Characteristics of 7 beta-hydroxycholesterol-induced cell death in a human monocytic blood cell line, U937, and a human hepatoma cell line, HepG2.
Oxysterols have been shown in a number of cell lines to induce apoptosis by a mechanism as yet unclear. The induction of apoptosis by certain agents has been associated with the generation of oxidative stress and the depletion of the endogenous antioxidant, glutathione, which may result in cytochrome c release and caspase activation. The aim of the present study was to determine whether 7 beta-hydroxycholesterol (7 beta-OH) alters glutathione levels or the activities of catalase, superoxide dismutase (SOD) or caspase-3 in association with cell death in either the U937 or the HepG2 cell lines. 7 beta-OH, which induced significant apoptosis at 12 h in the U937 cell line, was shown to cause a significant decrease in glutathione levels and an increase in the activity of SOD at this time point. An increase in caspase-3 activity was also observed in the U937 cell line following a 24-h incubation with 7 beta-OH. Glutathione concentration, SOD activity and caspase-3 activity were unchanged in the HepG2 cell line, which underwent necrosis following incubation with 7 beta-OH. The activity of the enzyme catalase remained unchanged in both cell lines. These results provide evidence that the generation of an oxidative stress may be a significant event occurring during 7 beta-OH-induced apoptosis.


The Ability of Comorbidity Indices to Predict Mortality After Heart Transplantation: A Validation of the Danish Comorbidity Index for Acute Myocardial Infarction, Charlson Comorbidity Index, and Elixhauser Comorbidity Index.
Advanced heart failure patients often have comorbidities of prognostic importance. However, whether total pretransplantation comorbidity burden predicts mortality in patients treated with heart transplantation (HTx) is unknown. We used population-based hospital and prescription data to examine the ability of the Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI), DANCAMI restricted to noncardiovascular diseases, Charlson Comorbidity Index, and Elixhauser Comorbidity Index to predict 30-d, 1-y, 5-y, and 10-y all-cause and cardiovascular mortality after HTx. We identified all adult Danish patients with incident HTx from the Scandiatransplant Database between March 1, 1995, and December 31, 2018 (n = 563). We calculated Harrell's C-Statistics to examine discriminatory performance. The C-Statistic for predicting 1-y all-cause mortality after HTx was 0.58 (95% confidence interval [CI], 0.50-0.65) for a baseline model including age and sex. Adding comorbidity score to the baseline model did not increase the C-Statistics for DANCAMI (0.58; 95% CI, 0.50-0.65), DANCAMI restricted to noncardiovascular diseases (0.57; 95% CI, 0.50-0.64), Charlson Comorbidity Index (0.59; 95% CI, 0.51-0.66), or Elixhauser Comorbidity Index (0.58; 95% CI, 0.51-0.65). The results for 30-d, 5-y, and 10-y all-cause and cardiovascular mortality were consistent. After accounting for patient age and sex, none of the commonly used comorbidity indices added predictive value to short- or long-term all-cause or cardiovascular mortality after HTx.


Cytogenetic activity of newly synthesized 1,5-benzodiazepines in normal human lymphocyte cultures.
Many different types of benzodiazepine medications exist to treat a wide array of psychological and physical diseases based on dosage and implications. Benzodiazepines are generally considered as safe and effective drugs in short term; however, cognitive impairments and paradoxical effects occasionally occur. Our recent studies have shown that some 1,4-benzodiazepines exhibit cytogenetic activity (alprazolam, diazepam, and lorazepam) in normal human lymphocyte cultures. 1,5-Benzodiazepine derivatives are used in the synthesis of fused ring compounds, to study the chemical structure-pharmacological activity correlation. We synthesized four compounds of this category with small structural differences. The aim of this study was to investigate their cytogenetic activity in vitro at doses equivalent to the per os doses of the used 1,4-benzodiazepines. Sister chromatid exchanges (SCEs), proliferation rate index, and mitotic index were evaluated in lymphocytes of peripheral blood cultures from two healthy donors. Three of the newly synthesized compounds exhibited positive cytogenetic activity (statistically significant reduction of SCEs, p < 0.01, t-test), without showing cytostatic properties. The observed reduction of the lymphocytes' SCEs because of 1,5-benzodiazepines' activity is remarkable and requires further investigation to improve pharmacological effects.


Hypnotherapy for agoraphobia: a case study.
In this case study, hypnosis combined with progressive relaxation effectively eliminated the cause of panic attacks in a 34 year old female. After an initial period of progressive relaxation, this patient was trained in desensitization techniques and in hypnosis. The introduction of hypnosis provided this young woman with long term relief from her symptoms of agoraphobia and panic. This study provides further evidence for the efficacy of hypnosis in the elimination of panic attacks.


Ratiometric Nanoparticle Probe Based on FRET-Amplified Phosphorescence for Oxygen Sensing with Minimal Phototoxicity.
Luminescent oxygen probes enable direct imaging of hypoxic conditions in cells and tissues, which are associated with a variety of diseases, including cancer. Here, a nanoparticle probe that addresses key challenges in the field is developed, it: i) strongly amplifies room temperature phosphorescence of encapsulated oxygen-sensitive dyes; ii) provides ratiometric response to oxygen; and iii) solves the fundamental problem of phototoxicity of phosphorescent sensors. The nanoprobe is based on 40 nm polymeric nanoparticles, encapsulating ≈2000 blue-emitting cyanine dyes with fluorinated tetraphenylborate counterions, which are as bright as 70 quantum dots (QD525). It functions as a light-harvesting nanoantenna that undergoes efficient Förster resonance energy transfer to ≈20 phosphorescent oxygen-sensitive platinum octaethylporphyrin (PtOEP) acceptor dyes. The obtained nanoprobe emits stable blue fluorescence and oxygen-sensitive red phosphorescence, providing ratiometric response to dissolved oxygen. The light harvesting leads to ≈60-fold phosphorescence amplification and makes the single nanoprobe particle as bright as ≈1200 PtOEP dyes. This high brightness enables oxygen detection at a single-particle level and in cells at ultra-low nanoprobe concentration with no sign of phototoxicity, in contrast to PtOEP dye. The developed nanoprobe is successfully applied to the imaging of a microfluidics-generated oxygen gradient in cancer cells. It constitutes a promising tool for bioimaging of hypoxia.


Skin Testing for Allergic Rhinitis: A Health Technology Assessment.
Allergic rhinitis is the most common type of allergy worldwide. The accuracy of skin testing for allergic rhinitis is still debated. This health technology assessment had two objectives: to determine the diagnostic accuracy of skin-prick and intradermal testing in patients with suspected allergic rhinitis and to estimate the costs to the Ontario health system of skin testing for allergic rhinitis. We searched All Ovid MEDLINE, Embase, and Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, CRD Health Technology Assessment Database, Cochrane Central Register of Controlled Trials, and NHS Economic Evaluation Database for studies that evaluated the diagnostic accuracy of skin-prick and intradermal testing for allergic rhinitis using nasal provocation as the reference standard. For the clinical evidence review, data extraction and quality assessment were performed using the QUADAS-2 tool. We used the bivariate random-effects model for meta-analysis. For the economic evidence review, we assessed studies using a modified checklist developed by the (United Kingdom) National Institute for Health and Care Excellence. We estimated the annual cost of skin testing for allergic rhinitis in Ontario for 2015 to 2017 using provincial data on testing volumes and costs. We meta-analyzed seven studies with a total of 430 patients that assessed the accuracy of skin-prick testing. The pooled pair of sensitivity and specificity for skin-prick testing was 85% and 77%, respectively. We did not perform a meta-analysis for the diagnostic accuracy of intradermal testing due to the small number of studies (n = 4). Of these, two evaluated the accuracy of intradermal testing in confirming negative skin-prick testing results, with sensitivity ranging from 27% to 50% and specificity ranging from 60% to 100%. The other two studies evaluated the accuracy of intradermal testing as a stand-alone tool for diagnosing allergic rhinitis, with sensitivity ranging from 60% to 79% and specificity ranging from 68% to 69%. We estimated the budget impact of continuing to publicly fund skin testing for allergic rhinitis in Ontario to be between $2.5 million and $3.0 million per year. Skin-prick testing is moderately accurate in identifying subjects with or without allergic rhinitis. The diagnostic accuracy of intradermal testing could not be well established from this review. Our best estimate is that publicly funding skin testing for allergic rhinitis costs the Ontario government approximately $2.5 million to $3.0 million per year.


Reconsiderations about the abnormalities of somatosensory evoked potentials in motor neuron disease.
The frequency of involvement of sensory pathways in motor neuron disease (MND) remains the matter of controversy. For this reason the purpose of the present work was to test how often sensory system involvement might be detected by somatosensory evoked potentials (SEP) studies and then to verify the presence of alteration of the sensory conduction and to detect the frequency of abnormalities of somatosensory peripheral, spinal, subcortical and cortical potentials in MND. SEP were tested after median nerve stimulation at the wrist, recorded from Erb's point, Ce2, Ce7 and scalp. Pearson's correlation coefficients test and Wilcoxon rank-sum test were used for statistical analysis. 74 patients (22 women and 52 men) were examined. Mean age of patients was 54.07 +/- 11.24 years; mean duration of the disease -19.25 +/- 15.87 months. SEP were abnormal in 39 of 74 patients (about 53%) whereas the sensory NCV in median nerve was abnormal in 14 of 74 patients (19%). The most frequent pattern of abnormalities consisted of the absence or delay of cortical responses. The mean values of SEP latencies (N9, N11, N13, N20 and P25) were significantly increased in MND patients (p < 0.05) as compared with controls. The N9 and N11 latencies correlated with the duration of the disease. The results of our study (concerning a large group of MND patients) suggest that the involvement of sensory pathways is not rare in MND.


Seronegative, non-neoplastic acute cerebellar degeneration.
Five women are presented with a subacute pure pancerebellar syndrome of ataxia and dysarthria to emphasize that this illness may occur without anti-Purkinje-cell or anti-Yo antibodies, or associated systemic cancer. The syndrome evolved over weeks or less and stabilized in four of the patients. Three had had a preceding infection and one, a rash, but there was no inflammatory response in the spinal fluid. Over the 5-year period during which these patients appeared in an individual general neurology practice, there was only one patient with paraneoplastic cerebellar degeneration. Despite the association of this syndrome with cancer, particularly in women, clinicians will still commonly confront the idiopathic variety.


