An elevated lipoprotein(a) plasma level as a cardiovascular risk factor.
The causal association of elevated lipoprotein(a) (Lp(a)) plasma levels with the increased cardiovascular risk is still controversial and presently there are no standard recommendations on managing of hyperLp(a)emia. Our retrospective analysis is aimed to explore the Lp(a) thresholds, the magnitude of various cardiovascular risk factors and their combinations. The files of 544 outpatients from our Outpatient Department of Lipid Disorders were divided into quintiles with respect to Lp(a) levels and reviewed regarding age, gender, Body Mass Index, dyslipidemias, arterial hypertension, diabetes mellitus, smoking and incidence of vascular events in coronaries, carotids and lower extremities. Furthermore we built 15 small quantiles to identify the Lp(a) threshold more precisely. The incidence odds ratio for cardiovascular events rose from 2.65 in the 2nd quintile with Lp(a) 483-821 mg/L to 6.36 in the 5th quintile (Lp(a) ≥ 1495 mg/L). The relative risk of cardiovascular events was 0.08 in subjects with a Lp(a) level under 232 mg/l and 3.6 at Lp(a) ≥ 315 mg/L. The magnitude of the combination of elevated Lp (a) with arterial hypertension factor exceeded that of gender, age and combination of arterial hypertension with smoking. A Lp(a) plasma level of higher than about 300 mg/L seems to be a threshold for occurring of cardiovascular events. The combination of raised Lp(a) with arterial hypertension was found to be the most important cardiovascular risk factor. Lp(a) levels under 232 mg/L appeared to be a marker for good prognosis.


[18F]-fluoride positron emission tomography for imaging condylar hyperplasia.
The management of condylar hyperplasia depends on the diagnosis of continued growth in the affected condyle, and there is currently no satisfactory way of imaging it. [(18)F]-fluoride positron emission tomography (PET) was included in the investigation of 5 patients who were suspected of having condylar hyperplasia, and the results were correlated with the operative findings. The technique correctly identified condylar hyperplasia in all patients. Our results suggest that [(18)F]-fluoride PET is a valid way of assessing patients with condylar hyperplasia.


The high thermal stability of white emitting phosphor Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ ,La3+ /Lu3+ for white light emitting diodes.
A series of Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ was prepared using a solid-state method, and the phosphor emitted white light by tuning the ratio of Dy3+ /Eu3+ . The effects of La3+ /Lu3+ on the structure and luminescence properties of Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ were explored. Under the influence of bond length and twist, the luminescence intensity of the materials increased first and then decreased under excitation with ultraviolet light. The lattice distortion of the trivalent cation La3+ -substituted Mg2 Y2 Al2 Si2 O12 :Dy3+ and Eu3+ phosphors was reduced, the symmetry of polyhedron occupied by the luminescence centre improved, and the thermal stability of the luminescence centre improved to a certain extent. White light emitting diodes (LEDs) were fabricated by combining a 370 nm LED chip and the Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ ,La3+ (Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ ,Lu3+ ) phosphor. The results showed that Mg2 Y2 Al2 Si2 O12 :Dy3+ ,Eu3+ ,La3+ /Lu3+ may have potential application in the area of white LEDs.


First report of concurrent mixed germs induced destructive emphysematous pyelonephritis and emphysematous endophthalmitis in the patient with COVID-19.
A 35-year-old diabetic woman was referred to the emergency department with fever, left flank pain, pneumaturia, and impaired vision of the left eye from 4 days ago. Fever, tachycardia, tachypnea, low blood pressure, metabolic acidosis, and azotemia were the first findings. The diagnosis was a coincidence of emphysematous pyelonephritis and emphysematous endophthalmitis due to computerized tomography of the patient. Immediate fluid and electrolytes resuscitation, intravenous antibiotic administration, and nephrectomy save the patient. Urine, blood, and vitreous cultures revealed mixed germ infection.


Use of the surgical glove in microsurgery.
The disposable surgical glove can serve as a model for toe-to-hand transfer, as a template for flap design, and as a ring tourniquet for the finger. The low cost, effectiveness, and easy handling of the glove warrant its role in reconstructive microsurgery.


Driving after drinking among young adults of different race/ethnicities in the United States: unique risk factors in early adolescence?
National guidelines for alcohol screening and brief interventions advise practitioners to consider age, drinking frequency, and context to identify at-risk youth. The purpose of this study was to identify the contextual risk and protective factors in high school-aged adolescents associated with future driving after drinking (Drinking Under the Influence [DUI] at age 21) by race/ethnicity. Data included 10,271 adolescents (67% white, 12% Hispanic, 16% black, 3.6% Asian; 49% Male) who participated in the National Longitudinal Study of Adolescent Health (Waves I, II, and III) from 1995 to 2001. A lagged panel design and survey logistic regression was used to examine the association between multiple contextual factors (e.g., demographics, parents, peers, social context) during adolescence and self-reported DUI in young adulthood. As expected, the likelihood of DUI was higher among whites followed by Hispanics, Asians, and blacks in all models. Perception of easy home access to alcohol increased risk for future DUI for whites (OR: 1.25 CI: 1.04-1.49), Hispanics (OR: 2.02 CI: 1.29-3.16), and Asians (OR: 1.90 CI: 1.13-3.22), but not for black youth. Drinking frequency and prior DUI were not risk factors for Hispanics. Risk-taking attitudes, marijuana use, and religious affiliation were risk factors for whites only. Findings suggest that in addition to screening for drinking behaviors, brief interventions and prevention efforts should assess perceived home access to alcohol and other race-specific factors to reduce alcohol-related injuries and harm.


Core defense hotspots within Pseudomonas aeruginosa are a consistent and rich source of anti-phage defense systems.
Bacteria use a diverse arsenal of anti-phage immune systems, including CRISPR-Cas and restriction enzymes. Recent advances in anti-phage system discovery and annotation tools have unearthed many unique systems, often encoded in horizontally transferred defense islands, which can be horizontally transferred. Here, we developed Hidden Markov Models (HMMs) for defense systems and queried microbial genomes on the NCBI database. Out of the 30 species with >200 completely sequenced genomes, our analysis found Pseudomonas aeruginosa exhibits the greatest diversity of anti-phage systems, as measured by Shannon entropy. Using network analysis to identify the common neighbors of anti-phage systems, we identified two core defense hotspot loci (cDHS1 and cDHS2). cDHS1 is up to 224 kb (median: 26 kb) with varied arrangements of more than 30 distinct immune systems across isolates, while cDHS2 has 24 distinct systems (median: 6 kb). Both cDHS regions are occupied in a majority of P. aeruginosa isolates. Most cDHS genes are of unknown function potentially representing new anti-phage systems, which we validated by identifying a novel anti-phage system (Shango) commonly encoded in cDHS1. Identifying core genes flanking immune islands could simplify immune system discovery and may represent popular landing spots for diverse MGEs carrying anti-phage systems.


Efficacy and safety of propiverine in children with overactive bladder.
Antimuscarinic therapy remains one of the most common forms of therapy for overactive bladder (OAB) in children. However, few clinical studies on the outcomes of antimuscarinics in children with OAB have been published. Therefore, we evaluated the efficacy and safety of propiverine, which is frequently prescribed for the treatment of pediatric OAB. We retrospectively reviewed children with OAB treated with propiverine within the past 5 years. The response rates were compared between the non-urge incontinence (non-UI) and urge incontinence (UI groups). The cumulative response rate by treatment duration was also compared between the two groups. Among a total of 68 children, 50 children (73.5%) experienced UI. The overall response rate was 86.8%. Functional bladder capacity after treatment was 150 ml, which represented an increase compared with the value (140 ml) before treatment. The voiding frequency per day decreased from 14.0 to 8.5 times. The overall response rate (88.0%) in the non-UI group was not significantly different from that seen in the UI group (83.3%; p>0.05). In non-UI children, the cumulative response rates were 36.0%, 54.0%, 68.0%, 74.0%, 76.0%, and 78.0% at 4, 8, 12, 16, 20, and 24 weeks, respectively. The cumulative response rates in the UI children were 11.1%, 33.3%, 44.4%, 50.0%, 50.0%, and 55.6%, respectively during the same respective time periods. Adverse effects were identified in only two (2.9%) patients, and neither case was severe. Propiverine is effective and well tolerated as a treatment for children suffering from OAB with or without UI.


Clinical trial of a new lightwand device (Trachlight) to intubate the trachea.
Transillumination of the soft tissue of the neck using a lighted stylet (lightwand) is an effective and safe intubating technique. A newly designed lightwand (Trachlight) incorporates modifications to improve the brightness of the light source as well as flexibility. The goal of this study was to determine the effectiveness and safety of this device in intubating the trachea of elective surgical patients. Healthy surgical patients were studied. Patients with known or potential problems with intubation were excluded. During general anesthesia, the tracheas were intubated randomly using either the Trachlight or the laryngoscope. Failure to intubate was defined as lack of successful intubation after three attempts. The duration of each attempt was recorded as the time from insertion of the device into the oropharynx to the time of its removal. The total time to intubation (TTI), an overall measure of the ease of intubation, was defined as the sum of the durations of all (as many as three) intubation attempts. Complications, such as mucosal bleeding, lacerations, dental injury, and sore throat, were recorded. Nine hundred fifty patients (479 in the Trachlight group and 471 in the laryngoscope group) were studied. There was a 1% failure rate with the Trachlight, and 92% of intubations were successful on the first attempt, compared with a 3% failure rate and an 89% success rate on the first attempt with the laryngoscope (P not significant). All failures were followed by successful intubation using the alternate device. The TTI was significantly less with the Trachlight compared with the laryngoscope (15.7 +/- 10.8 vs. 19.6 +/- 23.7 s). For laryngoscopic intubation, the TTI was longer for patients with limited mandibular protrusion and mentohyoid distance, with a larger circumference of the neck, and with a high classification according to Mallampatti et al. However, there was no relation between the TTI and any of the airway parameters for Trachlight. There were significantly fewer traumatic events in the Trachlight group than in the laryngoscope group (10 vs. 37). More patients complained of sore throat in the laryngoscope group than in the Trachlight group (25.3% vs. 17.1%). In contrast to laryngoscopy, the ease of intubation using the Trachlight does not appear to be influenced by anatomic variations of the upper airway. Intubation occasionally failed with the Trachlight but in all cases was resolved with direct laryngoscopy. The failures of direct laryngoscopy were resolved with Trachlight. Thus the combined technique was 100% successful in intubating the tracheas of all patients.


