Epitope-Based Peptide Vaccine against Glycoprotein G of Nipah Henipavirus Using Immunoinformatics Approaches.
Nipah belongs to the genus Henipavirus and the Paramyxoviridae family. It is an endemic most commonly found at South Asia and has first emerged in Malaysia in 1998. Bats are found to be the main reservoir for this virus, causing disease in both humans and animals. The last outbreak has occurred in May 2018 in Kerala. It is characterized by high pathogenicity and fatality rates which varies from 40% to 70% depending on the severity of the disease and on the availability of adequate healthcare facilities. Currently, there are no antiviral drugs available for NiV disease and the treatment is just supportive. Clinical presentations for this virus range from asymptomatic infection to fatal encephalitis. This study is aimed at predicting an effective epitope-based vaccine against glycoprotein G of Nipah henipavirus, using immunoinformatics approaches. Glycoprotein G of the Nipah virus sequence was retrieved from NCBI. Different prediction tools were used to analyze the epitopes, namely, BepiPred-2.0: Sequential B Cell Epitope Predictor for B cell and T cell MHC classes II and I. Then, the proposed peptides were docked using Autodock 4.0 software program. Results and Conclusions. The two peptides TVYHCSAVY and FLIDRINWI have showed a very strong binding affinity to MHC class I and MHC class II alleles. Furthermore, considering the conservancy, the affinity, and the population coverage, the peptide FLIDRINWIT is highly suitable to be utilized to formulate a new vaccine against glycoprotein G of Nipah henipavirus. An in vivo study for the proposed peptides is also highly recommended.


Plasma dopamine beta hydroxylase activity in affective disorders.
Plasma dopamine beta hydroxylase (DBH) activity was measured in patients with affective disorders and in their relatives. The groups studied had wide distributions of values for plasma DBH activity. No significant difference of plasma DBH activity was found between unipolar and bipolar patients, nor between patients given lithium or placebo. Exercise on a treadmill at 40 degrees or 10 degrees C elicited a different pattern of response for plasma DBH activity in three patients as compared to control subjects. In familial studies we found the values of plasma DBH activity to be almost identical in monozygotic twin pairs and quite similar in dizygotic twin pairs. All pairs, however, were discordant for affective illness. There was also a marked similarity of plasma DBH activity in 15 pairs of the same sex sibs discordant for affective illness. These studies suggest that the resting level of plasma DBH activity is not related to affective illness but is genetically determined.


What Is Qualitative Research?
The article is an in-depth explanation of qualitative research, an approach increasingly prevalent among today's research communities. After discussing its present spread within the health sciences, the author addresses: 1. Its definition. 2. Its characteristics, as well as its theoretical and procedural background. 3. Its procedures. 4. Differences between qualitative and quantitative approaches. 5. Mixed methods incorporating quantitative research. And in conclusion: 6. The importance of establishing an epistemological perspective in qualitative research.


Rydberg gas theory of a glow discharge plasma: II. Electrode kinetics (probe theory) and the thermal rate constant for Symmetrical charge transfer involving Rydberg atoms of Ar.
A steady state chemical kinetic model is developed to describe the conduction of electrical current between two probes, of relatively large surface area, immersed in a fast flowing plasma by the mechanism of charge transfer through a gas of Rydberg atoms. It correctly predicts the shape of current-voltage profiles which are similar to those of Langmuir, or floating double probe measurements. The difference is that the plateau current at the probe reflects the transport limited ion current at the cathodic electrode, even when the probe is being scanned in the anodic region. The sharp gradient leading up to the plateau of the I-V curve is associated with the field dependence of the efficiency of Rydberg atom ionisation, not the electron temperature. This approach gives a good qualitative explanation of experimental behaviour over a wide range of probe bias voltages and includes the occurrence of electron impact ionisation at the anode. It also gives a value for the thermal rate coefficient of symmetrical charge transfer between Rydberg atoms of Ar (8.2 x 10(-7) molecule(-1) cm(3) s(-1), at 313 K; plasma density approximately = 10(10) atoms cm(-3), total pressure = 2.7 mbar).


Simultaneous determination of four fluorescent whitening agents (including trans and cis isomers) in facial mask by dispersive solid-phase extraction combined with ultra high performance liquid chromatography and diode array detection.
A novel ultra high performance liquid chromatography with diode array detection method, based on the dispersive solid-phase extraction by using polymer weak anion exchange as the sorbent, was established for the simultaneous determination of fluorescent whitening agents 85, 28, 351, and 71 in facial mask. The amounts of polymer weak anion exchange, adsorption time, and volume of elution solvent in the dispersive solid-phase extraction technology were optimized, and the developed method was validated in terms of the method limit of detection, method limit of quantitation, linear range, recovery, accuracy, and precision. Results indicated that the standard curves were linear over the selected concentration ranges of 0.05-100 mg/L for four target analytes, with determination coefficients greater than 0.999. The method limits of quantitation of the target analytes were in the range of 0.6-2.8 mg/kg. Recoveries were calculated at the concentrations of 1.0-30 mg/kg spiked in negative samples and the values were between 89.3 and 102% with an RSD of 2.5-5.1% for intraday precision and 3.8-5.0% for interday precision. The method was successfully applied to analyze 20 facial mask samples and fluorescent whitening agent 85 was detected in one sample with the concentration of 4.7 mg/kg.


Adverse effects of breast cancer treatment.
As breast cancer outcomes improve and more people with breast cancer survive longer following diagnosis, many survivors must deal with the effects of treatment. Some adverse effects last a short time and have little influence on breast cancer patients' quality of life, yet others can cause long-term complications and add to increased morbidity and mortality among survivors. This article reviews the adverse effects of breast cancer treatments and how they affect the health and quality of life of those receiving treatment. The article also explains how adverse effects can interrupt treatment and how physicians and survivors can manage adverse effects of breast cancer treatment.


Coronal and Intraradicular Appearances Affect Radiographic Perception of the Periapical Region.
The influence of the radiographic appearances of the coronal and intraradicular areas on periapical radiographic interpretation has been minimally evaluated in dentistry and endodontics. The purpose of this study was to evaluate the effects that the coronal and intraradicular radiographic appearance has on endodontists' radiographic interpretations of periapical areas. In a split-group study design using an online survey format, 2 pairs of digital periapical radiographic images were evaluated by 2 groups (A and B) of endodontist readers for the presence of a periapical finding. The images in each pair were identical except that 1 image of each image pairs had coronal restorations and/or root canal fillings altered using Adobe Photoshop software (Adobe Systems, San Jose, CA). The periapical areas were not altered. Using a 5-point Likert scale, the endodontist readers were asked to "Please evaluate the periapical area(s)." A Mann-Whitney U test was used to statistically evaluate the difference between the groups. Significance was set at P < .01. There were 417 readers in group A and 442 readers in group B. The Mann-Whitney U test showed a significant difference in the responses between the groups for both image pairs (P < .01). Because the periapical areas of the image pairs were unaltered, the differing coronal and intraradicular areas of the radiographs appear to have influenced endodontists' interpretations of the periapical areas. This finding has implications for all radiographic outcome assessments.


A Clinical Trial of the Accuracy and Treatment Experience of the Flash Glucose Monitor FreeStyle Libre in Adults with Type 1 Diabetes.
In Sweden, FreeStyle Libre a flash glucose monitoring system came onto the market in 2014 as a complement to self-monitoring of blood glucose. The aim of this study was to evaluate the accuracy and treatment experience of the FreeStyle Libre system. Fifty-eight adults with type 1 diabetes used FreeStyle Libre for 10-14 days and measured capillary blood glucose levels with the HemoCue blood glucose measurement system at least six times a day simultaneously. For the entire study period, the mean absolute relative difference (MARD) was 13.2% (95% confidence interval [CI] 12.0%-14.4%). MARD was 13.6% (95% CI 12.1%-15.4%) during week 1 and 12.7% (95% CI 11.5%-13.9%) during week 2. The mean absolute difference (MAD) for the whole study period was 19.8 mg/dL (1.1 mmol/L) (95% CI 17.8-21.8 mg/dL), including 20.5 mg/dL (1.14 mmol/L) during week 1 and 19.0 mg/dL (1.05 mmol/L) during week 2. The overall correlation coefficient was 0.96. For glucose values <72, 72-180, and >180 mg/dL (<4, 4-10, and >10 mmol/L), the MARD was 20.3% (95% CI 17.7%-23.1%), 14.7% (95% CI 13.4%-16%), and 9.6% (95% CI 8.5%-10.8%), respectively, and respective MAD values were 12.3, 17.8, and 23.6 mg/dL (0.69, 0.99, and 1.31 mmol/L). Using the 10-item visual analog scale, patients rated their experience with FreeStyle Libre as generally positive, with mean values ranging from 8.22 to 9.8. FreeStyle Libre had a similar overall MARD as continuous blood glucose monitoring systems in earlier studies when studied in similar at-home conditions. The overall patient satisfaction was high.


Circulating microRNAs and adipokines as markers of metabolic syndrome in adolescents with obesity.
Circulating microRNAs (miRNAs) as valuable biomarkers yielded important insights into the pathogenesis of obesity. This study aimed to describe the circulating miRNA profile for adolescences and its association with the circulating levels leptin and adiponectin according to specific degree of obesity. RT-PCR and immunoassy analysis were used to study circulating miRNA profile, adipokines; adiponectin (A), leptin (L), and L/A ratio as well as other factors of metabolic syndrome (MS) in 250 adolescents with severe obesity. In morbidly obese adolescents, we identified at least 10 circulating miRNAs, including increased concentrations of miRNAS; miR-142-3p, miR-140-5p, miR-222 miR-143, miR-130, and decreased concentrations of miR-532-5p, miR-423-5p, miR-520c-3p, miR-146a, and miR-15a, which were strongly linked to measures of BMI, WHtR, adipokines; adiponectin, leptin, L/A ratio, and other MS related biomarkers such as FBS, insulin, HOMA-IR, C-peptide, and circulated plasma lipids such as TG, HDL-C, and LDL-C. Circulating miRNAs showed significant association with plasma levels of adipokines; adiponectin, leptin, and L/A ratios in adolescents with severe obesity. The study provides that regulation of miRNAs expression is associated with adipokines, and other related MS metabolic factors. Thus, early detection of any changes in circulating miRNAs profiles may play a promising role in identifying obese children or adolescents who may suffer from severe metabolic syndrome.