Second primary malignancy risk in thyroid cancer and matched patients with and without radioiodine therapy analysis from the observational health data sciences and informatics.
Risk of second primary malignancy (SPM) after radioiodine (RAI) therapy has been continuously debated. The aim of this study is to identify the risk of SPM in thyroid cancer (TC) patients with RAI compared with TC patients without RAI from matched cohort. Retrospective propensity-matched cohorts were constructed across 4 hospitals in South Korea via the Observational Health Data Science and Informatics (OHDSI), and electrical health records were converted to data of common data model. TC patients who received RAI therapy constituted the target group, whereas TC patients without RAI therapy constituted the comparative group with 1:1 propensity score matching. Hazard ratio (HR) by Cox proportional hazard model was used to estimate the risk of SPM, and meta-analysis was performed to pool the HRs. Among a total of 24,318 patients, 5,374 patients from each group were analyzed (mean age 48.9 and 49.2, women 79.4% and 79.5% for target and comparative group, respectively). All hazard ratios of SPM in TC patients with RAI therapy were ≤ 1 based on 95% confidence interval(CI) from full or subgroup analyses according to thyroid cancer stage, time-at-risk period, SPM subtype (hematologic or non-hematologic), and initial age (< 30 years or ≥ 30 years). The HR within the target group was not significantly higher (< 1) in patients who received over 3.7 GBq of I-131 compared with patients who received less than 3.7 GBq of I-131 based on 95% CI. There was no significant difference of the SPM risk between TC patients treated with I-131 and propensity-matched TC patients without I-131 therapy.


The ocular phenotype of stiff-skin syndrome.
PURPOSE Stiff skin syndrome (SSS; MIM#184900) is a rare autosomal dominantly inherited Mendelian disorder characterised by thickened and stone-hard indurations of the skin, mild hypertrichosis, and limitation of joint mobility with flexion contractures. It is autosomal dominant with high penetrance and results from mutations in the fibrillin 1 (FBN1; MIM*134797) gene. Here we present the associated ocular phenotype in a two generation nonconsanguineous Northern Irish family.METHODS The affected patients underwent complete ophthalmic and orthoptic assessment and genetic testing.RESULTS All three patients had ophthalmoplegia of varying degrees. Direct sequencing of the FBN1 gene detected a heterozygous pathogenic mutation (c.4710G>C; p.Trp1570Cys) in all affected patients.CONCLUSIONS This is the first report of ophthalmoplegia in association with SSS.


Employing pharmacologic treatment of bipolar disorder to greatest effect.
Mechanisms of action, onset and duration of action, and interactions with other medications--all of these pharmacokinetic properties of pharmacologic agents affect the efficacy and safety of therapeutic regimens for bipolar disorder. For example, antiglutamatergic agents such as lamotrigine may relieve depression but have no impact on mania. Atypical antipsychotics with the dual effect of blocking dopamine and serotonin receptors in the brain decrease psychosis, mania, and, according to some preliminary indications, possibly depression. The impact of these properties has been borne out in clinical studies. Mood stabilizers such as lithium and valproate stabilize mood by significantly decreasing the manic and hypomanic symptoms of bipolar disorder, although they can have effects on depressive symptoms too. Lamotrigine stabilizes mood by reducing depression. The atypical anti-psychotics have been shown to be effective either as monotherapy or in combination with mood stabilizers.


Development of the Sanofi Pasteur tetravalent dengue vaccine: One more step forward.
Sanofi Pasteur has developed a recombinant, live-attenuated, tetravalent dengue vaccine (CYD-TDV) that is in late-stage development. The present review summarizes the different steps in the development of this dengue vaccine, with a particular focus on the clinical data from three efficacy trials, which includes one proof-of-concept phase IIb (NCT00842530) and two pivotal phase III efficacy trials (NCT01373281 and NCT01374516). Earlier studies showed that the CYD-TDV candidate had a satisfactory safety profile and was immunogenic across the four vaccine serotypes in both in vitro and in vivo preclinical tests, as well as in initial phase I to phase II clinical trials in both flavivirus-naïve and seropositive individuals. Data from the 25 months (after the first injection) active phase of the two pivotal phase III efficacy studies shows that CYD-TDV (administered at 0, 6, and 12 months) is efficacious against virologically-confirmed disease (primary endpoint) and has a good safety profile. Secondary analyses also showed efficacy against all four dengue serotypes and protection against severe disease and hospitalization. The end of the active phases in these studies completes more than a decade of development of CYD-TDV, but considerable activities and efforts remain to address outstanding scientific, clinical, and immunological questions, while preparing for the introduction and use of CYD-TDV. Additional safety observations were recently reported from the first complete year of hospital phase longer term surveillance for two phase 3 studies and the first and second completed years for one phase 2b study, demonstrating the optimal age for intervention from 9 years. Dengue is a complex disease, and both short-term and long-term safety and efficacy will continue to be addressed by ongoing long-term follow-up and future post-licensure studies.


Performance of microbial fuel cell coupled constructed wetland system for decolorization of azo dye and bioelectricity generation.
A microbial fuel cell coupled constructed wetland (planted with Ipomoea aquatica) system (planted CW-MFC) was used for azo dye decolorization. Electricity was simultaneously produced during the co-metabolism process of glucose and azo dye. A non-planted and an open-circuit system were established as reference to study the roles of plants and electrodes in azo dye decolorization and electricity production processes, respectively. The results indicated that plants grown in cathode enhanced the cathode potential and slightly promoted dye decolorization efficiency. The electrodes promoted the dye decolorization efficiency in the anode. The planted CW-MFC system achieved the highest decolorization rate of about 91.24% and a voltage output of about 610 mV. The connection of external circuit promoted the growth of electrogenic bacteria Geobacter sulfurreducens and Beta Proteobacteria, and inhibited the growth of Archaea in anode.


Freezing and melting of water confined in silica nanopores.
In nanosized pores, liquid water can be thermodynamically stable down to temperatures well below the limit of homogeneous nucleation of bulk water ( approximately 235 K). Studies of water in such pores therefore offer an opportunity to reveal the anomalous behavior of deeply supercooled water. Herein we focus on recent studies of the limits of freezing and melting of water in the cylindrical pores of ordered mesoporous silicas with pore diameters in the range of 2-10 nm, based on vapor sorption measurements, calorimetric studies, NMR spectroscopy and cryoporometry, and neutron diffraction studies.


Sensitive detection of human cytomegalovirus peptide-specific cytotoxic T-lymphocyte responses by interferon-gamma-enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation.
Reconstitution of human cytomegalovirus (HCMV)-specific cytotoxic T lymphocytes (CTLs), predominantly directed against pp65, provides protective immunity for the development of HCMV disease after allogeneic stem cell transplantation (SCT). To define pp65-derived CTL epitopes that would allow sensitive detection of HCMV-specific immune reconstitution, a computer-based epitope prediction was performed. Peptide-specific CTL responses were assessed by interferon-gamma release. With this approach, pp65-derived epitopes presented by the HLA alleles A*0101, A*0201, A*1101, and B*0702 were identified. The frequency of CTLs in healthy HCMV-seropositive individuals ranged from about 0.1% to 3.3% of all CD8(+) T cells. In patients at risk of HCMV infection after allogeneic SCT, HCMV-peptide-specific CTLs were found in 14 of 19 patients at a median of 90 days after SCT (range, 35-234 days) and HCMV-antigen-specific CD4(+) T lymphocytes in 11 of 18 patients at a median of 90 days after SCT (range, 35->180 days). Peak counts of peptide-specific CD8(+) T cells ranged from 0.14 to 60.6 cells/microL; those of protein-specific CD4(+) T cells ranged from 0.64 to 18.97 cells/microL. Reconstitution of HCMV-peptide-specific CD8(+) T cells and protein-specific CD4(+) T cells was associated with clearance of HCMV infection (r(2) = 0.89, P <.0001 and r(2) = 0.61, P =.0045, respectively). HCMV infection recurred after documentation of HCMV-specific T-cell reconstitution (n = 4) when immunosuppression was intensified. Patients in whom late-onset HCMV disease developed lacked HCMV-protein-specific T cells at 3 months after SCT. In conclusion, prospective monitoring of HCMV-specific CD4(+) and CD8(+) T-cell reconstitution can be performed rapidly by using flow cytometry after specific stimulation with HCMV peptides and proteins and might help to further improve clinical management of HCMV infection after allogeneic SCT.


Thermodynamics of Self-Assembly of Dicarboxylate Ions with Binuclear Lanthanide Complexes.
Self-assembly of a range of carboxylic acids (benzoic acid, dinicotinic acid, nicotinic acid, and isophthalic acid) with the europium complex of 5-nitro-α,α'-bis(DO3Ayl)-m-xylene (where DO3A is 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) has been explored to establish the thermodynamics of binding in a range of solvent systems and in a range of aqueous buffer solutions. In this system, profound effects are observed as a consequence of competition by the hydroxide ion, which outcompetes even dinicotinate at high pH. In the case of isophthalate, which binds most strongly, and dinicotinate, both enthalpic and entropic contributions to binding have been identified. The europium complex with 5-nitro-α,α'-bis(DO3Ayl)-m-xylene is found to have a solution structure significantly different from the related europium complex of 5-amino-α,α'-bis(DO3Ayl)-m-xylene. It is found that phosphate binds strongly to the europium complex of the nitro derivate but not to the europium complex of amino derivative. Lactate, citrate, and pyruvate also bind strongly to 5-nitro-α,α'-bis(Eu⋅DO3Ayl)-m-xylene, and it is concluded that the solution structure of this binuclear lanthanide complex is significantly different from that of the amino-substituted complex.


The effects of methotrexate on the production and activity of interleukin-1.
To explore the possibility that the mechanism of action of methotrexate (MTX) in rheumatoid arthritis (RA) is related to modulation of interleukin-1 (IL-1), the effects of MTX on IL-1 production and activity were evaluated. Human peripheral blood mononuclear cells and murine peritoneal and splenic cells were stimulated by lipopolysaccharide to produce IL-1. No inhibition of IL-1 synthesis or secretion caused by MTX treatment could be demonstrated either in vitro or in vivo, in patients with RA or in mice treated with MTX. We did show, however, that MTX had an inhibitory effect on IL-1 activity in 2 assays that demonstrate 2 different functions of IL-1. In a 2-step assay using LBRM-33-1A5 (1A5) and CTLD cells, MTX inhibited the secretion of IL-2 by 1A5 lymphoma cells in response to phytohemagglutinin and IL-1. In an assay using D10.G4.1 (D10) cells, MTX inhibited IL-1-induced proliferation of the D10 T cell clone. No effect of the drug on IL-2 activity was observed. The results demonstrate that MTX is capable of inhibiting some IL-1 activities without affecting IL-1 production or secretion. We propose that the inhibition of IL-1 activity or IL-1-dependent events may be one of the mechanisms of action of MTX in RA.