EpiJSON: A unified data-format for epidemiology.
Epidemiology relies on data but the divergent ways data are recorded and transferred, both within and between outbreaks, and the expanding range of data-types are creating an increasingly complex problem for the discipline. There is a need for a consistent, interpretable and precise way to transfer data while maintaining its fidelity. We introduce 'EpiJSON', a new, flexible, and standards-compliant format for the interchange of epidemiological data using JavaScript Object Notation. This format is designed to enable the widest range of epidemiological data to be unambiguously held and transferred between people, software and institutions. In this paper, we provide a full description of the format and a discussion of the design decisions made. We introduce a schema enabling automatic checks of the validity of data stored as EpiJSON, which can serve as a basis for the development of additional tools. In addition, we also present the R package 'repijson' which provides conversion tools between this format, line-list data and pre-existing analysis tools. An example is given to illustrate how EpiJSON can be used to store line list data. EpiJSON, designed around modern standards for interchange of information on the internet, is simple to implement, read and check. As such, it provides an ideal new standard for epidemiological, and other, data transfer to the fast-growing open-source platform for the analysis of disease outbreaks.


Reoperation after selective amygdalohippocampectomy: an MRI analysis of the extent of temporomesial resection in ten cases.
Selective amygdalohippocampectomy (SAHE) yields 60-80% of patients with medically refractory mesial temporal lobe epilepsy seizure-free and seems to be equally effective compared to the more extended temporal lobe resections. The resection of the entire entorhinal cortex (EC) is of crucial importance to warrant complete seizure control for those patients. Thus, evidence of residual EC could be a predictor of a potentially successful reoperation in patients with recurrent seizures after SAHE. We performed an analysis of preoperative and postoperative magnetic resonance imaging (MRI) in patients who underwent a reoperation after an unsuccessful transsylvian SAHE to assess the presence of residual EC before reoperation and to determine whether certain anatomical variants may dispose patients to incomplete resection of EC. Ten patients who underwent reoperation after SAHE for the recurrence of medically refractory seizures were studied. MRI after SAHE was assessed for the presence of residual EC using T2-weighted and inversion recovery sequences perpendicularly to the main axis of the hippocampus. The results were compared with a control group of ten patients who became seizure-free after SAHE. In the nine patients of the study group, the sulcal anatomy of the basal temporal lobe was graphically outlined and analysed on MRI scans performed before SAHE to characterise the sulcal boundaries of the EC. Residual EC was found in nine of ten patients and was absent in the control group. After reoperation (median follow-up of 36.5 months), eight out of ten patients were completely seizure-free. In seven out of nine patients, a discontinuous course of the lateral sulcal boundaries of the EC was determined. Careful analysis of MRI verified residual mesiotemporal structures in the majority of patients who became seizure-free after reoperation. Certain temporobasal sulcal patterns might dispose for a higher risk of incomplete resection of the EC. The study confirms that reoperation is an effective treatment modality for patients with recurrent seizures after transsylvian SAHE.


Thin-fibre receptors responding to mechanical, chemical, and thermal stimulation in the skeletal muscle of the dog.
1. Unitary activities of muscular thin fibre afferents, which were not sensitive to muscle stretching, were recorded from the nerve of the medial gastrocnemius muscle of the dog. Responses to mechanical stimulation, intra-arterial injection and local application of chemical solutions, and thermal stimulation of the surface of the muscle were studied. It was observed that polymodal receptors which responded to all types of stimulation existed in the thin fibre afferents of the muscle.2. The receptive area of these units tested by mechanical stimulation was spot-like and appeared to be located not only on the surface but in the midst of the muscle.3. The mechanical response varied among these units with respect to the threshold and the pattern of discharges.4. In these units, NaCl, KCl, and bradykinin consistently evoked responses, with differences in the latencies and discharge patterns, while solutions of histamine, acetylcholine and sodium citrate caused responses less consistently and less effectively. In the stretch receptors, chemical stimulation applied in the same way as tested in the thin fibre afferents produced quite different features in their responses.5. Heating the receptive area of the muscle surface caused responses in twenty-five out of thirty-six units, which were sensitive both to mechanical and to chemical stimulations. The threshold varied from 38.0 to 48.3 degrees C, with a mean of 43.1 degrees C for C fibre units and 41 degrees C for A-delta fibre units.6. The responses to heating were consistently obtained in the units responding to the surface application of chemical solutions. However, the above response was never obtained in the units which did not respond to surface chemical stimulation but responded to intra-arterial injection. These results suggest a large population of polymodal receptors in the muscular thin fibre afferents.


Perforin-mediated myocardial damage in acute myocarditis.
Endomyocardial specimens were obtained from 7 patients with acute myocarditis. Immunohistochemical examination of the mononuclear infiltrate showed mainly cytotoxic T lymphocytes and natural killer cells. Perforin (a pore-forming protein found in cytotoxic lymphocytes) was identified in this myocardial lymphocytic infiltrate and electron microscopy showed myocardial cell damage that may have been associated with these perforin containing lymphocytes. The results indicate that in acute idiopathic and viral myocarditis, myocardial damage may be due to the action of perforin-secreting lymphocytes.


Mismatch negativity to the patient's own name in chronic disorders of consciousness.
Previous studies implicated potential value of mismatch negativity (MMN) in predicting recovery of consciousness in patients with disorders of consciousness (DOC). We have adopted a novel MMN evoked by subject's own name (SON), a self-referential stimulus thought to be powerful in evoking residual brain activity, and examined the correlation between the MMN and recovery of consciousness in patients with chronic (>1 month) DOC. Twelve patients and 12 age-matched healthy controls were investigated. The patients were diagnosed as coma (n=4), vegetative state (VS, n=6), and minimally conscious state (MCS, n=2), mainly based on the JFK Coma Recovery Scale-Revised. The SON-evoked MMN (SON-MMN) was present in seven patients. Critically, the presence of SON-MMN was significantly correlated with recovery of consciousness. While four of the five patients (three VS and two coma) showing SON-MMN changed to MCS 3 months later, the rest of the patients (three VS and two coma) without SON-MMN failed to show any clinical improvement. Our study thus illustrates that the subject's own name is effective in evoking MMN in patients with DOC, and that SON-MMN has potential prognostic values in predicting recovery of consciousness.


Importance of self-connections for brain connectivity and spectral connectomics.
Spectral analysis and neural field theory are used to investigate the role of local connections in brain connectivity matrices (CMs) that quantify connectivity between pairs of discretized brain regions. This work investigates how the common procedure of omitting such self-connections (i.e., the diagonal elements of CMs) in published studies of brain connectivity affects the properties of functional CMs (fCMs) and the mutually consistent effective CMs (eCMs) that correspond to them. It is shown that retention of self-connections in the fCM calculated from two-point activity covariances is essential for the fCM to be a true covariance matrix, to enable correct inference of the direct total eCMs from the fCM, and to ensure their compatibility with it; the deCM and teCM represent the strengths of direct connections and all connections between points, respectively. When self-connections are retained, inferred eCMs are found to have net inhibitory self-connections that represent the local inhibition needed to balance excitation via white matter fibers at longer ranges. This inference of spatially unresolved connectivity exemplifies the power of spectral connectivity methods, which also enable transformation of CMs to compact diagonal forms that allow accurate approximation of the fCM and total eCM in terms of just a few modes, rather than the full [Formula: see text] CM entries for connections between N brain regions. It is found that omission of fCM self-connections affects both local and long-range connections in eCMs, so they cannot be omitted even when studying the large-scale. Moreover, retention of local connections enables inference of subgrid short-range inhibitory connectivity. The results are verified and illustrated using the NKI-Rockland dataset from the University of Southern California Multimodal Connectivity Database. Deletion of self-connections is common in the field; this does not affect case-control studies but the present results imply that such fCMs must have self-connections restored before eCMs can be inferred from them.


Herpetic esophagitis in immunocompentent host: cases report.
Herpetic esophagitis (EH) usually affects those who are immunocompromised and is uncommon in immunocompetent patients. In these cases, EH may occasionally present as an acute and self-limited illness. Such cases are rare and only a few have beenreported and limited published reviews exist making the benefits of antiviral therapy in immunocompetent patients unknown. We report four cases of young patients who presented dysphagia, odynophagia and epigastric pain. Endoscopic findings revealed lesions in the distal esophagus and histopathological changes compatible with herpes virus infection confirmed by viral DNA in every case. After treatment, every patient showed significant improvement and tolerated oral intake after discharge. In this publication, we present four immunocompetent patients with EH, without relevant alterations in laboratory workup and with negative HIV status. This disease is infrequent in patients with such characteristics and there are few cases published. In order to better understand this pathology, we present the symptoms, the endoscopic alterations and the clinical evolution with treatment. In our series, 50% of patients had serology compatible with acute HVS type 1 infection, 25% had a subacute infection pattern (IgM and IgG positive antibodies) and in another 25% of patients, serology was not done. No patient presented leukocyte alterations, while all patients presented with anatomopathological findings compatible with acute herpetic esophagitis and responded to acyclovir therapy.


Prevalence and morphological changes of carotid kinking and coiling in growth: an echo-color Doppler study of 2856 subjects between aged 0 to 96 years.
Extracranial internal carotid artery (EICA) kinking and coiling are the most frequently reported carotid anomalies in the literature. Embryogenic and acquired causes for such anomalies have been postulated but the prevalence of kinking and coiling has not been well characterized across age categories. The aim of this study is to evaluate the prevalence of EICA coiling and kinking among different age groups to better understand its potential causes and changes during the course of life. A total of 2856 subjects aged 0 to 96 years were studied by echo-color Doppler (ECD). Morphology and anatomical anomalies of the EICA were assessed. Patients with anatomical anomalies were stratified by age groups and the prevalence of EICA abnormalities was calculated. The maximal velocity recorded at the level of the kinking was compared with that measured in the common carotid artery and the peak systolic velocity kinking ratio (PSVKR) was calculated. A total of 284 subjects (9.94% of the sample) were found to have kinking or coiling of the EICA. The prevalence was significantly higher at the extremes of age (≤ 20 and > 60 years old, p < 0.001) supporting the hypothesis of a reduction with growth and a new increase in the elderly. PSVKR was higher in subjects with more severity kinking. This study showed a higher prevalence of EICA coiling and kinking in the very young and in the elderly. This bimodal prevalence distribution supports the hypothesis of a congenital anomaly that resolves with somatic growth, while advanced age with its many anatomical changes leads to its reappearance or worsening. Studies with longitudinal follow-up and paired observation are required to support this hypothesis.


