravate many major illnesses. This review is aimed to present a global picture of multifaceted platelet biology and platelet involvement in selected non-hemostatic events.


Reactive oxygen species mediate p53 activation and apoptosis induced by sodium nitroprusside in SH-SY5Y cells.
Sodium nitroprusside (SNP) is a water-soluble iron nitrosyl complex clinically used as a powerful vasodilator for treatment of hypertension; and, in basic research, it has been used to mainly investigate the cytotoxic effects of nitrosative stress. Although NO is considered a pharmacologically active molecule, not all of the biological effects of SNP are dependent on its NO moiety. To elucidate the molecular executioner(s) responsible for SNP cytotoxicity, this study determines the involvement of oxidative stress in p53 activation and apoptotic induction elicited by SNP in SH-SY5Y neuroblastoma cells. We demonstrate that proapoptotic activity of SNP is independent of NO production, because SNP and its 2-day light-exhausted compound SNP(ex) trigger apoptosis to the same extent. We provide evidence for the occurrence of oxidative stress and oxidative damage during both SNP and SNP(ex) exposure and demonstrate that iron-derived reactive oxygen species (ROS) are the genuine mediators of their cytotoxicity. We show that p53 is equally activated upon both SNP and SNP(ex) treatments. Moreover, as demonstrated by small interfering RNA experiments, we indicate its primary role in the induction of apoptosis, suggesting the ineffectiveness of NO in its engagement. The attenuation of p53 levels, obtained by oxy-radical scavengers, is consistent with the recovery of cell viability and ROS decrease, demonstrate that SNP-mediated p53 activation is an event triggered by ROS and/or ROS-mediated damages. Together, our results suggest that investigations of the physiopathological effects of SNP should consider the role of ROS, other than NO, particularly in some conditions such as apoptotic induction and p53 activation.


[Genetic aspects of aging].
State of art in genetic of ageing is reviewed. Deciphering of human genome and recent advances in functional genomics contributed a lot to significant achievements in molecular medicine as well as in understanding of ageing mechanisms. Progressive transcriptome degeneration caused by expression modulations of specific aging genes underlies visible physiological, biochemical and hormonal changes in aging human bodies. Each human subject should be considered as physiological mosaic composed of the tissues and organs of different age. The existence of weak genetic chain confined to particular organ or tissue provides potential substrate for severe chronic disorders in aging people. Two main groups of the aging genes are highlighted: 1. Longevity genes identified in population studies of old people, and 2. The genes identified and proved in aging studies in experimental species. Already existing and feasible molecular approaches for extending of active human longevity are reviewed. They include targeted modulation of aging gene activity, as well as presymptomatic diagnostics and relevant preventive measures of severe and frequent multifactorial diseases. Combining of already known empirical methods of anti-aging medicine with unique genetic profile of each human (gene-pass) renders new awarding opportunities for the further advancements of human longevity programs.


Darkling beetles (Alphitobius diaperinus) and their larvae as potential vectors for the transfer of Campylobacter jejuni and Salmonella enterica serovar paratyphi B variant Java between successive broiler flocks.
Broiler flocks often become infected with Campylobacter and Salmonella, and the exact contamination routes are still not fully understood. Insects like darkling beetles and their larvae may play a role in transfer of the pathogens between consecutive cycles. In this study, several groups of beetles and their larvae were artificially contaminated with a mixture of Salmonella enterica serovar Paratyphi B Variant Java and three C. jejuni strains and kept for different time intervals before they were fed to individually housed chicks. Most inoculated insects were positive for Salmonella and Campylobacter just before they were fed to the chicks. However, Campylobacter could not be isolated from insects that were kept for 1 week before they were used to mimic an empty week between rearing cycles. All broilers fed insects that were inoculated with pathogens on the day of feeding showed colonization with Campylobacter and Salmonella at levels of 50 to 100%. Transfer of both pathogens by groups of insects that were kept for 1 week before feeding to the chicks was also observed, but at lower levels. Naturally contaminated insects that were collected at a commercial broiler farm colonized broilers at low levels as well. In conclusion, the fact that Salmonella and Campylobacter can be transmitted via beetles and their larvae to flocks in successive rearing cycles indicates that there should be intensive control programs for exclusion of these insects from broiler houses.


