Changes in CCR5 and CXCR4 expression and beta-chemokine production in HIV-1-infected patients treated with highly active antiretroviral therapy.
The effect of highly active antiretroviral therapy (HAART) on the expression of CCR5 and CXCR4 HIV coreceptors and the production of the beta-chemokines regulated upon activation, normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, and MIP-1beta has been investigated in 30 HIV-1-infected individuals during 12-36 months of therapy. CCR5 expression was increased in both CD4 + and CD8 + subsets, whereas CXCR4 expression was upregulated only in CD4 + cells. CCR5 levels normalized during 36 months of therapy and positively correlated with the levels of memory, CD95 +, and HLA-DR + T cells. In contrast, the frequency of CXCR4-expressing cells was not significantly modified by HAART, although a downregulation was observed early after starting treatment. CXCR4 levels were significantly associated with the frequencies of naive T cells and negatively correlated with plasma viral load, CD95, and HLA-DR expression. An increased production of both spontaneous and lectin-induced RANTES, MIP-1alpha, and MIP-1beta was found at baseline in HIV-infected individuals. The spontaneous beta-chemokines production was not modified by 12 months of HAART, although a significant reduction was seen during the first months of therapy. A transient decrease of lectin-stimulated RANTES production was also observed, whereas the reduction of lectin-induced MIP-1alpha persisted for up to 12 months of therapy. In contrast, MIP-1beta secreted by phytohemagglutinin antigen-stimulated peripheral blood mononuclear cells progressively increased during HAART. In conclusion, our data indicate a normalization of CCR5 but not CXCR4 expression during suppressive therapy and changes in beta-chemokine production that may play a part in dictating the efficiency of viral infection and consequently the disease course.


Seasonal dietary shifting in yellow-rumped warblers is unrelated to macronutrient targets.
Dietary shifting, for example from insects to fruits, is a common mechanism used in migratory songbirds to accumulate fat to fuel migratory flights. We examined a potential underlying cause of dietary shifting in yellow-rumped warblers (Setophaga coronata) by comparing energy and protein intake goals of birds during fall migration and winter. We offered captive warblers pairs of three diets differing in macronutrient composition in both the fall and winter. Using the principles of the geometric framework of nutrition we evaluated protein and energy intake to determine if consumption of the diet pairs was adjusted to meet an energy or protein intake target, and if the target differed seasonally. Regardless of season, the warblers preferred the diet with the lowest protein content and highest carbohydrate content. Total energy intake was maintained relatively constant during migration, at around 60 kJ/day, regardless of diet combination, and at about 50 kJ/day during winter. This suggests that warblers consume macronutrients available to them without protein limitations to reach their total energy intake target. When the diet combination offered allows, the warblers mixed their diet intake to consume roughly 0.5 g/day of protein, regardless of season, which suggested a constant protein target. Our findings suggest that songbirds prefer to alter non-protein energy intake proportionally to meet changing energy demand, rather than an overall increase in macronutrient intake. Additionally, they have the ability to shift their diet based on availability, resulting in high flexibility in their macronutrient intakes to maintain energy intake.


Sex differences in pain-related behaviors and clinical progression of disease in mouse models of colonic pain.
Previous studies have reported sex differences in patients with irritable bowel syndrome and inflammatory bowel disease, including differences in visceral pain perception. Despite this, sex differences in behavioral manifestations of visceral pain and underlying pathology of the gastrointestinal tract have been largely understudied in preclinical research. In this study, we evaluated potential sex differences in spontaneous nociceptive responses, referred abdominal hypersensitivity, disease progression, and bowel pathology in mouse models of acute and persistent colon inflammation. Our experiments show that females exhibit more nociceptive responses and referred abdominal hypersensitivity than males in the context of acute but not persistent colon inflammation. We further demonstrate that, after acute and persistent colon inflammation, pain-related behavioral responses in females and males are distinct, with increases in licking of the abdomen only observed in females and increases in abdominal contractions only seen in males. During persistent colon inflammation, males exhibit worse disease progression than females, which is manifested as worse physical appearance and higher weight loss. However, no measurable sex differences were observed in persistent inflammation-induced bowel pathology, stool consistency, or fecal blood. Overall, our findings demonstrate sex differences in pain-related behaviors and disease progression in the context of acute and persistent colon inflammation, highlighting the importance of considering sex as a biological variable in future mechanistic studies of visceral pain as well as in the development of diagnostics and therapeutic options for chronic gastrointestinal diseases.


Serotonergic transcriptional networks and potential importance to mental health.
Transcription regulatory networks governing the genesis, maturation and maintenance of vertebrate brain serotonin (5-HT) neurons determine the level of serotonergic gene expression and signaling throughout an animal's lifespan. Recent studies suggest that alterations in these networks can cause behavioral and physiological pathogenesis in mice. Here, we synthesize findings from vertebrate loss-of-function and gain-of-function studies to build a new model of the transcriptional regulatory networks that specify 5-HT neurons during fetal life, integrate them into CNS circuitry in early postnatal life and maintain them in adulthood. We then describe findings from animal and human genetic studies that support possible alterations in the activity of serotonergic regulatory networks in the etiology of mental illness. We conclude with a discussion of the potential utility of our model, as an experimentally well-defined molecular pathway, to predict and interpret the biological effect of genetic variation that may be discovered in the orthologous human network.


Data on Arc and Zif268 expression in the brain of the α-2A adrenergic receptor knockout mouse.
The α2-adrenergic receptor (α2-AR) is widely distributed in the brain with distinct roles for α2-AR subtypes (A, B and C). In this article, data are provided on Activity Regulated Cytoskeleton Associated Protein (Arc) and Zif268 expression in the brain of the α2A-AR knockout (α2A-AR KO) mouse. These data are supplemental to an original research article examining Arc and Zif268 expression in rats injected with the α2-AR antagonist, RX821002 (http://dx.doi.org/10.1016/j.neulet.2015.12.002. [1]).


Idiopathic and recurrent thromboembolic phenomena in cancer patients.
Venous thromboembolism (VTE) is one of the most common complications in cancer patients. It is not only associated with both reduced survival and a high number of recurrences, but an idiopathic VTE also increases the likelihood of a cancer diagnosis. Between January 2000 and October 2005 we reviewed the medical history of 88 patients who were admitted to a tertiary hospital and presented both a diagnosis of VTE and any type of tumour. The information collected included the type of tumour, the temporal association between tumour diagnosis and VTE, anticoagulation treatment applied and percentage of recurrences. Ten patients (11.4%) presented the VTE prior to the cancer diagnosis; only half of them underwent a posterior tumour screening routine. Fifteen patients (17%) were diagnosed simultaneously and 71% presented the VTE after the tumour was detected. In 47 patients (53.4%) no risk factors for VTEs were detected. Twenty-nine patients (31.7%) presented a recurrent VTE, mainly during chemotherapy treatment (66%). Less than half of the patients (47.57%) were receiving treatment with low-molecular- weight heparins (LMWH). Idiopathic VTEs may be the first manifestation of an occult neoplasia, but tumour screening is scheduled in only a few patients. Regarding the high incidence of recurrent VTE in cancer populations, a high percentage is attributed to the underuse of LMWH, whose efficacy in preventing recurrent phenomena is superior to oral dicumarinics.


Self-concepts of parents with a child of school age with a severe intellectual disability.
The self-concepts of Hong Kong Chinese parents with a child of school age with severe intellectual disability were explored. A 20-item Adult Sources of Self-Esteem Inventory (ASSEI) and open-ended questions on self-evaluation and interviewing were adopted as the major procedures to identify the source and basis of their self-conceptions. One hundred and nine parents--35 males and 74 females, aged 31 to 45--participated in this study. The results indicated that the participants showed similar life priorities as the control group (parents of non-handicapped children). However, the participants showed significantly lower concept of self than the control group in most areas of life. An exploratory factor-analytic result showed that the parents' concept of self had a one-dimensional structure, which might indicate the parents' lack variety in their life. An analysis of the contents of the open-ended responses showed that family and work were the most important domains of the concept of self. However, most of the respondents stated that poor family relationships, the health problems of their child, and work and financial problems made them 'feel bad'.


Mid- to Long-Term Outcomes of Hip Arthroscopy: A Systematic Review.
To assess mid- to long-term patient-reported outcomes (PROs) of hip arthroscopy as well as the rates of secondary surgery and to identify indications for surgery and noted predictors of failure. A systematic review of the current literature was performed with the terms "hip arthroscopy," "outcomes," "patient-reported outcomes," "mid-term," "5-year," "long-term," and "10-year" in the PubMed, Cochrane, and Embase databases in April of 2020 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data for study characteristics, patient demographics, follow-up time, indications for surgery, PROs, predictors of failure or unfavorable PROs, and rates of secondary hip preservation surgery and conversion to total hip arthroplasty were collected. Thirteen articles were included. Four studies were level III and 9 were level IV. In total, 1571 hips were included, and the average follow-up time ranged from 60 to 240 months. The most common indications for hip arthroscopy were labral tears and femoroacetabular impingement syndrome. Twelve studies reported on PROs and all reported improvement at latest follow-up. The most reported on scores were the modified Harris Hip Score, Harris Hip Score, and the Hip Outcome Score-Sport Specific Subscale. When grouped based on average follow-up time, the conversion rates at the 5- and 10-year time points ranged from 3.0% to 17.9% and 2.4% to 32.5%, respectively. One study with 20-year follow-up reported a conversion rate of 41.0%. Osteoarthritis and increased age were the most cited predictors for secondary surgery or decreased PROs. At mid- to long-term follow-up, patients who underwent primary hip arthroscopy demonstrated improvement in several PROs. There was great variability in rates for revision surgery and conversion to total hip arthroplasty. The most common indications for hip arthroscopy were labral tears and femoroacetabular impingement syndrome. Osteoarthritis and increased age were the most cited predictors for unfavorable outcomes. Level IV, systematic review of Level III and IV studies.


[What can be expected from the sub-trigonal injection of phenol in the treatment of idiopathic instability of the bladder?].
Sub-trigonal phenol injection ensures a satisfactory response in about 50% of patients with detrusor instability. When oral anticholinergic treatment is poorly tolerated or ineffective, this minimally invasive technique has been found, in our series of 11 patients, to be a useful adjunct, at least temporarily.