Extraventricular neurocytoma in neurofibromatosis Type 1: case report.
Neurocytomas are rare tumors of the central nervous system that are typically located in the ventricular system. The authors report a case of a child with neurofibromatosis Type 1 (NF1) who had a tumor of the optic nerves and chiasm with signal abnormality extending through the diencephalon, as well as an occipital lobe mass, which was presumed to be part of the visual pathway neoplasm. Because the occipital lobe lesion slowly increased in size over time, while the other areas remained stable, a biopsy was performed. Pathological evaluation revealed an extraventricular neurocytoma of extraventricular neurocytoma. To the authors' knowledge, neurocytomas have not been previously reported in patients with NF1. Because visual pathway gliomas are extremely common in children with NF1, they are often treated empirically as low-grade gliomas without histological confirmation. The importance of obtaining a biopsy in lesions that have atypical imaging features is highlighted.


Two-year follow-up of inpatients with dissociative identity disorder.
A group of 135 inpatients with dissociative identity disorder was followed for 2 years to monitor treatment outcome. Fifty-four of the patients were located and reassessed after a 2-year period through the use of the same self-report measures and structured clinical interviews that had been initially administered. The patients showed marked improvement on Schneiderian first-rank symptoms, mood and anxiety disorders, dissociative symptoms, and somatization, with a significant decrease in the number of psychiatric medications prescribed. Patients who were treated to integration were significantly more improved than those who had not yet reached integration. These findings, although preliminary, provide empirical validation of previous clinical impressions that patients with dissociative identity disorder may respond well to treatment.


Stroke surveillance in Manitoba, Canada: estimates from administrative databases.
This study investigated the use of population-based administrative databases for stroke surveillance. First, a meta-analysis was conducted of four studies, identified via a PubMed search, which estimated the sensitivity and specificity of hospital data for ascertaining cases of stroke when clinical registries or medical charts were the gold standard. Subsequently, case-ascertainment algorithms based on hospital, physician and prescription drug records were developed and applied to Manitoba's administrative data, and prevalence estimates were obtained for fiscal years 1995/96 to 2003/04 by age group, sex, region of residence and income quintile. The meta-analysis results revealed some over-ascertainment of stroke cases from hospital data when the algorithm was based on diagnosis codes for any type of cerebrovascular disease (Mantel-Haenszel Odds-Ratio [OR] - 1.70 [95% confidence interval (CI): 1.53 - 1.88]). Analyses of Manitoba administrative data revealed that while the total number of stroke cases varied substantially across the algorithms, the trend in prevalence was stable regardless of the algorithm adopted.


De Novo Fragment Design for Drug Discovery and Chemical Biology.
Automated molecular de novo design led to the discovery of an innovative inhibitor of death-associated protein kinase 3 (DAPK3). An unprecedented crystal structure of the inactive DAPK3 homodimer shows the fragment-like hit bound to the ATP pocket. Target prediction software based on machine learning models correctly identified additional macromolecular targets of the computationally designed compound and the structurally related marketed drug azosemide. The study validates computational de novo design as a prime method for generating chemical probes and starting points for drug discovery.


Characterization and clinical implications of ankle impedance during walking in chronic stroke.
Individuals post-stroke experience persisting gait deficits due to altered joint mechanics, known clinically as spasticity, hypertonia, and paresis. In engineering, these concepts are described as stiffness and damping, or collectively as joint mechanical impedance, when considered with limb inertia. Typical clinical assessments of these properties are obtained while the patient is at rest using qualitative measures, and the link between the assessments and functional outcomes and mobility is unclear. In this study we quantify ankle mechanical impedance dynamically during walking in individuals post-stroke and in age-speed matched control subjects, and examine the relationships between mechanical impedance and clinical measures of mobility and impairment. Perturbations were applied to the ankle joint during the stance phase of walking, and least-squares system identification techniques were used to estimate mechanical impedance. Stiffness of the paretic ankle was decreased during mid-stance when compared to the non-paretic side; a change independent of muscle activity. Inter-limb differences in ankle joint damping, but not joint stiffness or passive clinical assessments, strongly predicted walking speed and distance. This work provides the first insights into how stroke alters joint mechanical impedance during walking, as well as how these changes relate to existing outcome measures. Our results inform clinical care, suggesting a focus on correcting stance phase mechanics could potentially improve mobility of chronic stroke survivors.


Gap junction-mediated intercellular biochemical coupling in cochlear supporting cells is required for normal cochlear functions.
Dysfunction of gap junctions (GJs) caused by mutations in connexin26 (Cx26) and Cx30 accounts for nearly half of all cases of hereditary nonsyndromic deafness cases. Although it is widely held that GJs connecting supporting cells in the organ of Corti mainly provide ionic pathways for rapid removal of K+ around the base of hair cells, the function of GJs in the cochlea remains unknown. Here we show that GJs were not assembled in the supporting cells of the organ of Corti until 3 days after birth in mice and then gradually matured to connect supporting cells before the onset of hearing. In organotypic cochlear cultures that were confirmed to express GJs, GJs mediated the propagation of intracellular Ca2+ concentration waves in supporting cells by allowing intercellular diffusion of inositol 1,4,5-trisphosphate. We found that a subset of structurally mild Cx26 mutations located at the second transmembrane region (V84L, V95M, and A88S) and a Cx30 mutation located at the first cytoplasmic segment (T5M) specifically affect the intercellular exchange of larger molecules but leave the ionic permeability intact. Our results indicated that Cx26 and Cx30 mutations that are linked to sensorineural deafness retained ionic coupling but were deficient in biochemical permeability. Therefore, GJ-mediated intercellular exchange of biochemically important molecules is required for normal cochlear functions.


On the various forms of the glandular kallikrein from autolyzed porcine pancreas.
Kallikrein C, a minor form of the glandular kallikrein isolated form autolyzed porcine pancreas, has the same amino acid composition a porcine pancreatic beta-kallikreins A and B and comparable specific activity, but a much lower carbohydrate content. Dodecyl sulfate electrophoresis of the reduced enzyme indicated that it is composed of the same two polypeptide chains as the other pancreatic beta-kallikreins of the pig. The carbohydrate content of the two chains of beta-kallikrein B has been determined. Both the A and the B chain of beta-kallikreins from autolyzed porcine pancreas exist in a high-molecular (h) and a low-molecular (1) form which evidently differ only in their carbohydrate content. beta-Kallikrein B has the composition AhBh, beta-kallikrein A, AhB1, and beta-kallikrein C, A1B1. The properties of kallikrein III from porcine pancreas, recently described by Kira et al. (Adv. Exp. Med. Biol. 120A (1979) 273--290), indicate that is is the fourth conceivable form, A1Bh. A preparation of porcine pancreatic kallikrein d2 was found to have a specific activity comparable to that of other kallikrein preparations. Besides a main component migrating like pancreatic beta-kallikrein A, it also contained beta-kallikreins B and C. All four species of chains were observed to occur in this batch of the enzyme. Zuber and Sache (Biochemistry 13 (1974) 3098--3110) reported the resolution of porcine pancreatic kallikreins d1 and d2 into three electrophoretic components each after reduction. Evidently, all these preparations consist of a mixture of several forms of two-chain pancreatic beta-kallikrein.


The prevalence of urinary incontinence.
Urinary incontinence is a significant health problem with considerable social and economic impact. It is important to distinguish between prevalence and incidence with regard to incontinence, and prevalence-the probability of having incontinence within a defined population at a defined point in time-is the more important when considering its impact and the utilization of healthcare resources. There are large variations in the severity and impact of incontinence, and its severity, frequency, and predictability all need to be considered when evaluating its effects on patients, The degree of bother is particularly significant when determining who will need treatment. Incontinence may be a result of bladder dysfunction, sphincter dysfunction, or a combination of both, but large-scale studies are not designed to determine the etiology. In young women, the prevalence of incontinence is usually low, but prevalence peaks around menopause, with a steady rise there-after into later life. Although the prevalence of stress and mixed (stress and urge) incontinence is higher than urge incontinence, the latter is more likely to require treatment. In women, moderate and severe bother have a prevalence ranging from about 3% to 17%. Severe incontinence has a low prevalence in young women, but rapidly increases at ages 70 through 80. In men, the prevalence of incontinence is much lower than in women, about 3% to 11% overall, with urge incontinence accounting for 40% to 80% of all male patients. Stress incontinence accounts for less than 10% of cases and is attributable to prostate surgery, trauma, or neurological injury. Incontinence in men also increases with age, but severe incontinence in 70- to 80-year-old men is about half of that in women. The most effective therapy for incontinence will rely on targeting the correct populations to be treated, which depends on how data is collected on prevalence and severity.


Gargle lavage & saliva: Feasible & cheaper alternatives to nasal & throat swabs for diagnosis of COVID-19.
In the present scenario, the most common sample for diagnosis of COVID-19 by reverse transcription polymerase chain reaction (RT-PCR) is nasal and throat swab (NTS). Other sampling options such as gargle lavage have found limited application in clinical use mostly because of unavailability of an appropriate gargling liquid. This study was conducted to assess the stability of SARS-CoV-2 RNA in normal saline at 4°C that can serve as a gargling liquid as well as a transport medium. The study also looked at the agreement between NTS and gargle lavage/saliva for the detection of SARS-CoV-2. In 29 consecutive real-time RT-PCR (rRT-PCR) positive COVID-19 patients, paired NTS, gargle and saliva samples were taken. Samples were processed by rRT-PCR for the detection of SARS-CoV-2 RNA. To assess the SARS-CoV-2 RNA stability in normal saline, gargle lavage specimens were divided into two aliquots; one subset of the specimen was run within 4-6 h along with the routine samples (NTS and saliva) and the other subset was stored at 4°C and processed after 24-30 h. Agreement between cycle threshold (Ct) values from both the runs was compared using Bland-Altman (BA) analysis. The positivity rates of rRT-PCR in NTS, saliva and gargle lavage samples were 82.7 (24/29), 79.3 (23/29) and 86.2 per cent (25/29), respectively. BA plot showed a good agreement between the Ct values of fresh and stored gargle samples, stipulating that there were no significant differences in the approximate viral load levels between the fresh and stored gargle lavage samples (bias: E gene -0.64, N gene -0.51, ORF gene -0.19). Our study results show stability of SARS-CoV-2 RNA in the gargle samples collected using normal saline up to 24-30 h. Gargle lavage and saliva specimen collection are cost-effective and acceptable methods of sampling for the detection of SARS-CoV-2 RNA by rRT-PCR. These simplified, inexpensive and acceptable methods of specimen collection would reduce the cost and workload on healthcare workers for sample collection.