Comparative Study of Nonautolytic Mutant and Wild-Type Strains of Coprinopsis cinerea Supports an Important Role of Glucanases in Fruiting Body Autolysis.
Autolysis of Coprinopsis cinerea fruiting bodies affects its commercial value. In this study, a mutant of C. cinerea that exhibits pileus expansion without pileus autolysis was obtained using ultraviolet mutagenesis. This suggests that pileus expansion and pileus autolysis involve different enzymes or proteins. Among the detected hydrolytic enzymes, only β-1,3-glucanase activity increased with expansion and autolysis of pilei in the wild-type strain, but the increase was abolished in the mutant. This suggests that β-1,3-glucanases plays a major role in the autolysis. Although there are 43 possible β-1,3-glucoside hydrolases genes, only 4 known genes, which have products that are thought to act synergistically to degrade the β-1,3-glucan backbone of cell walls during fruiting body autolysis, and an unreported gene were upregulated during pileus expansion and autolysis in the wild-type stain but were suppressed in the mutant. This suggests that expression of these β-1,3-glucanases is potentially controlled by a single regulatory mechanism.


Distinct binding properties of the AT(1) receptor antagonist [(3)H]candesartan to intact cells and membrane preparations.
[(3)H]-2-Ethoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H-benzimidazoline-7-carboxylic acid ([(3)H]candesartan), a non-peptide angiotensin II type 1 receptor (AT(1) receptor) antagonist bound with high affinity and specificity to intact adherent human AT(1) receptor transfected Chinese hamster ovary cells. The binding characteristics were preserved when cells were suspended, but the dissociation was 3-4-fold faster and the affinity 2-fold lower, while examining [(3)H]candesartan binding to cell membranes. These data suggested the role of the intracellular organisation of living CHO-hAT(1) cells in antagonist-AT(1) receptor interactions. Yet, a specific role of microtubule or actin filaments of the cytoskeleton, receptor phosphorylation by Protein Kinase C, membrane polarity, cytoplasmic components like ATP and the need of an intact cell membrane could be excluded. The potential effect of protease degradation or receptor oxidation during the membrane preparation was also unlikely. The dissociation rate and the equilibrium dissociation constant of [(3)H]candesartan increased with the temperature for both intact cells and membranes. Thermodynamic studies suggested that the bonds between candesartan and the hAT(1) receptor may be of different nature in intact CHO-hAT(1) cells and membranes thereof. Whereas the binding was almost completely enthalpy-driven on intact cells, there was a mixed contribution of both enthalpy and entropy on membranes.


The unfolded protein response and its potential role in Huntington ´s disease elucidated by a systems biology approach.
Huntington ´s disease (HD) is a progressive, neurodegenerative disease with a fatal outcome. Although the disease-causing gene (huntingtin) has been known for over 20 years, the exact mechanisms leading to neuronal cell death are still controversial. One potential mechanism contributing to the massive loss of neurons observed in the brain of HD patients could be the unfolded protein response (UPR) activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). As an adaptive response to counter-balance accumulation of un- or misfolded proteins, the UPR upregulates transcription of chaperones, temporarily attenuates new translation, and activates protein degradation via the proteasome. However, persistent ER stress and an activated UPR can also cause apoptotic cell death. Although different studies have indicated a role for the UPR in HD, the evidence remains inconclusive. Here, we present extensive bioinformatic analyses that revealed UPR activation in different experimental HD models based on transcriptomic data. Accordingly, we have identified 58 genes, including RAB5A, HMGB1, CTNNB1, DNM1, TUBB, TSG101, EEF2, DYNC1H1 and SLC12A5 that provide a potential link between UPR and HD. To further elucidate the potential role of UPR as a disease-relevant process, we examined its connection to apoptosis based on molecular interaction data, and identified a set of 40 genes including ADD1, HSP90B1, IKBKB, IKBKG, RPS3A and LMNB1, which seem to be at the crossroads between these two important cellular processes.


Evaluation of Long-Term Surgical Success and Satisfaction of Patients After Vestibulectomy.
Vestibulectomy is one of the only proven therapeutic treatments for provoked vulvodynia (PVD). However, little is known about long-term surgical success. Patients who underwent vestibulectomy between 1991 and 2003 were interviewed to assess frequency of intercourse and degree of pain during various activities, as well as satisfaction with and willingness to recommend the surgery. We also examined the outcome relation to PVD type being primary or secondary. Differences in pain over time were assessed using a paired-sample t test or a Wilcoxon signed-rank test. Of 85 eligible patients, 50 (59%) were contacted and 32 (38%) participated. All underwent vestibulectomy 12-24 years prior by the same surgeon. All experienced sexual intercourse without pain at some point after surgery (median = 4 months). Penetration pain averaged 9.13 (scale = 0-10) before surgery and dropped to 0.47 at the time of follow up (p < .001). Other activities that were reported as painful before surgery also improved significantly. No patients reported worsening of pain over time; 87.5% were able to engage in sexual intercourse immediately after the recovery period, and 97% were able to do so at the time of follow up. Ninety-four percent of respondents were highly satisfied, 97% would undergo the surgery again, and 100% would recommend it to others. The type of PVD was unrelated to treatment outcome (p = .297). Vestibulectomy is an excellent treatment for PVD and has successful long-term outcomes.


ROCK inhibitors beneficially alter the spatial configuration of TGFβ2-treated 3D organoids from a human trabecular meshwork (HTM).
To elucidate molecular pharmacology of Rho-associated coiled-coil containing protein kinase inhibitors (ROCK-i, Ripasudil and Y27632) on their efficiency for aqueous outflow, 2D or 3D cultures of a human trabecular meshwork (HTM) were prepared in the presence of TGFβ2. Those were examined by transendothelial electrical resistance (TEER, 2D), electronic microscopy (EM, 2D and 3D), expression of the extracellular matrix (ECM) including collagen1 (COL1), COL4 and COL6, and fibronectin (FN) by immunolabeling and/or quantitative PCR (3D), and solidity of 3D organoids by a micro-squeezer. TGFβ2 significantly increased the TEER values in 2D cultures, and the ECM expression indicated that the 3D organoids assumed a more densely packed shape. ROCK-i greatly reduced the TGFβ2-induced enhancement of TEER and the immunolabeled ECM expression of the 3D organoids. In contrast, the mRNA expression of COL1 was increased, and those of COL4 and FN were unchanged. EM revealed that TGFβ2 caused the HTM cells to become more compact and abundant ECM deposits within the 3D organoids were observed. These were significantly inhibited by ROCK-i. The dense solids caused by the presence of TGFβ2 were significantly suppressed by ROCK-i. Current study indicates that ROCK-i cause beneficial effects toward the spatial configuration of TGFβ2-induced HTM 3D organoids.


Isolation and molecular characterisation of flavonoid 3'-hydroxylase and flavonoid 3', 5'-hydroxylase genes from a traditional Chinese medicinal plant, Epimedium sagittatum.
The epimedii herb, a traditional Chinese medicinal plant, has significant pharmacological effects on human health. The bioactive components in the herb (Epimedium sagittatum (Sieb. et Zucc.) Maxim) are mainly prenylated flavonol glycosides, which are end-products of the flavonoid biosynthetic pathway. This has not been clearly elucidated until recently. The genes encoding flavonoid 3'-hydroxylase (F3'H) and flavonoid 3', 5'-hydroxylase (F3'5'H) involved in the flavonoid biosynthetic pathway, designated as EsF3'H and EsF3'5'H, were isolated from E. sagittatum using a homology-based cloning method and deposited in the GenBank databases (GenBank ID: HM011054 and HM011055), respectively. EsF3'H and EsF3'5'H proteins shared high homology with other plant-specific flavonoid hydroxylases and were clustered into the CYP75B and CYP75A group, respectively. In addition, four conserved cytochrome P450-featured motifs were found in the amino acid sequences of both genes. Transcription levels of both genes were detected in all tissues tested and were high in most of the pigmented tissues. Moreover, the expression levels of both EsF3'H and EsF3'5'H correlated positively with the anthocyanin accumulation pattern in leaves from E. sagittatum. The cloning and molecular characterisation of EsF3'H and EsF3'5'H genes will accelerate progress in the study of the flavonoid biosynthetic pathway to elucidate the molecular mechanisms of the biosynthesis of the bioactive components in E. sagittatum.


Youth Culturally adapted Manual Assisted Problem Solving Training (YCMAP) in Pakistani adolescent with a history of self-harm: protocol for multicentre clinical and cost-effectiveness randomised controlled trial.
Suicide is a global health concern. Sociocultural factors have an impact on self-harm and suicide rates. In Pakistan, both self-harm and suicide are considered as criminal offence's and are condemned on both religious and social grounds. The proposed intervention 'Youth Culturally Adapted Manual Assisted Problem Solving Training (YCMAP)' is based on principles of problem-solving and cognitive-behavioural therapy. YCMAP is a brief, culturally relevant, scalable intervention that can be implemented in routine clinical practice if found to be effective. A multicentre rater blind randomised controlled trial to evaluate the clinical and cost-effectiveness of YCMAP including a sample of 652 participants, aged 12-18 years, presenting to general physicians/clinicians, emergency room after self harm or self referrals. We will test the effectiveness of 8-10 individual sessions of YCMAP delivered over 3 months compared with treatment as usual. Primary outcome measure is repetition of self-harm at 12 months. The seconday outcomes include reduction in suicidal ideation, hopelessness and distress and improvement in health related quality of life. Assessments will be completed at baseline, 3, 6, 9 and 12 months postrandomisation. The nested qualitative component will explore perceptions about management of self-harm and suicide prevention among adolescents and investigate participants' experiences with YCMAP. The study will be guided by the theory of change approach to ensure that the whole trial is centred around needs of the end beneficiaries as key stakeholders in the process. Ethics approval has been obtained from the Ethics Committee of University of Manchester, the National Bioethics Committee in Pakistan. The findings of this study will be disseminated through community workshops, social media, conference presentations and peer-reviewed journals. NCT04131179.


