[The analysis of prognostic factors in patients with thoracic ossification of the ligamentum flavum and thoracic ossification of posterior longitudinal ligament by posterior decompression].
To investigate the prognostic factors for patients with thoracic ossification of the ligamentum flavum (OLF) and thoracic ossification of posterior longitudinal ligament (OPLL). Clinical information of 83 patients suffering from thoracic OLF and OPLL was reviewed retrospectively from January 2006 to June 2010. The related factors such as gender, age, preoperative and postoperative Japanese Orthopedic Association (JOA) score, pathological segment, type of thoracic OPLL, degree of thoracic kyphosis, anteroposterior diameter of OPLL, range of circumferential decompression, cerebrospinal fluid leakage or not and dysfunction or not and carotid lumbar disorders or not were analyzed by Chi-square and Logistic regression. All cases were classified into desirable group (58 cases) and undesirable group (25 cases) based on the postoperative JOA score improvement rate. Comparison of physical characteristics between two groups of age, preoperative JOA and the course of the disease had not statistically significant (P > 0.05). Two groups in pathological segment of thoracic OPLL (χ(2) = 6.290, P = 0.043), the ossification type of OPLL (χ(2) = 5.361, P = 0.021) and dysfunction or not in preoperative (χ(2) = 27.711, P = 0.000) had significant difference. Logistic regression analysis showed that the upper thoracic segments (P = 0.044), beak type ossification (P = 0.023) and with dysfunction in preoperative (P = 0.009) were risk factors. There were 24 patients (28.9%) with cerebrospinal fluid leakage, 3 patients with early postoperative deep infection and neurological deterioration of 2 cases in postoperative. Patients with ossification on the upper section of thoracic have a better prognosis, but the beaked localized longitudinal ligament ossification in patients and associated with preoperative dysfunction show a poor prognosis, combined jumping segmental ossification and cervical or lumbar severe disorders are the influencing factor for poor prognosis.


[Virus and autoimmunity with emphasis on liver diseases].
The dualism virus pathogenesis and autoimmune pathogenesis in liver disease is given up increasingly. A survey is given about the development of autoimmunity and virus induction of the autoimmune hepatitis. The hypothesis of virus induction of autoimmune hepatitis put forward by Storch 1975 (19) is unproven up to now, but the concept of virus-associated autoimmune hepatitis put forward by Storch 1980 (23) is acknowledged today. First of all, antibodies against endoplasmic reticulum (liver and kidney microsomes) type 1, liver ribosomes, and liver cell cytoplasm are regarded as markers of a hepatitis C virus-associated autoimmune hepatitis. At present it is unknown, if antibodies against the surface of tongue epithelium, basal cells of squamous epithelium, Golgi apparatus, and nerve cells are further suitable markers.


Non-linear dynamics in parkinsonism.
Over the last 30 years, the functions (and dysfunctions) of the sensory-motor circuitry have been mostly conceptualized using linear modelizations which have resulted in two main models: the "rate hypothesis" and the "oscillatory hypothesis." In these two models, the basal ganglia data stream is envisaged as a random temporal combination of independent simple patterns issued from its probability distribution of interval interspikes or its spectrum of frequencies respectively. More recently, non-linear analyses have been introduced in the modelization of motor circuitry activities, and they have provided evidences that complex temporal organizations exist in basal ganglia neuronal activities. Regarding movement disorders, these complex temporal organizations in the basal ganglia data stream differ between conditions (i.e., parkinsonism, dyskinesia, healthy control) and are responsive to treatments (i.e., l-DOPA, deep brain stimulation). A body of evidence has reported that basal ganglia neuronal entropy (a marker for complexity/irregularity in time series) is higher in hypokinetic state. In line with these findings, an entropy-based model has been recently formulated to introduce basal ganglia entropy as a marker for the alteration of motor processing and a factor of motor inhibition. Importantly, non-linear features have also been identified as a marker of condition and/or treatment effects in brain global signals (EEG), muscular activities (EMG), or kinetic of motor symptoms (tremor, gait) of patients with movement disorders. It is therefore warranted that the non-linear dynamics of motor circuitry will contribute to a better understanding of the neuronal dysfunctions underlying the spectrum of parkinsonian motor symptoms including tremor, rigidity, and hypokinesia.