Risk Factors for Peri-Procedural Arterial Ischaemic Stroke in Children with Cardiac Disease.
Improved survival of children with congenital heart disease has led to increasing focus on neurodevelopmental outcome, as close to half of the infants undergoing cardiac surgery are affected by neurodevelopmental disability. Stroke is particularly important as it frequently results in permanent neurologic sequelae. The aim of this study was to investigate risk factors for peri-procedural arterial ischaemic stroke (AIS) in children with cardiac disease. A retrospective case-control analysis of children aged <18 years with radiologically confirmed AIS following a cardiac procedure admitted to the Royal Children's Hospital Melbourne between 1993 and 2010. Each case was matched with two controls with similar cardiac diagnosis, procedure type, age and date of procedure. Demographics and peri-procedural data were collected from medical records and departmental database. Fifty-two cases were identified. Multivariable analysis identified post-procedural infection (OR 6.1, CI 1.3-27, p = 0.017) and length of ICU stay (OR 4.0, CI 1.4-11, p = 0.009) as risk factors for AIS. Although the study is limited to a single-centre cohort, length of ICU stay and post-procedural infection were identified as risk factors for AIS. These findings demonstrate these factors to be important areas to focus attention for stroke prevention in children with cardiac disease.


Molecular toxicity identification evaluation (mTIE) approach predicts chemical exposure in Daphnia magna.
Daphnia magna is a bioindicator organism accepted by several international water quality regulatory agencies. Current approaches for assessment of water quality rely on acute and chronic toxicity that provide no insight into the cause of toxicity. Recently, molecular approaches, such as genome wide gene expression responses, are enabling an alternative mechanism based approach to toxicity assessment. While these genomic methods are providing important mechanistic insight into toxicity, statistically robust prediction systems that allow the identification of chemical contaminants from the molecular response to exposure are needed. Here we apply advanced machine learning approaches to develop predictive models of contaminant exposure using a D. magna gene expression data set for 36 chemical exposures. We demonstrate here that we can discriminate between chemicals belonging to different chemical classes including endocrine disruptors and inorganic and organic chemicals based on gene expression. We also show that predictive models based on indices of whole pathway transcriptional activity can achieve comparable results while facilitating biological interpretability.


Usefulness of L-[methyl-11C] methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma.
The authors retrospectively analyzed the data obtained in patients who had undergone L-[methyl-11C] methionine (MET)-positron emission tomography (PET) studies to clarify the relationship between MET uptake and tumor biological features and to discuss the clinical usefulness of MET-PET studies. One hundred ninety-four patients with cerebral glioma or suspected glioma underwent PET scanning 20 minutes after injection of MET, whose uptake into the tumor was expressed as a ratio to contralateral healthy brain tissue (T/N ratio). Analyses were performed to determine how MET uptake correlated with tumor pathological features and prognosis. The T/N ratios before and after various treatments were also examined. There were significant differences in the T/N ratio among the nonneoplastic lesions, low-grade gliomas, and malignant gliomas. Furthermore, there were significant correlations between patient survival and pretreatment T/N ratios. Among patients with malignant gliomas, a significant difference in survival was observed between cases with and without postoperative tumor remnant based on elevated MET uptake. The MET uptake was heterogeneous even among the homogeneous tumor areas demonstrated on MR imaging. Malignant pathological features were detected in the areas with the highest MET uptake. The effectiveness of radiotherapy or chemotherapy was expressed as a significantly decreased T/N ratio in some of the tumor types. The ability of MET-PET to reflect the biological nature of gliomas makes it an excellent method for monitoring active tumor tissue, and treatments based on its findings should provide a powerful clinical protocol in the course of glioma therapy.


Rhesus macaques (Macaca mulatta) with self-injurious behavior show less behavioral anxiety during the human intruder test.
Self-injurious behavior (SIB) has been linked to anxiety in the human literature, but relatively few studies have explored this link in rhesus macaques. A widely used behavioral assessment of anxiety, the human intruder test (HIT), employs the mildly stressful stimulus of an unfamiliar experimenter to assess anxious behavior in macaques. The HIT was conducted on 59 (20 male) laboratory housed rhesus macaques, 30 with a record of SIB (10 male). If monkeys with SIB have a more anxious phenotype, they should show stronger reactions to the HIT. However, contrary to our predictions, monkeys with SIB did not show higher levels of anxious behavior compared to controls. They spent significantly less time showing anxious behavior and displayed little aggression in response to the stare of the intruder. SIB and control monkeys did not differ in a range score (number of unique behaviors expressed per phase); however, SIB monkeys had a lower change score (total number of behaviors expressed including repetitions) than controls. In general, monkeys that paced regardless of SIB status, showed a reduction in pacing when the intruder entered the room. Possible explanations for the failure of SIB monkeys to show increased anxiety in the HIT include greater exposure of SIB monkeys to unfamiliar humans because of their condition, evidence for a subtype of SIB which is not anxiety related, and/or the presence of comorbid depressive-like symptoms. Am. J. Primatol. 79:e22569, 2017. © 2016 Wiley Periodicals, Inc.


Nucleophosmin, HDM2 and p53: players in UV damage incited nucleolar stress response.
p53 tumor suppressor protein acts as a critical monitor preventing survival of cells with irreparable genetic damage. Its levels are tightly controlled by its negative regulator HDM2, and are allowed to rise only during cellular stress. In our recent paper (Kurki, et al. Cancer Cell 2004; 5:465-75) we identify a novel mechanism leading to p53 stabilization following UV damage of the cells. This involves UV damage provoked nucleoplasmic relocalization of a nucleolar protein, nucleophosmin (NPM, B23) and its rapid and transient interactions with both p53 and HDM2. We discuss here implications of recent findings that several p53 pathway proteins interact with NPM and find that its participation in cellular damage responses is limited to transcriptional stress but absent in direct ds DNA breaks. These findings suggest divergence in the routes provoking p53 stability and implicate the nucleolus as a central site participating in transcriptional stress responses.


[Pediatric acute-onset neuropsychiatric syndrome: clinical/laboratory characteristics].
Based on the current conceptions on the genesis of hyperkinetic syndromes in children and adolescents, to single out a group of patients with suggestive PANS, compare clinical and laboratory results and determine clinical/laboratory characteristics of this syndrome. Sixty-nine patients with tics were studied using neurological examination, questionnaires and international scales for assessment of tics, obsessive-compulsive disorders and attention deficit hyperactivity disorder (ADHD). Laboratory tests included general blood tests, antistreptolysin O test, determination of rheumatoid factor, C-reactive protein, circulating immune complexes, nasopharyngeal wash for β-hemolytic streptococcus, antineuronal antibodies and immunoglobulins A, M, G, E, CD4, CD8-lymphocytes. The same tests were performed in the control group. Clinical symptoms were different by the severity and phenomenology of tic hyperkineses in patients with PANS compared to the patients with tics without immune disorders. Most of the patients were diagnosed with Tourette syndrome. ADHD was the most common diagnosis in the PANS group. Its frequency was 2.5 higher in the male patients. A chronic focus of infection did no predict the development of PANS. Based on the laboratory results, one can assume that β-hemolytic streptococcus A infection, lower JgM levels and an elevated CD8+ lymphocytes predict the development of autoimmune mental and neurological disorders in the group of PANS patients.


Human splenic galaptin: carbohydrate-binding specificity and characterization of the combining site.
A galactose-binding lectin (galaptin) from human spleen has been purified to homogeneity by affinity chromatography on asialofetuin-Sepharose. The carbohydrate-binding specificity of galaptin has been investigated by analyzing the binding of galaptin to asialofetuin in the presence of putative inhibitors. An enzyme-linked immunosorbent assay (ELISA) was developed that involved adsorption of asialofetuin to microtiter plates. Galaptin bound to asialofetuin was detected with polyclonal rabbit anti-galaptin serum followed by goat anti-rabbit IgG-peroxidase conjugate. The concentrations of inhibitors giving 50% inhibition of galaptin binding relative to controls were graphically determined and normalized relative to galactose or lactose. These analyses revealed that galaptin has a combining site at least as large as a disaccharide. The disaccharides having non-reducing-terminal beta-galactosyl residues linked (1,3), (1,4), and (1,6) to Glc or GlcNAc are better inhibitors than free Gal. GalNAc, either free or glycosidically linked, appears to have no affinity for the lectin. The nitrophenyl galactosides are better inhibitors than methyl galactosides, indicating the occurrence of hydrophobic interactions. The data indicate that OH groups at C-4 and C-6 of Gal and the OH at C-3 of GlcNAc in Gal beta(1,4)GlcNAc are important for lectin sugar interaction. Our data support the hypothesis that endogenous receptors for galaptin are most likely lactosaminoglycan moieties.


Clinical hyperthermia in the 1990s: does the buck stop here?
Clinical hyperthermia in the USA is entering difficult times. To describe the present state of this art (1) all of the clinical manuscripts published in the International Journal of Hyperthermia and the International Journal of Radiation Oncology, Biology and Physics in the period from 1 January 1990 to 30 June 1993 were reviewed; (2) the Radiotherapy Research Division of the National Cancer Institute was queried as to existing extramural funding of clinical hyperthermia projects; and (3) individual institutions known to have active clinical research programmes in hyperthermia were surveyed as to the status of current studies. At the present time there are no hyperthermia trials being conducted by US cooperative groups. The majority of reports and active scientific protocols continue to deal with phase I and pilot studies. Many studies in several sites continue to suggest improvement in CR rate and local control over historical controls when hyperthermia is used as an adjunct to radiotherapy; however phase III proof of these hypotheses is still lacking. Extramural funding of clinical hyperthermia is limited and third party funding is decreasing. Details and future portents are discussed.