Structural and cellular differences between metaphyseal and diaphyseal periosteum in different aged rats.
In both physiological and pathological processes, periosteum plays a determinant role in bone formation and fracture healing. However, no specific report is available so far focusing on the detailed structural and major cellular differences between the periostea covering different bone surface in relation to ageing. The aim of this study is to compare the structural and cellular differences in diaphyseal and metaphyseal periostea in different aged rats using histological and immunohistochemical methods. Four female Lewis rats from each group of juvenile (7 weeks old), mature (7 months old) and aged groups (2 years old) were sacrificed and the right femur of each rat was retrieved, fixed, decalcified and embedded. Five-micrometer thick serial sagittal sections were cut and stained with Hematoxylin and Eosin, Stro-1 (stem cell marker), F4/80 (macrophage marker), TRAP (osteoclast marker) and vWF (endothelial cell marker). One-millimeter lengths of middle diaphyseal and metaphyseal periosteum were selected for observation. The thickness, total cell number and positive cell number for each antibody were measured and compared in each periosteal area and different aged groups. The results were subjected to two-way ANOVA and SNK tests. The results showed that the thickness and cell number in diaphyseal periosteum decreased with age (p<0.001). In comparison with diaphyseal area, the thickness and cell number in metaphyseal periosteum were much higher (p<0.001). There were no significant differences between the juvenile and aged groups in the thickness and cell number in the cambial layer of metaphyseal periosteum (p>0.05). However, the juvenile rats had more Stro1(+), F4/80(+) cells and blood vessels and fewer TRAP(+) cells in different periosteal areas compared with other groups (p<0.001). The aged rats showed much fewer Stro1(+) cells, but more F4/80(+), TRAP(+) cells and blood vessels in the cambial layer of metaphyseal periosteum (p<0.001). In conclusion, structure and cell population of periosteum appear to be both age-related and site-specific. The metaphyseal periosteum of aged rats seems more destructive than diaphyseal part and other age groups. Macrophages in the periosteum may play a dual important role in osteogenesis and osteoclastogenesis.


Phosphonium salt incorporated hypercrosslinked porous polymers for CO2 capture and conversion.
Various novel hypercrosslinked porous polymers with phosphonium salt incorporated into their networks were developed. These porous materials have high BET surface areas (up to 1168 m(2) g(-1)) and can be used to selectively capture CO2 and efficiently convert CO2 into cyclic carbonates.


Glucose-6P dehydrogenase in Chlorella sorokiniana (211/8k): an enzyme with unusual characteristics.
In Chlorella sorokiniana (211/8k), glucose-6 phosphate dehydrogenase (G6PDH-EC 188.8.131.52) activity is similar in both N-starved cells and nitrate-grown algae when expressed on a PCV basis. A single G6PDH isoform was purified from Chlorella cells grown under different nutrient conditions; the presence of a single G6PDH was confirmed by native gels stained for enzyme activity and by Western blots. The algal G6PDH is recognised only by antibodies raised against higher plants plastidic protein, but not by chloroplastic and cytosolic isoform-specific antisera. Purified G6PDH showed kinetic parameters similar to plastidic isoforms of higher plants, suggesting a different biochemical structure which would confer peculiar regulative properties to the algal G6PDH with respect to higher plants enzymes. The most remarkable property of algal G6PDH is represented by the response to NADPH inhibition. The algal enzyme is less sensitive to NADPH effects compared to higher plants G6PDH: Ki(NADPH) is 103 microM for G6PDH from nitrogen-starved C. sorokiniana, similarly to root plastidic P2-G6PDH. In nitrate-grown C. sorokiniana the Ki(NADPH) decreased to 48 microM, whereas other kinetic parameters remained unchanged. These results will allow further investigations in order to rule out possible modifications of the enzyme, and/or the expression of a different G6PDH isoform during nitrate assimilation.


Spinal manipulation: current state of research and its indications.
Based on the most recent and comprehensive systematic reviews, there is moderate evidence of short-term efficacy for spinal manipulation in the treatment of both acute and chronic low back pain. There is insufficient data available to draw conclusions regarding the efficacy for lumbar radiculopathy. The evidence is also not conclusive for the long-term efficacy of spinal manipulation for any type of low back pain.


Melatonin in elderly patients with insomnia. A systematic review.
Melatonin is a hormone and antioxidant produced by the pineal gland of which four neurobiological roles have been claimed in the aged population: anti-ageing agent; free-radical scavenger; regulator of circadian rhythm; endogeneous sleep-inducer. The "melatonin replacement" hypothesis states that 1) the well-evidenced age-related decline contributes to insomnia and that 2) replacement with physiological doses of melatonin improves sleep. The aim of this review was to determine the evidence for the efficacy of melatonin in elderly insomniacs. MEDLINE's database from 1990-2000 was searched with "melatonin", "geriatrics" and "(frail)-elderly" as major sub-headings. This resulted in 78 articles: only studies with empirical treatment data were reviewed (N = 12). Six reports (abstract, research letter, retrospective case study, 3 open label studies) showed a trend towards efficacy of melatonin: sleep quality improved and in patients with Alzheimer's disease sundowning was reduced. In 6 double blind, randomised crossover trials, a total number of 95 patients (mean ages: 65-79 yrs) were treated. Melatonin doses ranged from 0.5 mg to 6 mg; most took a single dose 30-120 min before bedtime. In 3 studies a slow release form was used. Sleep quality was objectively measured by wrist actigraphy (n = 4) and polysomnography (n = 2), and additionally subjective sleep quality was assessed (n = 2). Sleep latency decreased significantly in 4 studies. In 3 studies other measures of sleep quality (sleep efficiency, total sleep time and wake time during sleep) improved. Subjective sleep quality did not improve. No early-morning sleepiness occurred. Comparison of the studies suggests that melatonin is most effective in elderly insomniacs who chronically use benzodiazepines and/or with documented low melatonin levels during sleep. There is sufficient evidence that low doses of melatonin improve initial sleep quality in selected elderly insomniacs. However, larger randomized controlled trials, with less strict inclusion criteria are necessary to yield evidence of effectiveness (i.e. clinical and subjective relevance) in geriatric patients who suffer from insomnia, before wide-spread use can be advocated.


Cost-Benefit and Cost-Utility Analyses to Demonstrate the Potential Value-for-Money of Supermarket Shelf Tags Promoting Healthier Packaged Products in Australia.
The supermarket environment impacts the healthiness of food purchased and consumed. Shelf tags that alert customers to healthier packaged products can improve the healthiness of overall purchases. This study assessed the potential value-for-money of implementing a three-year shelf tag intervention across all major supermarket chains in Australia. Cost-benefit analyses (CBA) and cost-utility analyses (CUA) were conducted based on results of a 12-week non-randomised controlled trial of a shelf tag intervention in seven Australian supermarkets. The change in energy density of all packaged foods purchased during the trial was used to estimate population-level changes in mean daily energy intake. A multi-state, multiple-cohort Markov model estimated the subsequent obesity-related health and healthcare cost outcomes over the lifetime of the 2019 Australian population. The CBA and CUA took societal and healthcare sector perspectives, respectively. The intervention was estimated to produce a mean reduction in population body weight of 1.09 kg. The net present value of the intervention was approximately AUD 17 billion (B). Over 98% of the intervention costs were borne by supermarkets. CUA findings were consistent with the CBA-the intervention was dominant, producing both health benefits and cost-savings. Shelf tags are likely to offer excellent value-for-money from societal and healthcare sector perspectives.


Correlation between maximal radial muscle displacement and stiffness in gastrocnemius muscle.
Tensiomyography (TMG) and myotonometry (MMT) are two novel technologies that measure neuromuscular properties. These two devices measure the stiffness of the soft tissue as well as other variables. The aim of this study is to analyze if there is any correlation between maximal radial displacement (Dm) and Stiffness in the medial and lateral gastrocnemius muscles. An observational study was carried out in both of the limbs of 154 young adults (n = 154). The TMG and MMT neuromuscular response was measured in gastrocnemius medial and lateral muscles. Correlation coefficients were calculated to observe if there were any relationships between Dm and Stiffness. Differences between the dominant and the non-dominant sides and gender were assessed. Negative correlations between Dm versus Stiffness were found for the lateral (r = -0.278 and rho = -0.248) and medial gastrocnemius (r = -0.207 and rho = -0.163) in both dominant and non-dominant limbs respectively. A weak correlation between Dm and Stiffness may indicate that they assess different aspects of neuromuscular function. The MMT and TMG are independent tools, and their values cannot be extrapolated when assessing muscular stiffness. There might be some other factors that influence in this relationship; therefore, more studies are needed in order to better understand the correlation.


[Recent advance in the discovery of allosteric inhibitors binding to the AMP site of fructose-1,6-bisphosphatase].
Fructose-1, 6-bisphosphatase (FBPase), a rate-limiting enzyme involved in the pathway of gluconeogenesis, can catalyze the hydrolysis of fructose-1, 6-bisphosphate to fructose-6-phosphate. Upon inhibiting the activity of FBPase, the production of endogenous glucose can be decreased and the level of blood glucose lowered. Therefore, inhibitors of FBPase are expected to be novel potential therapeutics for the treatment of type II diabetes. Recent research efforts were reviewed in the field of developing allosteric inhibitors interacting with the AMP binding site of FBPase.


Zeeman splitting via spin-valley-layer coupling in bilayer MoTe2.
Atomically thin monolayer transition metal dichalcogenides possess coupling of spin and valley degrees of freedom. The chirality is locked to identical valleys as a consequence of spin-orbit coupling and inversion symmetry breaking, leading to a valley analog of the Zeeman effect in presence of an out-of-plane magnetic field. Owing to the inversion symmetry in bilayers, the photoluminescence helicity should no longer be locked to the valleys. Here we show that the Zeeman splitting, however, persists in 2H-MoTe2 bilayers, as a result of an additional degree of freedom, namely the layer pseudospin, and spin-valley-layer locking. Unlike monolayers, the Zeeman splitting in bilayers occurs without lifting valley degeneracy. The degree of circularly polarized photoluminescence is tuned with magnetic field from -37% to 37%. Our results demonstrate the control of degree of freedom in bilayer with magnetic field, which makes bilayer a promising platform for spin-valley quantum gates based on magnetoelectric effects.Monolayer transition metal dichalcogenides host a valley splitting in magnetic field analogous to the Zeeman effect. Here, the authors report that the Zeeman splitting still persists in bilayers of MoTe2 without lifting the valley degeneracy, due to spin-valley-layer coupling.


Directed evolution of TetR for constructing sensitive and broad-spectrum tetracycline antibiotics whole-cell biosensor.
Antibiotic abuse is the main reason for the drug resistance of pathogenic bacteria, posing a potential health risk. Antibiotic surveillance is critical for preventing antibiotic contamination. This study aimed to develop a sensitive and broad-spectrum whole-cell biosensor for tetracycline antibiotics (TCs) detection. Wild-type TCs-responsive biosensor was constructed by introducing a tetracycline operon into a sfGFP reporter plasmid. Using error-prone PCR, mutation libraries containing approximately 107 variants of the tetracycline repressor (TetR) gene were generated. The tigecycline-senstive mutants were isolated using high-throughput flow cytometric sorting. After 2 rounds of directed evolution, a mutant epS2-22 of TerR was isolated and assembled as a TCs biosensor. The epS2-22 biosensor was more sensitive and broad-spectrum than the wild-type biosensors. The detection limits of the epS2-22 biosensor for seven TCs were 4- to 62-fold lower than the wild-type biosensor (no response to tigecycline). Meanwhile, the epS2-22 biosensor had a shorter detection time and a stronger signal output than the wild type. In addition, the evolved epS2-22 biosensor showed excellent performance in detecting low traces of TCs in environmental water. These results suggest that directed evolution is a powerful tool for developing high-performance whole-cell biosensors, and the evolved epS2-22 biosensors have the potential for wider applications in real-world TCs detection.