Rph1 coordinates transcription of ribosomal protein genes and ribosomal RNAs to control cell growth under nutrient stress conditions.
Coordinated regulation of ribosomal RNA (rRNA) synthesis and ribosomal protein gene (RPG) transcription by eukaryotic RNA polymerases (RNAP) is a key requirement for growth control. Although evidence for balance between RNPI-dependent 35S rRNA production and RNAPII-mediated RPG transcription have been described, the molecular basis is still obscure. Here, we found that Rph1 modulates the transcription status of both rRNAs and RPGs in yeast. We show that Rph1 widely associates with RNAPI and RNAPII-transcribed genes. Deletion of RPH1 remarkably alleviates cell slow growth caused by TORC1 inhibition via derepression of rRNA and RPG transcription under nutrient stress conditions. Mechanistically, Rim15 kinase phosphorylates Rph1 upon rapamycin treatment. Phosphorylation-mimetic mutant of Rph1 exhibited more resistance to rapamycin treatment, decreased association with ribosome-related genes, and faster cell growth compared to the wild-type, indicating that Rph1 dissociation from chromatin ensures cell survival upon nutrient stress. Our results uncover the role of Rph1 in coordination of RNA polymerases-mediated transcription to control cell growth under nutrient stress conditions.


Facilitators and Barriers of Participation in "Uptime" Activities in Girls and Women With Rett Syndrome: Perspectives From Parents and Professionals.
Rett syndrome (RTT) is a rare neurodevelopmental disorder usually affecting females. It is associated with intellectual and multiple disabilities leading to a high level of dependency in all aspects of daily living including participation in physical activities. This study explored facilitators and barriers to "uptime" (non-sedentary) activities in Danish girls and women with RTT as perceived by parents and professionals using focus groups. Through thematic analysis, one central theme emerged: a constant balance to do the best thing for the girl or woman. Within the central theme, five subthemes of facilitators and barriers were identified relating to the individual and the physical, organizational, social, and attitudinal environments. Environmental barriers can be reduced through policy and management-level changes in health promotion and strong advocacy of physical activity by health professionals. Targeting both facilitators and barriers of "uptime" activities enables the planning and implementing of health-promoting interventions in individuals with RTT.


[Isolation and culture of type 2 innate lymphoid cells (ILC2) in lungs of newborn mice].
Objective To investigate the isolation and culture of the type 2 innate lymphoid cell (ILC2) in the lungs of newborn mice. Methods Immunomagnetic bead enrichment and fluorescence activated cell sorting (FACS) were used to isolate ILC2s. Flow cytometry was used to identify the purity of ILC2s. Inverted microscope was used to observe the growth of cells. ELISA was used to detect the expression levels of interleukin 5 (IL-5) and IL-13. Results The purity of the isolated ILC2s reached more than 95%. The isolated ILC2s were round or oval, and suspended in cell culture medium. After stimulation with IL-2 and IL-7 combined with IL-33, the contents of IL-5 and IL-13 produced by ILC2s and the proliferation ability of ILC2s increased significantly. Conclusion A rapid and efficient method for isolation and culture of ILC2s in the lung of newborn mice has been found.


Glycosyltransferases of the human cervical epithelium. I. Characterization of a beta-galactoside alpha-2-L-fucosyltransferase and the identification of a beta-N-acetylglucosaminide alpha-3-L-fucosyltransferase.
Using phenyl beta-D-galactoside as an acceptor, alpha-2-L-fucosyltransferase activity was identified in human cervical epithelium with pH optima at 6.0 and 7.2. The different response to p-chloromercuribenzoate, and ability to utilise asialofetuin as an acceptor, suggests the presence of two fucosyltransferases. The acid form is probably involved in glycoprotein synthesis in vivo. At pH 6.0, fucosyltransferase has a temperature optimum of 25 degrees C, requires the presence of Triton X-100 and either manganese or magnesium for maximal activity, and has Km values for GDP-L-[14-C]fucose and phenyl beta-D-galactoside of 32.1 . 10(-6) M and 8.2 . 10(-3) M, respectively. Guanosine nucleotides are potent inhibitors of the fucosyltransferase reaction; GDP is a competitive inhibitor while, depending on its concentration, GTP can either inhibit or activate the reaction. The alpha-L-fucosidase present in cervical tissue has negligible activity towards the enzyme product, phenyl-alpha-2-L-[14C]fucosyl-beta-D-galactoside. The use of high and low molecular weight acceptors indicates the presence of a beta-N-acetylglucosaminide alpha-3-L-fucosyltransferase and an N-acetylgalactosaminide fucosyltransferase.