Impairment of the host's antibacterial resistance by norepinephrine activated neutrophils.
The susceptibility of mice to infectious complications is dramatically increased in an accompaniment with systemic inflammatory response syndrome (SIRS). Polymorphonuclear neutrophils with immunosuppressive ability (PMN-II) that appear in response to SIRS have been classified as one of the cells responsible for the increased susceptibility of mice with SIRS (SIRS mice) to sepsis induced by cecal-ligation and puncture (CLP). Since a high level of norepinephrine (NE) is demonstrated in the plasma of SIRS mice, in the present study, the role of NE on the appearance of PMN-II in SIRS mice was studied. Similar to SIRS mice, normal mice became susceptible to CLP-induced infectious complications after inoculation with NE-treated PMN. CCL2 and IL-10 (biomarkers for PMN-II) were equally produced by PMN-II prepared from SIRS mice and NE-treated PMN. However, CCL3 and IL-12 (biomarkers for immunostimulatory PMN, PMN-I) were not detected in culture fluids from either PMN preparation. These results indicate that NE mass-produced in association with SIRS development plays a role on the generation of PMN-II and the appearing PMN-II are responsible, in part, for increased susceptibility of SIRS mice to CLP-induced infectious complications.


[The organization of health services: the comparison as contribution].
This article discusses about a recent procedure in health care studies, the comparison as a methodology of analysis. The different analytical currents refer to a particular method of understanding health-disease process. They are: functionalism, the historical-materialism and the new currents. Their phylosophical and sociological basis, concepts, analysis instruments and purposes are showed here by a review of the principal works from representative authors as Navarro, Terris, Roemer, Fry, Illich, Capra and others. The paper suggests that comparative analysis can take two directions: the first is a operational approach for analysing the concrete situations of health's service organization, the second, a more conceptual one, aimed at identifying critical questions and international tendencies in health's systems. The recent discussion search for the overcoming of these dichotomies toward the progress of the production of knowledge and its effects in health's services organization.


Antioxidant properties of various solvent extracts of potato peel, sugar beet pulp and sesame cake.
Growing interest in the replacement of synthetic food antioxidants by natural ones has fostered research on vegetable sources and screening of raw materials to identify new antioxidants. The food-processing industry generates substantial quantities of phenolic-rich by-products that could be valuable natural sources of antioxidants. In this study the antioxidant properties and total phenolic, flavonoid and flavonol contents of three industrial by-products, sugar beet pulp, sesame cake and potato peel, extracted with various solvents were examined. Since different antioxidant compounds have different mechanisms of action, several methods were used to assess the antioxidant efficacy of extracts. Among the six solvents tested, methanol gave the highest extract yield of potato peel and sugar beet pulp, while diethyl ether gave the highest extract yield of sesame cake. Methanol exhibited the highest extraction ability for phenolic compounds, with total phenolics amounting to 2.91, 1.79 and 0.81 mg gallic acid equivalent g(-1) dry weight in potato peel, sugar beet pulp and sesame cake extracts respectively, and also showed the strongest antioxidant capacity in the three assays used. All three methods proved that potato peel extract had the highest antioxidant activity owing to its high content of phenolic compounds and flavonoids. On the basis of the results obtained, potato peel, sugar beet pulp and sesame cake extracts could serve as natural antioxidants owing to their significant antioxidant activity. Therefore they could be used as preservative ingredients in the food and/or pharmaceutical industries.


Substance P/Neurokinin 1 and Trigeminal System: A Possible Link to the Pathogenesis in Sudden Perinatal Deaths.
Sudden demise of a healthy fetus or a neonate is a very tragic episode in the life of parents. These deaths have been a mystery since ages but still remain unexplained. This review proposes the involvement of trigeminal nerve, neurotransmitter substance P (SP), and its receptor neurokinin 1 (NK-1R) in regulation of cardiorespiratory control in fetuses and newborns. Anomalies and immaturity of neuroregulatory systems such as trigeminal system in medulla oblongata of brainstem may provide a possible mechanism of sudden perinatal deaths. Vulnerable infants are born with respiratory center immaturity which in combination with any stressor such as cold, hypoxia, and smoking may lead to cessation of breathing and ventilatory response. SP/NK-1R may be involved in regulating the ventilatory control in neonates while it is decreased in fetal and adult life in humans, and any alterations from these may lead to irreversible sleep apnea and fatal breathing, ultimately sudden death. This review summarizes the studies performed to highlight the expression of SP or NK-1R in sudden perinatal deaths and proposes the involvement of trigeminal ganglion along with its nerve and SP/NK-1R expression alteration as one of the possible pathophysiological underlying mechanism. However, further studies are required to explore the role of SP, NK-1R, and trigeminal system in the pathogenesis of sudden infant deaths, sudden intrauterine deaths, stillbirths, and sudden deaths later in human life.


Anaerobic metabolism of the agro-pesticide nitroxinil by bovine ruminal fluid.
Metabolism of three different agro-pesticides widely used in Uruguay, the insecticides imidacloprid and thiamethoxam and the antiparasite nitroxinil, by bovine ruminal fluid, as supply of anaerobic microorganims, was studied. Complete ruminal fluid was incubated with each of the agrochemicals in different conditions, varying time, nutrients, and nitroethane supplementation as methanogenesis modificator. Only biotransformation was detected for nitroxinil in some of the studied variables. In the optimized condition only one product was generated and the chemical structure of this main metabolite was elucidated using combined spectroscopies evidencing a structural motive unrelated with the products of the corresponding mammal biotransformation results of reduction, and substitution processes. The ruminal generation of the metabolite was confirmed. In order to employ this anaerobic microbial system as potential bioremediator of agrochemical-contaminated soils, the toxicity, against mammal cells, and the mutagenicity, using Ames test, of the product of biotransformation were studied. The lack of toxic effects encouraged us to propose the ruminal system as a plausible system for agrochemicals bioremediation.


Transient neonatal hyperparathyroidism associated with maternal hypoparathyroidism.
The newborn infant of a mother with hypoparathyroidism following thyroidectomy showed transient hypercalcemia and hypermagnesemia. Hypophosphatemia, as found in adult hyperparathyroidism, was not noted in this case, or in three of five other reported cases of neonatal hyperparathyroidism secondary to maternal hypoparathyroidism.


A model-based approach to characterize the population pharmacokinetics and the relationship between the pharmacokinetic and safety profiles of RBP-7000, a new, long-acting, sustained-released formulation of risperidone.
RBP-7000 is a sustained-release (once-monthly injection for subcutaneous administration) formulation of risperidone using the ATRIGEL® Delivery System, developed for treatment of schizophrenia to address compliance issues associated with oral administration. The objective of this analysis was to report the results of a population pharmacokinetic analysis and to describe the relationship between risperidone and 9-hydroxyrisperidone levels with dopamine (DA) D2-receptor occupancy, prolactin levels, and adverse events using data collected in 45 clinically stable schizophrenic patients receiving RBP-7000 in single ascending doses (risperidone) of 60, 90, and 120 mg. The population PK model accounted for an initial peak, a delayed and slow delivery, the disposition of risperidone, and the conversion of risperidone to 9-hydroxyrisperidone. BMI was a covariate affecting absorption of risperidone and ultimately formation of 9-hydroxyrisperidone. A logistic analysis indicated a correlation between the increase in Active Moiety (risperidone + 9-OH-risperidone) exposure (Cmax ) and the probability of observing GI disorders. An Emax population PK/prolactin model best described the relationship between the circulating Active Moiety and the serum prolactin levels. Gender was a significant covariate associated with Emax . These data provided a comprehensive characterization of the relationship between circulating Active Moiety and the efficacy/safety profile of RBP-7000 in clinically stable schizophrenic patients.


Seasonal variations in cellular expression of neuropeptide Y (NPY) in testis of the catfish, Clarias batrachus and its potential role in regulation of steroidogenesis.
The present study demonstrates seasonal variation in the cellular expression of neuropeptide Y (NPY), a known orexigenic neuropeptide, in the testis of the catfish, Clarias batrachus and its relation with testicular steroids. In vitro effects of NPY on androgen production and activities of steroidogenic enzymes were also analyzed to reaffirm the relation between NPY and steroids. NPY-immunoprecipitation was observed in Sertoli cells, interstitial cells and germ cells in recrudescing testis. Intensity of NPY-immunoreaction in the interstitial cells increased steadily with initiation of spermatogenesis and reached maximal in fully grown testes, and then decreased suddenly in the spermiating/spent testis. NPY was also expressed considerably in Sertoli cells in recrudescing testis, but disappeared in the fully grown testis. A moderate NPY-immunoreactivity was also seen in spermatogonial cells in recrudescing testis, but intense NPY-immunoprecipitation was detected in advanced germ cells (spermatids/spermatozoa) in fully mature testis. NPY-immunoreation intensity in interstitial cells showed positive correlation with increasing levels of testicular testosterone and 11-ketotestosterone, and with activities of 3β-HSD & 17β-HSD coinciding with advancing testicular activities. NPY treatment of testicular fragments in vitro stimulated the activities of 3β-HSD & 17β-HSD and increased testosterone & 11-ketotestosterone levels. This study for the first time demonstrates the existence of NPY peptide at cellular levels in fish testis, which stimulates androgen production by acting directly at testicular level.


An observational study on patients treated or not for acute HIV infection.
A vast majority of HIV-infected subjects who experience HIV acute seroconversion actually receive treatment. Open questions are how can we identify patients who will be slow progressors or long-term non progressors, and, as a consequence, do not require treatment. An observational retrospective study on patients who experienced acute HIV seroconversion from August 1995 to June 2001, who are still alive and followed as outpatients at the Clinic of Infectious Diseases of Modena, Italy. Twelve patients were studied. Five patients (45.4%) were treated during acute seroconversion, while 7 were not treated. Two of these seven subjects received antiretroviral treatment 12 and 26 weeks after acute seroconversion. All the untreated patients were in good viro-immunological condition 6 months after seroconversion, and 2 of them also after 3 and 7 years. Patients who were treated showed a significant daily increase in CD4/CD8 T cell ratio with longer time spent on therapy (0.04% increase per day longer on antiretroviral therapy, p=0.02). This study suggests that treatment during primary HIV infection should not be considered in all patients. Randomized clinical trials enrolling patients with an asymptomatic primary HIV infection, with a high CD4 count and low HIV plasma viremia are needed to evaluate the indications for treatment in this subgroup of patients. On the other hand, this study confirms the good viro-immunological response obtained after treating patients during primary HIV infection.