Emergency resection versus bridge to surgery with stenting in patients with acute right-sided colonic obstruction: a systematic review focusing on mortality and morbidity rates.
No consensus exists on the optimal treatment of acute malignant right-sided colonic obstruction (RSCO). This systematic review aims to compare procedure-related mortality and morbidity rates between primary resection and stent placement as a bridge to surgery followed by elective resection for patients with acute RSCO. PubMed, Embase and Cochrane library were searched for all relevant literature. Primary endpoints were procedure-related mortality and morbidity. Methodological quality of the included studies was assessed using the MINORS criteria. Fourteen cohort studies were eligible for analysis. A total of 2873 patients were included in the acute resection group and 155 patients in the stent group. Mean mortality rate for patients who underwent acute resection with primary anastomosis was 10.8% (8.1-18.5%). Overall mortality for patients initially treated with a colonic stent followed with elective resection was 0%. Major morbidity was 23.9% (9.3-35.6%) and 0.8% (0-4.8%), respectively. Both mortality and major morbidity were significantly different. In addition, stent placement shows lower rates of anastomotic leakages (0 vs 9.1%) and fewer permanent ileostomies (0 vs 1.0%). Primary resection for patients with acute RSCO seems to be associated with higher mortality and major morbidity rates than stent placement and elective resection. In addition, stent placement resulted in fewer anastomotic leakages and permanent ileostomies. However, as no high-level studies are available on the optimal treatment of RSCO and proximal stenting is considered technically challenging, future comparative studies are warranted for the development of an evidence-based clinical decision guideline.


Association between dietary fiber intake and risk of incident aortic stenosis.
Although aortic stenosis is the most common valvular heart disease requiring intervention in Europe, the role that diet plays in development of the disease is largely unknown. The pathophysiology of aortic stenosis is however similar to other cardiovascular diseases that fiber intake has been associated with. The aim of this study was consequently to investigate the association between dietary fiber intake as well as the main food sources of fiber, i.e. fruit and vegetables and whole grains, and risk of incident aortic stenosis. The Malmö Diet and Cancer Study is a Swedish prospective population-based cohort study with baseline data collection performed between year 1991-1996. Dietary habits were recorded through seven-day food diaries, 168-item diet questionnaires, and interviews, and data on incident aortic stenosis was collected through national registers. Among the 26,063 participants, 672 cases were ascertained during a mean follow-up period of 20 years. Cox regression was used to estimate the association between dietary intakes and incident aortic stenosis. No associations were found between incident aortic stenosis and intake of dietary fiber (HR for the highest vs lowest quintile: 0.93; 95% CI: 0.72-1.24), fruit and vegetables (HR: 0.98; 95% CI: 0.76-1.28), or whole grains (HR: 1.00; 95% CI: 0.79-1.26) in the main model. The findings of this study do not indicate that consumption of dietary fiber or fiber rich foods are associated with incident aortic stenosis.


[Determinants of carotid subclinical atherosclerosis in patients with rheumatoid arthritis. A case-control study].
Rheumatoid arthritis (RA) is characterized by high cardiovascular (CV) mortality, which seems related to systemic inflammation. Our aim was to quantify carotid atherosclerosis in RA and its relationship with the disease. 73 RA patients and the same number of sex and age matched controls were enrolled, without history of cardiovascular events. Carotid intima-media thickness (IMT) and plaques were measured by ultrasonography. Its relationship with risk factors (RF), rheumatic disease characteristics, and inflammatory markers were analysed. Controls showed higher body mass index (BMI) and dyslipidemia. There were no differences in other risk factors or IMT. Age (p = 0.001), sex (p = 0.02), BMI (p = 0.002), waist perimeter (p = 0.001), and hypertension (p = 0.005) had a relationship with IMT. Among disease characteristics, only time elapsed since RA diagnosis was associated with IMT. There was not an increased carotid subclinical atherosclerosis in patients with RA, beyond the effects of classical RF.


A toolkit for quantification of biological age from blood chemistry and organ function test data: BioAge.
Methods to quantify biological aging are emerging as new measurement tools for epidemiology and population science and have been proposed as surrogate measures for healthy lifespan extension in geroscience clinical trials. Publicly available software packages to compute biological aging measurements from DNA methylation data have accelerated dissemination of these measures and generated rapid gains in knowledge about how different measures perform in a range of datasets. Biological age measures derived from blood chemistry data were introduced at the same time as the DNA methylation measures and, in multiple studies, demonstrate superior performance to these measures in prediction of healthy lifespan. However, their dissemination has been slow by comparison, resulting in a significant gap in knowledge. We developed a software package to help address this knowledge gap. The BioAge R package, available for download at GitHub ( http://github.com/dayoonkwon/BioAge ), implements three published methods to quantify biological aging based on analysis of chronological age and mortality risk: Klemera-Doubal biological age, PhenoAge, and homeostatic dysregulation. The package allows users to parametrize measurement algorithms using custom sets of biomarkers, to compare the resulting measurements to published versions of the Klemera-Doubal method and PhenoAge algorithms, and to score the measurements in new datasets. We applied BioAge to safety lab data from the CALERIE™ randomized controlled trial, the first-ever human trial of long-term calorie restriction in healthy, non-obese adults, to test effects of intervention on biological aging. Results contribute evidence that CALERIE intervention slowed biological aging. BioAge is a toolkit to facilitate measurement of biological age for geroscience.


CEST 2022 - Differences in APT-weighted signal in T1 weighted isointense lesions, black holes and normal-appearing white matter in people with relapsing-remitting multiple sclerosis.
To evaluate amide proton transfer weighted (APTw) signal differences between multiple sclerosis (MS) lesions and contralateral normal-appearing white matter (cNAWM). Cellular changes during the demyelination process were also assessed by comparing APTw signal intensity in T1weighted isointense (ISO) and hypointense (black hole -BH) MS lesions in relation to cNAWM. Twenty-four people with relapsing-remitting MS (pw-RRMS) on stable therapy were recruited. MRI/APTw acquisitions were undertaken on a 3 T MRI scanner. The pre and post-processing, analysis, co-registration with structural MRI maps, and identification of regions of interest (ROIs) were all performed with Olea Sphere 3.0 software. Generalized linear model (GLM) univariate ANOVA was undertaken to test the hypotheses that differences in mean APTw were entered as dependent variables. ROIs were entered as random effect variables, which allowed all data to be included. Regions (lesions and cNAWM) and/or structure (ISO and BH) were the main factor variables. The models also included age, sex, disease duration, EDSS, and ROI volumes as covariates. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performance of these comparisons. A total of 502 MS lesions manually identified on T2-FLAIR from twenty-four pw-RRMS were subcategorized as 359 ISO and 143 BH with reference to the T1-MPRAGE cerebral cortex signal. Also, 490 ROIs of cNAWM were manually delineated to match the MS lesion positions. A two-tailed t-test showed that mean APTw values were higher in females than in males (t = 3.52, p < 0.001). Additionally, the mean APTw values of MS lesions were higher than those of cNAWM after accounting for covariates (mean lesion = 0.44, mean cNAWM = 0.13, F = 44.12, p < 0.001).The mean APTw values of ISO lesions were higher than those of cNAWM after accounting for covariates (mean ISO lesions = 0.42, mean cNAWM = 0.21, F = 12.12, p < 0.001). The mean APTw values of BH were also higher than those of cNAWM (mean BH lesions = 0.47, mean cNAWM = 0.033, F = 40.3, p < 0.001). The effect size (i.e., difference between lesion and cNAWM) for BH was found to be higher than for ISO (14 vs. 2). Diagnostic performance showed that APT was able to discriminate between all lesions and cNAWM with an accuracy of >75% (AUC = 0.79, SE = 0.014). Discrimination between ISO lesions and cNAWM was accomplished with an accuracy of >69% (AUC = 0.74, SE = 0.018), while discrimination between BH lesions and cNAWM was achieved at an accuracy of >80% (AUC = 0.87, SE = 0.021). Our results highlight the potential of APTw imaging for use as a non-invasive technique that is able to provide essential molecular information to clinicians and researchers so that the stages of inflammation and degeneration in MS lesions can be better characterized.


A sibship with neuroaxonal dystrophy and renal tubular acidosis: a new syndrome?
The clinical and pathological features of three siblings from nonconsanguineous parents are described. Two of the children died at 6 1/2 and 7 months of age of a central nervous system disorder characterized by severe behavioral retardation, hypotonia, and pyramidal tract signs. The third child, now 8 years old, has global mental retardation, inability to talk, marked tremors, and gait disturbances. All children exhibited inability to concentrate or acidify the urine, with growth delay partially corrected in the living child by alkali therapy. Computed tomographic scans revealed hyperdense lesions in the thalamus of one of the siblings and more striking hyperdensity of the basal ganglia in the eldest child. Findings at postmortem examination in two children, and by renal and sural nerve biopsy in the third, include swollen axons in the internal capsule and peripheral nerves, and neurons with iron-staining deposits, gliosis, and macrophages containing lipofuscin pigments in the brain. The renal findings include material positive for periodic acid-Schiff and hyperdense granular deposits in renal tubules.


Interfacial interactions between proteins and mammalian lipases.
The effects of proteins, both endogenous and exogenous, on the activity of lipases against water soluble and water insoluble substrates have been reviewed. The enzymes considered are pancreatic and gastric lipases, and lipoprotein, bile-salt-stimulated human milk and pancreatic carboxyl ester lipases. A brief account is given of the function of each enzyme and of the physical properties of the interacting proteins, which include albumins, lysozymes, globulins and immunoglobulins, myoglobin, transferrins, alpha-lactalbumin and melittin. With few exceptions (for example, the effect of colipase on pancreatic lipase), the interaction of proteins with lipases which act at the lipid-water interface of water insoluble substrates results in deactivation of enzymic activity. It seems that the amphiphilic nature of proteins allows them to aggregate at interfaces, thereby altering the nature of the interface and decreasing accessibility of the substrate to the enzyme. This discussion gives consideration to association of the proteins with the enzyme or the interface and to whether the interactions with specific binding sites or interfacial inactivation are responsible for the observations. However, the effect of proteins on lipases acting against water soluble substrates varies from protein to protein. Activation of enzyme-activity occurs if the interacting proteins are able to act as acyl transfer agents and thus introduce another catalytic hydrolysis pathway into the reaction mechanism. Inhibition may be caused by specific interactions between the protein and the enzyme or the substrate.