A family with hereditary thrombocythaemia and normal genes for thrombopoietin and c-Mpl.
Hereditary thrombocythaemia (HT) is an inherited autosomal dominant disorder. Recent studies reported six different mutations, four within the thrombopoietin (TPO) gene and two within c-Mpl (TPO receptor) gene in six unrelated families with HT. This study investigated the molecular basis of hereditary thrombocythaemia in an Israeli-Jewish family. We screened the genes for TPO and c-Mpl by amplification and sequencing of all the corresponding exons including exon/intron boundaries and promoters. In addition, plasma levels of TPO and erythropoietin (EPO) were measured. No abnormality in the TPO/c-Mpl genes has been identified in affected HT family members. Plasma TPO and EPO levels were found to be normal/low or normal respectively in the individuals affected. In conclusion, lack of a molecular lesion within either TPO or cMpl genes indicate that HT may be caused by factors other than TPO-cMpl axis in this family.


Synthesis of 4, 4-difluoro analogs of retinol and retinoic acid.
Oxidation of retinol at the C-4 position is a major metabolic route to biologically inactive excretory products. Thus, the replacement of hydrogen with fluorine at C-4 might well modify the rate of metabolism, biological activity, and pharmacological activity of vitamin A, 4,4-Difluororetinyl acetate and related analogs were consequently synthesized by the following procedure. Retinoic acid (1), upon methylation to methyl retinoate (2), was oxidized with manganese dioxide to methyl 4-oxoretinoate (3). Methyl 4,4-difluororetinoate (4), prepared from methyl 4-oxoretinoate (3) by reaction with diethylaminosulfurtrifluoride (DAST), was further converted to 4,4-difluororetinoic acid (5), 4,4-difluororetinol (6), 4,4-difluororetinyl acetate (7), and 4,4-difluororetinyl palmitate (8). 4,4-Difluororetinyl acetate was also prepared directly from 4-oxoretinyl acetate (9) by reaction with DAST. The purified, often crystalline, analogs were characterized by UV absorption, mass spectrometry, and 1H-NMR and 19F-NMR spectra.


Phosphorylation of hepatitis B virus core C-terminally truncated protein (Cp149) by PKC increases capsid assembly and stability.
The HBV (hepatitis B virus) core is a phosphoprotein whose assembly, replication, encapsidation and localization are regulated by phosphorylation. It is known that PKC (protein kinase C) regulates pgRNA (pregenomic RNA) encapsidation by phosphorylation of the C-terminus of core, which is a component packaged into capsid. Neither the N-terminal residue phosphorylated by PKC nor the role of the C-terminal phosphorylation have been cleary defined. In the present study we found that HBV Cp149 (core protein C-terminally truncated at amino acid 149) expressed in Escherichia coli was phosphorylated by PKC at Ser(106). PKC-mediated phosphorylation increased core affinity, as well as assembly and capsid stability. In vitro phosphorylation with core mutants (S26A, T70A, S106A and T114A) revealed that the Ser(106) mutation inhibited phosphorylation of core by PKC. CD analysis also revealed that PKC-mediated phosphorylation stabilized the secondary structure of capsid. When either pCMV/FLAG-Cp149[WT (wild-type)] or pCMV/FLAG-S106A Cp149 was transfected into Huh7 human hepatoma cells, mutant capsid level was decreased by 2.06-fold with the S106A mutant when compared with WT, although the same level of total protein was expressed in both cases. In addition, when pUC1.2x and pUC1.2x/S106A were transfected, mutant virus titre was decreased 2.31-fold compared with WT virus titre. In conclusion, PKC-mediated phosphorylation increased capsid assembly, stability and structural stability.