Suicidal expressions in young Swedish Sami, a cross-sectional study.
To investigate the experience of suicidal expressions (death wishes, life weariness, ideation, plans and attempts) in young Swedish Sami, their attitudes toward suicide (ATTS), and experience of suicidal expressions and completed suicide in significant others and to compare with Swedes in general. A cross-sectional study comprising 516 Swedish Sami, 18-28 years of age together with an age and geographically matched reference group (n=218). Parts of the ATTS questionnaire have been used to cover different aspects of the suicidal complex. Data were analysed with regard to gender, occupation, counties and experience of negative societal treatment due to Sami background. Both young Sami and young Swedes reported suicidal ideation, life weariness, and death wishes in a high degree (30-50%), but it was more common among the Sami. Having had plans to commit suicide showed a significant gender difference only in the Sami. The prevalence of suicide attempts did not differ significantly between Sami and Swedes. Subgroups of the Sami reported a higher degree of suicidal behaviour, Sami women and reindeer herders reported a 3, 5-fold higher odds of suicide attempts and a 2-fold higher odds having had plans committing suicide. Sami living in Vasterbotten/Jamtland/Vasternorrland and Sami with experience of ethnicity related bad treatment 2-fold higher odds of suicidal plans compared to those living in other counties. An increased occurrence of suicidal ideation/death wishes/life weariness in young Sami compared to young majority Swedes was found, but not an increased prevalence of suicide attempts and positive attitudes together with an increased awareness to handle suicide problems could be a contributing factor. Severe circumstances and experience of ethnicity-related bad treatment seems to contribute to increased levels of suicidal plans and attempts in subgroups of Sami.


The role of posteriorly directed shear loads acting on a pre-rotated growing spine: a hypothesis on the pathogenesis of idiopathic scoliosis.
Despite years of extensive research, the etiology of idiopathic scoliosis still has not been resolved. A hypothesis on the role of posteriorly directed shear loads was studied in several biomechanical and imaging studies. So far, it has been shown that: on the human erect spine these posteriorly directed shear loads act; these loads decrease the rotational stability of the spine vitro and in vivo; once rotation occurs, it logically follows an already built-in vertebral rotational pattern, that is pre-existent in the human spine; this pre-existent rotational pattern is related to organ anatomy, and not to handedness; certain areas in the female spine are more subject to posteriorly directed shear loads as certain areas in the female spine are more backwardly inclined. Although it is appreciated that the cause of idiopathic scoliosis is multi-factorial, we believe that the delicate upright spinal sagittal balance and the unique posteriorly directed shear loads acting on the erect human spine play a crucial role in the rotational stability of the human spine, and thus in the pathogenesis of idiopathic scoliosis.


Coexistence of longitudinally extensive transverse myelitis and diffuse midline glioma in the brainstem in an adolescent boy with acute flaccid paralysis.
We present the case of a previously healthy 13-year-old boy who was admitted to the emergency department with acute flaccid paralysis. Magnetic resonance imaging revealed radiological evidence of longitudinally extensive transverse myelitis. Additionally, homogeneous T2 signal increase was observed in the pons and medulla oblongata, initially indicating brainstem encephalitis. Subsequent evaluations confirmed a coexistence of diffuse midline glioma (DMG) in the brain stem alongside acute transverse myelitis (ATM). Children with ATM generally have a more favorable prognosis than adults. However, despite the implementation of advanced treatment methods, the patient's quadriplegia did not improve and resulted in spinal cord sequela atrophy. DMG exhibits an aggressive growth pattern and lacks a known curative treatment. This case represents an exceedingly rare synchronous occurrence of aggressive conditions, underscoring the importance of raising awareness among physicians. Furthermore, we aim to discuss the radiologic differential diagnosis, as this is the first documented instance in the literature.


Methylene Blue for Vasoplegic Syndrome.
Vasoplegic syndrome is a form of vasodilatory shock that occurs frequently in patients who undergo cardiac surgery requiring cardiopulmonary bypass (CBP). Treatment often demands high doses of vasopressors over sustained periods for hypotension that can be refractory to standard vasoactive medications. Furthermore, the development of vasoplegia greatly contributes to morbidity and mortality following cardiac surgery. Methylene blue (MB) has become a popular therapy for cardiac vasoplegia despite a paucity of prospective data to direct its use. Therefore, the aim of this study was to review available data regarding mechanisms, dosing strategies, and side effects of MB, with a focus on its applications for vasoplegia in cardiac surgery.


Investigation of Size Effects in Multi-Stage Cold Forming of Metallic Micro Parts from Sheet Metal.
Product miniaturisation and functional integration are currently global trends to save weight, space, materials and costs. This leads to an increasing demand for metallic micro components. Thus, the development of appropriate production technologies is in the focus of current research activities. Due to its efficiency, accuracy and short cycle times, microforming at room temperature offers the potential to meet the steadily increasing demand. During microforming, size effects occur which negatively affect the part quality, process stability, tool life and handling. Within this contribution, a multi-stage bulk microforming process from sheet metal is investigated for the materials Cu-OFE and AA6014 with regard to the basic feasibility and the occurrence of size effects. The results reveal that the process chain is basically suitable to produce metallic micro parts with a high repeatability. Size effects are identified during the process. Since several studies postulate that size effects can be minimised by scaling down the metallic grain structure, the grain size of the aluminium material AA6014-W is scaled down to less than one micrometre by using an accumulative roll bonding process (ARB). Subsequently, the effects of the ultrafine grain (UFG) structure on the forming process are analysed. It could be shown that a strengthened material state increases the material utilization. Furthermore, too soft materials can cause damage on the part during ejection. The occurring size effects cannot be eliminated by reducing the grain size.