The Drosophila developmental gene snail encodes a protein with nucleic acid binding fingers.
Pattern formation in the Drosophila embryo requires the concerted expression of maternal and zygotic genes. At least nineteen genes, twelve of which are maternally expressed, are involved in the establishment of dorsal-ventral polarity. Mutations in any one of these genes result in distinct alterations of cell fates and in the formation of an abnormal dorsal-ventral pattern. Mutants of the 'dorsal group', eleven of the maternal genes, have a common recessive phenotype similar to that described for dorsal, in that cells located at ventral and lateral positions assume dorsal fates and ventral structures fail to develop. Thus the dorsal group gene products may be involved in the establishment of a gradient of positional information along the dorsal-ventral axis. We have cloned snail (sna), a zygotic gene, whose expression is essential for the correct specification of dorsal-ventral pattern. In this report, we present evidence that the complementary DNA-deduced protein product of sna contains five copies of a nucleic acid-binding finger motif previously identified in two transcription factors, and in the protein product of several putative regulatory genes.


Retrospective evaluation of prognostic score performances in cirrhotic patients admitted to an intermediate care unit.
The prognosis of cirrhotic patients in the Intensive Care Unit requires the development of predictive tools for mortality. We aimed to evaluate the ability of different prognostic scores to predict hospital mortality in these patients. A single-centre retrospective analysis was conducted of 281 hospital stays of cirrhotic patients at an Intermediate Care Unit between June 2009 and December 2010. The performance of the Simplified Acute Physiology Score (SOFA), the Simplified Acute Physiology Score (SAPS) II or III, Child-Pugh, Model for End-Stage Liver Disease (MELD), MELD-Na and the Chronic Liver Failure-Consortium Acute-on-Chronic Liver Failure score (CLIF-C ACLF) in predicting hospital mortality were compared. Mean age was 58.2±12.1 years; 77% were male. The main cause of admission was acute gastrointestinal bleeding (47%). The in-hospital mortality rate was 25.3%. Receiver operating characteristic curve analyses demonstrated that SOFA (0.82) MELD-Na (0.82) or MELD (0.81) scores at admission predicted in-hospital mortality better than Child-Pugh (0.76), SAPS II (0.77), SAPS III (0.75) or CLIF-C ACLF (0.75). We then developed the cirrhosis prognostic score (Ci-Pro), which performed better (0.89) than SOFA. SOFA, MELD and especially the Ci-Pro score show the best performance in predicting hospital mortality of cirrhotic patients admitted to an Intermediate Care Unit.


The role of wine polysaccharides on salivary protein-tannin interaction: A molecular approach.
Polysaccharides are described to inhibit aggregation between food polyphenols and salivary proteins (SP) and may hence lead to astringency modulation. In this work, the effect of two wine polysaccharides (arabinogalactan proteins-AGPs and rhamnogalacturonan II- RGII) on SP-polyphenol interaction was evaluated. In general, both polysaccharides were effective to inhibit or reduce SP-polyphenol interaction and aggregation. They can act by two different mechanisms (ternary or competitive) depending on the SP-tannin pair. In the case of salivary P-B peptide, AGPs and RGII seem to act by a ternary mechanism, in which they surround this complex, enhancing its solubility. Concerning acidic proline-rich proteins (aPRPs), it was possible to observe both mechanisms, depending on the tannin and the polysaccharide involved. Overall, this work point out for a specific property of wine polysaccharides important to modulate this and other beverages and food astringency perception.


The analysis of nickel-obsidian composite formation on mild steel surface through electrocodeposition process.
Composite, the engineering material consisting of two different macroscopic phases, can be synthesized through electro co-deposition reaction by adding particles into the solution of the electroplating process. The obsidian powder as dispersed particles and the nickel-metal as the matrix are the materials that can be synthesized using that technique. The hardness of obsidian is in the range of 650-900 HV, whereas nickel is 380 HV. We have investigated the formation mechanism of the coated composite layer made via electrocodeposition reaction. The electrocodeposition of the obsidian particle was controlled by kinetic, electrophoretic, and gravity forces that act on the particles. The resultant of these forces determines the direction of particles. The experimental result shows that increasing particle concentration from 0 to 25 g/L increased the hardness of the coated layer from 380 to 504 HV. The kinetic force can keep the particles suspended in solution at this concentration range. However, a further increase in particle concentration to 50 g/L decreases the kinetic energy of particles significantly, causing the particles to fall without depositing at the cathode and reducing the hardness down to 430 HV. Meanwhile, increasing current density increase the rapidness of the electro co-deposition reaction. At the increasing current density at a range of 3.3-10 Ampere/dm2, the hardness of the coated layer is at the range of 420-540 HV. Coated layer thickness decreases slightly as particle concentration increases but increases significantly as current density increases. The highest hardness of the coated layer, 540 HV, was obtained at a particle concentration of 25 g/L and a current density of 10 A/dm2.


Outcome of accelerated radiotherapy alone or accelerated radiotherapy followed by exenteration of the nasal cavity in dogs with intranasal neoplasia: 53 cases (1990-2002).
To compare long-term results of radiotherapy alone versus radiotherapy followed by exenteration of the nasal cavity in dogs with malignant intranasal neoplasia. Retrospective study. 53 dogs with malignant intranasal neoplasia. All dogs underwent radiotherapy consisting of administration of 10 fractions of 4.2 Gy each on consecutive weekdays. For dogs in the surgery group (n=13), follow-up computed tomography was performed, and dogs were scheduled for surgery if persistent or recurrent tumor was seen. Perioperative complications for dogs that underwent surgery included hemorrhage requiring transfusion (2 dogs) and subcutaneous emphysema (8). Rhinitis and osteomyelitis-osteonecrosis occurred significantly more frequently in dogs in the radiotherapy and surgery group (9 and 4 dogs, respectively) than in dogs in the radiotherapy-only group (4 and 3 dogs, respectively). Two- and 3-year survival rates were 44% and 24%, respectively, for dogs in the radiotherapy group and 69% and 58%, respectively, for dogs in the surgery group. Overall median survival time for dogs in the radiotherapy and surgery group (477 months) was significantly longer than time for dogs in the radiotherapy-only group (19.7 months). Results suggest that exenteration of the nasal cavity significantly prolongs survival time in dogs with intranasal neoplasia that have undergone radiotherapy. Exenteration after radiotherapy may increase the risk of chronic complications.


The impact of gender and academic achievement on the violation of academic integrity for medical faculty students, a descriptive cross-sectional survey study.
The aim of this study is to determine the characteristics of medical faculty students about violations of academic integrity. From the whole population of the 572 students of the Muğla Sıtkı Koçman University Faculty of Medicine, 271 students participated voluntarily in a descriptive cross-sectional survey. Descriptive data were recorded in the survey and a five-point Likert-type instrument, namely the Tendency towards Academic Dishonesty Scale, was used as the data collection tool in the study. The scale included 22 items' means that are considered to evaluate "Tendency towards academic dishonesty" (TTAD) score. In addition, four subscales, namely "Tendency towards cheating", "Dishonesty in works such as assignments and projects", "Tendency towards dishonesty in research and reporting processes" and "Tendency towards citation dishonesty" scores were evaluated separately. Of the participants, 138 (53.3%) were male. TTAD scores were 2.15 ± 0.61, showing a slight tendency towards academic dishonesty, according to the scale. TTAD scores and standard deviations (SD) were 2.26 ± 0.65 and 2.04 ± 0.55 for men and women, respectively (P = 0.005). There was no difference in the TTAD scores for students whether they had read the ethics code. Significant differences were observed in the TTAD scores for students with gender, different academic achievements and in different academic years. However, when multivariate analysis was performed, the significance shown in the results disappeared. In our study, a slight tendency to academic dishonesty was found for medical faculty students and there were no differences between all of the recorded individual factors of students.


Stereotactic body radiotherapy for small hepatocellular carcinoma: a retrospective outcome analysis in 185 patients.
Since 2005, we have treated hepatocellular carcinoma (HCC) with stereotactic body radiotherapy (SBRT) uniformly at two dose levels, according to baseline liver function and normal liver dose. We retrospectively examined the outcomes for these patients. Between 2005 and 2012, 221 HCC patients were treated with SBRT. Eligibility criteria for SBRT included a single (either solitary or recurrent) HCC lesion; unfeasible, difficult or refusal to undergo other surgery or percutaneous ablative therapies; Child-Pugh Classification (CPC) A or B; tumors ≤ 5 cm; dose to the bowels < 25 Gy/5 fractions; curative intent. Patients followed up ≥ 6 months were eligible. The prescribed dose depended on liver function and liver dose: 40 Gy for CPC-A and 35 Gy for CPC-B, in 5 fractions, requiring a 5-Gy dose reduction if the proportion of the liver receiving ≥ 20 Gy exceeded 20%. Treatment outcomes and safety were analyzed. A total of 185 patients (n = 48 in the 35-Gy group; n = 137 in the 40-Gy group) were eligible, with a median follow-up duration of 24 months (range 3-80). The three-year local control and overall survival rates were 91% and 70%, respectively. There were no significant differences in outcomes between dose levels: the three-year local control and overall survival rates in the 35-Gy and 40-Gy groups were 91% and 89% (log-rank p = 0.99) and 66% and 72% (p = 0.54), respectively. Acute toxicities ≥ grade 3 were observed in 24 (13.0%) patients, and 19 (10.3%) patients had worsening of CPC score by two points. All but three (1.6%) patients promptly recovered to grade 1-2. Grade 5 liver failure occurred in two patients in the 35-Gy group. SBRT for HCC was safe and provided equivalent outcomes when administered either in 35 or 40 Gy/5 fractions.


Role of pentoxifylline and sparfloxacin in prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients.
This study was directed to evaluate the role of sparfloxacin and pentoxifylline in the prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients. Forty cirrhotic patients with ascites were included in the study. Patients were randomized into four groups in a blind fashion; each group consists of ten patients. Group one received ciprofloxacin (control group), group two received sparfloxacin, group three received pentoxifylline, and group four received a combination of sparfloxacin and pentoxifylline. Treatment duration was six months. Serum TNF- α level was the primary inflammatory marker of the study to evaluate the effect of the used medications. In group two, TNF- α level showed a statistically significant decrease in comparison with group one (P = 0.001), while in group three, TNF- α level showed nonsignificant difference in comparison with the control group (P > 0.05). In addition, group four showed a statistically significant decrease in TNF- α level compared to the other three groups (P < 0.05). The finding from our study indicates that sparfloxacin as well as pentoxifylline could be used in prophylaxis of spontaneous bacterial peritonitis. Combination of sparfloxacin and pentoxifylline showed some of synergism which may be useful in decreasing emergence of resistant strains.