[Biomimetic oxidation of benzene by a polynuclear manganese complex [Mn12O12(CH3CO2)16(H2O)4] under mild conditions].
The possibility of monooxygenase enzymes biomimetic construction models with the use of polynuclear manganese complexes was shown. It was demonstration that benzene is oxidized by polynuclear manganese complex [Mn12O12(CH3CO2)16(H2O)4] in acetonitrile solution at room temperature and atmospheric pressure yielding phenol with the selectivity more than 80%. It was determined that the addition of air oxygen as the reoxidizer to the reaction mixture didn't transfer the reaction into the catalytic mode.


The relationship between structural features of peripheral nerves and suture methods for nerve repair.
Based on techniques for identifying and distinguishing motor, sensory, and mixed fasciculi in peripheral nerves, the authors propose guidelines for selecting suture methods for nerve repair. When many mixed fasciculi are known to exist at the nerve lesion, epineurial repair is preferable; fascicular (perineurial) repair is more suitable when pure motor and sensory fasciculi are clearly recognized. Generally, epineurial repair is indicated for more proximal injuries, with fascicular repair most appropriate for more distal sites. A greater ratio of epineurial connective tissue to intrafascicular nervous tissue implies an inclination toward fascicular repair.


Relative importance of designation and accreditation of trauma centers during evolution of a regional trauma system.
Improved survival after injury has been demonstrated with trauma system implementation and designation of trauma centers. Local designating health authorities or national verification (United States) or accreditation (Canada) programs audit trauma center performance. The relative importance of designation versus accreditation with respect to improved outcomes is not clear. The purpose of this study was to measure outcomes within a single regional trauma system after designation of trauma centers and to compare outcomes in the one accredited center to the nonaccredited centers. Data from three trauma centers were studied. All were large, university-affiliated regional medical centers, integrated into a regional trauma system and served by a single ambulance service. The study period was 1992 to 1999, immediately after trauma center designation in 1991. The British Columbia Trauma Registry was used to identify trauma patients, mechanism of injury, length of stay, case mix, case volume, acuity, pediatric caseload, and proportion of transfers at each center. A questionnaire was circulated to each hospital to determine the level of institutional support and programmatic development for trauma. The Trauma Registry was used to calculate z scores (TRISS methodology) for each center and TRISS-adjusted mortality odds ratios between institutions. Differences in covariables were controlled for in subgroup analysis. Two centers (hospitals A and C) had a high trauma caseload; one (hospital B) had a small and diminishing caseload. Only one center (hospital A) developed a trauma program consistent with Canadian accreditation criteria; z scores for center A were consistently better than at hospital B or C and survival odds ratios were significant. This finding applied to the total trauma population, blunt adult trauma patients (whether or not transfers and hip fracture patients were excluded), and in the more severely injured blunt trauma subgroups. There were no differences between hospitals for the relatively small number of patients with penetrating trauma. Differences between hospitals were apparent from the outset of the trauma system. However, designation as a trauma center does not appear to necessarily improve survival in large regional medical centers. Development of a trauma program and commitment to meeting national guidelines through the accreditation process does appear to be associated with improved outcome after injury.


An Engineered Bacteria-Hybrid Microrobot with the Magnetothermal Bioswitch for Remotely Collective Perception and Imaging-Guided Cancer Treatment.
Microrobots driven by multiple propelling forces hold great potential for noninvasively targeted delivery in the physiologic environment. However, the remotely collective perception and precise propelling in a low Reynold's number bioenvironment remain the major challenges of microrobots to achieve desired therapeutic effects in vivo. Here, we reported a biohybrid microrobot that integrated with magnetic, thermal, and hypoxia sensitivities and an internal fluorescent protein as the dual reporter of thermal and positioning signals for targeted cancer treatment. There were three key elements in the microrobotic system, including the magnetic nanoparticle (MNP)-loaded probiotic Escherichia coli Nissle1917 (EcN@MNP) for spatially magnetic and hypoxia perception, a thermal-logic circuit engineered into the bacteria to control the biosynthesis of mCherry as the temperature and positioning reporter, and NDH-2 enzyme encoded in the EcN for enhanced anticancer therapy. According to the fluorescent-protein-based imaging feedback, the microrobot showed good thermal sensitivity and active targeting ability to the tumor area in a collective manner under the magnetic field. The cancer cell apoptosis was efficiently triggered in vitro and in vivo by the hybrid microrobot coupled with the effects of magnetothermal ablation and NDH-2-induced reactive oxygen species (ROS) damage. Our study demonstrates that the biohybrid EcN microrobot is an ideal platform to integrate the physical, biological, and chemical properties for collective perception and propelling in targeted cancer treatment.