Protocol for a systematic review of the associations between inflammatory markers and lung function, muscle force and exercise capacity in people with COPD.
The prevalence of chronic obstructive pulmonary disease (COPD) has been on the rise, with acute exacerbation of COPD associated with the highest burden and multiple pulmonary and systemic consequences. People with COPD have been found to have an abnormal response of systemic inflammation. To date, although limited, there are studies that suggest negative associations between inflammatory markers and important clinical outcomes such as exercise capacity and muscle force. This protocol aims to systematically review the evidence for (i) the associations between inflammatory markers and lung function, muscle force and exercise capacity and (ii) the influence of other factors (eg, hospitalisation, exercise programme) on the level of inflammatory markers in people with COPD. Scopus, PubMed, Cochrane, Web of Science and ProQuest will be searched from database inception to February 2023 using PEO search strategy (Population: adults with COPD; Exposure: inflammatory markers; Outcomes: lung function, muscle force and exercise capacity). Four reviewers working in pairs will independently screen articles for eligibility and extract data that fulfilled the inclusion criteria. Depending on the design of the included studies, either Cochrane risk-of-bias version 2 or the Newcastle-Ottawa Scale tools will be used to rate the methodological quality of the included studies. Effect sizes reported in each individual study will be standardised to Cohen's d and a random effects model will be used to calculate the pooled effect size for the association. Ethical approval is unnecessary as this study will only use publicly available data. The findings will be disseminated through publication in peer-reviewed journals and conferences. CRD42022284446.


Reciprocal Relationship between Internet Addiction and Network-Related Maladaptive Cognition among Chinese College Freshmen: A Longitudinal Cross-Lagged Analysis.
This study explored the reciprocal relationship between Internet addiction (IA) and network-related maladaptive cognition (NMC) in Chinese college freshmen. A short-term longitudinal survey with a sample of 213 college freshmen was conducted in Shandong province, China. The results revealed that IA can significantly predict the generation and development of NMCs, and that when such maladaptive cognitions have been established, they can further adversely affect the extent of the students' IA. A vicious cycle was observed between these two variables, with IA having predictive priority in its relationship with NMC. This study also determined that the relationship between these two variables was the same for both males and females; therefore, the final model we established can be extensively applied to Chinese college freshmen, regardless of gender. Understanding the reciprocal relationship between these two variables can assist in interventions in IA at the outset of students' college life.


Laboratory capacity building for the International Health Regulations (IHR[2005]) in resource-poor countries: the experience of the African Field Epidemiology Network (AFENET).
Laboratory is one of the core capacities that countries must develop for the implementation of the International Health Regulations (IHR[2005]) since laboratory services play a major role in all the key processes of detection, assessment, response, notification, and monitoring of events. While developed countries easily adapt their well-organized routine laboratory services, resource-limited countries need considerable capacity building as many gaps still exist. In this paper, we discuss some of the efforts made by the African Field Epidemiology Network (AFENET) in supporting laboratory capacity development in the Africa region. The efforts range from promoting graduate level training programs to building advanced technical, managerial and leadership skills to in-service short course training for peripheral laboratory staff. A number of specific projects focus on external quality assurance, basic laboratory information systems, strengthening laboratory management towards accreditation, equipment calibration, harmonization of training materials, networking and provision of pre-packaged laboratory kits to support outbreak investigation. Available evidence indicates a positive effect of these efforts on laboratory capacity in the region. However, many opportunities exist, especially to support the roll-out of these projects as well as attending to some additional critical areas such as biosafety and biosecuity. We conclude that AFENET's approach of strengthening national and sub-national systems provide a model that could be adopted in resource-limited settings such as sub-Saharan Africa.


[Cephalic duodenopancreatectomy with pylorus preservation. An experience of 52 surgically-treated cases].
From february, 1985, to december, 1990, we carried out 52 pylorus preserving duodenopancreatecomies (41 times for cancerous lesions, 11 times for chronic pancreatitits). Our current observations suggest that PPDP is better than the conventional Whipple's procedure as far as nutrition and digestion are concerned, this being confirmed by digestive and endocrine functional tests. The procedure also has the advantage of being confined to the supramesocolic level, thus being less traumatising and more rapidly carried out. Postoperative nutrition and digestion are less disturbed, owing to the conservation of the gastroduodenal functional entity. The endocrine potential of the pancreas seems also to benefit from this procedure.


Airway Anesthesia for Awake Tracheal Intubation: A Review of the Literature.
Airway topicalization is frequently utilized by anesthesiologists to facilitate open airway procedures, aid intubation for a difficult airway, and prevent adverse respiratory events. This review article summarizes the techniques available for airway topicalization for a patient who is deemed to be difficult to intubate. We focus on the indications for use, local anesthetic maximum dosages and safety profiles, sedation techniques, and trials and pitfalls during airway topicalization for difficult intubation.


Lack of human relevance for rat developmental toxicity of flumioxazin is revealed by comparative heme synthesis assay using embryonic erythroid cells derived from human and rat pluripotent stem cells.
Fetal rat anemia from flumioxazin, an N-phenylimide herbicide, is caused by suppression of heme synthesis resulting from inhibition of protoporphyrinogen oxidase (PPO). A series of studies to investigate the effects of flumioxazin have revealed that developmental toxicity is caused in rats but not in rabbits, and the adverse effects are not likely to occur in humans. In this study, as a final weight-of-evidence approach for assessing the human safety of flumioxazin, we compared the toxic potential of inhibition of heme synthesis leading to anemia between human and rat embryonic erythroid cells, which were degenerated as the target of flumioxazin in the rat developmental toxicity. To obtain embryonic erythroid cells, we established respective differentiation methods for embryonic erythroid cells from both human and rat pluripotent stem cells. Derived human and rat embryonic erythroid cells were treated with flumioxazin or dihydroartemisinin (DHA), an anti-malarial drug that causes reduction of embryonic erythroid cells and leads to anemia without species differences. In the human embryonic erythroid cells, DHA inhibited cell proliferation and heme synthesis, whereas there were no effects on heme content or cell proliferation with flumioxazin. In the rat embryonic erythroid cells, however, a dose-related reduction in heme synthesis occurred with treatment of flumioxazin and of DHA. These results confirmed that flumioxazin has no effect on heme synthesis in human embryonic erythroid cells. The present data were in accordance with the results of previous studies and demonstrated that there are no concerns in humans regarding the developmental toxicity of flumioxazin observed in rats.


Religious Belief at the Level of the Brain: Neural Correlates and Influence of Culture.
This article summarizes key functional magnetic resonance imaging studies that correlate the neural substrate of religious belief and the influence of culture. I searched and updated PubMed (http://www.ncbi.nlm.nih.gov/pubmed) publications until March 2018 on religious belief and related topics. Belief, whether religious or nonreligious, is associated with greater signal in the ventromedial prefrontal cortex (vMPFC), a brain region important for self-representation, emotional associations, reward, and goal-driven behavior. However, religious belief, compared with nonreligious belief, registers greater signal in the precuneus, anterior insula, ventral striatum, anterior cingulate cortex, and posterior medial cortex-areas associated with governance of emotion, self-representation, and cognitive conflict. In contrast, nonreligious belief registers more signal in the left hemisphere memory networks (Harris et al. PLoS One 2009;4:e0007272). Moreover, cultural studies revealed self-judgment tasks in nonbelievers involved more the vMPFC, whereas Christians had significantly increased activation in the dorsomedial prefrontal cortex (Han et al. Soc Neurosci 2008;3:1-15). Consequently, the Christian belief of "surrendering to Christ" seemed to weaken neural coding of stimulus self-relatedness but enhanced neural activity underlying evaluative processes of self-referential stimuli. The findings suggest a transformation of the semantic autobiographical self to Christ's conceptual self.


State variations in nursing home social worker qualifications.
This is the first published account of state administrative code variations in nursing home social worker qualifications. It is important to review state codes because the majority of nursing homes in the U.S. have fewer than 121 beds and therefore are not required by the federal government to employ at least one full-time qualified social worker. States have the option of extending the federal regulations to homes with 120 or fewer beds, or strengthening the federal requirements in other ways. Findings indicate enormous variation in state requirements for qualifications of nursing home social workers, and even when states define a qualified nursing home social worker (not all do), they often exempt facilities from employing one. Seven states were found to be out of federal compliance. Research describing the qualifications of people employed in nursing home social services is called for, as well as research documenting effective psychosocial interventions, especially as they relate to resident quality of life. Ten recommendations for enhancing nursing home social work services are included.


Association of Neonatal Hyperbilirubinemia with UGT1A1 Gene Polymorphisms: A Meta-Analysis.
The results of studies on association between the polymorphisms in the coding region and the promoter of uridine diphosphateglucuronosyl transferase 1A1 (UGT1A1) and neonatal hyperbilirubinemia are controversial. This study aimed to determine whether the UGT1A1 gene polymorphisms of Gly71Arg and TATA promoter were significant risk factors associated with neonatal hyperbilirubinemia. The PubMed, Cochrane Library, and Embase databases were searched for papers that describe the association between UGT1A1 polymorphisms and neonatal hyperbilirubinemia. Summary odds ratios and 95% confidence intervals (CI) were estimated based on a fixed-effects model or random-effects model, depending on the absence or presence of significant heterogeneity. A total of 32 eligible studies and 6520 participants were identified. Among them, 24 studies focused on the association of neonatal hyperbilirubinemia with UGT1A1 Gly71Arg polymorphisms, and a significant difference was found for the comparison of AA vs. AG+GG (OR=3.47, 95% CI=2.29-5.28, P<0.0001). We included 19 studies on the association of neonatal hyperbilirubinemia with UGT1A1 TATA promoter polymorphism, which also found a statistically significant difference between 7/7 and 6/7 + 6/6 (OR=2.24, 95% CI=1.29-3.92, P=0.004). This meta-analysis demonstrated that UGT1A1 polymorphisms (Gly71Arg and TATA promoter) significantly increase the risk of neonatal hyperbilirubinemia.