Data supporting the shedding of larger extracellular vesicles by multidrug resistant tumour cells.
To date, there are no simple and minimally invasive methods to diagnose MDR. Extracellular vesicles (EVs) are shed by all cells, carry a specific cargo from the donor cells and are present in several body fluids, which means that they can potentially be easily collected from cancer patients and become the source of biomarkers to diagnose cancer. This data article contains a full list of the proteins identified in the EVs shed by an isogenic pair of chronic myeloid leukaemia cells (MDR cells and their drug-sensitive counterparts) by LC/MS/MS analysis, together with their GeneOntology analysis. In addition, it also contains data from protein content analysis and Dynamic light scattering count-rate events of the referred EVs as well as of the EVs shed from an isogenic pair of non-small cell lung cancer cells (MDR cells and their drug-sensitive counterparts). The interpretation of the data presented in this article and further extensive insights can be found in "Multidrug resistant tumour cells shed more microvesicles-like EVs and less exosomes than their drug-sensitive counterpart cells" [1].


Sex differentiation and vitellogenin and 11-ketotestosterone levels in chub, Leuciscus cephalus L., exposed to 17 beta-estradiol and testosterone during early development.
The effects of 17 beta-estradiol (E(2)) and testosterone (T) singly and in combination were tested on juvenile chub (Leuciscus cephalus L.). Vitellogenin (VTG) and 11-ketotestosterone (11-KT) were determined by ELISA in whole body homogenates and the gonads were examined histologically. Testosterone and estradiol, in combination, significantly increased whole body VTG (p < 0.01), but not 11-KT, compared to controls and the T treated groups. The only intersex observed (1/80) was in the combined treatment group. We suggest that VTG measured in whole body homogenates could be used to determine the effects of exogenous steroids in juvenile chub.


Microwave observations reveal the deep extent and structure of Jupiter's atmospheric vortices.
Jupiter's atmosphere has a system of zones and belts punctuated by small and large vortices, the largest being the Great Red Spot. How these features change with depth is unknown, with theories of their structure ranging from shallow meteorological features to surface expressions of deep-seated convection. We present observations of atmospheric vortices using the Juno spacecraft's Microwave Radiometer. We found vortex roots that extend deeper than the altitude at which water is expected to condense, and we identified density inversion layers. Our results constrain the three-dimensional structure of Jupiter's vortices and their extension below the clouds.


Quantitative solid phase microextraction - gas chromatography mass spectrometry analysis of the pesticides lindane, heptachlor and two heptachlor transformation products in groundwater.
This paper describes the development and validation of a method for the determination of lindane, heptachlor and two heptachlor transformation products (exo- and endo-heptachlor epoxide) in groundwater. Samples were extracted using a simple solid phase microextraction (SPME) method with a polyacrylate fibre prior to detection by gas chromatography mass spectrometry in electron impact ionisation mode (GC-EI-MS). The linearity of the method ranged from 0.015 to 5.0 μg L(-1), with correlation coefficients greater than 0.99. Recoveries ranged from 96 to 101% at several fortification levels with all coefficients of variation (CV%) less than 10.5%. The method was validated to the permitted limits laid down in the European Union drinking water directive (98/83/EC). The limit of quantitation (LOQ) was 0.015 μg L(-1) in groundwater samples. Samples had to be analysed within 24h of collection otherwise degradation occurred and disposable SPME polyacrylate fibres lasted up to 51 injections. Both endo-heptachlor epoxide and lindane were detected in groundwater samples with concentrations ranging between 0.033 and 0.048 μg L(-1).


Benign, malignant salivary gland tumors: comparison of immunohistochemical expression of e-cadherin.
The aim of the present study was to assess any variation in the immunohistochemical expression of E-cadherin in benign and malignant salivary gland tumors. A total of 60 cases of benign and malignant salivary gland tumors were evaluated immunohistochemically for E-cadherin expression. These included 10 cases of pleomorphic adenoma (PA), 2 cases of canalicular adenoma (CA), 2 cases of myoepithelioma (MY), 24 cases of adenoid cystic carcinoma (ACC), 12 cases of mucoepidermoid carcinoma (MEC), 9 cases of adenocarcinoma (AC) and 1 case of carcinoma ex pleomorphic adenoma (Ca Ex PA). 48 cases (80%) showed positive expression, in which benign tumors exhibited relatively increased reactivity (85.7%) as compared to the malignant tumors (78.3%). 10 PA, 2 MY, 20 ACC, 9 MEC, 6 AC and 1 Ca Ex PA expressed E-cadherin. Negative expression was evident in CA, ACC, MEC and AC. Statistically significant reduction in reactivity was evident in mucoepidermoid carcinoma and adenocarcinoma, when compared to pleomorphic adenoma.


Ubiquitin metabolism in HeLa cells starved of amino acids.
Radio-iodinated ubiquitin (Ub) was introduced into HeLa cells by red blood cell-mediated microinjection. The half-life and solubility of Ub, as well as the molecular weight distributions of Ub conjugates, were then measured in HeLa cells grown in complete medium or in medium lacking amino acids and fetal calf serum. Ub metabolism was similar in the two sets of cells. Thus, the dramatic changes in Ub metabolism induced by thermal stress are not observed upon amino acid deprivation.


Correction to: Strengthening Surgery Strengthens Health Systems: A New Paradigm and Potential Pathway for Horizontal Development in Low- and Middle-Income Countries.
In the original article, Ziad C. Sifri's first and last names were interchanged. It is correct as reflected here.


Lipoprotein lipase of cultured mesenchymal rat heart cells. IV. Modulation of enzyme activity by VLDL added to the culture medium.
Lipoprotein lipase activity was studied in rat heart cell cultures grown in the presence of 20% fetal calf and horse serum and a medium concentration of triacylglycerol of 0.03 mg/ml. After 6--8 days, when the enzyme activity had reached high levels, the cells were incubated for 24 h in a medium containing 20% serum derived from fasted or fed rats. No change in enzyme activity occurred in the presence of fasted rat serum, but a 50% fall was observed with fed rat serium. When the complete culture medium was supplemented with rat plasma VLDL (0.075--0.75 mg triacylglycerol) a pronounced decrease in lipoprotein lipase activity occurred after 3--5 h of incubation. Similar extent of enzyme fall was observed also in the presence of triacylglycerol-rich lipoproteins isolated from rat plasma after feeding of safflower oil or lard, even though the fatty acid composition of the triacylgylcerol varied markedly. As the addition of VLDL to the culture medium resulted in a lesser fall of heparin releasable than residual activity it seems that there was no direct inhibition of surface bound enzyme activity and that the transport of the enzyme to the cell surface was not affected. These data indicate that addition of VLDL to the culture medium resulted in a fall in enzyme synthesis, while total protein synthesis as determined by incorporation of [3H]leucine, remained unchanged. This inhibition could be reproduced by increasing free fatty acid concentration of the medium, however addition of excess albumin to VLDL-containing medium did not prevent the fall in enzyme activity. The present results obtained with cultured rat hearts cells suggest that in vivo plasma levels of triacylglycerol-rich lipoproteins could modulate the lipoproteins could modulate the lipoprotein lipase activity of the heart.


Diagnostic performance of MRI relative to CT for metastatic nodes of head and neck squamous cell carcinomas.
To compare the diagnostic abilities of magnetic resonance imaging (MRI) and computed tomography (CT) based on the architectural changes in the nodal parenchyma. We retrospectively studied histologically proven 70 metastatic and 52 reactive nodes in the necks of 38 patients with head and neck squamous cell carcinomas who had undergone both CT and MRI. We assessed the detectability of the architectural changes in the nodal parenchyma that were suggestive of cancer focus (cancer nest, necrosis, and keratinization). The diagnostic abilities of CT and MRI were assessed by three observers separately for the small (<10 mm in minimum axis diameter) and large (>or=10 mm) nodes. MRI was significantly more effective than CT in diagnosing small metastatic nodes, yielding 83% sensitivity, 88% specificity, and 86% accuracy. However, the diagnostic abilities of MRI and CT were similar for large metastatic nodes; MRI yielded 100% sensitivity, 98% specificity, and 99% accuracy. receiver operating characteristic analysis also indicated that the Az values were significantly higher for MRI than for CT (0.927 vs. 0.822, P = 0.00054) for the detection of small nodes. MRI is superior to CT in the diagnosis of metastatic nodes from head and neck squamous cell carcinomas.


All tangled up: interactions of the fibrinolytic and innate immune systems.
The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked process has resulted in the coining of the terms "thromboinflammation" and "immunothrombosis." Once a thrombus is formed it is up to the fibrinolytic system to resolve these clots and remove them from the vasculature. Immune cells contain an arsenal of fibrinolytic regulators and plasmin, the central fibrinolytic enzyme. The fibrinolytic proteins in turn have diverse roles in immunoregulation. Here, the intricate relationship between the fibrinolytic and innate immune system will be discussed.


Long-term effects of sulfur mustard on civilians' mental health 20 years after exposure (The Sardasht-Iran Cohort Study).
Sulfur mustard (SM) is an alkylating agent that induces short and long term toxicity on various organs. The aim of this study was to assess the long-term psychological symptoms among samples of exposed to sulfur mustard gas compared with unexposed civilians 20 years after exposure. This historical cohort study was conducted on 495 civilians of Sardasht and Rabat in two age matched groups, including 367 sulfur mustard exposed participants from Sardasht and 128 unexposed subjects from Rabat. Psychological symptoms was assessed using the Symptom Check List-90 Revised (SCL-90-R) including measures of somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism providing three global distress indices namely: Global Severity Index (GSI), Positive Symptom Total (PST) and Positive Symptom Distress Index (PSDI). Comparison was made between exposed and unexposed civilians. There were significant differences in somatization (P = 0.002), obsessive-compulsive (P = 0.031), depression (P = 0.007), anxiety (P = 0.042), and hostility (P = 0.002), between the exposed and unexposed groups. In addition there were significant differences between two groups concerning the GSI (P = 0.045) and the PSDI (P < 0.001). The differences between two groups in other subscales were not significant. The findings from this study showed that civilians who exposed to sulfur mustard gas were suffering from a number of psychological symptoms even 20 years after exposure. Providing mental health services and more resource allocation for this community are highly recommended.