Giant cell arteritis mimicking multiple myeloma; diagnosed by PET scan.
This case report describes a patient who presented with severe anemia, monoclonal gammopathy, a high erythrocyte sedimentation rate and significant weight loss. These features were highly suggestive of multiple myeloma. Bone marrow aspiration was negative for myeloma on two occasions. A positron emission tomography (PET) scan showed extensive 2-flourodeoxy-glucose uptake in the vascular tree consistent with arteritis. A temporal artery biopsy established the diagnosis of giant cell arteritis (GCA). There were no typical symptoms of GCA, such as headache, visual disturbance, or polymyalgia rheumatica. The patient was treated with steroids, which resulted in the resolution of anemia, monoclonal gammapathy, and other symptoms.


Comparison between diurnal distribution of onset of infarction in patients with acute myocardial infarction and circadian variation of blood pressure in patients with coronary artery disease.
We analyzed the diurnal distribution of the onset of infarction in 636 patients with acute myocardial infarction (MI) and compared it with the circadian variation of blood pressure in 57 patients with coronary artery disease (CAD). In addition, we studied the modification of the circadian blood pressure variation during treatment with antianginal medications in 20 patients with CAD. A marked diurnal periodicity (p < 0.05) was observed for the onset of MI, with peaks seen in the late morning, late evening, and very early morning. The blood pressure in the patients with CAD was elevated in the morning, reduced in the late evening, and was the lowest in the very early morning. The peaks of onset of infarction temporally corresponded to the characteristic feature of blood pressure profile observed in the patients with CAD, that is, the morning rise, the late evening decline, and the very early morning reduction. Antianginal medications significantly reduced the blood pressure, not only during the day (p < 0.02) but also at night (p < 0.05). These observations suggest that the decline in blood pressure, as well as the morning surge in blood pressure, may be closely related to the onset of MI. Therefore, when treating patients with CAD with antianginal medications which can potentially reduce blood pressure, the effects on the circadian variation of blood pressure should be considered.


COLQ-mutant Congenital Myasthenic Syndrome with Microcephaly: A Unique Case with Literature Review.
Congenital Myasthenic Syndrome (CMS) is a group of inherited neuromuscular junction disorders caused by defects in several genes. Clinical features include delayed motor milestones, recurrent respiratory illnesses and variable fatigable weakness. The central nervous system involvement is typically not part of the CMS. We report here a Saudi girl with genetically proven Collagen Like Tail Subunit Of Asymmetric Acetylcholinesterase (COLQ) mutation type CMS who has global developmental delay, microcephaly and respiratory failure. We have reviewed the literature regarding COLQ-type CMS and to the best of our knowledge this is the first ever reported association of congenital myasthenia syndrome with microcephaly.


Association between nutrition label use and chronic disease in Korean adults: the Fourth Korea National Health and Nutrition Examination Survey 2008-2009.
Nutrition labels are helpful for chronic disease management in patients requiring balanced nutritional intake. This study aimed to investigate the association between the use of nutrition labels and chronic diseases (hypertension, diabetes mellitus, and hyperlipidemia) by using the 2008-2009 Korea National Health and Nutrition Examination Survey data. A total of 10,695 individuals aged 20 and over was included in the analysis. Using multiple logistic regressions, there was no difference in nutrition label use between the chronic disease and normal groups (men with hypertension OR, 0.97; 95% CI, 0.75-1.27; women with hypertension OR, 0.83; 95% CI, 0.67-1.03; men with diabetes OR, 0.70; 95% CI, 0.45-1.08; women with diabetes OR, 1.13; 95% CI, 0.84-1.53; men with hyperlipidemia OR, 0.85; 95% CI, 0.59-1.23; women with hyperlipidemia OR, 1.14; 95% CI, 0.91-1.44). In hyperlipidemia patients, awareness (OR, 1.55; 95% CI, 1.03-2.35) and control (OR, 2.19; 95% CI, 2.32-3.63) of disease were related to nutrition label use; however, no significant associations were found for the hypertension and diabetes mellitus patients. Considering the importance of dietary habits in the management of chronic diseases, an improvement in nutrition label use by patients with these diseases is required.