Diffuse low grade glioma and pregnancy: Practical considerations and clinical tips.
The interaction between pregnancy and diffuse low-grade glioma (DLGG) is poorly investigated. The goal of this study was to provide further insights into the relationship between pregnancy and DLGG. A total of 12 patients were selected from a shared database of DLGGs, according to the following inclusion criteria: DLGG diagnosis in post-partum, DLGG recurrence after pregnancy in patients previously operated for DLGG. The extent of surgical resection (EOR) at first surgery were evaluated. All cases were assessed based on the 2016 WHO classification. The tumor growing patter, expresses by preoperative ΔT2T1 MRI index was evaluated. In four cases newly diagnosed DLGG were detected patients in post-partum. Seven women, previously operated for DLGG, experienced pregnancy during the natural history of glioma, and were affected by tumor recurrence after pregnancy. One singular had an incidental LGG not surgically treated, who presented an important tumor growth after pregnancy. Radiological and surgical data were discussed according to literature. Pregnancy does not seem to have an impact on the survival of women with DLGG. The potential role of pregnancy as risk factor in tumor recurrence is described, however, not proven. In this regard, the association between pregnancy and Tumor recurrence is extremely doubtful, and currently attributable to the simple coincidence. Further multicenter molecular investigations are required to better understand the mechanisms by which the pregnancy, in patients with a pervious surgery for DLGG, may influence tumor regrowth in comparison with the natural history of the disease.


Scopolamine effects on functional brain connectivity: a pharmacological model of Alzheimer's disease.
Scopolamine administration may be considered as a psychopharmacological model of Alzheimer's disease (AD). Here, we studied a group of healthy elderly under scopolamine to test whether it elicits similar changes in brain connectivity as those observed in AD, thereby verifying a possible model of AD impairment. We did it by testing healthy elderly subjects in two experimental conditions: glycopyrrolate (placebo) and scopolamine administration. We then analyzed magnetoencephalographic (MEG) data corresponding to both conditions in resting-state with eyes closed. This analysis was performed in source space by combining a nonlinear frequency band-specific measure of functional connectivity (phase locking value, PLV) with network analysis methods. Under scopolamine, functional connectivity between several brain areas was significantly reduced as compared to placebo, in most frequency bands analyzed. Besides, regarding the two complex network indices studied (clustering and shortest path length), clustering significantly decreased in the alpha band while shortest path length significantly increased also in alpha band both after scopolamine administration. Overall our findings indicate that both PLV and graph analysis are suitable tools to measure brain connectivity changes induced by scopolamine, which causes alterations in brain connectivity apparently similar to those reported in AD.


Compensatory but not anticipatory adjustments are altered in older adults during lateral postural perturbations.
This study investigated anticipatory postural adjustments (APAs) and compensatory postural adjustments (CPAs) and their relationship in older adults during lateral postural perturbations. Unpredictable and predictable postural disturbances were induced by a swinging pendulum that impacted at the shoulder level of two groups of older adults, non-fallers (20) and fallers (20), and in a group of young control subjects (20). The electromyographic (EMG) activity of the postural muscles and the center of pressure (COP) displacement were recorded and quantified within the time intervals typical for APAs and CPAs. Both groups of older adults (non-fallers and fallers) showed higher magnitude of EMG activity in the lateral muscles and increased COP displacement, particularly, during the CPAs time interval when compared to the young group. Older adults, however, were able to change the electrical activity of the muscles during the predictable task by generating APAs with similar magnitudes of those found in young subjects. Compensatory but not anticipatory adjustments are altered in older adults during predictable lateral postural perturbations. These findings provide new data on the role of APAs and CPAs in their relationship in older adults during external lateral perturbations and may advance current rehabilitative management strategies to improve balance control in older individuals.


The neural structures involved in cross-modal recognition and tactile discrimination performance: an investigation using 2-DG.
Given the failure of the ablation method to identify the neural structures/systems that are crucial for cross-modal recognition (CMR) and for tactile discrimination performance (TDP), we injected radioactive 2-deoxy-[14C]glucose (2-DG) into monkeys trained to a high level of CMR or TDP. Nine monkeys were trained to recognize in one sense-modality, to a level greater than 80% correct, the objects experienced in the alternate modality on only a single prior trial. After injection, CMR was continued (Expt. 1a) exactly as before, except that all CMR problems were now in only one direction; or (Expt. 1b) the second--the CMR--trial of each problem was not realized (i.e. no objects were available in the second modality) so that the monkey merely 'expected' the cross-modal trial. Nine other monkeys were trained on a graded roughness discrimination task with conventional 'titration' procedures to a stable level of performance, either (Expt. 2a) without having undergone any cortical removal, or (Expt. 2b) after unilateral removal--contralateral or ipsilateral to the preferred hand--of the posterior insula or of the second somatosensory projection cortex (SII). Exactly the same training procedures were continued in Expt. 2 after injection of 2-DG. Coronal radiographs were made at 490 microns for all 18 monkeys (and also for a 19th, which served as a control in Expt. 1b). The optical densities of the autoradiographs were measured quantitatively in respect of 50 structures or part-structures (e.g. sulci, thalamic nuclei, subcortical structures); they were rated either with the aid of 'pseudo-colours' produced by the computer, or directly by judging the black/white optical densities, in respect of 29 other structures. These 79 structures were then the dependent variables in MANOVAs or ANOVAs, to determine differences between groups; or within groups with respect to the left/right and ipsilateral/contralateral hemispheres; or interaction effects. It was found that certain structures (e.g. the ventral portion of the claustrum, the insula with its extension ventrally into the fundus, nucleus Medialis dorsalis and nucleus Pulvinar oralis) repeatedly, whereas others (e.g. the amygdala) never gave rise to significant outcomes. Structures in the left cerebral hemisphere were frequently found to be more strongly labelled than those in the right hemisphere.(ABSTRACT TRUNCATED AT 400 WORDS)


Mutation of the nm23 gene, loss of heterozygosity at the nm23 locus and K-ras mutation in ovarian carcinoma: correlation with tumour progression and nm23 gene expression.
Alteration of expression levels of the nm23 genes has previously been correlated with metastatic status of ovarian epithelial carcinoma. To elucidate the relevance of the qualitative changes of the nm23 genes to progression of ovarian carcinoma and/or to nm23 expression levels of the tumour, 41 samples of epithelial ovarian tumours [three benign, three low malignant potential (LMP), and 35 frankly malignant tumours] were studied for mutation of the nm23-H1 and the nm23-H2 genes using single-strand conformational polymorphism (SSCP) analysis. In addition, loss of heterozygosity (LOH) at the nm23 locus on chromosome 17q was studied by CA repeat polymorphism analysis. Mutation of the K-ras gene was also analysed in the same specimens. A novel mutation of the nm23 gene was found in one case of stage III serous carcinoma without lymph model metastases. Sequencing of the subcloned mutant cDNA revealed a missense mutation from TGG to CGG at codon 133 of the nm23-H2 gene, resulting in a change from Trp to Arg. LOH at the nm23 locus was detected in 5 of 23 (21.7%) informative cases of ovarian carcinoma. Mutation of the K-ras gene was detected in 2 of 35 (5.7%) carcinomas at codons 12 and 13 respectively. There was no correlation between clinical stage or metastatic status of ovarian carcinoma and nm23 mutation, LOH at the nm23 locus or K-ras mutation. The expression levels of both the nm23-H1 and the nm23-H2 genes were lower in the tumour with nm23-H2 mutation and higher in those with K-ras mutation. This suggests that mutation of the nm23 genes and the K-ras gene affects carcinogenesis or progression of ovarian carcinoma by modulating expression of the nm23 genes.


Hypogalactosylation of serum N-glycans fails to predict clinical response to methotrexate and TNF inhibition in rheumatoid arthritis.
Rheumatoid arthritis (RA) is associated with hypogalactosylation of immunoglobulin G (IgG). We examined whether a proxy measure for galactosylation of IgG N-glycans could predict response to therapy or was differentially affected by methotrexate (MTX) or TNF blockade. Using a previously defined normal phase high-performance liquid chromatography approach, we ascertained the galactosylation status of whole serum N-glycans in two well-defined RA clinical cohorts: the Autoimmune Biomarkers Collaborative Network (n = 98) and Nested I (n = 64). The ratio of agalactosylated to monogalactosylated N-glycans in serum (sG0/G1) was determined before and during therapy with MTX or TNF inhibition and correlated with anticitrullinated peptide antibody (ACPA) status and clinical response as assessed by 28-joint Disease Activity Score utilizing C-reactive peptide and European League Against Rheumatism response criteria. RA patients from both cohorts exhibited elevation of sG0/G1 at baseline. Improvement in clinical scores correlated with a reduction in sG0/G1 (Spearman's ρ = 0.31 to 0.37; P < 0.05 for each cohort). However, pretreatment sG0/G1 was not predictive of clinical response. Changes in sG0/G1 were similar in the MTX and TNF inhibitor groups. Corrected for disease activity, ACPA positivity correlated with higher sG0/G1. Baseline serum N-glycan hypogalactosylation, an index previously correlated with hypogalactosylation of IgG N-glycans, did not distinguish patients with rheumatoid arthritis who were likely to experience a favorable clinical response to MTX or TNF blockade. Clinical improvement was associated with partial glycan normalization. ACPA-positive patients demonstrated enhanced N-glycan aberrancy compared with ACPA-negative patients.


Exploring ionic liquids based on pyrrolidinium and imidazolium cations with low toxicity towards Escherichia coli for designing sustainable bioprocesses.
Ionic liquids (ILs) are widely applied in many bioprocesses involving microorganisms due to their unique properties. In this work, the toxicity of imidazolium and pyrrolidinium ionic liquids towards E. coli., a bacterium for which there are limited toxicity data in the literature, was determined. For its simplicity, the nephelometry method was used to estimate ionic liquid toxicity values. The influence of the cation and the alkyl chain length of the cation and anion was analysed. Pyrrolidinium cations were seen to be less toxic than imidazolium cations, while an increase in the alkyl chain length of both pyrrolidinium and imidazolium cations increased the toxicity. Among the anions studied, dimethylphosphate ([Me2PO4]) was the less toxic, while the EC50 for the ionic liquid 1-butyl-3-methylpyrrolidinium dimethylphosphate ([C1C4Pyr][Me2PO4]) was close to 200 mM. Furthermore, a dicationic ionic liquid based on imidazolium and pyrrolidinium cations was synthetized and its toxicity toward E. coli was analysed, maintaining a growth rate of 100 % in the range 0-0.76 mM. The methodology used in this work allows to easily find the less toxic ionic liquids that are biocompatible with E. coli to be used in new bioprocesses.