Laryngeal muscle recovery after suxamethonium. Detection during intratracheal jet ventilation by pressure curve monitoring.
Complications due to intratracheal jet ventilation are often caused by the unrecognized recovery of laryngeal muscles. The rate of rise of pressure in a main bronchus alters with changes of the glottic aperture during jet ventilation. The special pressure curve monitor sets off an alarm when the steepness of the rising curve changes. During recovery these alarms, as well as the onset of phonation, coughing, spontaneous breathing and forearm muscle activity are recorded simultaneously. Forearm muscle activity always appears later than the alarm, and often later than the other recorded phenomena. Pressure curve monitoring provides advance warning of returning muscle activity in the larynx, but conventional muscle activity monitoring in the forearm does not.


The effects of elevated temperature on coronary artery dimensions.
The interpretation of deaths occurring in fires is often complicated by numerous tissue artefacts. The aim of this experimental study was to see whether coronary arteries exposured to heat may have altered morphology. Two specimens of coronary arteries were taken from each of 10 previously healthy men, who died due to trauma, who had no macroscopic evidence of coronary atherosclerosis - one specimen was immediately fixed in formalin (control group), while the other was exposed to high temperature (70°C for five minutes), and then fixed (experimental group). Morphometric analysis of arterial walls showed significant thickening of about 45 % in tissue samples from the experimental group (control vs. experimental: 604.8μm vs. 879.2μm, p<0.002), with much more prominent thickening of the tunica intima and externa (70 % and>50 %), compared to the tunica media (4%). Another feature was either partial or complete loss of the internal elastic lamina in all of the heated arteries. The results of the current study suggest that the morphology of coronary arteries in cases of fire-related deaths should be carefully interpreted, since the thickness of their wall could be increased not due to underlying disease states, but simply due to heat exposure, which may lead to inaccurate pathological interpretations. This may have considerable medicolegal significance if a deceased driver or pilot is being assessed for liability in an accident.


Small bowel volvulus caused by migrating mesh plug.
The choice of material and technique for repair of inguinal hernias is broad. The mesh plug technique has become one of these techniques. The local complications of this technique are well known and include entrapment and damage of nervous and reproductive structures causing pain and even infertility. Migration of the mesh recently has become evident. We found a few cases of migrating mesh plug in the literature. We report a 76-year-old male patient who presented during admission for a neurosurgical procedure. His hospital course was complicated by migrating mesh eroding into the small intestine presenting as a small bowel obstruction. During exploratory laparotomy, a small bowel volvulus was found and reduced along with resection of the bowel-mesh complex. We discuss and review this technique's complications, including a 9-year review of adverse events reported to the U.S. Food and Drug Administration.


Does light drinking during pregnancy improve pregnancy outcome? A critical commentary.
A recent study published from the University College London suggests that children of women who were light drinkers during pregnancy demonstrate better cognitive outcome at three years of age when compared to children of abstinent women based on data from the UK Millennium Cohort Study. Unfortunately, methodological pitfalls and limited external validity of the results presented make conclusions very tenuous. This paper was widely quoted by the media, sometimes concluding that drinking is beneficial. At the present state of knowledge, the poor quality of this study may cause more damage than benefit, as demonstrated by the media response.


Pomalidomide Inhibits PD-L1 Induction to Promote Antitumor Immunity.
: Thalidomide-like drugs have been approved for the treatment of human multiple myeloma, with their direct antitumor effects and immunomodulatory functions well documented. However, the exact molecular mechanisms that govern these effects remain unclear. Here we demonstrate that pomalidomide promotes immune response by inhibiting expression of PD-L1. Pomalidomide inhibited PD-L1 expression on tumor cells to promote CTL activity in vitro and suppressed PD-L1 upregulation on antigen-presenting cells to prevent peptide-induced T-cell tolerance. Knockout of PD-L1 on tumor cells or in mice completely eliminated the immunomodulatory effect of pomalidomide. Furthermore, pomalidomide synergized with other immunotherapies to improve anticancer therapy. Taken together, this study identifies a new mechanism for the immunomodulatory functions of pomalidomide in cancer therapy. These results also offer a clinical approach for blocking PD-L1 induction and potentially promoting antitumor immunity. SIGNIFICANCE: These findings report that the immunomodulatory drug pomalidomide, widely used to treat myeloma and other cancers, enhances antitumor immunity by inhibiting PD-1/PD-L1 expression.


Use of very short answer questions compared to multiple choice questions in undergraduate medical students: An external validation study.
Multiple choice questions (MCQs) offer high reliability and easy machine-marking, but allow for cueing and stimulate recognition-based learning. Very short answer questions (VSAQs), which are open-ended questions requiring a very short answer, may circumvent these limitations. Although VSAQ use in medical assessment increases, almost all research on reliability and validity of VSAQs in medical education has been performed by a single research group with extensive experience in the development of VSAQs. Therefore, we aimed to validate previous findings about VSAQ reliability, discrimination, and acceptability in undergraduate medical students and teachers with limited experience in VSAQs development. To validate the results presented in previous studies, we partially replicated a previous study and extended results on student experiences. Dutch undergraduate medical students (n = 375) were randomized to VSAQs first and MCQs second or vice versa in a formative exam in two courses, to determine reliability, discrimination, and cueing. Acceptability for teachers (i.e., VSAQ review time) was determined in the summative exam. Reliability (Cronbach's α) was 0.74 for VSAQs and 0.57 for MCQs in one course. In the other course, Cronbach's α was 0.87 for VSAQs and 0.83 for MCQs. Discrimination (average Rir) was 0.27 vs. 0.17 and 0.43 vs. 0.39 for VSAQs vs. MCQs, respectively. Reviewing time of one VSAQ for the entire student cohort was ±2 minutes on average. Positive cueing occurred more in MCQs than in VSAQs (20% vs. 4% and 20.8% vs. 8.3% of questions per person in both courses). This study validates the positive results regarding VSAQs reliability, discrimination, and acceptability in undergraduate medical students. Furthermore, we demonstrate that VSAQ use is reliable among teachers with limited experience in writing and marking VSAQs. The short learning curve for teachers, favourable marking time and applicability regardless of the topic suggest that VSAQs might also be valuable beyond medical assessment.


Vestibular signs and symptoms of volumetric abnormalities of the vestibular aqueduct.
The objective of this study was to identify a pattern of signs, symptoms and neuroradiological findings which would assist investigation of vestibular function (especially otolith function) in a group of adult patients with anatomical alterations of the endolymphatic aqueduct and sac. Fifteen subjects affected by volumetric abnormalities of the vestibular aqueduct were selected from a cohort of patients referred to a tertiary referral neurotological centre between 1 January 2004 and 30 June 2006. All patients underwent accurate clinical history-taking and were evaluated using a standardised set of bedside and instrumental neurotological tests (i.e. audiometry, auditory brainstem response and vestibular evoked myogenic potentials). After these tests, each patient underwent computed tomography and magnetic resonance imaging in order to accurately evaluate the middle ear, labyrinthine capsule and internal auditory canals. These evaluations confirmed clinical suspicion of volumetric abnormalities of the vestibular aqueduct and endolymphatic sac. All the patients with a defined volumetric alteration in the region of the vestibular aqueduct and endolympatic sac reported a typical pattern of symptoms and signs. The most obvious and frequent symptoms in these patients were migraine-related vertigo (using the Neuhauser criteria, 10 of 15, 66.6 per cent), 'motion sickness' (12 of 15, 80 per cent), oscillopsia (nine of 15, 60 per cent) and dizziness (14 of 15, 93.3 per cent). Clinical examination results for the selected patients allowed some useful speculative conclusions. During neurotological evaluation, two instrumental methodologies were especially useful diagnostically: vestibular evoked myogenic potentials of the neck, and the mastoid vibration test at 100 Hz. Dysfunction of the vestibular aqueduct is suggested by symptomatology characterised by: migraine-related vertigo, unstable or recurring oscillopsia, lowering of the vestibular evoked myogenic potential threshold, hypoacusis, anamnestic report of motion sickness, and nystagmus induced by mastoid vibration and head-shaking. Computed tomography and magnetic resonance imaging are needed in order to confirm clinical suspicions.


Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients.
Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin, characterized by infiltration of tissues by spumous histiocytes. ECD features heterogeneous systemic manifestations, and the general prognosis remains poor despite various treatment options. We treated 8 patients with multisystemic ECD with subcutaneous interferon-alpha (IFNalpha) at a dosage of 3-9 x 10(6) units 3 times weekly, for a median duration of 23 months (range 1-46 months). Treatment was generally well tolerated, and side effects remained limited to fever following injections. Treatment was discontinued in 1 patient, because of severe depression. During treatment, some manifestations of ECD disappeared (i.e., xanthelasma, exophthalmos, papilledema, and intracranial hypertension). The efficacy of IFNalpha on cardiovascular ECD was variable, however. Treatment resulted in partial regression of "coated aorta" in some cases and clear failure in others; 2 patients died. The level of C-reactive protein diminished sharply in 5 patients. IFNalpha might be a valuable first-line therapy for prolonged treatment of ECD. However, the efficacy of IFNalpha varies among patients and according to the sites of disease involvement, and symptoms may fail to respond to treatment, especially in patients with severe multisystemic forms of ECD with central nervous system and cardiovascular involvement.