Cell cycle regulation by oncogenic tyrosine kinases in myeloid neoplasias: from molecular redox mechanisms to health implications.
Neoplastic expansion of myeloid cells is associated with specific genetic changes that lead to chronic activation of signaling pathways, as well as altered metabolism. It has become increasingly evident that transformation relies on the interdependency of both events. Among the various genetic changes, the oncogenic BCR-ABL tyrosine kinase in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) has been a focus of extensive research. Transformation by this oncogene is associated with elevated levels of intracellular reactive oxygen species (ROS). ROS have been implicated in processes that promote viability, cell growth, and regulation of other biological functions such as migration of cells or gene expression. Currently, the BCR-ABL inhibitor imatinib mesylate (Gleevec) is being used as a first-line therapy for the treatment of CML. However, BCR-ABL transformation is associated with genomic instability, and disease progression or resistance to imatinib can occur. Imatinib resistance is not known to cause or significantly alter signaling requirements in transformed cells. Elevated ROS are crucial for transformation, making them an ideal additional target for therapeutic intervention. The underlying mechanisms leading to elevated oxidative stress are reviewed, and signaling mechanisms that may serve as novel targeted approaches to overcome ROS-dependent cell growth are discussed.


Mechanical circulatory support: new advances, new pumps, new ideas.
Mechanical circulatory support (MCS) is a viable therapy for severe end-stage heart disease. Most obstacles to long-term MCS therapy have been overcome, and a number of clinical trials, including the recent REMATCH trial, have shown a clear benefit in terms of survival and improved quality of life. MCS should therefore no longer be considered as simply a temporary bridge to other therapies, but also a destination therapy whose potential should continue to expand through the development and use of newer, more innovative devices such as continuous flow pumps, next-generation centrifugal pumps, and total artificial hearts. The homebound heart failure patient and the patient facing imminent death from massive myocardial infarction receive little statistical benefit from current therapies, and the new and evolving MCS technologies offer the potential for effective therapy to these desperately ill patients.


[Withdrawal syndrome caused by selective serotonin reuptake inhibitors: apropos of a case].
During the past 4 years, several case reports have been published on the withdrawal syndrome which may be observed after acute interruption of a treatment with selective serotonin reuptake inhibiting antidepressants (SSRI). Paroxetine is the most frequently cited antidepressant in the literature, whereas fluoxetine is the less frequently cited of this type of drugs. The withdrawal symptoms appear a few days after stopping treatment or after a decrease of the dose. The typical symptoms are of the gastro-intestinal type, such as loss of appetite, nausea, vomiting, diarrhea and abdominal cramps. Other symptoms are sensation of instability, vertigo, dizziness, headache, malaise, muscular pains, asthenia, as well as a syndrome of pseudo-influenza. Brief electric shocks throughout the body, which last one or two seconds, have also been reported. A case is reported in detail by the authors, who observed some of these symptoms in a patient after stopping his treatment with paroxetine. This withdrawal syndrome may be due to a rebound phenomenon of the serotonergic systems after interruption of the treatment with SSRIs. It is, therefore, recommended that treatment with SSRIs is progressively stopped over a period of several weeks.


Conservation of Epstein-Barr virus cytotoxic T-cell epitopes in posttransplant lymphomas: implications for immune therapy.
Posttransplant lymphoproliferative disease can be treated by the infusion of Epstein-Barr virus-specific cytotoxic T lymphocytes, which were raised against lymphocytes immortalized with a laboratory strain of Epstein-Barr virus (B95.8). Whether the immunodominant epitopes in B95.8 are shared in virus from tumors will affect the general applicability of this therapy. We have characterized the viral strain and the sequence of commonly recognized cytotoxic T-lymphocyte epitopes in 25 posttransplant lymphoproliferative disease specimens from 19 patients. Type A virus was present in 24 of 25 specimens. No variation in two LMP2A epitopes and a few variations mostly outside the targeted epitopes or silent in three EBNA3C epitopes were found, with one variation (Arg to Lys) detected in an EBNA3C epitope in 12 of 24 tumors. However, cytotoxic T lymphocytes to B95-8-derived EBNA3C peptides specifically lysed both B95-8 and the Lys-variant peptide-loaded target cells, although with less efficiency. These results suggest that adoptive immunotherapy using cytotoxic T lymphocytes expanded with B95.8 stimulators or vaccine strategies using B95.8-derived sequence will generally target Epstein-Barr virus strains present in posttransplant lymphoproliferative disease tumors.


Characterization of high level ampicillin- and aminoglycoside-resistant enterococci isolated from non-hospital sources.
High level ampicillin- and aminoglycoside-resistant enterococci are being increasingly reported from non-hospital sources. This study was carried out to characterize these strains from non-hospital sources in Nigeria. A collection of Enterococcus faecium isolated from vegetables, soil, farm animals and manure and observed to be resistant to ampicillin (n=63) and gentamicin (n=37) discs, were screened for resistance to high levels of ampicillin and aminoglycoside using E-test strips. Putative high level ampicillin- and aminoglycoside-resistant strains were screened for pbp5 and aminoglycoside modifying enzyme genes, respectively, by PCR. The C-terminal region of the amplified pbp5 gene was also sequenced. Five (5/63) and thirty-five (35/37) of the ampicillin- and aminoglycoside-resistant strains were identified as high level ampicillin- and aminoglycoside-resistant E. faecium strains, respectively, based on the MIC results. The amplified pbp5 gene from the high level ampicillin-resistant isolates displayed 96-99 % nucleotide sequence similarity with the reference strains and three novel insertions (500Glu→Leu, 502Asp→Arg and 614Ile→Phe) in the amino acid sequence. Aminoglycoside modifying enzyme genes aac(6')-Ie-aph(2″) (100 %), aph(2')-Ic (88.8 %), aph(3')-IIIa (90 %) and ant(4')-Ia (40 %) were detected among the high level aminoglycoside-resistant isolates. This is the first report on the characterization of high level ampicillin- and aminoglycoside-resistant Enterococcus faecium among animals and vegetables in Nigeria. The results show that non-hospital sources can constitute a reservoir for potential dissemination of these strains and genes to humans via the food chain or by direct contact.


Malignant astrocytoma containing bone.
A case of a malignant cerebral astrocytoma containing bone in a 56-year old woman is reported. In spite of total removal and radiotherapy the tumour recurred and the patient died 18 months postoperatively. The histological features and immunohistochemical findings are presented. The literature is reviewed and probable mechanisms by which these mesodermal derivatives develop in neuroepithelial neoplasms are discussed.


CPEB4 promotes cell migration and invasion via upregulating Vimentin expression in breast cancer.
Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a member of CPEB family which is overexpressed in variety of cancers. However, the biological role and regulatory mechanism of CPEB4 in cancers remain unknown. Here, we first investigate the role of CPEB4 in breast cancer progression and metastasis. The expression of CPEB4 is elevated in breast cancer tissues compared with adjacent normal tissues. Furthermore, high expression levels of CPEB4 is associated with tumor metastasis in breast cancer patients. Ectopic expression of CPEB4 dramatically promotes EMT, migration and invasion of breast cancer cells, while silencing CPEB4 expression significantly reduces these events. Mechanically, overexpression of CPEB4 upregulates Vimentin expression and silencing Vimentin expression blocks CPEB4-induced migration and invasion of breast cancer cells. These results implicate the potential role of CPEB4 and Vimentin in breast cancer metastasis, which is further confirmed by the finding that there is a physical interaction between the two proteins. Altogether, our results provide a novel insight into CPEB4 in regulating breast cancer progression and metastasis.


A comparison of the Neuropen against standard quantitative sensory-threshold measures for assessing peripheral nerve function.
To investigate the efficacy of the Neuropen, a new clinical device that assesses both pain and pressure perception, to evaluate peripheral nerve function in diabetic patients compared with standard clinical testing methods. Peripheral nerve function was assessed in 124 diabetic patients attending a multidisciplinary diabetes clinic, using (i) the modified Neuropathy Disability Score (NDS), derived from assessment of vibration, pinprick (pain), temperature sensation plus ankle reflexes, and (ii) vibration perception threshold (VPT) measured at the hallux. Patients were stratified into various neuropathic groups according to their NDS score. In addition, nerve function was assessed using the Neuropen, a device combining a 10-g monofilament and a weighted Neurotip. Inability to feel sensation on either or both feet for each test of the Neuropen (i.e. the monofilament or the Neurotip) was defined as an abnormal response. The sensitivity of the Neuropen to detect neuropathy compared with the NDS (score > or = 6/10) was high using either an abnormal monofilament response (87.8%), an abnormal Neurotip response (91.8%) or a combination of the two (82.0%). Neuropen specificity improved, however, when the combination of abnormal monofilament and abnormal Neurotip responses was used (68%), rather than the individual tests (57% and 41%, respectively). The Neuropen is a sensitive device for assessing nerve function and may provide an inexpensive alternative screening method to identify patients with moderate to severe neuropathy.


The Amazonian kambô frog Phyllomedusa bicolor (Amphibia: Phyllomedusidae): Current knowledge on biology, phylogeography, toxinology, ethnopharmacology and medical aspects.
Phyllomedusa bicolor (Phyllomedusidae), popularly known as the kambô in Brazil, is a tree frog that is widely distributed in South American countries and is known for producing a skin secretion that is rich in bioactive peptides, which are often used in indigenous rituals. The biological effects of the skin secretion were observed in the first studies with indigenous communities. Over the last six decades, researchers have been studying the chemical composition in detail, as well as the potential pharmacological applications of its constituents. For this reason, indigenous communities and health agents fear the misuse of the kambô, or the inappropriate use of the species, which can result in health complications or even death of users. This article seeks to provide a transdisciplinary review that integrates knowledge regarding the biology of P. bicolor, ethnoknowledge about the ritual of the kambô, and the chemistry and pharmacology of the skin secretion of this species, in addition to medical aspects of the indiscriminate use of the kambô. Furthermore, this review seeks to shed light on perspectives on the future of research related to the kambô.