Prophylactic perioperative antibiotic use in endoscopic sinus surgery: a systematic review and meta-analysis.
Perioperative antibiotics are widely used to improve the outcomes of endoscopic sinus surgery. The aim of this study was to summarize the evidence on the effect of perioperative antibiotic prophylaxis on outcomes of endoscopic sinus surgery. We searched electronic databases from inception through May 2011 for any relevant clinical trials or observational studies. Two reviewers working independently extracted study characteristics, quality, and the outcomes of interest. Random-effects meta-analysis was used to pool the relative risks (RRs) and the standardized mean differences (SMDs) across trials. We found 4 eligible trials with varying quality, of which 3 were included in the quantitative analysis. Antibiotic prophylaxis was associated with a nonsignificant reduction in the incidence of infections (relative risk, 0.76; 95% confidence interval [CI], 0.64 to 1.09), symptoms scores (SMD, -0.04; 95% CI, -0.46 to 0.38), and endoscopic scores (SMD, -0.09; 95% CI, 0.30 to 0.13). The heterogeneity associated with the analysis was significant only for the outcome of change in symptoms score (I-squared values, 0%, 70%, and 0% for the 3 outcomes, respectively). Trial data available to date are unable to demonstrate a statistically significant reduction in infection, symptom scores, or endoscopic scores to support the routine use of postoperative prophylactic antibiotics following endoscopic sinus surgery. Our analysis was limited by the number of published trials related to this topic.


Deconstructing iNKT cell development at single-cell resolution.
Invariant natural killer T (iNKT) cells are increasingly regarded as disease biomarkers and immunotherapeutic targets. However, a greater understanding of their biology is necessary to effectively target these cells in the clinic. The discovery of iNKT1/2/17 cell effector subsets was a milestone in our understanding of iNKT cell development and function. Recent transcriptomic studies have uncovered an even greater heterogeneity and challenge our understanding of iNKT cell ontogeny and effector differentiation. We propose a refined model whereby iNKT cells differentiate through a dynamic and continuous instructive process that requires the accumulation and integration of various signals within the thymus or peripheral tissues. Within this framework, we question the existence of true iNKT2 cells and discuss the parallels between mouse and human iNKT cells.


Structures of Antafumicins A and B, Novel Antifungal Substances Produced by the Fungus Aspergillus niger NH-401.
Novel antifungal substances, antafumicins A and B, were isolated from a culture of Aspergillus niger NH-401 and determined to be trans- and cis-4-(3-acetyl-2,6-dihydroxyphenyl)-2-methoxy-4- butanolide, respectively, by spectroscopic and single crystal X-ray analyses.


A miniature fiber optic surface plasmon resonance sensor for fast detection of Staphylococcal enterotoxin B.
A fiber optic surface plasmon resonance (SPR) biosensor for detection of Staphylococcal enterotoxin B (SEB) is reported. The sensor is based on spectral interrogation of surface plasmons in a miniature sensing element based on a side-polished single-mode optical fiber with a thin metal overlayer. For specific detection of SEB, the SPR sensor is functionalized with a covalently crosslinked double-layer of antibodies against SEB. The SPR biosensor is demonstrated to be able to detect ng/ml concentrations of SEB in less than 10 min.


Cyclooxygenase-2 expression is associated with increased size in human sporadic colorectal adenomas.
Cyclooxygenase-2 (COX-2) has been implicated in colorectal carcinogenesis but its role is not completely defined. The expression of COX-2 was evaluated in 68 paraffin-embedded sporadic colorectal adenomas by immunohistochemistry. Associations between COX-2 expression and the clinicopathological characteristics of the adenomas were studied by contingency tables and the Chi-square test. Cytoplasmic staining for COX-2 protein was present in epithelial cells of 62 out of the 68 adenomas. COX-2 expression was not associated with age or gender. Furthermore, no significant correlations were found between the expression of the protein and histology (tubular vs tubulovillous), localization (proximal vs distal) or morphology (sessil vs pedunculated) of the adenomas. Both stromal and epithelial COX-2 expressions were higher in larger (>4 mm) compared with smaller (< or =4 mm) adenomas (p =0. 037 and p=0. 024). These data support the hypothesis that the expression of COX-2 may occur as a general phenomenon in colorectal adenomas. A size-dependent increase of COX-2 expression might be involved in colorectal carcinogenesis.


Fragmentation of GW4064 led to a highly potent partial farnesoid X receptor agonist with improved drug-like properties.
The ligand activated transcription factor farnesoid X receptor (FXR) is a crucial regulator of several metabolic and inflammatory pathways and its activation by agonistic ligands seems a valuable therapeutic approach for many disorders. Most known non-steroidal FXR agonists however, have limitations that hinder their clinical development and novel FXR ligands are required. Evaluation of the co-crystal structures of the widely used FXR agonist GW4064 and related compounds in complex with the FXR ligand binding domain indicated that their disubstituted isoxazole moiety is especially relevant for FXR activation. By investigation of GW4064-fragments missing the aromatic tail, we discovered a highly potent and soluble partial FXR agonist (14, ST-1892) as well as a fluorescent FXR ligand (15) as potential pharmacological tool.


A decade of riboswitches.
Riboswitches were discovered in 2002 in bacteria as RNA-based intracellular sensors of vitamin derivatives. During the last decade, naturally occurring RNA sensor elements have been found to bind a range of small metabolites and ions and to exert regulatory control of transcription, translation, splicing, and RNA stability. Extensive biochemical, structural, and genetic studies have established the basic principles underpinning riboswitch function in all three kingdoms of life with implications for developing antibiotics, designing new molecular sensors, and integrating riboswitches into synthetic circuits.


Implication of the TRPM4 nonselective cation channel in mammalian sinus rhythm.
The transient receptor potential melastatin 4 (TRPM4) channel is expressed in the sinoatrial node, but its physiologic roles in this tissue with cardiac pacemaker properties remain unknown. This Ca(2+)-activated nonselective cation channel (NSCCa) induces cell depolarization at negative potentials. It is implicated in burst generation in neurons and participates in induction of ectopic beating in cardiac ventricular preparations submitted to hypoxia/reoxygenation. Accordingly, TRPM4 may participate in action potential (AP) triggering in the sinoatrial node. The purpose of this study was to investigate the influence of TRPM4 on spontaneous heart beating. Spontaneous APs were recorded using intracellular microelectrodes in mouse, rat, and rabbit isolated right atria. In the spontaneously beating mouse atrium, superfusion of the TRPM4-specific inhibitor 9-phenanthrol produced a concentration-dependent reduction in AP rate (maximal reduction = 62% that of control; EC50 = 8 × 10(-6) mol●L(-1)) without affecting other AP parameters. These effects were absent in TRPM4(-/-) mice. 9-Phenanthrol exerted a rate-dependent reduction with a higher effect at low rates. Similar results were obtained in rat. Moreover, application of 9-phenanthrol produced a reduction in diastolic depolarization slope in rabbit sinus node pacemaker cells. These data showed that TRPM4 modulates beating rate. Pacemaker activity in the sinoatrial node results from the slow diastolic depolarization slope due to the "funny" current, Na/Ca exchange, and a Ca(2+)-activated nonselective cation current, which can be attributable in part to TRPM4 that may act against bradycardia.


In silico prediction of ARB resistance: A first step in creating personalized ARB therapy.
Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are among the most prescribed drugs. However, ARB effectiveness varies widely, which may be due to non-synonymous single nucleotide polymorphisms (nsSNPs) within the AT1R gene. The AT1R coding sequence contains over 100 nsSNPs; therefore, this study embarked on determining which nsSNPs may abrogate the binding of selective ARBs. The crystal structure of olmesartan-bound human AT1R (PDB:4ZUD) served as a template to create an inactive apo-AT1R via molecular dynamics simulation (n = 3). All simulations resulted in a water accessible ligand-binding pocket that lacked sodium ions. The model remained inactive displaying little movement in the receptor core; however, helix 8 showed considerable flexibility. A single frame representing the average stable AT1R was used as a template to dock Olmesartan via AutoDock 4.2, MOE, and AutoDock Vina to obtain predicted binding poses and mean Boltzmann weighted average affinity. The docking results did not match the known pose and affinity of Olmesartan. Thus, an optimization protocol was initiated using AutoDock 4.2 that provided more accurate poses and affinity for Olmesartan (n = 6). Atomic models of 103 of the known human AT1R polymorphisms were constructed using the molecular dynamics equilibrated apo-AT1R. Each of the eight ARBs was then docked, using ARB-optimized parameters, to each polymorphic AT1R (n = 6). Although each nsSNP has a negligible effect on the global AT1R structure, most nsSNPs drastically alter a sub-set of ARBs affinity to the AT1R. Alterations within N298 -L314 strongly effected predicted ARB affinity, which aligns with early mutagenesis studies. The current study demonstrates the potential of utilizing in silico approaches towards personalized ARB therapy. The results presented here will guide further biochemical studies and refinement of the model to increase the accuracy of the prediction of ARB resistance in order to increase overall ARB effectiveness.


Coral gardens: paternity and drug testing on the reef.
An international team has used molecular genetics and chemical tagging to trace how baby clownfish travel from their mother's nest through the ocean to the anemone they will live on. More than one out of five juveniles came from nests that were only meters away, despite spending over a week drifting in ocean currents. Such surprising fidelity to a small area of the coral reef bodes well for efforts to preserve coral reef diversity with reserves.


Identifying the RNA signatures of coronary artery disease from combined lncRNA and mRNA expression profiles.
Coronary artery disease (CAD) is the most common cardiovascular disease. CAD research has greatly progressed during the past decade. mRNA is a traditional and popular pipeline to investigate various disease, including CAD. Compared with mRNA, lncRNA has better stability and thus may serve as a better disease indicator in blood. Investigating potential CAD-related lncRNAs and mRNAs will greatly contribute to the diagnosis and treatment of CAD. In this study, a computational analysis was conducted on patients with CAD by using a comprehensive transcription dataset with combined mRNA and lncRNA expression data. Several machine learning algorithms, including feature selection methods and classification algorithms, were applied to screen for the most CAD-related RNA molecules. Decision rules were also reported to provide a quantitative description about the effect of these RNA molecules on CAD progression. These new findings (CAD-related RNA molecules and rules) can help understand mRNA and lncRNA expression levels in CAD.


A mixture approach to the mechanics of skin.
Skin can be considered to be a mixture of a solid and a fluid. A general theory for the description of the behaviour of mixtures is presented and applied to a mixture of a solid and a fluid. A numerical procedure is presented to solve the non-linear field equations describing such a mixture. The abilities of the procedure are demonstrated by means of a confined compression test.