Metformin action on AMP-activated protein kinase: a translational research approach to understanding a potential new therapeutic target.
Clinical studies in Type 2 diabetes mellitus have shown that the effects of metformin go beyond improving HbA(1c) and include reductions in cardiovascular endpoints. Metformin therapy has been widely used in the treatment of Type 2 diabetes for many years, yet the precise mode of action remains uncertain. It has recently been proposed that metformin-mediated stimulation of hepatic AMP-activated protein kinase (AMPK) underlies the hypoglycaemic effects of metformin. AMPK is a heterotrimeric enzyme that is expressed in many tissues and plays a central role in the regulation of energy homoeostasis. Furthermore, there is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. The generation of more specific and potent activators of AMPK, however, could have additional metabolic and vascular benefits for patients with Type 2 diabetes.


Regulation of migration of primary prostate epithelial cells by secreted factors from prostate stromal cells.
Stromal-epithelial interactions, which regulate the migration of prostate epithelial cells, play an important role in prostate development, prostatic hyperplasia, and prostate cancer. The objective of this study was to determine how the prostate stroma stimulates the migration of primary prostate epithelial cells (PECs). In the Boyden chamber assay, PEC migration was strongly induced by the conditioned medium of primary prostate stromal cells (PSC-CM). Stimulation of PEC migration depended on the concerted action of adhesion and motility factors in the PSC-CM. Immobilized proteins from PSC-CM mediated adhesion, spreading, and head-to-tail polarization of PECs. Migration induced by immobilized PSC-CM proteins was significantly increased by hepatocyte growth factor/scatter factor (HGF/SF). Inhibition of P13-kinase or Src-family kinases, but not MEK or PLCchi, abolished migration in the Boyden chamber assay. Consistent with their concerted activity in migration assays, the combination of adhesion and motility factors was required for efficient activation of the P13-kinase/Akt pathway. HGF/SF in the PSC-CM was the principal stimulator of the P13-kinase/Akt pathway and an important mediator of PSC-CM-induced PEC migration. In conclusion, our data show that the migration of primary PECs is regulated by the P13-kinase and Src-family kinase signaling pathways and that the activation of the P13-kinase pathway requires adhesion and motility factors from the prostate stroma.


Preliminary results of a new surgical technique in total knee arthroplasty (TKA) using the native ligament tension for femoral implant positioning in varus osteoarthritis.
Individual implant alignment in total knee arthroplasty (TKA) has seen growing interest over the past years. This study therefore aimed to develop a surgical technique for implant alignment based on native ligament tension, and to present the results obtained using this technique. 25 patients were included in this prospective study. Patient-specific instrumentation (PSI) was used for the resection of the extension gap. Ligament tension was measured after the removal of all accessible osteophytes. In the event of asymmetry, the distal femur resection was adjusted up to 2.5° using an adjustable cutting block. The aim was to achieve a symmetrical extension gap without release, not a neutral leg axis. Femoral rotation was aligned on the basis of ligament tension. Patients were followed up to 3 months postoperatively. The postoperative whole-leg axis was 2.8° ± 1.6° varus. Patients achieved a flexion of 118° ± 9°, a Knee Score of 91.5 ± 3.2 and a Function Score of 86.8 ± 8.3 points. For the first time, the new surgical technique described here permits a ligament tension based femoral implant alignment together with PSI. It was shown to be safe, with encouraging clinical and radiological results. Therapeutic study level IV.


Principal components analysis as a tool for the optimization of experimental conditions.
Principal Components Analysis is used to display the variation in a data set consisting of the free amino-acid patterns in serum from dogs as a function of fasting time. Inhomogeneities found in the data set resulted in an optimization of the experimental conditions. Moreover important observations concerning sampling time and biological variability could be made.


The relationship between perceived social support and psychological distress in carers of older relatives: A longitudinal cross-lagged analysis.
Although a large body of research has examined the relationship between social support and psychological health of family carers of frail older people, the exact nature and direction of this relationship is not well understood with most research to date being cross-sectional. This longitudinal study explored the relationship between perceived social support and psychological distress in carers of older relatives. We used data from two longitudinal cohorts which included a total of 332 family carers of frail older people. We used cross-lagged panel analysis to investigate the longitudinal association between perceived social support and carer psychological distress controlling for a number of covariates over time. Fully-adjusted Generalised Estimating Equations (GEE) and cross-lagged models indicated that higher social support was significantly associated with lower carer psychological distress over time (regression coefficient [B] = -0.178, standard error [SE] = 0.028), with levels of perceived social support exerting an effect on psychological distress rather than vice versa (β = 0.03, p = 0.32). All observations were based on self-report data, and there may be other variables that may explain the results that we did not account for. Our study finds that the directionality of the relationship appears to be from perceived social support to carer psychological distress suggesting that social support directly affects carer psychological health but not vice versa. This finding has important implications for the provision of social support interventions for carers of frail older people at risk of experiencing psychological distress.


An evaluation of different approaches for behavior genetic analyses with psychiatric symptom scores.
We used a simulation study to evaluate six approaches for behavior genetic analyses of psychiatric symptom scores. For the selection of the correct model, the best results were obtained with approaches using transformed scores in combination with a procedure involving p-values. With normalizing transformations, the chi 2 test statistic gave a reasonable impression of the overall fit of the model but was less accurate when used as a difference test. The asymptotic distribution free estimation methods yielded chi 2s that were much too large. All data analysis techniques yielded substantially biased parameter estimates. The most biased results were obtained with normalizing transformations. The least biased results were obtained with tobit correlations, but because of its large standard errors the most precise estimates were obtained with polychoric correlations and optimal scale scores. An empirical study showed that a recognition of the role of methodological factors was helpful to understand part of the differences between assessment instruments, raters, and data analysis techniques that were found in the real data.


Effects of verapamil on the pharmacokinetics of daunomycin in the rat.
We compared the pharmacokinetics of daunomycin in two groups of rats: one group was treated with daunomycin (7.5 mg/kg) alone and the other group was treated with daunomycin (7.5 mg/kg) plus the calcium antagonist verapamil (2 X 50 mg/kg i.p.). Due to a much slower decrease in plasma concentrations the daunomycin AUC0----infinity was dramatically increased (8 times) in the animals treated with anthracycline plus verapamil. The daunomycin plasma clearance was found to be decreased about 9 times in the verapamil-treated group. Verapamil had a differential effect on the tissue distribution of daunomycin. Of the organs examined the heart, liver, and lungs showed an increased (about 2-3 times) AUC of daunomycin. In the kidneys and spleen the AUCs of daunomycin were about equal in both groups of rats, while in the femoral bone marrow the daunomycin AUC was significantly reduced by the simultaneous administration of verapamil. Our data suggest that an increased risk for anthracycline-induced cardiotoxicity can be anticipated by the combined treatment of anthracycline drugs with calcium antagonists.


Laparoscopic restoration of intestinal continuity (the LapRICon procedure): a safe and feasible technique for restoration of transanal defecation.
The restoration of intestinal continuity after open abdominal surgery can be technically challenging. The authors describe their experience with the laparoscopic approach to attempted reversal for patients with an exteriorized intestine. A consecutive series of patients under the care of a single surgeon (D.B.) underwent laparoscopic restoration of intestinal continuity (LapRICon). All the patients first underwent exclusion of intraabdominal sepsis with computed tomography (CT) scanning and then preoperative localization of proximal and distal bowel ends via water-soluble contrast studies. Stomal sites were used for initial access, establishment of capnoperitoneum, and formation of anastomoses extracorporeally. All adhesiolysis and mobilization of bowel ends were performed intracorporeally. Pre-, intra-, and postoperative data were collected for all the patients. Return of intestinal function, overall hospital length of stay, and postoperative complications were collected. Nonparametric statistics were used to analyze the data. A total of 13 patients (6 women) were followed up for 9 months (interquartile range [IQR], 5-16 months). The median age of the patients was 39 years (IQR, 28-64 years). Nine patients were categorized as American Society of Anesthesiology (ASA) class 1. One patient was ASA 2, and the remaining patients were ASA 3. The median colorectal physiologic and operative severity scores for the enumeration of mortality and morbidity (CR-POSSUM) were 0.68 (IQR, 0.68-1.72). The intraoperative blood loss was minimal (median 30 ml; IQR, 20-125 ml). The median operative duration was 240 min (IQR, 180-240 min), and a median of 4 ports (IQR, 3-5 ports) were used. Enterocolonic anastomoses were fashioned in six patients, enterorectal anastomoses in two patients, and enteroentero anastomoses in three patients. A single patient had multiple anastomoses. The median time to return of intestinal function was 5 days (IQR, 3-13 days), and the overall hospital stay was 8 days (IQR, 5-24 days). Four complications (25%) (2 recurrent fistulas, 1 anastomotic leak, and 1 open conversion) occurred in this series of patients. The LapRICon procedure is a feasible technique with acceptable morbidity. Several principles and techniques are described to aid the surgeon who wishes to embark on use of such a technique.


Adverse childhood experiences are associated with migraine and vascular biomarkers.
Migraine is a risk factor for stroke in young women. Biomarker studies implicate endothelial activation as a possible mechanism. Emerging relationships of childhood adversity with migraine, and with inflammation, a component of endothelial activation, suggest that it may play a role in the migraine-stroke association. Our objective is to evaluate the relationship between adverse childhood experiences (ACEs), migraine, and vascular biomarker levels in premenopausal women. Vascular and metabolic biomarkers from women 18-50 years, including 125 with migraine (interictal) and 50 without migraine, were evaluated. An ACE questionnaire was later collected by mail (response rate 80.6%, 100 migraineurs, 41 controls). Migraineurs and controls were demographically similar. Migraineurs reported adversity more commonly than controls (71% vs 46%, odds ratio [OR] = 1.53, 95% confidence interval 1.07-2.17). Average ACE scores were elevated in migraineurs as compared with controls (2.4 vs 0.76, P < .001). ACE scores correlated with headache frequency (0.37, P = .001) and younger age of headache onset (-0.22, P = .04). It also correlated with body mass index (r = 0.43, P = .0001), von Willebrand factor activity (r = 0.21, P = .009), tissue plasminogen activator antigen (r = 0.28, P = .004), prothrombin activation fragment (r = 0.36, P = .001), high-sensitivity C-reactive protein (r = 0.98, P = .0001), transforming growth factor-beta1 (r = 0.28, P = .003), tissue necrosis factor-alpha (r = 0.20, P = .03), interleukin-6 (r = 0.22, P = .03), adiponectin (r = -0.29, P = .003), and nitrate/nitrite concentration (r = -314, P = .001). Logistic regression analyses (adjusted for vascular risk factors and migraine) demonstrated an association of childhood adversity with inflammatory factors (high-sensitivity C-reactive protein, interleukin-6, and tissue necrosis factor-alpha). In young women, adverse childhood events are associated with migraine, particularly chronic and transformed migraine, and with vascular biomarkers, especially inflammatory biomarkers. These findings implicate early life stress as a link between migraine and endothelial activation.