Coping with pediatric migraine.
Strategies used by latency-aged children to cope with pediatric migraine pain are identified in this exploratory study. The following three broad categories of coping and their subtypes emerged from the data: affective, cognitive, and problem-focused coping. Implications for practice, research, and education, particularly regarding the use of spirituality and prevention, are discussed.


Effects of coordination sphere on unusually large zero field splitting and slow magnetic relaxation in trigonally symmetric molecules.
Geometric control in mononuclear complexes has come to the forefront in the field of molecular magnets due to its profound effects on relaxation pathways and blocking temperature in single molecule magnets (SMMs). Herein we report the synthesis and magnetic characterization of six trigonally symmetric, divalent Fe, Co, and Ni molecules, with the rigid geometry enforced via the use of the tris-anionic, tetradentate ligand MST (N,N',N''-[2,2',2''-nitrilotris-(ethane-2,1-diyl)]tris(2,4,6-trimethylbenzenesulfonamide)). A systematic study on the effect of converting between trigonal monopyramidal complexes, (Me4N)[M(MST)], and trigonal bipyramidal complexes, (Me4N)[M(MST)(OH2)] was conducted experimentally and computationally. It was found that (Me4N)[Ni(MST)] exhibits a very large, near record zero-field splitting parameter (D) value of -434 cm-1, owing to an extremely low lying first excited state. The trigonal monopyramidal cobalt and iron complexes exhibit slow magnetic relaxation under applied fields, resulting in barriers of 45 K and 63.9 K respectively. Coordination of a single water molecule in the open axial site of the trigonal monopyramidal complexes exerts drastic dampening effects on the D value as well as slow relaxation. Computations reveal that coordination of water rotates the D zz axis away from the C 3 axis of symmetry resulting in a smaller D value. The aquo species (Me4N)[Co(MST)(OH2)] also exhibits magnetic relaxation under an applied field, but the barrier is reduced to 9.9 K. Water coordination totally quenches the magnetic behavior in the iron complex, and reduces the D value for nickel to -185 cm-1. These results showcase the drastic effect that a small change in the coordination environment can have on magnetic behavior, as well as that trigonal monopyramidal geometry can lead to near record D values.


Integrative biology of injury in animals.
Mechanical injury is a prevalent challenge in the lives of animals with myriad potential consequences for organisms, including reduced fitness and death. Research on animal injury has focused on many aspects, including the frequency and severity of wounding in wild populations, the short- and long-term consequences of injury at different biological scales, and the variation in the response to injury within or among individuals, species, ontogenies, and environmental contexts. However, relevant research is scattered across diverse biological subdisciplines, and the study of the effects of injury has lacked synthesis and coherence. Furthermore, the depth of knowledge across injury biology is highly uneven in terms of scope and taxonomic coverage: much injury research is biomedical in focus, using mammalian model systems and investigating cellular and molecular processes, while research at organismal and higher scales, research that is explicitly comparative, and research on invertebrate and non-mammalian vertebrate species is less common and often less well integrated into the core body of knowledge about injury. The current state of injury research presents an opportunity to unify conceptually work focusing on a range of relevant questions, to synthesize progress to date, and to identify fruitful avenues for future research. The central aim of this review is to synthesize research concerning the broad range of effects of mechanical injury in animals. We organize reviewed work by four broad and loosely defined levels of biological organization: molecular and cellular effects, physiological and organismal effects, behavioural effects, and ecological and evolutionary effects of injury. Throughout, we highlight the diversity of injury consequences within and among taxonomic groups while emphasizing the gaps in taxonomic coverage, causal understanding, and biological endpoints considered. We additionally discuss the importance of integrating knowledge within and across biological levels, including how initial, localized responses to injury can lead to long-term consequences at the scale of the individual animal and beyond. We also suggest important avenues for future injury biology research, including distinguishing better between related yet distinct injury phenomena, expanding the subjects of injury research to include a greater variety of species, and testing how intrinsic and extrinsic conditions affect the scope and sensitivity of injury responses. It is our hope that this review will not only strengthen understanding of animal injury but will contribute to building a foundation for a more cohesive field of 'injury biology'.