Why people select the outpatient clinic of medical centers: a nationwide analysis in Taiwan.
In contrast to other countries, Taiwan's National Health Insurance (NHI) program allows patients to freely select the specialists and tiers of medical care facility without a referral. Some medical centers in Taiwan receive over 10,000 outpatients per day. In the NHI program, the co-payment was increased for high-tier facilities for outpatient visits in 2002, 2005, and 2017. However, the policies only mildly reduced the use of high-tier medical care facilities. The main purpose of this study was to evaluate the factors contributing to the patients' selection of the outpatient clinic of medical centers without a referral. An online anonymous survey was conducted by using the Google Forms platform utilizing a self-constructed questionnaire from September to October 2018. A nationwide sample in Taiwan was recruited using convenience sampling through social media. Based on a literature review and a focus group, 20 factors that may affect the choice of the outpatient institution were constructed. The associations between items that affect the patients selection of outpatient clinics were assessed using exploratory factor analysis. Principal axis factoring was performed to identify the major factors affecting the decision. Multiple logistic regression was performed to determine which factors satisfactorily explained "visiting the outpatient clinic of the medical center for an illness without a referral." During the survey period, 5,060 people browsed the online survey, and 1,003 responded and completed the online questionnaire. Therefore, the response rate was 19.8%. A total of 987 valid responses was collected. Exploratory factor analysis revealed that three main factors, namely the "physician factor", "image and reputation factor", and "facility and medication factor", affected the selection of outpatient clinics. A series of logistic regressions indicated that patients who reported that hospital facilities, high-quality drugs, and diverse specialties were very important were more likely to select the outpatient clinic of a medical center (OR = 2.218, 95% CI [1.514-3.249]). Patients who reported that physician factors were very important were less likely to select a medical center (OR = 0.717, 95% CI [0.523-0.984]). Patients who were previously satisfied with their experience of the primary clinics or had a regular family doctor were less likely to choose a medical center (OR = 0.509, 95% CI -0.435-0.595] and OR = 0.676, 95% CI [0.471-0.969]). In Taiwan, patients with good primary medical experience and regular family physicians had significantly lower rates by selecting the outpatient clinic of a medical center. The results of this study support that the key to establishing graded medical care is to prioritize the strengthening of the primary medical system.


Cells of origin of the descending afferents to the lateral hypothalamic area in the rat, studied with the horseradish peroxidase method.
Cells of origin of the descending afferents to the lateral hypothalamic area (LHA) were examined following iontophoretic injections of horseradish peroxidase (HRP). HRP-positive neurons were found ipsilaterally and mainly in the following structures: the infralimbic cortex (area 25), septal area including the nucleus of the diagonal band, nucleus accumbens, olfactory tubercle, medial and lateral preoptic areas, preoptic magnocellular nucleus, substantia innominata, bed nucleus of the stria terminalis and the central amygdaloid nucleus. Of these, neurons of the nucleus accumbens, olfactory tubercle, preoptic magnocellular nucleus and substantia innominata were preferentially labeled when the enzyme was deposited in the lateral part of the LHA.


[The study of the relationship between the face type and condyle morphology (a cephalometric and anthropometric study)].
The main purpose of this investigation was to study the shape and size of the mandibular condyles for any correlation with type of mandibular rotation. 40 mandibular bones that belongs to modern man, and late Roman stage were examined regarding the size and shape of condyles. The cephalograms of the mandibles were taken and the type of mandibular rotation was recorded on them according to Leiba analysis. The Leiba analysis results showed statistically significant differences while, the differences between the condyle sizes were found to be insignificant between the groups.


A Second Order Cone Formulation of Continuous CTA Model.
In this paper we consider a minimum distance Controlled Tabular Adjustment (CTA) model for statistical disclosure limitation (control) of tabular data. The goal of the CTA model is to find the closest safe table to some original tabular data set that contains sensitive information. The measure of closeness is usually measured using ℓ1 or ℓ2 norm; with each measure having its advantages and disadvantages. Recently, in [4] a regularization of the ℓ1-CTA using Pseudo-Huber function was introduced in an attempt to combine positive characteristics of both ℓ1-CTA and ℓ2-CTA. All three models can be solved using appropriate versions of Interior-Point Methods (IPM). It is known that IPM in general works better on well structured problems such as conic optimization problems, thus, reformulation of these CTA models as conic optimization problem may be advantageous. We present reformulation of Pseudo-Huber-CTA, and ℓ1-CTA as Second-Order Cone (SOC) optimization problems and test the validity of the approach on the small example of two-dimensional tabular data set.


Transducin activation state controls its light-dependent translocation in rod photoreceptors.
Light-dependent redistribution of transducin between the rod outer segments (OS) and other photoreceptor compartments including the inner segments (IS) and synaptic terminals (ST) is recognized as a critical contributing factor to light and dark adaptation. The mechanisms of light-induced transducin translocation to the IS/ST and its return to the OS during dark adaptation are not well understood. We have probed these mechanisms by examining light-dependent localizations of the transducin-alpha subunit (Gtalpha)in mice lacking the photoreceptor GAP-protein RGS9, or expressing the GTPase-deficient mutant GtalphaQ200L. An illumination threshold for the Gtalpha movement out of the OS is lower in the RGS9 knockout mice, indicating that the fast inactivation of transducin in the wild-type mice limits its translocation to the IS/ST. Transgenic GtalphaQ200L mice have significantly diminished levels of proteins involved in cGMP metabolism in rods, most notably the PDE6 catalytic subunits, and severely reduced sensitivity to light. Similarly to the native Gtalpha, the GtalphaQ200L mutant is localized to the IS/ST compartment in light-adapted transgenic mice. However, the return of GtalphaQ200L to the OS during dark adaptation is markedly slower than normal. Thus, the light-dependent translocations of transducin are controlled by the GTP-hydrolysis on Gtalpha, and apparently, do not require Gtalpha interaction with RGS9 and PDE6.


Serotonin uptake in blood platelets of Duchenne muscular dystrophy patients.
Serotonin (5-HT) uptake was studied in the blood platelets of 10 patients with Duchenne-type muscular dystrophy (DMD) and 7 age-matched controls. Vmax (maximum number of uptake sites) of platelet 5-HT uptake in the DMD patients was significantly less than that of the normal controls. There was no difference in the affinity for 5-HT (Km) between the two groups. There was a significant negative correlation between serum creatine kinase activity and Km of 5-HT uptake in blood platelets of these patients. However, no correlation was found between Km or Vmax and ambulatory status of DMD.


Complex rearrangement involving 9p deletion and duplication in a syndromic patient: genotype/phenotype correlation and review of the literature.
We describe a 7-year-old boy with a complex rearrangement involving the whole short arm of chromosome 9 defined by means of molecular cytogenetic techniques. The rearrangement is characterized by a 18.3 Mb terminal deletion associated with the inverted duplication of the adjacent 21,5 Mb region. The patient shows developmental delay, psychomotor retardation, hypotonia. Other typical features of 9p deletion (genital disorders, midface hypoplasia, long philtrum) and of the 9p duplication (brachycephaly, down slanting palpebral fissures and bulbous nasal tip) are present. Interestingly, he does not show trigonocephaly that is the most prominent dysmorphism associated with the deletion of the short arm of chromosome 9. Patient's phenotype and the underlying flanking opposite 9p imbalances are compared with that of reported patients and the proposed critical regions for 9p deletion and 9p duplication syndromes.


Appetite and food preference in depression: effects of imipramine treatment.
A nutritional survey, the Pittsburgh Appetite Test (PAT), was developed to study potential changes in appetite and food preference reported by patients during a depressive episode and during antidepressant treatment. We examined a group of 50 depressed outpatients who were drug-free for 2 weeks prior to treatment with imipramine and psychotherapy for 4 months. A significant increase in the desire for "sweets" (carbohydrate--fat-rich foods) was observed during a depressive episode, compared to periods when patients recalled feeling well (retrospective data). During imipramine treatment, no further changes were observed in preference for either "sweets" or carbohydrates when compared to the medication-free period. Alterations in patient self-reports of appetite and body weight change were noted during imipramine treatment.


Early results of mechanochemical ablation for small saphenous vein incompetency using 2% polidocanol.
The aim of the present study was to investigate the early results of mechanochemical ablation (MOCA) for the treatment of small saphenous vein (SSV) incompetence. We performed a single-center, retrospective analysis of a prospectively collected database of 60 patients treated with MOCA for single-axis SSV incompetence. All procedures were performed with the patient under local anesthesia using the ClariVein catheter (Merit Medical, South Jordan, Utah) combined with 2% polidocanol and, where appropriate, additional microphlebectomy. The primary study endpoint was to assess the SSV occlusion rate at the 1-, 6-, and 12-month follow-up examinations. The secondary endpoints included the Venous Clinical Severity Score, quality of life (QoL) assessment, periprocedural pain, and further complications after the intervention and during the follow-up period. Patient QoL was assessed using the Aberdeen Varicose Vein Questionnaire. Pain was measured using a 100-mm visual analog scale. Technical success was achieved in 100% of the cases. The mean visual analog scale score on the first postoperative day was 15 mm. No major events were recorded. No neurological complications or deep vein thrombosis were observed. Minor complications included ecchymosis in 3.3% of cases (2 of 60), transient phlebitis of the SSV in 5% of cases (3 of 60), and itching in 3.3% of cases (2 of 60). At the 1-, 6-, and 12-month follow-up examinations, the occlusion rate was 100% (60 of 60), 98.3% (57 of 58), and 92.6% (50 of 54). The median Venous Clinical Severity Score had significantly decreased from 5 (interquartile range [IQR], 3-6) at baseline to 2 (IQR, 1-4) at the 1-month follow-up (P < .001), 1 (IQR, 1-2) at the 6-month follow-up (P < .001) and 1 (IQR, 0-1) at the 12-month follow-up (P < .001). The mean Aberdeen Varicose Vein Questionnaire score had improved from the baseline score of 25 ± 14.61 to 15.81 ± 13.76 at the 1-month follow-up (P < .001), to 9.81 ± 7.42 at the 6-month follow-up (P < .001) and 4.73 ± 3.32 at the 12-month follow-up (P < .001). The results of our study have shown that MOCA is a feasible, safe, and painless procedure for the treatment of SSV incompetence with an occlusion rate of 92.6% at the 12-month examination. No sural nerve injuries or other major complications were observed. The procedure also provided good clinical results and positive effects on patient QoL.