Targeted therapy of multiple myeloma: the changing paradigm at the beginning of the new millennium.
Multiple myeloma (MM) is a malignant hematological neoplasmand constitutes 10% of blood cancers. Recently, it has become evident that almost all cases of MM are preceded by gammopathy of undetermined significance (MGUS). MM is diagnosed by the presence of paraprotein in serum or urine, detected by serum electrophoresis and immunofixation, infiltration of malignant plasma cells in the bone marrow and related organ, or tissue damage. Cytogenetic status, International Staging System (ISS) and the quality of response to therapy are the most important prognostic factors. In the last decade the availability of new effective drugs, such as thalidomide, lenalidomide and bortezomib have provided a new therapeutic scenario expected to impact favorably on the outcome of MM patients. Today, for younger patients a triple-agent induction regimen incorporating novel agents followed by autologous stem cell transplantation (ASCT) is the best approach. In this setting ongoing clinical trials are evaluating the efficacy of consolidation and maintenance therapy based on the use of new drugs. For patients noteligible for ASCT the best initial regimens are combination therapy with melphalan and prednisone plus either thalidomide or bortezomibor the combination of lenalidomide and dexamethasone. Supportive therapy includes the use of erythropoietin and bisphosphonates according to the updated guidelines. In the future the identification of candidate therapeutic targets through gene expression profiling (GEP) and single-nucleotide polymorphism (SNP) analysis, as well as the availability of the targeted investigative agents will lead to a substantial progress in the development and implementation of personalized medicine in MM.


Role of p/q-Ca2+ channels in metabotropic glutamate receptor 2/3-dependent presynaptic long-term depression at nucleus accumbens synapses.
The nucleus accumbens (NAc) is an important cerebral area involved in reward and spatial memory (Pennartz et al., 1994), but little is known about synaptic plasticity in this region. Here, electron microscopy revealed that, in the NAc, metabotropic glutamate receptors 2/3 (mGlu2/3) immunostaining was essentially associated with axonal terminals and glial processes, whereas postsynaptic dendrites and neuronal cell bodies were unstained. Electrophysiological techniques in the NAc slice preparation demonstrated that activation of mGlu2/3 with synaptically released glutamate or specific exogenous agonist, such as LY354740 (200 nm, 10 min), induced long-term depression of excitatory synaptic transmission (mGlu2/3-LTD). Tetanic-LTD and pharmacological mGlu2/3-LTD occluded each other, suggesting common mechanisms. The mGlu2/3-LTD did not require synaptic activity but depended on the cAMP-protein kinase A cascade. Selective inhibition of P/Q-type Ca(2+) channels with omega-agatoxin-IVA occluded the expression of mGlu2/3-LTD, and, conversely, the inhibitory effects of omega-agatoxin-IVA were abolished during mGlu2/3-LTD. Thus, mGlu2/3 play an important role in the control of use-dependent synaptic plasticity at prelimbic cortex-NAc synapses: their activation causes a form of LTD mediated by the long-lasting reduction of P/Q-type Ca(2+)channels contribution to transmitter release.


Anesthesia of polar bears using xylazine-zolazepam-tiletamine or zolazepam-tiletamine.
Immobilization features and physiologic effects of combinations of xylazine-zolazepam-tiletamine (XZT) and zolazepam-tiletamine (ZT or Telazol) were compared in nine captive and 17 free-ranging polar bears (Ursus maritimus) between 1998 and 2001. Although induction time was similar between drugs, induction dosage and volume were less with XZT. Induction of immobilization with XZT was predictable and smooth, muscle relaxation was good, and all bears remained completely immobilized and unresponsive to stimuli throughout a 1 hr handling period. The combination XZT was safely tolerated at two to three times the recommended dosage of 5 mg/kg (i.e., xylazine at 2 mg/kg + Telazol at 3 mg/kg). Bears immobilized with XZT had slower pulse rates, higher mean arterial pressures, and lower arterial oxygen tensions than bears immobilized with ZT. Rectal temperature increased slowly over time (approximately 0.5 C per hr) following immobilization with XZT. Based on response to a painful stimulus (compression of a claw bed), XZT was a more effective analgesic than ZT. Although the immobilization effects of XZT could not be reversed with the alpha 2-antagonist drug tolazoline, they were reversed with yohimbine or atipamezole. However, the time to complete reversal of effects (i.e., standing and ambulatory) was highly variable among bears.