Noninvasive neurophysiological mapping of the lower urinary tract in adult and aging rhesus macaques.
The lower urinary tract (LUT) may be activated by spinal cord stimulation, but the physiological mapping characteristics of LUT activation with noninvasive transcutaneous spinal cord stimulation (TSCS) are not known. The effects of aging on the contractile properties of the detrusor are also not well understood. Therefore, TSCS was applied over the T10/T11 to L6/L7 spinous processes in adult ( n = 6) and aged ( n = 9) female rhesus macaques. A combination of urodynamic studies and electromyography recordings of the external urethral sphincter (EUS), external anal sphincter (EAS), and pelvic floor muscles was performed. Distinct functional maps were demonstrated for TSCS-evoked detrusor and urethral pressures and for the activation of the EUS, EAS, and pelvic floor muscles. The magnitude of responses for each peripheral target organ was dependent on TSCS location and strength. The strongest detrusor contraction was observed with TSCS at the L1/L2 site in adults and the L3/L4 site in aged subjects. TSCS-evoked bladder pressure at the L1/L2 site was significantly higher for the adults compared with the aged subjects ( P < 0.05). Cumulative normalized TSCS-evoked pressures, calculated for five consecutive sites between the T11/T12 and L3/L4 levels, were significantly lower for aged compared with adult subjects ( P < 0.05). The aged animals also showed a caudal shift for the TSCS site that generated the strongest detrusor contraction. We conclude that natural aging in rhesus macaques is associated with decreased detrusor contractility, a finding of significant translational research relevance as detrusor underactivity is a common occurrence with aging in humans. NEW & NOTEWORTHY Transcutaneous spinal cord stimulation (TSCS) was used to map lower urinary tract function in adult and aged rhesus macaques. Aging was associated with decreased peak pressure responses to TSCS, reduced cumulative normalized evoked bladder pressure responses, and a caudal shift for the site generating the strongest TSCS-induced detrusor contraction. We demonstrate the utility of TSCS as a new diagnostic tool for detrusor contractility assessments and conclude that aging is associated with decreased detrusor contractility in primates.


Dual phase and rate coding in hippocampal place cells: theoretical significance and relationship to entorhinal grid cells.
We review the ideas and data behind the hypothesis that hippocampal pyramidal cells encode information by their phase of firing relative to the theta rhythm of the EEG. Particular focus is given to the further hypothesis that variations in firing rate can encode information independently from that encoded by firing phase. We discuss possible explanation of the phase-precession effect in terms of interference between two independent oscillatory influences on the pyramidal cell membrane potential, and the extent to which firing phase reflects internal dynamics or external (environmental) variables. Finally, we propose a model of the firing of the recently discovered "grid cells" in entorhinal cortex as part of a path-integration system, in combination with place cells and head-direction cells.


Association and linkage analysis of aluminum tolerance genes in maize.
Aluminum (Al) toxicity is a major worldwide constraint to crop productivity on acidic soils. Al becomes soluble at low pH, inhibiting root growth and severely reducing yields. Maize is an important staple food and commodity crop in acidic soil regions, especially in South America and Africa where these soils are very common. Al exclusion and intracellular tolerance have been suggested as two important mechanisms for Al tolerance in maize, but little is known about the underlying genetics. An association panel of 282 diverse maize inbred lines and three F2 linkage populations with approximately 200 individuals each were used to study genetic variation in this complex trait. Al tolerance was measured as net root growth in nutrient solution under Al stress, which exhibited a wide range of variation between lines. Comparative and physiological genomics-based approaches were used to select 21 candidate genes for evaluation by association analysis. Six candidate genes had significant results from association analysis, but only four were confirmed by linkage analysis as putatively contributing to Al tolerance: Zea mays AltSB like (ZmASL), Zea mays aluminum-activated malate transporter2 (ALMT2), S-adenosyl-L-homocysteinase (SAHH), and Malic Enzyme (ME). These four candidate genes are high priority subjects for follow-up biochemical and physiological studies on the mechanisms of Al tolerance in maize. Immediately, elite haplotype-specific molecular markers can be developed for these four genes and used for efficient marker-assisted selection of superior alleles in Al tolerance maize breeding programs.


Neem leaf glycoprotein activates CD8(+) T cells to promote therapeutic anti-tumor immunity inhibiting the growth of mouse sarcoma.
In spite of sufficient data on Neem Leaf Glycoprotein (NLGP) as a prophylactic vaccine, little knowledge currently exists to support the use of NLGP as a therapeutic vaccine. Treatment of mice bearing established sarcomas with NLGP (25 µg/mice/week subcutaneously for 4 weeks) resulted in tumor regression or dormancy (Tumor free/Regressor, 13/24 (NLGP), 4/24 (PBS)). Evaluation of CD8(+) T cell status in blood, spleen, TDLN, VDLN and tumor revealed increase in cellular number. Elevated expression of CD69, CD44 and Ki67 on CD8(+) T cells revealed their state of activation and proliferation by NLGP. Depletion of CD8(+) T cells in mice at the time of NLGP treatment resulted in partial termination of tumor regression. An expansion of CXCR3(+) and CCR5(+) T cells was observed in the TDLN and tumor, along with their corresponding ligands. NLGP treatment enhances type 1 polarized T-bet expressing T cells with downregulation of GATA3. Treg cell population was almost unchanged. However, T∶Treg ratios significantly increased with NLGP. Enhanced secretion/expression of IFNγ was noted after NLGP therapy. In vitro culture of T cells with IL-2 and sarcoma antigen resulted in significant enhancement in cytotoxic efficacy. Consistently higher expression of CD107a was also observed in CD8(+) T cells from tumors. Reinoculation of sarcoma cells in tumor regressed NLGP-treated mice maintained tumor free status in majority. This is correlated with the increment of CD44(hi)CD62L(hi) central memory T cells. Collectively, these findings support a paradigm in which NLGP dynamically orchestrates the activation, expansion, and recruitment of CD8(+) T cells into established tumors to operate significant tumor cell lysis.


Damage detection of carbon fiber reinforced polymer composite materials based on one-dimensional multi-scale residual convolution neural network.
Carbon fiber reinforced polymers (CFRPs) have been widely applied in the aerospace industry, and the health conditions of CFRPs largely affect aerospace safety. Due to the limitations of traditional detection methods, electrical impedance tomography (EIT) has been gradually applied in the damage detection of CFRP composite materials. Aiming at the problems of poor imaging quality and low identification rate in the traditional EIT reconstruction algorithm, an EIT algorithm based on the one-dimensional multi-scale residual convolution neural network (1D-MSK-ResNet) is proposed in this paper. A "voltage vector-conductivity media distribution" dataset is first established, and the training results of the testing dataset are used to verify and evaluate the algorithm. Simulation and experimental results indicated that the 1D-MSK-ResNet EIT algorithm could enhance the ability of damage identification and significantly improve the imaging quality.


Efficacy of amlodipine besylate and Valsartan for the treatment of mild to moderate hypertension.
Clinical researchers found that Amlodipine besylate and Valsartan (ABVS) can effectively treat mild to moderate hypertension (MMH). However, no study has systematically investigated its efficacy and safety for patients with MMH. Thus, present study will systematically assess the efficacy and safety of ABVS for patients with MMH. MEDICINE, Cochrane Library, EMBASE, Ovid, PsycINFO, Web of Science, Allied and Complementary Medicine Database, and China National Knowledge Infrastructure will be searched for literatures related to the topic from inception to the present without language limitations. All randomized controlled trials that assess the efficacy and safety of ABVS for patients with MMH will be considered for inclusion. Two researchers will independently select study, extract data, and assess risk of bias for all eligible studies. The primary outcome includes the change of seated diastolic blood pressure. The secondary outcomes consist of the change of seated systolic blood pressure, health-related quality of life, and the tolerability. The results of this study will summarize the latest evidence on ABVS for the treatment of MMH. This study does not need ethical approval, because it will not use individual data. The results of this study are expected to be published at peer-reviewed journals. PROSPERO CRD42019133123.


Formation of Magnesium Carbonates on Earth and Implications for Mars.
Magnesium carbonates have been identified within the landing site of the Perseverance rover mission. This study reviews terrestrial analog environments and textural, mineral assemblage, isotopic, and elemental analyses that have been applied to establish formation conditions of magnesium carbonates. Magnesium carbonates form in five distinct settings: ultramafic rock-hosted veins, the matrix of carbonated peridotite, nodules in soil, alkaline lake, and playa deposits, and as diagenetic replacements within lime-and dolostones. Dominant textures include fine-grained or microcrystalline veins, nodules, and crusts. Microbial influences on formation are recorded in thrombolites, stromatolites, crinkly, and pustular laminites, spheroids, and filamentous microstructures. Mineral assemblages, fluid inclusions, and carbon, oxygen, magnesium, and clumped isotopes of carbon and oxygen have been used to determine the sources of carbon, magnesium, and fluid for magnesium carbonates as well as their temperatures of formation. Isotopic signatures in ultramafic rock-hosted magnesium carbonates reveal that they form by either low-temperature meteoric water infiltration and alteration, hydrothermal alteration, or metamorphic processes. Isotopic compositions of lacustrine magnesium carbonate record precipitation from lake water, evaporation processes, and ambient formation temperatures. Assessment of these features with similar analytical techniques applied to returned Martian samples can establish whether carbonates on ancient Mars were formed at high or low temperature conditions in the surface or subsurface through abiotic or biotic processes. The timing of carbonate formation processes could be constrained by 147Sm-143Nd isochron, U-Pb concordia, 207Pb-206Pb isochron radiometric dating as well as 3He, 21Ne, 22Ne, or 36Ar surface exposure dating of returned Martian magnesium carbonate samples.


Jodhpur and the aeroplane: aviation and diplomacy in an Indian state 1924-1952.
This paper is a study of the intersection between aviation and diplomacy in the semi-autonomous Indian state of Jodhpur in the final decades of British colonial rule in India. Jodhpur's Maharaja Umaid Singh established a major international aerodrome, patronized one of India's first flying clubs and collaborated with British authorities to make aviation laws for the Indian states. He would also serve in the Royal Air Force during the war and placed Jodhpur state's aviation resources at the disposal of the king-emperor. This paper argues that Jodhpur was able to leverage its aviation resources to wield substantial influence both within and beyond the British Empire through both war and peace. An analysis of Jodhpur's engagement with aviation diplomacy is also revealing of some of the limitations as well as possibilities for the deployment of science diplomacy frameworks, especially in non-Western contexts.


Medication errors: analysis not blame.
This article summarizes current knowledge regarding neonatal medication errors and explicates the key concepts of human error and system error. A case report illustrates the sources of error. Medication error analysis must go beyond the blaming of individuals for active errors and explore the latent errors that exist in a complex health care environment. Using correct language to describe and define medication error may facilitate the development of a nonpunitive culture and enable effective evaluation of the causes of error.