Moderate-intensity aerobic exercise training as an adjunct to trauma-focused psychotherapy in traumatized refugees and asylum seekers: study protocol of a randomized controlled trial.
Background: Refugees with exposure to multiple traumatic events are at high risk for developing posttraumatic stress disorder (PTSD) and depression. Narrative exposure therapy (NET) is an effective treatment for the core symptoms of PTSD, but it does not reliably reduce depressive symptoms. Endurance exercise on the other hand was consistently found to be effective in treating depression making it a promising adjunct to NET. Up to date, no studies exist investigating the combination of NET and endurance exercise in a sample of refugees with PTSD and comorbid depression.Objectives: In the proposed randomized controlled trial, we aim to investigate whether a combination of NET and moderate-intensity aerobic exercise training (MAET) enhances treatment outcome for refugees with PTSD and comorbid depressive symptoms. We expect a greater improvement in psychopathology in participants who receive the combined treatment.Methods and analysis: 68 refugees and asylum seekers with PTSD and clinically relevant depressive symptoms will be recruited in the proposed study. Participants will be randomly assigned to receive either NET only (NET-group) or NET plus MAET (NET+-group). All participants will receive 10 NET sessions. Participants in the NET+-group will additionally take part in MAET. Primary (PTSD, depression) and secondary (general mental distress, agoraphobia and somatoform complaints, sleep quality) outcome measures will be assessed before treatment, after treatment, and at six-month follow-up. The hypotheses will be tested with multiple 2 × 3 mixed ANOVA's.Trial registration: German Clinical Trials Register identifier: DRKS00022145.


Emergence and Transmission of Drug-/Multidrug-resistant Mycobacterium leprae in a Former Leprosy Colony in the Brazilian Amazon.
Leprosy has been treated with multidrug therapy, which has been distributed for free across the globe and regarded as highly efficient. However, the impossibility of growing Mycobacterium leprae in axenic media has historically impaired assessments of M. leprae resistance, a parameter only recently detectable through molecular methods. A systematic, population-based search for M. leprae resistance in suspected leprosy relapse cases and contacts was performed in Prata Village, an isolated, hyperendemic, former leprosy colony located in the Brazilian Amazon. Results led to an extended active search involving the entire Prata population. Confirmed leprosy cases were investigated for bacterial resistance using a combination of in vivo testing and direct sequencing of resistance genes folP1, rpoB, and gyrA. A molecular epidemiology analysis was performed using data from 17 variable number tandem repeats (VNTR). Mycobacterium leprae was obtained from biopsies of 37 leprosy cases (18 relapses and 19 new cases): 16 (43.24%) displayed drug-resistance variants. Multidrug resistance to rifampicin and dapsone was observed in 8 relapses and 4 new cases. Single resistance to rifampicin was detected in 1 new case. Resistance to dapsone was present in 2 relapses and 1 new case. Combined molecular resistance and VNTR data revealed evidence of intra-familial primary transmission of resistant M. leprae. A comprehensive, population-based systematic approach to investigate M. leprae resistance in a unique population revealed an alarming scenario of the emergence and transmission of resistant strains. These findings may be used for the development of new strategies for surveillance of drug resistance in other populations.


Validation of the ureteral diameter ratio for predicting early spontaneous resolution of primary vesicoureteral reflux.
Management of primary vesicoureteral reflux (VUR) remains controversial, and reflux grade currently constitutes an important prognostic factor. Previous reports have demonstrated that distal ureteral diameter ratio (UDR) may be more predictive of outcome than vesicoureteral reflux (VUR) grade. We performed an external validation study in young children, evaluating early spontaneous resolution rates relative to reflux grade and UDR. Voiding cystourethrograms (VCUGs) were reviewed. UDR was computed by measuring largest ureteral diameter within the pelvis and dividing by the distance between the L1 and L3 vertebral bodies (Figure). VUR grade and UDR were tested in univariate and multivariable analyses. Primary outcome was status of VUR at last clinical follow-up (i.e. resolution, persistence, or surgical intervention). Demographics, VUR timing, laterality, and imaging indication were also assessed. One-hundred and forty-seven children (98 girls, 49 boys) were diagnosed with primary VUR at a mean age of 5.5 ± 4.7 months. Sixty-seven (45.6%) resolved spontaneously, 55 (37.4%) had persistent disease, and 25 (17%) were surgically corrected. Patients who spontaneously resolved had significantly lower VUR grade, refluxed later during bladder filling, and had significantly lower UDR. In a multivariable model, grade of VUR (p = 0.001), age <12 months (p = 0.008), ureteral diameter (p = 0.02), and UDR (p < 0.0001) achieved statistical significance. For every 0.1 unit increase in UDR, there was a 2.6 (95% CI 1.58-4.44) increased odds of persistent VUR, whereas a 1.6 (95% CI 0.9-3.0) increased odds was observed for every unit increase in grade. Both grade of reflux and UDR were statistically significant in a multivariable model; however, UDR had a higher likelihood ratio and was more predictive of early spontaneous resolution than grade alone. Furthermore, unlike traditional VUR grading where children with grade 1-5 may outgrow reflux depending on other factors, there appears to be a consistent UDR cutoff whereby patients are unlikely to resolve. In the present study, no child with a UDR greater than 0.43 experienced early spontaneous resolution, and only three (4.5%) of those with spontaneous resolution had a UDR above 0.35. UDR correlates with reflux grade, and is predictive of early resolution in children with primary VUR. UDR is an objective measurement of VUR, and provides valuable prognostic information about spontaneous resolution, facilitating more individualized patient care.


Comparison of Load-Sharing Responses Between Graded Posterior Cervical Foraminotomy and Conventional Fusion Using Finite Element Modeling.
Following the diagnosis of unilateral cervical radiculopathy and need for surgical intervention, anterior cervical diskectomy and fusion (conventional fusion) and posterior cervical foraminotomy are common options. Although patient outcomes may be similar between the two procedures, their biomechanical effects have not been fully compared using a head-to-head approach, particularly, in relation to the amount of facet resection and internal load-sharing between spinal segments and components. The objective of this investigation was to compare load-sharing between conventional fusion and graded foraminotomy facet resections under physiological loading. A validated finite element model of the cervical spinal column was used in the study. The intact spine was modified to simulate the two procedures at the C5-C6 spinal segment. Flexion, extension, and lateral bending loads were applied to the intact, graded foraminotomy, and conventional fusion spines. Load-sharing was determined using range of motion data at the C5-C6 and immediate adjacent segments, facet loads at the three segments, and disk pressures at the adjacent segments. Results were normalized with respect to the intact spine to compare surgical options. Conventional fusion leads to increased motion, pressure, and facet loads at adjacent segments. Foraminotomy leads to increased motion and anterior loading at the index level, and motions decrease at adjacent levels. In extension, the left facet load decreases after foraminotomy. Recognizing that foraminotomy is a motion preserving alternative to conventional fusion, this study highlights various intrinsic biomechanical factors and potential instability issues with more than one-half facet resection.


DNA microarray and signal transduction analysis in pulmonary artery smooth muscle cells from heritable and idiopathic pulmonary arterial hypertension subjects.
Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular smooth muscle contraction and proliferation. Here, we analyze genome-wide mRNA expression in human pulmonary arterial smooth muscle cells (HPASMC) isolated from three control, three hereditary (HPAH), and three idiopathic PAH (IPAH) subjects using the Affymetrix Human Gene ST 1.0 chip. The microarray analysis reveals the expression of 537 genes in HPAH and 1024 genes in IPAH changed compared with control HPASMC. Among those genes, 227 genes show similar directionality of expression in both HPAH and IPAH HPASMC. Ingenuity™ Pathway Analysis (IPA) suggests that many of those genes are involved in cellular growth/proliferation and cell cycle regulation and that signaling pathways such as the mitotic activators, polo-like kinases, ATM signaling are activated under PAH conditions. Furthermore, the analysis demonstrates downregulated mRNA expression of certain vasoactive receptors such as bradykinin receptor B2 (BKB2R). Using real time PCR, we verified the downregulated BKB2R expression in the PAH cells. Bradykinin-stimulated calcium influx is also decreased in PAH PASMC. IPA also identified transcriptional factors such p53 and Rb as downregulated, and FoxM1 and Myc as upregulated in both HPAH and IPAH HPASMC. The decreased level of phospho-p53 in PAH cells was confirmed with a phospho-protein array; and we experimentally show a dysregulated proliferation of both HPAH and IPAH PASMC. Together, the microarray experiments and bioinformatics analysis highlight an aberrant proliferation and cell cycle regulation in HPASMC from PAH subjects. These newly identified pathways may provide new targets for the treatment of both hereditary and idiopathic PAH.


Super-resolution imaging of live sperm reveals dynamic changes of the actin cytoskeleton during acrosomal exocytosis.
Filamentous actin (F-actin) is a key factor in exocytosis in many cell types. In mammalian sperm, acrosomal exocytosis (denoted the acrosome reaction or AR), a special type of controlled secretion, is regulated by multiple signaling pathways and the actin cytoskeleton. However, the dynamic changes of the actin cytoskeleton in live sperm are largely not understood. Here, we used the powerful properties of SiR-actin to examine actin dynamics in live mouse sperm at the onset of the AR. By using a combination of super-resolution microscopy techniques to image sperm loaded with SiR-actin or sperm from transgenic mice containing Lifeact-EGFP, six regions containing F-actin within the sperm head were revealed. The proportion of sperm possessing these structures changed upon capacitation. By performing live-cell imaging experiments, we report that dynamic changes of F-actin during the AR occur in specific regions of the sperm head. While certain F-actin regions undergo depolymerization prior to the initiation of the AR, others remain unaltered or are lost after exocytosis occurs. Our work emphasizes the utility of live-cell nanoscopy, which will undoubtedly impact the search for mechanisms that underlie basic sperm functions.This article has an associated First Person interview with the first author of the paper.