Isolated right atrial tamponade by serous fluid simulating tricuspid stenosis.
Echocardiography is a key diagnostic tool in the recognition of pericardial tamponade. A 56-year-old man in whom severe dyspnea developed 22 days after cardiac surgery is described. Echocardiography suggested tricuspid valve disease but showed no pericardial abnormalities. Catheterization revealed functional stenosis of a normal tricuspid valve caused by loculated serous pericardial fluid.


Airway stenosis associated with a mycotic pseudoaneurysm of the common carotid artery.
A 56-year-old woman was seen who had been under hemodialysis treatment. In September 2003, the patient was sent to our hospital with fever and dyspnea, and artificial respiration was initiated. Bronchoscopy detected stenosis due to compression of the bronchus. Contrast computed tomography and angiography detected a pseudoaneurysm of the right common carotid artery. We performed emergency excision of the mycotic pseudoaneurysm, which was closed with an autologous pericardial patch. We also performed median sternotomy to obtain an adequate surgical view. A perfusion tube was inserted into the internal carotid artery. The inflammatory findings and dyspnea resolved postoperatively.


Use of preoperative factors including urodynamic evaluations and nerve-sparing status for predicting urinary continence recovery after robot-assisted radical prostatectomy: Nerve-sparing technique contributes to the reduction of postprostatectomy incontinence.
To examine which preoperative factors, including urodynamic evaluations, and operative procedures could predict continence status after robot-assisted radical prostatectomy (RARP) in this study. Univariate and multivariate logistic regression analyses of preoperative factors such as age, body mass index, prostate-specific antigen level before biopsy, prostate size before surgery, membranous urethral length measured using magnetic resonance imaging (MRI), bladder compliance and maximum urethral closure pressure (MUCP) measured by urodynamic study (UDS), and nerve-sparing (NS) status predicting 24-hr pad test >2 g/day at 1 year after RARP were examined in 111 patients enrolled in this study. The number of patients with incontinence at 1 year after RARP was 39 (35.1%). The only predictive factor for urinary continence was NS grades. To investigate the contribution of NS to urinary continence, 84 patients underwent UDS three times; before, immediately after, and 1 year after RARP. Chronological UDS revealed that recovery patterns of storage and voiding functions were the same among non-NS, unilateral-NS, and bilateral-NS groups, and that higher degrees of NS contributed to lesser decreases in MUCP and longer functional urethral length (FUL) after RARP. Preoperative factors, including the results of UDS, could not predict continence 1 year after RARP. The NS procedure contributed to continence status. NS favorably affected MUCP and FUL; however, it did not affect bladder function after RARP. Neurourol. Urodynam. 35:1034-1039, 2016. © 2015 Wiley Periodicals, Inc.


[Changes in the concentration of extracellular potassium in the cerebral cortex with different parameters of electrical stimulation].
In anesthetized cats, a recording macroelectrode, a K+-sensitive microelectrode and a stimulating electrode were placed on the surface of the suprasylvian gyrus. As the duration or intensity of stimulus increased, the amplitude of K+-potential reflecting the changes in the extracellular concentration of K+ ions (delta [K+]o) was augmented, while the half time of decay decreased. delta [K+]o also increased when the number of stimuli increased. Repetitive tetanic stimulation resulted in impairment of the effect also in the case when [K+]o following the preceding stimulus, reached the initial level. K-potential started to decay in the course of prolonged tetanic stimulation; impairment of the neuronal activity is supposed to underlie this event.


Cancer chemoprevention: lessons learned and future directions.
The concept of delaying or preventing epithelial transformation remains a viable and attainable goal for the future. Drug-based strategies for chemoprevention of the future may predominantly rely upon targeted therapies with tolerable but defined toxicities for treatment of individuals diagnosed with intraepithelial neoplasias. Foods, diet manipulation strategies, or nutraceuticals may be more appropriate to delay or prevent carcinogenesis progression in healthy populations with genetic or epidemiologic evidence of risk for future transformation.


Continuous electrocardiographic monitoring in patients with sickle-cell anemia during pain crisis.
Electrocardiographic studies in patients with sickle-cell anemia have been performed during the normal resting state with routine twelve-lead ECGs. We studied 30 patients with sickle-cell disease in acute crisis with 24-hour continuous electrocardiographic monitoring. The standard ECG demonstrated a high incidence of abnormalities, but only three patients had arrhythmias. These findings contrasted sharply with the results of continuous monitoring, during which arrhythmias were detected in 24 of 30 patients. They were fairly evenly split between atrial (60%) and ventricular (67%). Nine of the patients had "complex arrhythmias" including two with episodes of ventricular tachycardia. Seventeen patients subsequently underwent equilibrium gated-blood pool scans. Eight patients had abnormal contractility and tended to have more arrhythmias on monitoring than those with normal contractility. Thus, continuous electrocardiographic monitoring of sickle-cell patients during crisis revealed a higher incidence of arrhythmias than previously thought.


Afferent fiber connections from lower brain stem to hypothalamus studied by the horseradish peroxidase method with special reference to noradrenaline innervation.
Attempts were made to determine the afferent projections to the anterior hypothalamus including the preoptic area from the lower brain stem by means of the horseradish peroxidase method combined with monoamine oxidase staining to identify noradrenaline (NA) neurons. In addition to this technique, a histofluorescence analysis was performed. NA fibers in the medial part of the anterior hypothalamus were mainly supplied by A1 and A2 NA neuron groups, while the lateral part and periventricular zone received NA terminals from both pontine and medulla oblongata NA neuron groups. Furthermore, the present study indicated that there were direct projections to the anterior hypothalamus from non-noradrenergic neurons in the lower brain stem: nuclei raphe dorsalis, centralis superior, cells in the mesencephalic and pontine central gray matter, nuclei parabrachialis lateralis and medialis, cells around fasciculus longitudinalis medialis.


Early to Mid-Term Follow-Up Outcomes of Percutaneous Closure of Atrial Septal Defects Using Recent Generation Devices: a Single-Center Experience.
This study aimed to describe our early to mid-term experience with transcatheter atrial septal defect (ASD) closure using the Occlutech Figulla® Flex II device (FSO), Gore® Cardioform septal occluder (GSO), and Amplatzer® septal occluder (ASO) after they were first approved in Korea in 2014, and to compare the three aforementioned kinds of ASD closure devices. Between September 2014 and August 2016, 267 patients underwent transcatheter ASD closure in our institution. Baseline characteristics, hemodynamic features, comorbidities, and procedural success and complication rates were analyzed retrospectively. The unpaired Student t-test or variance analysis was used in the statistical analysis. The FSO was most commonly used (n=152, 56.9%), followed by the ASO (n=98, 36.7%) and GSO (n=17, 6.4%). Baseline characteristics and hemodynamic features were similar between the devices, except that the defect size and pulmonary flow-to-systemic flow ratio were lower in the GSO group than in the other groups. Overall, the procedural success rate remained at 100%, and major complication rate was <1%. No late complication occurred during the follow-up. The FSO and GSO are feasible, safe options for use in transcatheter ASD closure, and they are comparable to the ASO.


Vertical changes in the positions of the cleft segments of patients with unilateral cleft lip and palate. Changes from birth to palatoplasty at the age of 10-14 months.
Clinically discernible vertical deviations of the cleft segments in nasal direction were registered and visualized using model series of 16 patients with unilateral cleft lip and palate. All patients were treated according to the cleft concept of the University of Leipzig, with labioplasty being performed at the age of 4-6 months and palatoplasty at the age of 10-14 months. All patients had a modified Hotz plate inserted until the palate was closed. Casts of a collective of non-cleft infants served as controls. The vertical deviations of the segments from the reference plane, defined by us through the tuber points and the canine point of the non-cleft side, were registered metrically by three-dimensional (3D) measuring of maxillary casts, using a reflex microscope. The registered values were represented three-dimensionally, and the absolute growth was compared with the relative vertical changes. The results show that 3D representation with superimposition of the individual results offers the clinician clear, continuous monitoring of the treatment progress. In comparison with the control group, the cleft patients showed significantly greater vertical deviations in nasal direction in the region of the incisor and canine points at each observation timepoint. A significant reduction in vertical divergences was recorded only in the region of the cleft pole point of the larger segment during the study period. The results furthermore suggest that investigation of absolute changes in segment positions alone in comparison with relative growth changes may lead to misinterpretations.


Prevalence of polycystic ovary syndrome in European countries and USA: A systematic review and meta-analysis.
We conducted a systematic review and meta-analyses of the prevalence of Polycystic Ovary Syndrome (PCOS) and the frequency of its phenotypes in Europe and the USA, also focusing on temporal trends of the condition, to compare the PCOS prevalence among populations with a similar level of diagnostic resources availability and attitudes toward health problems, to improve comparability of estimates. We considered Europe and USA, two high-income areas with these characteristics. The overall PCOS prevalence according to the NIH1990, ESHRE/ASRM 2003, AES-PCOS diagnostic criteria was respectively 6.2 % (95%CI 5.3-7.0), 19.5 % (95%CI 17.3-21.6), and 15.0 % (95%CI 12.9-17.1), with no appreciable heterogeneity across geographic areas. Phenotype A, the "complete PCOS", showed higher prevalence in all areas (44.8%, 95%CI 40.3-49.3), followed by phenotype D, called "non-hyperandrogenic PCOS" (19.5%), phenotype C termed as "ovulatory PCOS" (16.2%), and phenotype B, presenting as phenotype A but without polycystic ovarian morphology (14.9%). In all the studies analysing temporal trends of PCOS, an increase in prevalence of PCOS was reported, due, at least in part, to changing diagnostic criteria. The prevalence of PCOS is similar in European countries and the USA. Interestingly, some differences in the frequency of PCOS phenotypes emerged between the two areas with a higher frequency of phenotype A and a lower one of phenotype C in the USA. Recognizing the factors which explain these differences would lead to a better understanding of the etiopathogenesis and the clinical expression of PCOS.