Brain malformation in syndromic craniosynostoses, a primary disorder of white matter: a review.
Syndromic craniosynostoses (Saethre-Chotzen, Pfeiffer 1, 2, 3, Apert, Crouzon, mainly) are particular in this that a single gene defect (mostly fibroblast growth factor receptor [FGFR] 2) generates different clinical phenotypes that characterize these syndromes. Significant brain abnormalities have been reported in all syndromes. However, whether these abnormalities are secondary to the bone disease or primary (e.g. callosal agenesis) is still controversial. Recent evidence suggests that the white matter defect might be a primary disorder. From the review of the literature and the analysis of our cases, it appears that three categories of brain abnormalities can be found. (1) The global distortion of the brain is likely mechanical and in keeping with the deformity of the skull. (2) The chronic tonsillar herniation (Chiari I deformity) is likely mechanical also and a consequence of the small size of the posterior fossa, especially after an early closure (before 24 m) of the lambdoid suture. (3) On the contrary, the constellation of abnormalities that selectively involve the white matter (non-progressive, non-destructive ventriculomegaly, callosal agenesis or thinning, agenesis of septum pellucidum, paucity of the antero-mesial temporal white matter, pyramidal hypoplasia) is much more likely to constitute a primary disorder. Recent neurobiological evidence supports this point of view. L1 cell adhesion molecule (L1CAM) gene plays a major role in the development of the white matter and its mutation in humans (callosal agenesis, retardation, adducted thumbs, spasticity, and hydrocephalus syndrome, Bickers-Adams syndrome) or in mice causes similar defects of the corpus callosum, septum pellucidum, centrum semi-ovale, and cortico-spinal tracts. To operate, L1CAM need interactions with FGFRs, whose defects are causal to the syndromic craniosynostoses. It seems logical to assumes that the FGFR defects generate both the skull abnormalities and, by lack of interaction with L1CAM, the primary defect of the white matter. The mental deficiency that is common in these patients therefore is likely to be part of the disease (through the L1CAM-FGFR interaction) rather than a consequence of the skull size or of the associated hydrocephalus.


Ultrastructural properties of the extra membranes of Escherichia coli O111a as revealed by freeze-fracturing and negative-staining techniques.
Escherichia coli O111a is a thermosensitive strain which, when grown at 40 C, accumulates large quantities of intracellular membranes. The ultrastructure of these membranes in cells which have been chemically fixed, embedded, and examined as thin sections has been compared with that of membranes in cells negatively stained or freeze-fractured. Results indicate that the extra membranes are present in the three types of preparations examined and, therefore, clearly are not artifacts of chemical fixation. Negative staining has proved also to be a valuable tool as a rapid means of monitoring cells for the accumulation of large amounts of extra membranes. Also, examination of thin sections has shown that distinct continuities between the plasma membrane and the extra membranes exist. In general, membrane surfaces in freeze-fractured cells containing extra membranes appear smooth and lack the particles associated with the plasma membranes of many cells.


Sporadic non-A, non-B hepatitis and Epstein-Barr hepatitis associated with the Guillain-Barré syndrome.
Three cases of Guillain-Barré syndrome (GBS) complicating sporadic non-A, non-B viral hepatitis (NANB) are reported. One case occurred in the incubation period for NANB hepatitis, and the other cases were noted to have hepatitis at the time of hospital admission due to paralysis. Three patients (13%) in a prospective series of 23 patients with GBS were found to have subclinical hepatitis (two patients with NANB hepatitis, and one patient with Epstein-Barr viral hepatitis). This unexpectedly high incidence of hepatitis associated with GBS is discussed and a possible causal link between NANB hepatitis and surgery-related GBS is proposed.


[Detection of low-avidity IgG antibodies in the diagnosis of primary acute infection by hepatitis C virus].
Differential diagnosis of the acute primary infection by hepatitis C virus (HCV) from reactivations and reinfections presents specific problems, especially among patients with impaired humoral immunity. the IgG avidity assay might contribute to resolve these problems. A simple modification of a commercial enzyme immunoassay, allowing evaluation of the avidity of IgG antibody to HCV, was developed and evaluated on a part of 37 serum samples from 14 patients with acute primary infection or reinfection by HCV and 12 samples from 12 seropositive patients lacking evidence of acute infection Eight of the former 14 had impaired ability for antibody response. The method rendered high percentages of reduction of the antibody signal in samples from acute primary infections taken within two months from onset and significantly lower percentages in samples from reinfections or patients without evidence of acute infection (mean value: 90 degrees C Vs 43% and 25%, respectively. The mean duration of the low-avidity IgG antibody was around six months, but showed wide variations depending on the patient. Detection of low-avidity IgG antibody to HCV is easy to perform and may help the study of the HCV infection in some patients. Every method should, however, be carefully validated before using with diagnostic purposes.


[miR-100-5p is involved in non-traumatic osteonecrosis of the femoral head by inhibiting the migration and osteogenic differentiation of BMSCs].
Objective To investigate the role of miR-100-5p in the pathogenesis of non-traumatic osteonecrosis of the femoral head (NONFH). Methods The miRNA expression in patients with NONFH was detected by real-time quantitative PCR, the high expression of miR-100-5p in femoral head tissues of the patients determined. Rat bone marrow mesenchymal stem cells (rBMSCs) were cultured and divided into 5 groups: blank control group, dexamethasone treatment group (treated with dexamethasone for 3 days), miR-NC group (transfected with miR-NC), agomiR-100-5p group (overexpression of miR-100-5p), and antagomiR-100-5p group (transfected with miR-100-5p antagonist). The mRNA expression levels of miR-100-5p, alkaline phosphatase (ALP), Runt-associated transcription factor 2 (RUNX2), and collagen type I (Col1) were detected by real-time quantitative PCR. The protein expressions of ALP, RUNX2, Col1, and bone morphogenetic protein receptor 2 (BMPR2) were detected by Western blotting. The effect of miR-100-5p on the migration ability of rBMSCs was evaluated by scratch healing assay. And the effect of miR-100-5p on osteogenic differentiation ability of rBMSCs was investigated by alizarin red staining. Results miR-100-5p was significantly upregulated in the femoral head bone tissue of NONFH patients compared with normal femoral head bone tissue. Compared with those in the normal rBMSCs, the expression of miR-100-5p in rBMSCs treated with 20 μmol/L of dexamethasone was up-regulated. The upregulation of miR-100-5p in rBMSCs reduced the expressions of ALP, RUNX2, Col1, and BMPR2, and inhibited the osteogenic differentiation and migration abilities of rBMSCs. Conclusion The expression of miR-100-5p is elevated in bone tissues of NONFH patients and in rBMSCs treated with 20 μmol/L of dexamethasone. The up-regulated miR-100-5p may be involved in the pathogenesis of NONFH by inhibiting the migration and osteogenic differentiation of rBMSCs.


Long-Term Outcome of Consecutive Patients With Previous Coronary Bypass Surgery, Treated With Newer-Generation Drug-Eluting Stents.
Percutaneous coronary intervention (PCI) in patients with previous coronary artery bypass grafting (CABG) is associated with adverse clinical events. Although newer generation drug-eluting stents showed favorable short-term safety profiles, there is a lack of long-term outcome data. We evaluated the impact of previous CABG on 5-year clinical outcomes of patients treated with PCI using newer-generation drug-eluting stents. In this patient-level pooled analysis of the prospective TWENTE (The Real-World Endeavor Resolute versus Xience V Drug-Eluting Stent Study in Twente) trial and nonenrolled TWENTE registry, we assessed a consecutive series of patients who underwent PCI with newer-generation drug-eluting stents for non-ST-segment-elevation acute coronary syndromes or stable angina. Of all 1709 patients, 202 (11.8%) had a history of CABG. Patients with previous CABG had significantly higher 5-year rates of cardiac death (10.4% versus 4.3%; P<0.001) and target vessel revascularization (25.0% versus 8.1%; P<0.001). These differences remained statistically significant after adjustment for differences in baseline characteristics. Landmark analysis revealed that from 1- to 5-year follow-up, the rates of cardiac death (8.1% versus 3.2%; P<0.001) and target vessel revascularization (17.1% versus 5.9%; P<0.001) were significantly higher in patients with previous CABG. Among patients with a history of CABG, PCI of an obstructed vein graft was associated with a higher rate of 5-year target vessel revascularization (P=0.003). At 5-year follow-up after PCI with newer-generation drug-eluting stents, the risk of cardiac death and target vessel revascularization was significantly higher in patients with previous CABG. The target vessel revascularization rate was highest in patients who underwent PCI of obstructed vein grafts.


Gastric Varices in Absence of Splenic Vein Thrombosis: A Rare Entity of Idiopathic Non-Cirrhotic Portal Hypertension.
Idiopathic non-cirrhotic portal hypertension (INCPH) is portal hypertension (PHT) without cirrhosis and other identifiable causes. Esophageal and gastric varices are seen in INCPH which are mostly asymptomatic. We present a rare case of symptomatic isolated gastric varices (IGV) in the setting of INCPH. We report a case of a 60-year-old man who presented with an acute onset of hematemesis and no identifiable history. Upon further evaluation, he was found to have non-bleeding dilated gastric varices on esophagogastroduodenoscopy (EGD) and PHT without cirrhosis. Our patient is unique because he has symptomatic IGV and INCPH.


Filling the periorbital hollows with hyaluronic acid gel: initial experience with 244 injections.
To review our initial experience using hyaluronic acid gel (Restylane) as a filler to treat the periorbital hollows. This is a retrospective, anecdotal case review of 244 cosmetic hyaluronic acid gel injections in 155 patients. An average volume of 0.9 ml per injection session was used in an individualized pattern that variably included the orbital rim hollow, zygomatic hollow, septal confluence hollow, and eyebrow and cheek fat pad. To achieve smooth contours, a layered, feathered threading technique was used, placing the filler deep to the orbicularis. Hyaluronidase injections were used in 11% of patients at follow-up visits to "dissolve" some of the filler to reduce contour irregularities. One hundred eight of 121 (89%) patients with follow-up visits were satisfied with the cosmetic improvement after hyaluronic acid gel injections. For maintenance, the interval to second injection averaged 6.5 months. Side effects included lumps or contour irregularities (11%), bruising (10%), color change (7%), and fluid (15%). Twelve patients were unsatisfied and were not interested in additional injections: 5 with malar fluid, 3 with lumpy irregularity, and 3 with color change. Complex 3-dimensional contours and thin skin over bone render periorbital filling difficult. However, with individualized planning and with care taken to create smooth, feathered contours, it is possible to achieve acceptable improvement. We found that most patients considered themselves improved cosmetically, despite occasional side effects including contour irregularity or lumps, bruising, color change, and fluid accumulation. Patients with very thin skin, preexisting color problems, or preexisting eyelid fluid may not be good candidates for periorbital filling with hyaluronic acid gel. The effect of the filler is temporary, of course, and we counsel patients to anticipate maintenance injections at 6- to 12-month intervals.