Senescence is accelerated, and several proteases are induced by carbon "feast" conditions in barley (Hordeum vulgare L.) leaves.
Leaf senescence is characterized by nitrogen remobilization to developing seeds of annual plants, or surviving organs of perennial species. It has been demonstrated that high carbohydrate levels (carbon "feast") are associated with the onset of the senescence process. Therefore, the development of model systems allowing the manipulation of leaf carbohydrates constitutes a logical first step in the investigation of processes important during early phases of senescence, such as plastidial protein degradation. In this study, sugar accumulation was induced either by the incubation of excised, mature barley (Hordeum vulgare L.) leaves under relatively strong light, or by the interruption of sieve tubes at the base of the leaf lamina by "steam-girdling". Accelerated chlorophyll degradation and net proteolysis confirmed successful senescence induction in both model systems, but suggested that girdled leaves are more useful than excised leaves to study proteolysis. Activities or transcript levels of several proteolytic enzymes, including plastidial (aminopeptidases, Clp protease), cytosolic (proteasome) and vacuolar (thiol proteases, an aspartic protease and a serine carboxypeptidase) proteases were clearly induced under these conditions; some of these genes also reacted to other stimuli such as leaf excision. The most interesting finding was the specific induction of a carboxypeptidase gene (cp-mIII) in girdled leaves accumulating high carbohydrate levels. As a previous study from our laboratory, using a genetic approach, has indicated that one or several carboxypeptidases are involved in leaf N remobilization, the detailed characterization of cp-mIII (and, possibly, closely related genes) may considerably improve our understanding of whole-plant N recycling.


Effects of binge drinking and depression on cognitive-control processes during an emotional Go/No-Go task in emerging adults.
The goal of the current study was to examine differences in neurocognitive processes across groups marked by binge drinking and depression to identify patterns of cognitive and affective processing impairments. Undergraduate students (N = 104; 64% female) were recruited based on self-reported symptoms of depression and alcohol use. They completed an emotional Go/No-Go task while undergoing EEG. Mean amplitudes for N2 and P3 components were examined with 2 (Depressed/Non-depressed) X 2 (Binge/Non-binge drinkers) X 4 (Happy/Sad/Angry/Calm) X 3 (Left/Middle/Right) X 2 (Go/No-Go) repeated measures ANOVAs. There were significant Trial Type X Valence X Depression X Binge Drinking interactions for N2 (F(3, 80) = 6.62, p < .01) and P3 (F(3, 80) = 4.65, p < .01) components. There was a significant Valence X Depression X Binge Drinking interaction for response bias (F(3, 65) = 3.11, p < .05). The source of our sample may be a limitation, as all participants were university students, potentially making the results less generalizable. Further, we cannot be certain that social desirability did not interfere with honest reporting of alcohol use in this population. Differences in early inhibitory control were observed across emotions based on trial type among depressed non-binge drinkers, and these differences were attenuated in the presence of binge drinking. Further, the effects of depression on later inhibitory control were specific to non-binge drinkers. Results help to clarify the nature of underlying patterns of neurocognitive and affective risk processes that could be targeted by prevention and intervention programs.


The function of long non-coding RNA SNHG11 and its working mechanism in triple-negative breast cancer.
Triple-negative breast cancer (TNBC) seriously affects woman's health. The present work is to study the working mechanism of lncRNA SNHG11 in TNBC. The expressions of SNHG11, microRNA (miR)- 7-5p, specificity protein 2 (SP2) and mucin 1 (MUC-1) in TNBC tissues and cells were detected. SNHG11, miR-7-5p and SP2 expressions were then evaluated for TNBC cell malignant behaviors. The relationships among SNHG11, miR-7-5p and SP2 were predicted and verified. Finally, the binding of the transcription factor SP2 to MUC-1 promoter was detected. Abnormally elevated SNHG11, SP2 and MUC-1 expressions were observed in cultured TNBC cells and tumor tissues. SNHG11 knockdown in TNBC cells. Silencing SP2 weakened the promoting effect of SNHG11 on TNBC progression. SNHG11 negatively regulated miR-7-5p expression and positively regulated SP2 expression. SP2 bound to the P2 site of MUC-1 promoter, and SP2 knockdown suppressed MUC-1 expression. It was demonstrated that lncRNA SNHG11 promoted TNBC cell malignant behaviors to facilitate TNBC progression. The study is first of its kinds to unravel the potential of lncRNA SNHG11 in relation to TNBC.


The toxicity and behavioural effects of neem limonoids on Cnaphalocrocis medinalis (Guenée), the rice leaffolder.
Meliaceae plant products have been shown to exert pesticidal properties against a variety of insect species. In agricultural pest control programs, such products may have the potential to be used successfully as botanical insecticides. The effect of the neem (Azadirachta indica) limonoids azadirachtin, salannin, deacetylgedunin, gedunin, 17-hydroxyazadiradione and deacetylnimbin on the biology and mortality of rice leaffolder larvae was investigated. In laboratory experiments, treatment with neem limonoids suppressed leaf folding behaviour of C. medinalis. Biological parameters (larval duration, pupal duration adult longevity and fecundity) were also affected by the treatment. Azadirachtin, salannin, and deacetylgedunin showed high bioactivity at all doses, while the rest of the neem limonoids were less active, and were only biologically active at high doses. Azadirachtin was most potent in all experiments and produced almost 100% larval mortality at 1 ppm concentration. These results indicate neem limonoids affect the larval behaviour. These effects are most pronounced in early instars.


Advances in adaptive optics-based two-photon fluorescence microscopy for brain imaging.
Deep tissue imaging using two-photon fluorescence (TPF) techniques have revolutionized the optical imaging community by providing in depth molecular information at the single-cell level. These techniques provide structural and functional aspects of mammalian brain at unprecedented depth and resolution. However, wavefront distortions introduced by the optical system as well as the biological sample (tissue) limit the achievable fluorescence signal-to-noise ratio and resolution with penetration depth. In this review, we discuss on the advances in TPF microscopy techniques for in vivo functional imaging and offer guidelines as to which technologies are best suited for different imaging applications with special reference to adaptive optics.


Using multiple group modeling to test moderators in meta-analysis.
Meta-analysis is a popular and flexible analysis that can be fit in many modeling frameworks. Two methods of fitting meta-analyses that are growing in popularity are structural equation modeling (SEM) and multilevel modeling (MLM). By using SEM or MLM to fit a meta-analysis researchers have access to powerful techniques associated with SEM and MLM. This paper details how to use one such technique, multiple group analysis, to test categorical moderators in meta-analysis. In a multiple group meta-analysis a model is fit to each level of the moderator simultaneously. By constraining parameters across groups any model parameter can be tested for equality. Using multiple groups to test for moderators is especially relevant in random-effects meta-analysis where both the mean and the between studies variance of the effect size may be compared across groups. A simulation study and the analysis of a real data set are used to illustrate multiple group modeling with both SEM and MLM. Issues related to multiple group meta-analysis and future directions for research are discussed. Copyright © 2016 John Wiley & Sons, Ltd.


Effect of fluence smoothing on the quality of intensity-modulated radiation treatment plans.
A fluence-smoothing function applied for reducing the complexity of a treatment plan is an optional requirement in the inverse planning optimization algorithm of intensity-modulated radiation therapy (IMRT). In this study, we investigated the consequences of fluence smoothing on the quality of highly complex and inhomogeneous plans in a treatment-planning system, Eclipse™. The smoothing function was applied both in the direction of leaf travel (X) and perpendicular to leaf travel (Y). Twenty IMRT plans from patients with cancer of the nasopharynx and lung were selected and re-optimized with use of various smoothing combinations from X = 0, Y = 0 to X = 100, Y = 100. Total monitor units (MUs), dose-volume histograms, and radiobiological estimates were computed for all plans. The study yielded a significant reduction in the average total MUs from 2079 ± 265.4 to 1107 ± 137.4 (nasopharynx) and from 1556 ± 490.3 to 791 ± 176.8 (lung) while increasing smoothing from X, Y = 0 to X, Y = 100. Both the tumor control and normal tissue complication probabilities were found to vary, but not significantly so. No appreciable differences in doses to the target and most of the organs at risk (OARs) were noticed. The doses measured with the I'MRT MatriXX 2-D system indicated improvements in deliverability of the plans with higher smoothing values. Hence, it can be concluded that increased smoothing reduced the total MUs exceptionally well without any considerable changes in OAR doses. The observed progress in plan deliverability in terms of the gamma index strongly supports the recommendation of smoothing levels up to X = 70 and Y = 60, at least for the nasopharynx and lung.


mTOR Signaling in Parkinson's Disease.
As a key regulator of cell metabolism and survival, mechanistic target of rapamycin (mTOR) emerges as a novel therapeutic target for Parkinson's disease (PD). A growing body of research indicates that restoring perturbed mTOR signaling in PD models can prevent neuronal cell death. Nevertheless, molecular mechanisms underlying mTOR-mediated effects in PD have not been fully understood yet. Here, we review recent progress in characterizing the association of mTOR signaling with PD risk factors and further discuss the potential roles of mTOR in PD.