Effect of a community-based nursing intervention on mortality in chronically ill older adults: a randomized controlled trial.
Improving the health of chronically ill older adults is a major challenge facing modern health care systems. A community-based nursing intervention developed by Health Quality Partners (HQP) was one of 15 different models of care coordination tested in randomized controlled trials within the Medicare Coordinated Care Demonstration (MCCD), a national US study. Evaluation of the HQP program began in 2002. The study reported here was designed to evaluate the survival impact of the HQP program versus usual care up to five years post-enrollment. HQP enrolled 1,736 adults aged 65 and over, with one or more eligible chronic conditions (coronary artery disease, heart failure, diabetes, asthma, hypertension, or hyperlipidemia) during the first six years of the study. The intervention group (n = 873) was offered a comprehensive, integrated, and tightly managed system of care coordination, disease management, and preventive services provided by community-based nurse care managers working collaboratively with primary care providers. The control group (n = 863) received usual care. Overall, a 25% lower relative risk of death (hazard ratio [HR] 0.75 [95% CI 0.57-1.00], p = 0.047) was observed among intervention participants with 86 (9.9%) deaths in the intervention group and 111 (12.9%) deaths in the control group during a mean follow-up of 4.2 years. When covariates for sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use were included, the adjusted HR was 0.73 (95% CI 0.55-0.98, p = 0.033). Subgroup analyses did not demonstrate statistically significant interaction effects for any subgroup. No suspected program-related adverse events were identified. The HQP model of community-based nurse care management appeared to reduce all-cause mortality in chronically ill older adults. Limitations of the study are that few low-income and non-white individuals were enrolled and implementation was in a single geographic region of the US. Additional research to confirm these findings and determine the model's scalability and generalizability is warranted. ClinicalTrials.gov NCT01071967. Please see later in the article for the Editors' Summary.


Cerebral Neuroschistosomiasis Presenting as a Brain Mass.
Neuroschistosomiasis is a rare manifestation of schistosomal infections presenting with cerebral and spinal cord involvement. We reported a case of a 31-year-old woman who presented with a history of headache, dizziness, and nausea. Brain MRI with contrast showed features suggestive of brain lesion with edema, and a serology test for Schistosoma was positive. She was diagnosed with neuroschistosomiasis and treated with intravenous steroids followed by praziquantel resulting in a significant regression of the brain mass. Cerebral neuroschistosomiasis is a rare complication of Schistosoma infection, and clinicians should consider it among the differential diagnosis of unexplained brain lesions.


The use of a rigid disc to protect exposed structures in wounds treated with negative pressure wound therapy: effects on wound bed pressure and microvascular blood flow.
There are increasing reports of deaths and serious complications associated with the use of negative pressure wound therapy (NPWT). Bleeding may occur in patients when NPWT is applied to a wound with exposed blood vessels or vascular grafts, possibly due to mechanical deformation and hypoperfusion of the vessel walls. Recent evidence suggests that using a rigid barrier disc to protect underlying tissue can prevent this mechanical deformation. The aim of this study was to examine the effect of rigid discs on the tissue exposed to negative pressure with regard to tissue pressure and microvascular blood flow. Peripheral wounds were created on the backs of eight pigs. The pressure and microvascular blood flow in the wound bed were measured when NPWT was applied. The wound was filled with foam, and rigid discs of different designs were inserted between the wound bed and the foam. The discs were created with or without channels (to accommodate exposed sensitive structures such as blood vessels and nerves), perforations, or a porous dressing that covered the underside of the discs (to facilitate pressure transduction and fluid evacuation). When comparing the results for pressure transduction to the wound bed, no significant differences were found using different discs covered with dressing, whereas pressure transduction was lower with bare discs. Microvascular blood flow in the wound bed decreased by 49 ± 7% when NPWT was applied to control wounds. The reduction in blood flow was less in the presence of a protective disc (e.g., -6 ± 5% for a dressing-covered, perforated disc, p = 0.006). In conclusion, NPWT causes hypoperfusion of superficial tissue in the wound bed. The insertion of a rigid barrier counteracts this effect. The placement of a rigid disc over exposed blood vessels or nerves may protect these structures from rupture and damage.


Acute clozapine suppresses synchronized pyramidal synaptic network activity by increasing inhibition in the ferret prefrontal cortex.
Recent studies have indicated that impaired neural circuitry in the prefrontal cortex is a prominent feature of the neuropathology of schizophrenia. Clozapine is one of the most effective antipsychotic drugs used for this debilitating disease. Despite its effectiveness, the mechanism by which clozapine acts on prefrontal cortical circuitry remains poorly understood. In this study, in vitro multiple whole cell recordings were performed in slices of the ferret prefrontal cortex. Clozapine, which effectively inhibited the spontaneous synchronized network activities in the prefrontal neurons, achieved the suppressive effect by decreasing the recurrent excitation among pyramidal neurons and by enhancing the inhibitory inputs onto pyramidal cells through a likely network mechanism. Indeed, under the condition of disinhibition, the depressing effects were reversed and clozapine enhanced the recurrent excitation. These results suggest that the therapeutic actions of clozapine in alleviating the positive symptoms of schizophrenia are achieved, at least partially, through the readjustment of synaptic balance between the excitation and inhibition in the prefrontal cortical circuitry.


Impact of Point-Spread Function Modeling on PET Image Quality in Integrated PET/MR Hybrid Imaging.
The aim of this study was to systematically assess the quantitative and qualitative impact of including point-spread function (PSF) modeling into the process of iterative PET image reconstruction in integrated PET/MR imaging. All measurements were performed on an integrated whole-body PET/MR system. Three substudies were performed: an (18)F-filled Jaszczak phantom was measured, and the impact of including PSF modeling in ordinary Poisson ordered-subset expectation maximization reconstruction on quantitative accuracy and image noise was evaluated for a range of radial phantom positions, iteration numbers, and postreconstruction smoothing settings; 5 representative datasets from a patient population (total n = 20, all oncologic (18)F-FDG PET/MR) were selected, and the impact of PSF on lesion activity concentration and image noise for various iteration numbers and postsmoothing settings was evaluated; and for all 20 patients, the influence of PSF modeling was investigated on visual image quality and number of detected lesions, both assessed by clinical experts. Additionally, the influence on objective metrics such as changes in SUVmean, SUVpeak, SUVmax, and lesion volume was assessed using the manufacturer-recommended reconstruction settings. In the phantom study, PSF modeling significantly improved activity recovery and reduced the image noise at all radial positions. This effect was measurable only at a high number of iterations (>10 iterations, 21 subsets). In the patient study, again, PSF increased the detected activity in the patient's lesions at concurrently reduced image noise. Contrary to the phantom results, the effect was notable already at a lower number of iterations (>1 iteration, 21 subsets). Lastly, for all 20 patients, when PSF and no-PSF reconstructions were compared, an identical number of congruent lesions was found. The overall image quality of the PSF reconstructions was rated better when compared with no-PSF data. The SUVs of the detected lesions with PSF were substantially increased in the range of 6%-75%, 5%-131%, and 5%-148% for SUVmean, SUVpeak, and SUVmax, respectively. A regression analysis showed that the relative increase in SUVmean/peak/max decreases with increasing lesion size, whereas it increases with the distance from the center of the PET field of view. In whole-body PET/MR hybrid imaging, PSF-based PET reconstructions can improve activity recovery and image noise, especially at lateral positions of the PET field of view. This has been demonstrated quantitatively in phantom experiments as well as in patient imaging, for which additionally an improvement of image quality could be observed.


[Activity of fosfomycin against extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae].
Infection due to extended-spectrum beta-lactamase (ESBL)-producing microorganisms is an emerging problem in the community; a high proportion of these microorganisms have been isolated from urine samples of women with uncomplicated urinary tract infections (UTI). The options for oral treatment of uncomplicated UTI are limited because of the multiple drug resistance typical of ESBL-producing strains. The in vitro activity of fosfomycin (FOS) was determined against 428 ESBL-producing strains, including 290 (68%) E. coli and 138 (32%) K. pneumoniae. Activity of fosfomycin was compared with that of amoxicillin-clavulanate (AMC), ciprofloxacin (CIP) and cotrimoxazole (SxT). MICs of AMC, CIP, and SxT, and detection of ESBL production were tested by the broth microdilution method, whereas FOS MICs were determined by the agar dilution method. ESBLs were characterized by isoelectric focusing, polymerase chain reaction (PCR) and direct sequencing of encoding genes. The genetic relationship among the isolates was determined by REP-PCR. Among the 428 ESBL-producing isolates studied, 417 (97.4%) were susceptible to FOS (MIC < or = 64 microg/mL). The resistance rate of E. coli to FOS was 0.3%, and was lower than resistance to AMC (11.7%), whereas the resistance rate of K. pneumoniae was 7.2% and was equal to resistance to AMC. SxT and CIP were the least active antibiotic agents against ESBL-producing isolates (sensitivity < 50%). There were no differences in fosfomycin activity against strains expressing different types of ESBLs. Fosfomycin showed maintained activity against ESBL-producing strains and did not present co-resistance with other antimicrobial groups.


Spigelian hernia: diagnosis by high-resolution real-time sonography.
The purpose of this study was to demonstrate the role of high-resolution real-time sonography in the diagnosis of spigelian hernias. The sonographic findings in three patients, two of whom had surgical confirmation, are presented. We also discuss and demonstrate the anatomic and pathologic factors that predispose to these hernias. In all three cases, real-time high-resolution sonography was very helpful in providing detailed images of the abdominal wall defect, the hernial sac and contents, and the relationship of the contents to the spigelian fascia and the rectus, external oblique, and internal oblique muscles. The role of the Valsalva and other provocative maneuvers in demonstrating the "in and out" sliding movement of the contents of the hernia also is discussed. Although the number of cases in our study is small, we think that this modality may be the most effective means for establishing this diagnosis, especially in cases with equivocal clinical findings.


Surface transport mechanisms in molecular glasses probed by the exposure of nano-particles.
For a glass-forming liquid, the mechanism by which its surface contour evolves can change from bulk viscous flow at high temperatures to surface diffusion at low temperatures. We show that this mechanistic change can be conveniently detected by the exposure of nano-particles native in the material. Despite its high chemical purity, the often-studied molecular glass indomethacin contains low-concentration particles approximately 100 nm in size and 0.3% in volume fraction. Similar particles are present in polystyrene, another often-used model. In the surface-diffusion regime, particles are gradually exposed in regions vacated by host molecules, for example, the peak of a surface grating and the depletion zone near a surface crystal. In the viscous-flow regime, particle exposure is not observed. The surface contour around an exposed particle widens over time in a self-similar manner as 3 (Bt)1/4, where B is a surface mobility constant and the same constant obtained by surface grating decay. This work suggests that in a binary system composed of slow- and fast-diffusing molecules, slow-diffusing molecules can be stranded in surface regions vacated by fast-diffusing molecules, effectively leading to phase separation.