Disclosing and overcoming the trade-off between noise and scanning speed in atomic force microscopy.
Traditional dynamic modalities for atomic force microscopy imaging suffer from a stringent trade-off between fast scanning speed, weak interaction forces and accurate topography reconstruction. Finding an effective compromise between these aspects is often challenging, especially for soft biological samples for which stringent requirements hold when imaged in vivo. In this paper the main causes of this undesired trade-off in standard systems are analyzed and the exploitation of the intrinsic dynamics of the cantilever through a nonlinear control strategy is proposed as a method to overcome this limitation. A direct application to imaging of biological samples is reported to validate the results and show the effectiveness of the proposed technique.


Cost-effective use of antiemetics.
Direct comparison of intravenous and oral 5-HT3 antagonists has shown equivalent efficacy if appropriate doses are given, thus allowing widespread use of the more convenient and economical oral route. Effective antiemesis generates additional cost savings by decreasing the resources necessary for salvage antiemetic preparation and administration, additional physician and nursing evaluation, clean-up and maintenance of the patient area, and possible additional hospitalization necessitated by uncontrolled emesis. If ondansetron and metoclopramide are compared strictly on an acquisition cost basis, ondansetron is 4 to 15 times more expensive. However, if the additional savings attributable to better antiemetic control are taken into account, ondansetron is only 2 to 3 times more expensive and quality of life is markedly improved. In cost-utility analysis such improvement in quality of life is taken into account through the use of a utility score. Utility scores for antiemetic protection, however, have not been well defined. We recently performed a pilot study asking patients receiving chemotherapy to rate globally their quality of life (utility score) over the preceding chemotherapy cycle, assuming that a small amount of nausea and vomiting either had or had not occurred. An incremental utility score of 0.52 based solely on the presence or absence of nausea and vomiting was identified. Further careful investigations to identify the incremental utility resulting from use of various modes of oncologic supportive care are required.


[Viral vaccines in the national vaccination program--views of the near future].
Both conventional virus vaccines and those being introduced in the near future are either live attenuated viruses or nonliving inactivated viruses, mere virus-like particles (VLP) or purified proteins. Live vaccines yield a "more natural" immunity, but in many cases also a nonliving vaccine is sufficient to protect from viral infections. Influenza vaccines are of both types. The commencing HPV vaccination program will be conducted with a VLP vaccine comprising two serotypes. A live chickenpox vaccine will be introduced in the national vaccination program in the next few years. In addition, a shingles vaccine is needed. The live oral rotavirus vaccine works well.


Assessing information of soleous and gastrocnemius motor unit H-reflex response to paired stimulation.
In this study we compared soleous and gastrocnemius muscles responses to paired stimulation in order to reveal the embedded information in H-reflex of these muscles. Four men with ages between 20 and 26 were tested. Since there was no ideal point based on the scientific rules to record H-reflex from gastrocnemius muscle, we were to determine an ideal point and electrode placement from anatomical and physiological point of view. Then, soleous and gastrocnemius muscles were subjected to paired stimulus and H-reflex recovery curve of these muscles were recorded To record the recovery curve, 11 pairs of stimulus were delivered to the posterior tibial nerve. Time interval between the 1st pair of stimulus was 50 ms and increased by 20 ms steps in the next pairs up to 250 ms. The second H-reflex amplitude was divided to the first H-reflex amplitude and expressed in percent, then the recovery curve was drawn accordingly. While the time interval of the paired stimulus was less than 110 ms, the behavior of the curves was similar. In this stage we guessed that the muscles were impressed by the renshaw cells inhibition and the induced fatigue by the first stimulus. When the interval in a pair was 110 ms or more, the recovery percent of soleous was significantly higher than that of the gastrocnemius. This behavior may be due to the less fatigability of soleous motoneurons and less renshaw inhibition on slow motoneurons of soleous. When the time interval of a pair stimulus increases to more than 170 ms, both of the curves behave alike. This may be due to the diminishing of renshaw cell inhibition and the reduction of fatigue. Because of motoneurons physiological properties, when we evoke H-reflex, smaller motoneurons recruit predominantly; but the comparison of the soleous (slow) and gastrocnemius (fast) recovery curves behavior shows that the information about the fast motoneuron are included in H-reflex using this procedure. So we can indirectly assess different motoneurons and renshaw cell activities.


[Clinical picture and diagnosis of renovascular hypertension in children and adolescents].
The diagnostic methods of vasorenal hypertension were analyzed in a series of 120 children and adolescents. The clinical picture of the disease was found to depend on etiological factors. The differential diagnosis of vasorenal hypertension is offered. The principal diagnostic test used in the study was angiography which made it possible to determine the nature, degree, extent and localization of the lesion. The findings obtained by other functional methods utilized in the diagnosis of vasorenal hypertension are also outlined.


Cross-Linking Mass Spectrometry on P-Glycoprotein.
The ABC transporter P-glycoprotein (Pgp) has been found to be involved in multidrug resistance in tumor cells. Lipids and cholesterol have a pivotal role in Pgp's conformations; however, it is often difficult to investigate it with conventional structural biology techniques. Here, we applied robust approaches coupled with cross-linking mass spectrometry (XL-MS), where the natural lipid environment remains quasi-intact. Two experimental approaches were carried out using different cross-linkers (i) on living cells, followed by membrane preparation and immunoprecipitation enrichment of Pgp, and (ii) on-bead, subsequent to membrane preparation and immunoprecipitation. Pgp-containing complexes were enriched employing extracellular monoclonal anti-Pgp antibodies on magnetic beads, followed by on-bead enzymatic digestion. The LC-MS/MS results revealed mono-links on Pgp's solvent-accessible residues, while intraprotein cross-links confirmed a complex interplay between extracellular, transmembrane, and intracellular segments of the protein, of which several have been reported to be connected to cholesterol. Harnessing the MS results and those of molecular docking, we suggest an epitope for the 15D3 cholesterol-dependent mouse monoclonal antibody. Additionally, enriched neighbors of Pgp prove the strong connection of Pgp to the cytoskeleton and other cholesterol-regulated proteins. These findings suggest that XL-MS may be utilized for protein structure and network analyses in such convoluted systems as membrane proteins.


Cushing's syndrome in a child with pancreatic acinar cell carcinoma.
A case of pancreatic acinar cell tumor (ACC) is presented in a 10-year-old boy. The tumor manifested clinically with Cushing's syndrome, high serum adrenocorticotropic hormone (ACTH) and cortisol concentrations. In addition, excessive serum levels of alpha-fetoprotein (AFP) were detected. Surgical resection was not possible due to retroperitoneal invasion. Biopsy of the mass showed a solid, poorly differentiated ACC of the pancreas. Periodic acid Schiff positive cytoplasmic granules, trypsinogen, keratins, alpha-1-antitrypsin, and AFP were identified in the tumor cells. Electron microscopy demonstrated zymogen granules as well as isolated dense core granules. Using immunochemiluminometric assay, a high quantity of ACTH was found in the fresh frozen tumor extract. ACTH, chromogranin A, and corticotropin-releasing factor were identified only in a few cells by immunohistochemistry. Combined radiochemotherapy was temporarily effective in reducing the tumor mass and serum AFP. Serum ACTH and cortisol levels dropped progressively and definitively to normal values after chemotherapy, and the Cushing's syndrome subsided. Two years later, the patient died with metastatic disease. The presented case of ACC is interesting due to high serum AFP values and ectopic ACTH secretion resulting in Cushing's syndrome.


Managing an acute adverse event in a radiology department.
Many local and national regulatory organizations require that all serious adverse events be promptly investigated, managed, and reported, with the first goal being to institute actions to prevent or minimize the occurrence of similar events. However, the tools and processes necessary for effective incident review and management have been developed largely by industrial organizations, and radiologists may not be familiar with such processes. Data analysis requires a root cause analysis to identify all possible active and latent contributors to the event, as well as the use of algorithms to determine the degree of responsibility when human error is implicated. Acceptable corrective actions that are reasonable, achievable, and measurable should be instituted. These changes should be monitored according to defined timelines by a designated person. In some cases, additional training or even remediation may be required. Subsequently, the focus should be on actively managing and improving error detection and reporting systems, as well as on seeking strategies for minimizing the occurrence of preventable errors.


VS2DRTI: Simulating Heat and Reactive Solute Transport in Variably Saturated Porous Media.
Variably saturated groundwater flow, heat transport, and solute transport are important processes in environmental phenomena, such as the natural evolution of water chemistry of aquifers and streams, the storage of radioactive waste in a geologic repository, the contamination of water resources from acid-rock drainage, and the geologic sequestration of carbon dioxide. Up to now, our ability to simulate these processes simultaneously with fully coupled reactive transport models has been limited to complex and often difficult-to-use models. To address the need for a simple and easy-to-use model, the VS2DRTI software package has been developed for simulating water flow, heat transport, and reactive solute transport through variably saturated porous media. The underlying numerical model, VS2DRT, was created by coupling the flow and transport capabilities of the VS2DT and VS2DH models with the equilibrium and kinetic reaction capabilities of PhreeqcRM. Flow capabilities include two-dimensional, constant-density, variably saturated flow; transport capabilities include both heat and multicomponent solute transport; and the reaction capabilities are a complete implementation of geochemical reactions of PHREEQC. The graphical user interface includes a preprocessor for building simulations and a postprocessor for visual display of simulation results. To demonstrate the simulation of multiple processes, the model is applied to a hypothetical example of injection of heated waste water to an aquifer with temperature-dependent cation exchange. VS2DRTI is freely available public domain software.


Generalisability of and lessons learned from a mixed-methods study conducted in three low- and middle-income countries to identify care pathways for atrial fibrillation.
Identifying existing care pathways is the first step for understanding how services can be improved to enable early diagnosis and effective follow-up care for non-communicable diseases (NCDs); however, evidence on how care pathways can and should be identified in low- and middle-income countries (LMICs) is lacking. To describe generalisability and lessons learned from recruitment and data collection for the quantitative component of a mixed methods study designed to determine the care pathway for atrial fibrillation (AF) in Brazil, China and Sri Lanka. Adults (≥18 years) that spoke the local language and with an AF diagnosis were eligible. We excluded anyone with a hearing or cognitive impairment or ineligible address. Eligible participants were identified using electronic records in Brazil and China; in Sri Lanka, researchers attended the outpatient clinics to identify eligible participants. Data were collected using two quantitative questionnaires administered at least 2-months apart. A minimum sample size of 238 was required for each country. The required sample size was met in Brazil (n = 267) and China (n = 298), but a large proportion of AF patients could not be contacted (47% and 27%, respectively) or refused to participate (36% and 38%, respectively). In Sri Lanka, recruitment was challenging, resulting in a reduced sample (n = 151). Mean age of participants from Brazil, China and Sri Lanka was 69 (SD = 11.3), 65 (SD = 12.8) and 58 (SD = 11.7), respectively. Females accounted for 49% of the Brazil sample, 62% in China and 70% in Sri Lanka. Generalisability was an issue in Brazil and China, as was selection bias. Recruitment bias was highlighted in Sri Lanka. Additional or alternative recruitment methods may be required to ensure generalisability and reduce bias in future studies aimed at identifying NCD care pathways in LMICs.