The functional networks of a novel environment: Neural activity mapping in awake unrestrained rats using positron emission tomography.
Novel environment stimulation is thought to have an important role in cognitive development and has been shown to encourage exploratory behavior in rats. However, psychopathology or perceived danger or stress can impede this exploratory drive. The balance between brain circuits controlling the exploratory drive elicited by a novel environment, and the avoidance response to stressors, is not well understood. Using positron emission tomography (PET) and the glucose analog [18 F]fluorodeoxyglucose (18F-FDG), we assessed awake brain glucose metabolism (BGluM) in rats while in a novel environment (cage of an unfamiliar male rat) and non-novel environment (the animal's home cage). Exposure to the novel environment increased BGluM in regions associated with vision (visual cortex), motor function and motivated behavior (striatum and motor cortex), and anxiety (stria terminalis), and decreased BGluM in regions associated with auditory processing (auditory cortex, insular cortex, inferior colliculus), locomotor activity (globus pallidus, striatum, motor cortex, ventral thalamic nucleus), spatial navigation (retrosplenial cortex), and working memory (hippocampus, cingulate cortex, prelimbic cortex, orbitofrontal cortex). These results suggest that the novel cage is a stressful environment that inhibits activity in brain regions associated with exploratory behavior. Patterns of inhibition in the novel cage also support the proposed rat default mode network, indicating that animals are more cognitively engaged in this environment. Additionally, these data support the unique capability of combining FDG-PET with psychopharmacology experiments to examine novelty seeking and brain activation in the context of decision making, risk taking, and cognitive function more generally, along with response to environmental or stress challenges.


Application of Metabolomics in Childhood Leukemia Diagnostics.
Metabolomics is a new field of science dealing with the study and analysis of metabolites formed in living cells. The biological fluids used in this test method are: blood, blood plasma, serum, cerebrospinal fluid, saliva and urine. The most popular methods of assessing the composition of metabolites include nuclear magnetic resonance spectroscopy and mass spectrometry (MS) in combination with gas chromatography-MS or liquid chromatography-MS. Metabolomics is used in many areas of medicine. The variability of biochemical processes in neoplastic cells in relation to healthy cells is the starting point for this type of research. The aim of the research currently being carried out is primarily to find biomarkers for quick diagnosis of the disease, assessment of its advancement and treatment effectiveness. The development of metabolomics may also contribute to the individualization of treatment of patients, adjusting drugs depending on the metabolic profile, and thus may improve the effectiveness of therapy, reduce side effects and help to improve the quality of life of patients. Here, we review the current and potential applications of metabolomics, focusing on its use as a biomarker method for childhood leukemia.


Accelerated short-TE 3D proton echo-planar spectroscopic imaging using 2D-SENSE with a 32-channel array coil.
MR spectroscopic imaging (MRSI) with whole brain coverage in clinically feasible acquisition times still remains a major challenge. A combination of MRSI with parallel imaging has shown promise to reduce the long encoding times and 2D acceleration with a large array coil is expected to provide high acceleration capability. In this work a very high-speed method for 3D-MRSI based on the combination of proton echo planar spectroscopic imaging (PEPSI) with regularized 2D-SENSE reconstruction is developed. Regularization was performed by constraining the singular value decomposition of the encoding matrix to reduce the effect of low-value and overlapped coil sensitivities. The effects of spectral heterogeneity and discontinuities in coil sensitivity across the spectroscopic voxels were minimized by unaliasing the point spread function. As a result the contamination from extracranial lipids was reduced 1.6-fold on average compared to standard SENSE. We show that the acquisition of short-TE (15 ms) 3D-PEPSI at 3 T with a 32 x 32 x 8 spatial matrix using a 32-channel array coil can be accelerated 8-fold (R = 4 x 2) along y-z to achieve a minimum acquisition time of 1 min. Maps of the concentrations of N-acetyl-aspartate, creatine, choline, and glutamate were obtained with moderate reduction in spatial-spectral quality. The short acquisition time makes the method suitable for volumetric metabolite mapping in clinical studies.


Anti-NMDA receptor encephalitis and MOG-associated demyelination - a case report with long-term follow-up and a systematic review.
Overlap syndromes of anti-NMDA receptor encephalitis and MOG-mediated demyelination have been reported. In this case we provide a long-term longitudinal follow-up of clinical and imaging characteristics as well as of antibody dynamics. We report a 32-year-old male patient who presented with psychosis, decreased consciousness and movement disorders and was tested positive for anti-NMDA receptor antibodies. Forty-four months after symptom onset and diagnosis of autoimmune encephalitis, he suffered from relapse. At this time, the patient developed anti-MOG and anti-Caspr2 antibodies. Treatment with plasmapheresis, steroids and rituximab eventually led to substantial clinical and radiological improvement. Anti-Caspr2 antibodies persisted, anti-NMDA receptor antibodies decreased, while anti-MOG antibodies turned negative again. We provide long-term longitudinal follow-up of a patient with anti-NMDA receptor encephalitis who developed triple antibody positivity at the time of relapse. Antibody dynamics were associated with clinical disease course.


Synaptic destabilization by neuronal Nogo-A.
Formation and maintenance of a neuronal network is based on a balance between plasticity and stability of synaptic connections. Several molecules have been found to regulate the maintenance of excitatory synapses but nothing is known about the molecular mechanisms involved in synaptic stabilization versus disassembly at inhibitory synapses. Here, we demonstrate that Nogo-A, which is well known to be present in myelin and inhibit growth in the adult CNS, is present in inhibitory presynaptic terminals in cerebellar Purkinje cells at the time of Purkinje cell-Deep Cerebellar Nuclei (DCN) inhibitory synapse formation and is then downregulated during synapse maturation. We addressed the role of neuronal Nogo-A in synapse maturation by generating several mouse lines overexpressing Nogo-A, starting at postnatal ages and throughout adult life, specifically in cerebellar Purkinje cells and their terminals. The overexpression of Nogo-A induced a progressive disassembly, retraction and loss of the inhibitory Purkinje cell terminals. This led to deficits in motor learning and coordination in the transgenic mice. Prior to synapse disassembly, the overexpression of neuronal Nogo-A led to the downregulation of the synaptic scaffold proteins spectrin, spectrin-E and beta-catenin in the postsynaptic neurons. Our data suggest that neuronal Nogo-A might play a role in the maintenance of inhibitory synapses by modulating the expression of synaptic anchoring molecules.


Long-term continuous spinal anesthesia in severe tetanus with autonomic disturbance.
The mortality rate from tetanus is still high if the disease is accompanied by signs of autonomic nervous system dysfunction. We treated a 75-year-old woman with tetanus and autonomic dysfunction with continuous high spinal anesthesia for 23 days. She recovered. Spinal anesthesia may be a useful adjunct for the treatment of severe tetanus.


Chemokine receptor-mediated delivery of mycobacterial MPT51 protein efficiently induces antigen-specific T-cell responses.
Here we evaluated the effects of immunization with a DNA vaccine encoding a fusion protein consisting of macrophage inflammatory protein-1alpha (MIP-1alpha) and MPT51 (a major secreted protein from Mycobacterium tuberculosis) on induction of specific CD8+ T cells. The DNA vaccine encoding the fusion protein could induce significantly higher number of the antigen-specific CD8+ T cells in mice than DNA vaccine encoding MPT51 alone. Also, splenocytes from mice immunized with the fusion DNA vaccine expressed higher level of IFN-gamma mRNA and protein upon stimulation with an epitope peptide derived from MPT51 than those from mice immunized with a mixture of two DNA vaccines encoding either MPT51 or MIP-1alpha. These results suggest that DNA vaccine encoding MIP-1alpha-antigen fusion protein is able to be efficiently internalized into antigen-presenting cells via the chemokine receptor and induce higher level of antigen-specific CD8+ T-cell responses.


Phosphatidylserine is polarized and required for proper Cdc42 localization and for development of cell polarity.
Polarity is key to the function of eukaryotic cells. On the establishment of a polarity axis, cells can vectorially target secretion, generating an asymmetric distribution of plasma membrane proteins. From Saccharomyces cerevisiae to mammals, the small GTPase Cdc42 is a pivotal regulator of polarity. We used a fluorescent probe to visualize the distribution of phosphatidylserine in live S. cerevisiae. Remarkably, phosphatidylserine was polarized in the plasma membrane, accumulating in bud necks, the bud cortex and the tips of mating projections. Polarization required vectorial delivery of phosphatidylserine-containing secretory vesicles, and phosphatidylserine was largely excluded from endocytic vesicles, contributing to its polarized retention. Mutants lacking phosphatidylserine synthase had impaired polarization of the Cdc42 complex, leading to a delay in bud emergence, and defective mating. The addition of lysophosphatidylserine resulted in resynthesis and polarization of phosphatidylserine, as well as repolarization of Cdc42. The results indicate that phosphatidylserine--and presumably its polarization--are required for optimal Cdc42 targeting and activation during cell division and mating.


A case of iliac-artery-ureteral fistula managed with a combined endoscopic approach.
A 66-year-old man presented to hospital with gross hematuria and clots. He had previously undergone surgical repair of a right iliac artery aneurysm with placement of a vascular prosthesis at the same hospital, which had resulted in iliac urethral stricture that required the placement of a right ureteral stent. He had attended repeatedly for recurrent ureteral stent replacement, with the most recent replacement having occurred 1 month before the current presentation. Ultrasonography, cystography, retrograde pyelography and provocative arteriography via a percutaneous right femoral arterial approach. An iliac-artery-ureteral fistula between the right ureter and a pseudoaneurysm of the right common iliac artery. The patient underwent placement of a covered, self-expandable vascular stent with angioplasty balloon, which resulted in complete exclusion of the pseudoaneurysm and fistula and resolution of the patient's hematuria. A pigtail catheter was placed in the right ureter for 5 days and replaced with a double-J ureteral stent on day 6 after exclusion of the pseudoaneurysm; the patient was discharged from hospital on the same day. Color-Doppler ultrasonography of the right iliac vessels performed 2 months later showed patency of the right iliac artery. The patient's ureteral stent has been replaced every 2 months since his discharge without recurrence of hematuria.


A retrospective survey of liver fluke disease in livestock based on abattoir data in Shiraz, south of Iran.
Meat-inspection records in an abattoir located in the Fars province (southern part of Iran) from 20 March 1999 to 19 March 2004 were used to determine the prevalence and long-term trend of liver fluke disease in sheep, cattle and goats in the region. A total of 844,039 animals (cattle 131,716; sheep 577,090; goats 135,233) slaughtered in the 5-year period and overall 34,856 (4.1%) livers were condemned. Fasciolosis and dicrocoeliosis were responsible for 54 and 21% of total liver condemnations, respectively. The prevalence of liver condemnations due to fasciolosis was decreased from 3.89, 3.20 and 2.63% in 1999-2000 to 1.07, 0.59 and 0.24% in 2003-2004 for cattle, sheep and goats, respectively. The corresponding features for dicrocoeliosis were similar, declining from 1.47, 1.76 and 2.10% in 1999-2000 to 0.69, 0.34 and 0.25% in 2003-2004, respectively. Drought climatic conditions in conjunction with a greater awareness among farmers could be responsible factors.