Induction of CTGF by TGF-beta1 in normal and radiation enteritis human smooth muscle cells: Smad/Rho balance and therapeutic perspectives.
Transforming Growth Factor beta1 (TGF-beta1) and its downstream effector Connective Tissue Growth Factor (CTGF/CCN2), are well known fibrogenic activators and we previously showed that the Rho/ROCK pathway controls CTGF expression in intestinal smooth muscle cells isolated from patients with delayed radiation enteritis. The aim of the present work was to investigate the balance between Smad and Rho signalling pathways in the TGF-beta1 CTGF induction and modulation of radiation-induced fibrogenic differentiation after addition of pravastatin, an inhibitor of Rho isoprenylation. Primary human smooth muscle cells isolated from normal (N-SMC) or radiation enteritis (RE-SMC) biopsies were incubated with TGF-beta1 (10 ng/ml). Induction of CTGF, as well as nucleo-cytoplasmic distribution of phospho-Smad2/3, Smad2/3 and Smad4 were analysed by Western blot and immunocytochemistry. Smad DNA binding was assessed by EMSA and Rho activation was measured by pull-down assay. After TGF-beta1 addition, Smads were translocated to the nucleus in both cell types. Nuclear accumulation of Smad as well as their DNA-binding activity were higher in N-SMC than in RE-SMC, whereas the opposite was observed for Rho activation, suggesting a main involvement of Rho pathway in sustained fibrogenic differentiation. This hypothesis was further supported by the antifibrotic effect observed in vitro after cell treatment with pravastatin (i.e. decreased expression of CTGF, TGF-beta1 and Collagen Ialpha2). Our results suggest that TGF-beta1-induced CTGF transactivation mainly depends on the Smad pathway in N-SMC, whereas in RE-SMC, Smad and Rho pathways are involved. Inhibition of Rho activity by pravastatin alters fibrogenic differentiation in vitro which opens up new therapeutic perspectives.


Poziotinib in non-small-cell lung cancer patients with HER2 exon 20 mutations: A pooled analysis of randomized clinical trials.
Non-small-cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) exon 20 mutant occurs in 3% of NSCLCs. Targeted agents for this population remain an unmet need. In this analysis, we pooled-analyzed the efficacy and safety of poziotinib, a novel tyrosine kinase inhibitor, in HER2 exon 20 mutant NSCLC. PubMed, Embase, Web of Science, and Cochrane CENTRAL databases were systematically searched on March 9, 2022. The primary endpoints were objective response rate (ORR) and disease control rate. The secondary endpoint was treatment-related adverse events. Three prospective clinical trials, involving 126 patients, were identified. The pooled ORR and disease control rate of poziotinib in HER2 exon 20 mutant NSCLC were 27% (95% CI, 19-35) and 72% (95% CI, 64-80), respectively. Patients with G778_P780dupGSP had the highest ORR (88%; 95% CI, 33-100; n = 12), followed by Y772_A775dupYVMA (20%; 95% CI, 12-30; n = 88) and G776delinsVC (19%; 95% CI, 0-50; n = 13). The most common grade 3 to 4 treatment-related adverse events were skin rash (36%), diarrhea (23%), and oral mucositis (13%). Poziotinib demonstrates moderate antitumor activity in previously treated HER2 exon 20 mutant NSCLC patients with a manageable safety profile. In addition, different subgroup mutations show various benefits of poziotinib treatment. Large-scale and multiarm clinical trials are warranted to confirm a suitable population and therapeutic strategies.


Glyphidohaptor safiensis n. sp. (Monogenea: Ancyrocephalidae) from the white-spotted rabbitfish Siganus canaliculatus (Park) (Perciformes: Siganidae) off Oman, with notes on its phylogenetic position within the Ancyrocephalidae Bychowsky & Nagibina, 1968 (sensu lato).
A new ancyrocephalid monogenean is described from the gills of wild White-spottedrabbitfish Siganus canaliculatus (Park) based on morphological and molecular analyses. Glyphidohaptor safiensis n. sp. can be distinguished from other members of the genus by the shape of the accessory piece of the male copulatory organ (MCO). Unlike its congeners, the rod-shaped accessory piece of G. safiensis n. sp. is distally broad and flattened. The MCO of G. safiensis n. sp. is curved, enclosed in a heavy sheath with a terminal flap. Partial large subunit (LSU), partial small subunit (SSU) and the partial SSU, entire internal transcribed spacer region 1 (ITS1) and partial 5.8S rDNA of the new species and two species of Tetrancistrum Goto & Kikuchi, 1917 from the same host and locality were sequenced and subjected to phylogenetic analysis. The LSU rDNA analysis grouped G. safiensis n. sp. with Tetrancistrum sp. from the gills of Siganus fuscescens Houttuyn from Australia, indicating a possible misidentification of the latter. Sequences of the SSU rDNA of the new species were most similar to those for Pseudohaliotrema sphincteroporus Yamaguti, 1953, demonstrating the close relatedness of the genera Pseudohaliotrema Yamaguti, 1953 and Glyphidohaptor Kritsky, Galli & Yang, 2007 within the Ancyrocephalidae. The comparison of the partial SSU (424 bp) and entire ITS1 and partial 5.8S rDNA (246 bp) sequences obtained for G. safiensis n. sp. with the only available sequence of another member of Glyphidohaptor Kritsky, Galli & Yang, 2007, G. pletocirra Paperna, 1972 (HE601931-HE601933) yielded on average 1.08% dissimilarity (a difference of 7 bases), with a p-distance of 0.010 ± 0.004%. This is the first record of a species of Glyphidohaptor from S. canaliculatus and from the Persian Gulf, the Gulf of Oman and the Arabian Sea.


Lipoyl-Based Antagonists of Transient Receptor Potential Cation A (TRPA1) Downregulate Osteosarcoma Cell Migration and Expression of Pro-Inflammatory Cytokines.
Osteosarcoma is a heterogeneous tumor intimately linked to its microenvironment, which promotes its growth and spread. It is generally accompanied by cancer-induced bone pain (CIBP), whose main component is neuropathic pain. The TRPA1 ion channel plays a key role in metastasis and is increasingly expressed in bone cancer. Here, a novel TRPA1 inhibitor is described and tested together with two other known TRPA1 antagonists. The novel lipoyl derivative has been successfully assessed for its ability to reduce human osteosarcoma MG-63 cell viability, motility, and gene expression of the CIBP pro-inflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α). A putative three-dimensional (3D) model of the inhibitor covalently bound to TRPA1 is also proposed. The in vitro data suggest that the novel inhibitor described here may be highly interesting and stimulating for new strategies to treat osteosarcomas.


Defining the "disruptive" in preschool behavior: what diagnostic observation can teach us.
This paper presents the clinical/developmental framework underlying a new diagnostic observational tool, the Disruptive Behavior Diagnostic Observation Schedule (DB-DOS). The special importance of observation for clinical assessment during the preschool period is delineated. The developmental rationale for a multi-dimensional assessment of disruptive behavior in young children, including problems in modulation of negative affect and low competence is discussed. The ways in which the DB-DOS will elucidate distinctions between normative and atypical behavior during this developmental period via (a) the integration of qualitative and quantitative dimensions of behavior within a clinically-sensitive coding system, (b) the observation of child behavior both within, and outside of, the parent-child context and (c) the use of specially designed tasks to "press" for clinically salient behaviors are addressed. The promise of this new method for yielding a more precise, developmentally based description of the phenotype of early onset disruptive behavior problems and for providing a standardized clinical tool for observational assessment of disruptive behavior in young children is presented. Large-scale validation of the measure is currently underway.


Measurement of oxygen partial pressure in the mandibular bone using a polarographic fine needle probe.
In this study, the oxygen partial pressure in the cancellous bone substance of the mandible was measured for the first time with a polarographic fine needle probe. This has so far only been established in soft tissue. The aim was to prove and to test the feasibility in principle of this method of measurement in order to ascertain the normal values for the O2 partial pressure in healthy bone. These values were afterwards compared with the results of measurements in areas of different pathological bone conditions in order to assess the clinical suitability of the method for "mapping" during mandibular resection. Measurements of oxygen partial pressure were made in a total of 42 patients (16 women, 26 men). Of these, 12 patients with clinically normal bones served as a control group. Seventeen patients had osteoradionecrosis following radiation treatment, and 13 patients presented with chronic osteomyelitis of the mandible. All measurements were carried out with a polarographic fine needle probe applied to the cancellous bone substance. The statistical analysis included a comparison of the mean values of the oxygen partial pressures measured. No statistical correlation between oxygen partial pressure and pH and hemoglobin values could be detected. The average oxygen partial pressure in the healthy mandibular bone was 71.4 mmHg. In non-healthy bone, the value fell to an average of 30.6 mmHg (osteoradionecrosis 32.3 mmHg, chronic osteomyelitis of the mandibular bone 28.4 mmHg). Statistically, the differences in the group values ascertained were highly significant (P < 0.005). The data found show that this method can be successfully used to detect poorly perfused bone. The values are reproducible and reflect the clinical situation. In the long term, the method appears to be a suitable diagnostic tool for assessing the oxygen supply in bone in studying various clinical problems related to bone surgery.


Is the disease risk associated with good self-reported health constant across the socio-economic spectrum?
Self-reported health is likely to be dependent on two key assessments: that of one's own health and that of the best health that could be expected. As many health outcomes are known to vary according to socio-economic position (SEP), it is possible that assessments of the best health that could be expected will vary with SEP. It is, therefore, possible that the disease risk associated with different levels of self-reported health varies according to SEP. We investigated this using data from the 1998 Health Survey for England. Disease risk was measured as systolic blood pressure and body mass index (BMI), and SEP was measured as occupational social class. Associations between social class and the markers of disease risk were investigated in those reporting different levels of self-reported health using linear regression in order to control for age. There were statistically significant socio-economic variations in systolic blood pressure and BMI (in women only) in those who reported their health as good or very good. No such socio-economic variations in disease risk were seen amongst those reporting their health as less than good. The meaning of self-reported health, in terms of disease risk, may not be comparable across the socio-economic spectrum.


Pancreatic pseudocyst arising from ectopic pancreas and isolated intestinal duplication in mesocolon caused hydronephrosis in a girl with horseshoe kidney.
Ectopic pancreas is a relatively common congenital anomaly and is usually asymptomatic. Pancreatitis in the ectopic site and pseudocyst formation is extremely rare. To date, only 2 cases have been reported. We present a case of a 3-year-old girl with recurrent pancreatitis and unilateral hydronephrosis of the horseshoe kidney, which was produced by pancreatic pseudocyst arising from ectopic pancreas and isolated intestinal duplication in mesocolon. This is the first case of pancreatic pseudocyst that expanded to the retroperitoneal space and caused urinary tract obstruction.


Cerebellar glioblastoma in an NF1 patient. Is it surgical debulking really necessary?
Introduction: Neurofibromatosis type 1 is an autosomal dominant tumour syndrome with an increased risk of developing central nervous system neoplasms, mostly benign low-grade gliomas involving the optic pathway and the brainstem. High-grade astrocytomas or glioblastoma multiforme (GBM) are rare. Cerebellar GBMs are rarer still, only seven cases NF1 patients have been reported Case description: We report a case of a cerebellar GBM in a 25-year-old male with NF1 who survived 18 months from the initial diagnosis without surgical debulking but only chemo and radiotherapy.Conclusion: A literature review found that the best outcomes were achieved in NF1 patients who didn't undergo gross surgical resection. Possible reasons and future directions are discussed.