Clinical breast examination and its relevance to diagnosis of palpable breast lesion.
To evaluate if clinical breast examination (CBE) is a reliable tool for diagnosis of palpable breast lesions, from July 2002 to October 2003, 371 patients (445 palpable breast lesions) were examined by single experienced clinician and compared with fine needle aspiration (FNA) results. CBE had sensitivity of 57.14%, specificity 97.11%, positive predictive value (PPV) 76.60%, negative predictive value (NPV) 93.20%, false negative (FN) 0.06%, false positive (FP) 0.02%, and overall accuracy 91.44%. There was concordance in 91.44%. Of a total of 397 benign clinical suspections, 199 episodes were found to be cysts (50.13%). CBE alone even in an experienced clinician is not a reliable tool for diagnosis of palpable breast lesion whether it is malignant or not, but it can be used as a primary and simple tool for benign suspicious palpable breast lesion, particularly cystic breast lesion.


Amperometric biosensors for detection of the prostate cancer marker (PSA).
Prostate specific antigen (PSA) has been identified as the most reliable clinical tool for diagnosing and monitoring prostate cancer (CAP). Since, there is no curative therapy available for prostate cancer, detecting the disease at the early stage is the best hope of increasing mortality rate. There are some procedures available for the detection of prostate cancer e.g. Tandem-R PSA, Hybritech Inc. (USA), IMx-PSA Abbott Laboratories (USA). However, these are time consuming and costly. We have developed a very simple and cost effective technique for identification and monitoring of prostate cancer using amperometric immunosensor. PSA is a glycoprotein with 93% peptide and 7% sugar content and isoelectric pH of 6.9. It may exist in the human serum as free (f-PSA) and complex (PSA-ACT) forms. Normally if the total PSA (t-PSA) level is more than 10 ng/ml, CAP is suspected. This paper presents an amperometric detection procedure for t-PSA using three electrode system in which working electrode (WE) is made of hydroxyethyl cellulose (HEC) and rhodinised carbon. The method used is rapid, very easy to use and involves low cost compared with other procedures. The electrochemical response was directly observed due to enzymatic reaction via a sandwich immunoassay on the WE. Monoclonal capture antibody (Mab) to PSA was immobilised on the WE and the other Mab labelled by the enzyme marker, horseradish peroxidase (HRP), was used as a tracer antibody.


Detection, Localization and Tyrosine Phosphorylation Status of Ser/Thr Protein Phosphatase1γ in Freshly Ejaculated, In Vitro Capacitated and Cryopreserved Buffalo Spermatozoa.
Several recent studies have indicated the important roles of Ser/Thr protein phosphatase1γ (PP1γ) in regulating the motility and capacitation of mammalian spermatozoa. Here, we report the presence and distribution of PP1γ protein in freshly ejaculated, in vitro capacitated and cryopreserved buffalo spermatozoa. The presence of PP1γ and its distribution were assessed by Western blotting and indirect immunofluorescence techniques, whereas the isoforms of PP1γ and their tyrosine phosphorylation status were identified by using 2D electrophoresis. The number of isoforms and the status of tyrosine phosphorylation of PP1γ were increased in capacitated spermatozoa when compared with freshly ejaculated spermatozoa. Differential pattern of expression and tyrosine phosphorylation of PP1γ were observed in cryopreserved spermatozoa, wherein some isoforms were degraded and some were tyrosine phosphorylated. In addition, immunofluorescence technique revealed that PP1γ was localized to principle, mid-piece, post-acrosomal and equatorial regions of buffalo spermatozoa. Differential distribution of tyrosine-phosphorylated proteins were observed in fresh, capacitated and cryopreserved spermatozoa. The tyrosine phosphorylation of several proteins (20, 37, 38, 52, 60, 79 and 100 kDa) were increased when sperm cells were incubated with PP1γ inhibitor, okadaic acid. Together, our results suggest that buffalo spermatozoa express different isoforms of PP1γ protein. The protein expression and tyrosine phosphorylation of PP1γ were increased during capacitation. Furthermore, the differential pattern of expression and tyrosine phosphorylation of PP1γ were observed in cryopreserved spermatozoa. In addition, the inhibition of PP1γ protein increases protein tyrosine phosphorylation in capacitation.


Visual thinking strategies for interprofessional education and promoting collaborative competencies.
Interprofessional education (IPE) curricula require approaches that address the needs of learners from multiple professions and levels of clinical experience. Frameworks based in the arts and humanities, which can improve learners' skills in collaborative competencies such as communication and team building, remain limited in IPE. We describe the development, implementation and evaluation of a visual arts-based IPE session for over 400 interprofessional learners. During the 90-min session held in 2021, an art museum educator first guided learners through observations of art works using the Visual Thinking Strategies (VTS) approach. Subsequently, small groups of six to eight interprofessional learners and two trained facilitators explored how their observations were influenced by personal and professional identities and made connections to interprofessional collaborative practice. Two hundred eleven of the 407 student attendees responded to the post-session survey (52%). Eighty percent of the respondents agreed or strongly agreed that 'the art of observation activity is an effective means of starting discussions with interprofessional teams.' On the Interprofessional Collaborative Competency Attainment Survey, a validated tool assessing changes in interprofessional collaboration-related competencies, there was a significant increase between pre- (M = 45.73, SD = 8.05, p < 0.001) and post-session scores (M = 51.46, SD = 7.97, p < 0.001), using a paired t-test analysis. Qualitative analysis of learners' takeaways identified themes of open-mindedness, hearing other opinions and perspectives, collaboration/teamwork, patient-centeredness and awareness of biases. Our curricular approach shows how integrating visual arts-based pedagogies into IPE activities with learners from diverse disciplines and clinical experiences is both feasible and helpful for developing collaborative competencies.


A hypokalaemic woman with nephrocalcinosis: rebirth of old knowledge.
The coexistence of hypokalaemia and nephrocalcinosis poses a challenge in rapid diagnosis and appropriate management. We describe a 38-year-old woman who presented with thirst, intermittent carpopedal spasm, paresthaesia of both hands and progressive weakness of lower extremities for two years. She had a history of chronic hypokalaemia of unknown cause with intermittent potassium supplementation for 7-8 y and bilateral nephrocalcinosis notable for one year. She denied vomiting, diarrhoea or use of laxatives, alcohol or diuretics. Her blood pressure was normal. Laboratory investigations showed hypokalaemia (2.7 mmol/L) and metabolic alkalosis (HCO3(-) 32.6 mmol/L, pH 7.46). Two random urine samples both showed a consistently high urine K(+) excretion but with excretion rates of Na(+), Cl(-) and divalent cations which were high in one sample but not the other. Ingestion of furosemide 120 mg daily for body image for 7-8 y was uncovered. With furosemide cessation and potassium supplementation, her hypokalaemia with neuromuscular symptoms was corrected but nephrocalcinosis persisted. Surreptitious use of diuretics for various purposes should be kept in mind as an important cause of hypokalaemia and/or nephrocalcinosis. Measurement of electrolyte concentrations in at least two random urine samples is warranted to distinguish it from true renal tubular disorders and extrarenal causes.


The linked survival prospects of siblings: evidence for the Indian states.
This paper reports an analysis of micro-data for India that shows a high correlation in infant mortality among siblings. In 13 of 15 states, we identify a causal effect of infant death on the risk of infant death of the subsequent sibling (a scarring effect), after controlling for mother-level heterogeneity. The scarring effects are large, the only other covariate with a similarly large effect being mother's (secondary or higher) education. The two states in which evidence of scarring is weak are Punjab, the richest, and Kerala, the socially most progressive. The size of the scarring effect depends upon the sex of the previous child in three states, in a direction consistent with son-preference. Evidence of scarring implies that policies targeted at reducing infant mortality will have social multiplier effects by helping avoid the death of subsequent siblings. Comparison of other covariate effects across the states offers some interesting new insights.


Assessment and prediction of road accident injuries trend using time-series models in Kurdistan.
Road traffic accidents are commonly encountered incidents that can cause high-intensity injuries to the victims and have direct impacts on the members of the society. Iran has one of the highest incident rates of road traffic accidents. The objective of this study was to model the patterns of road traffic accidents leading to injury in Kurdistan province, Iran. A time-series analysis was conducted to characterize and predict the frequency of road traffic accidents that lead to injury in Kurdistan province. The injuries were categorized into three separate groups which were related to the car occupants, motorcyclists and pedestrian road traffic accident injuries. The Box-Jenkins time-series analysis was used to model the injury observations applying autoregressive integrated moving average (ARIMA) and seasonal autoregressive integrated moving average (SARIMA) from March 2009 to February 2015 and to predict the accidents up to 24 months later (February 2017). The analysis was carried out using R-3.4.2 statistical software package. A total of 5199 pedestrians, 9015 motorcyclists, and 28,906 car occupants' accidents were observed. The mean (SD) number of car occupant, motorcyclist and pedestrian accident injuries observed were 401.01 (SD 32.78), 123.70 (SD 30.18) and 71.19 (SD 17.92) per year, respectively. The best models for the pattern of car occupant, motorcyclist, and pedestrian injuries were the ARIMA (1, 0, 0), SARIMA (1, 0, 2) (1, 0, 0)12, and SARIMA (1, 1, 1) (0, 0, 1)12, respectively. The motorcyclist and pedestrian injuries showed a seasonal pattern and the peak was during summer (August). The minimum frequency for the motorcyclist and pedestrian injuries were observed during the late autumn and early winter (December and January). Our findings revealed that the observed motorcyclist and pedestrian injuries had a seasonal pattern that was explained by air temperature changes overtime. These findings call the need for close monitoring of the accidents during the high-risk periods in order to control and decrease the rate of the injuries.


The architecture of the gammadelta resolvase crossover site synaptic complex revealed by using constrained DNA substrates.
Activated mutants of the serine recombinase, gammadelta resolvase, form a simplified recombinogenic synaptic complex containing a tetramer of resolvase and two crossover sites. We have probed the architecture of this complex by measuring the efficiency of recombination of a series of constrained DNA substrates (with phased recombination sites separated by an IHF-induced U-turn); this serves as a direct report on the topology of a productive synapse. Our data show that in the active complex, the catalytic domains from two resolvase dimers form a central core, while the DNA binding domains and the DNA lie on the outside. In addition, the crossover sites cross one another to form a local positive node. The implications of our data for the mechanism of strand exchange and the process of resolvase activation are discussed.


Ultradian oscillations in somatostatin and growth hormone-releasing hormone mRNAs in the brains of adult male rats.
In the adult male rat, growth hormone (GH) secretion is characterized by an ultradian rhythm generated by the rhythmic interplay of the stimulatory effects of GH-releasing hormone (GHRH) and the inhibitory effects of somatostatin (Ss). Although considerable evidence indicates that GHRH and Ss are secreted in reciprocal 3- to 4-hr rhythms, the mechanism underlying the rhythmic secretion of these two neuropeptides is unknown. We tested the hypothesis that the rhythmic and reciprocal oscillations in secretion of Ss and GHRH are associated with parallel changes in synthesis and that this would be reflected by coincident oscillations in levels of the respective mRNAs. In the first experiment, Ss mRNA was significantly greater in the periventricular nucleus of animals sacrificed at the time of a presumed peak in the GH rhythm than in animals sacrificed at the time of a presumed trough; this variation was limited to the anterior third of this nucleus. Conversely, GHRH mRNA content throughout the arcuate nucleus was significantly greater at the time of a GH trough. In the second experiment, groups of animals were sacrificed during two consecutive cycles. In this set of animals, Ss mRNA content was 40% greater (P less than 0.005) during peak GH concentrations, whereas GHRH mRNA content was 42% greater (P less than 0.005) during the GH trough. This difference persisted when the two cycles were analyzed separately. The findings that the cellular mRNA content for Ss and GHRH varies in a reciprocal manner with the presumed secretion of these neuropeptides suggest that, like secretion, the synthesis of Ss and GHRH also varies rhythmically. The occurrence of this rhythm suggests a model for a transcriptional oscillator that may subserve the generation of this and possibly other neuroendocrine rhythms.


Community perception of school-based deworming program in Sanliurfa, Turkey.
This article presents an evaluation of the community perception of the recently implemented School Based Health Program, which delivered anthelmintics to 96,000 schoolchildren in Sanliurfa, Turkey. One hundred forty-four parents and 140 teachers were interviewed through questionnaires, focus group discussions, and in-depth interviews. The evaluation indicated that most of the parents and teachers reported that the program was beneficial as it led to improvement in children's health and well being. The evaluation also indicated that 99% of the parents and 98.4% of the teachers approved of the teacher's role in this program. Nearly all of the teachers and parents showed willingness to continue the program in the future and 75% of the parents indicated willingness to pay for the drugs. The evaluation also highlighted that there were critical issues for the successful implementation of the program such as the issue of educating illiterate mothers, higher involvement of families in the mass treatment process, ability to reach a larger number of school absentees, and overcoming the prejudice against externally funded measures, which are perceived by some of the members of the community as an experiment run by foreigners on the local population and the concern of some parents that anthelmintic drug (mebendazole) might cause sexual sterility.


Hyperbranched Zwitterionic Polymer-Functionalized Underwater Superoleophobic Microfiltration Membranes for Oil-in-Water Emulsion Separation.
Inspired by mussel adhesion chemistry, a kind of hydrophilic poly(vinylidene fluoride) (PVDF) microfiltration membrane with underwater superoleophobicity was prepared using thiolated hyperbranched zwitterionic poly(sulfobetaine methacrylate) (HPS) as a nanoscale surface modifier. The HPS was first synthesized via reversible addition fragmentation chain transfer (RAFT) copolymerization and followed by sulfonation reaction and then coated onto polydopamine (PD) adhesive PVDF membranes via thiol-mediated Michael addition reaction. The successful and uniform coating of HPS onto the membrane surface was demonstrated by X-ray photoelectron spectroscopy and by using an energy dispersive X-ray detector. The surface micro-nano morphology and increased roughness of the PD/HPS-modified (M-PD/HPS) membrane were also investigated by using a field emission scanning electron microscope and an atomic force microscope. The M-PD/HPS membrane could be wetted completely by water, and the underwater oil contact angles were about 160°, indicating the M-PD/HPS membrane has excellent hydrophilicity and underwater superoleophobicity. Compared with the pure PVDF membrane, the M-PD/HPS membrane for hexane-in-water emulsion separation exhibited an enhanced water filtration flux of 10 707 L m-2 h-1 (0.1 MPa), and the oil rejection ratio was above 99.9%. Besides, the excellent antifouling ability and recyclable properties of the M-PD/HPS membranes would make them suitable for long-time use. Thus, the approach of mussel adhesion chemistry employing the RAFT-mediated nanosized hyperbranched zwitterionic polymers as postmodification reagents showed a good application prospect in purification of oily waste water and oil recovery.


Pediatric dermatopathology: an overview.
Dermatopathology is a subspecialty of pathology and dermatology involving correlation of clinical information with microscopic observations of skin biopsies to provide diagnostic information. Pediatric dermatology is a subspecialty of dermatology for which specific points need to be known for evaluating and managing skin disorders in children. The histopathological approach and other important factors for definitive diagnoses in pediatric dermatopathology are reviewed. Skin diseases in children are not necessarily smaller versions of those that develop in adults and some diaseases may be confined to pediatric age group. An experienced team of dermatology and pathology increases the success of skin biopsies in pediatric dermatology besides the excellent technical skills. The histopathologic findings of skin lesions in children should be evaluated by pediatric pathologists, who have a specific interest for pediatric dermatopathology, in close collaboration with pediatric dermatologists.


[Palliative medicine].
Palliative medicine has its origin in the modern hospice movement. It is based upon an integrated-care concept for seriously ill and dying patients. The first consideration of this particular form of treatment is not to prolong life, but to reach the best possible quality of a patient's remaining lifetime. Therefore, palliative medicine consists of: (1) excellent pain treatment and symptom control; (2) an integrated approach towards the psychic, social, and spiritual needs of the patient, relatives, and attending staff during the periods of illness, dying, and, after the patient's death; (3) competence in dealing with vital matters of communication and ethics; and (4) acceptance of death as a normal process. Palliative medicine clearly rejects euthanasia. Practical implementation of the idea of hospice services can be realised anywhere when taking care of seriously ill and dying patients, whether at home, in a nursing home, or in hospital. Experience shows that quite a few patients cannot be treated successfully without additional services, such as home-care services, day-care centres, in patient hospices, and palliative-care units. Up to now, severely ill tumour patients have benefited most from these services. In palliative care units an interdisciplinary team of doctors and nursing staff assisted by physiotherapists and members of psycho-social professions is taking care of and treating patients. Additional support is given by voluntary services and the integration of the patient's relatives in the caring process. Palliative medicine is the overall term for this special kind of treatment and care. In Great Britain, Canada, and Scandinavia considerable progress has been achieved in this field, including recognition as an independent clinical discipline and the establishment of lectureships in palliative medicine.


Aggression in the demented patient: a double-blind study of loxapine versus haloperidol.
Aggression is common in dementia, with devastating social consequences. While high or low potency neuroleptics are the usual treatment of choice, they have been shown to yield inconsistent behavioral improvement and significant iatrogenic disability. This double-blind study was undertaken with aggressive demented patients to assess the efficacy and safety of a mid-potency neuroleptic, loxapine, in comparison to the more commonly prescribed high potency drug, haloperidol. Using an optimizing dosage regime, the outcome variables studied were aggression frequency and the number and nature of emergent side effects. Results demonstrated no significant difference regarding efficacy, but significantly fewer side effects with loxapine administration. The clinical and theoretical implications of these findings are discussed.


Anatomy of the distal biceps brachii tendon and its clinical relevance.
Rupture of the distal biceps tendon is a relatively uncommon injury. Different methods have been described for its surgical repair. According to published reports, current surgical techniques result in decreased strength and endurance of upper extremity functions requiring supination and flexion. In our anatomic study of 74 cadaveric elbows, we observed that the distal biceps tendon spirals in a predictable manner and has a complex fiber arrangement. Successful surgical repair of a ruptured distal biceps tendon should be predicated on an understanding of the tendon anatomy, but current surgical techniques do not take into account the salient anatomic features of the distal biceps tendon. To our knowledge, there is no description in the surgical literature of the fiber arrangement of the distal biceps tendon. We provide a basis for developing an anatomically accurate protocol for repairing a distal biceps tendon rupture.


Scoliosis in patients with Prader-Willi Syndrome.
Our goals were to determine the prevalence and estimate the evolution of spinal deformities in patients suffering from Prader-Willi syndrome; find out which kind of spine deformity predominates regarding genotype and clinical patterns; and evaluate the affect of growth-hormone treatment on the onset and progression of spinal deformities. This was a retrospective longitudinal, clinical, and radiologic study. One hundred forty-five children followed between 1980 and 2006 were studied in 2 referral centers for Prader-Willi syndrome. Genetic testing confirmed the diagnosis in 133 patients. Ninety-three patients (64%) received growth-hormone therapy. For statistical analysis, age-adjusted comparison between groups was performed by using multivariate logistic regression. Mean age of the patients was 10.2 +/- 6.2 years. Sixty-three (43.4%) patients were afflicted with scoliosis. Scoliosis frequency steadily rose with age, and a large majority of patients were affected at skeletal maturity (66.7%). Scoliosis prevalence was not affected by the genotype or by growth-hormone treatment. Patients with higher BMI values had an increased risk of developing a kyphotic deformity in association with scoliosis. We found a statistical association between kyphotic deformity and the need for surgical treatment. Scoliosis is a major concern for patients with Prader-Willi syndrome, and a regular (annual) systematic back examination is mandated. The role of growth-hormone treatment on the natural history of scoliosis could not be determined, and careful monitoring during treatment is recommended.


Periventricular neuronal heterotopia, oro-facio-digital anomalies, and microphthalmia. A new syndrome?
Congenital malformations involving the face, oral cavity, and digits are the main findings in the oro-facio-digital (OFD) syndromes. Various eye anomalies and central nervous system involvement have also been reported in this condition. Here we report on a Brazilian boy with features belonging to the clinical spectrum of the OFD syndromes. He also had additional findings of periventricular nodular heterotopia (PVNH), asymmetric limb involvement, and microphthalmia. This unusual pattern of anomalies has not been reported previously and appears to be unique.