Antidiabetic drug voglibose is protective against ischemia-reperfusion injury through glucagon-like peptide 1 receptors and the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathway in rabbits.
Glucagon-like peptide 1 (GLP-1) reportedly exerts a protective effect against cardiac ischemia. We hypothesized that the alpha-glucosidase inhibitor voglibose, an unabsorbable antidiabetic drug with cardioprotective effects, may act through stimulation of GLP-1 receptors. The results of the present study suggest oral administration of voglibose reduces myocardial infarct size and mitigates cardiac dysfunction in rabbits after 30 minutes of coronary occlusion and 48 hours of reperfusion. Voglibose increased basal and postprandial plasma GLP-1 levels and reduced postprandial plasma glucose levels. The infarct size-reducing effect of voglibose was abolished by treatment with exendin(9-39), wortmannin, Nomega-nitro-L-arginine methylester, or 5-hydroxydecanoate), which inhibit GLP-1 receptors, phosphoinositide 3-kinase, nitric oxide synthase, and K(ATP) channels, respectively. Western blot analysis showed that treatment with voglibose upregulated myocardial levels of phospho-Akt, phosphoendothelial nitric oxide synthase after myocardial infarction. The upregulation of phospho-Akt was inhibited by exendin(9-39) and wortmannin. These findings suggest that voglibose reduces myocardial infarct size through stimulation of GLP-1 receptors, activation of the phosphoinositide 3-kinase-Akt-endothelial nitric oxide synthase pathways, and the opening of mitochondrial K(ATP) channels. These findings may provide new insight into therapeutic strategies for the treatment of patients with coronary artery disease.


[Mid-term results after stentless mitral valve replacement. Comparison to conventional mitral valve replacement and mitral valve repair].
To evaluate the clinical results after stentless (SMV) in comparison to mitral valve repair (MV-rep) and conventional mitral valve replacement (MVR) at 5 years. From 08/1997 onward, 155 patients with degenerative mitral valve (MV) disease received an SMV (n=53, 68+/-8 years, 37 female), MV-rep (n=51, 69+/-9 years, 32 female), or MVR (n=51, 66+/-9 years, 32 female). The underlying MV disease was stenosis in 13 (SMV)/1 (MV-rep)/4 (MVR), incompetence in 13 (SMV)/50 (MV-rep)/30 (MVR), and combined lesion in 27 (SMV)/0 (MV-rep)/12 (MVR) patients, respectively. Preoperative New York Heart Association (NYHA) functional class was 3.1+/-0.6 (SMV)/2.9+/-0.5 (MV-rep)/2.9+/-0.6 (MVR), Euroscore 5.2+/-2.3 (SMV), 5.0+/-1.9 (Mv-rep), 4.8+/-2.6 (MVR), left ventricular ejection fraction 60.5+/-10% (SMV)/57.3+/-13% (MV-rep)/58.7+/-13% (MVR), and cardiac index 2.1+/-0.8/2+/-0.7/2+/-0.8 l/min/m2 (not significant). Follow-up includes 64+/-18 months (21-89 months). Surgery was performed via conventional sternotomy (32 SMV/20 MVR-rep/34 MVR) or right anterolateral minithoracotomy (21/31/17). Cross-clamp duration was 81+/-33 (SMV)/58+/-24 (MV-rep)/54+/-23 min (MVR; p<0.05). Mean pressure gradients amounted to 4.8+/-1.9/3.6+/-1.7/4.3+/-1.4 mmHg, and valve opening areas to 2.5+/-0.6/3+/-0.9/2.6+/-0.9 cm2, respectively. In-hospital mortality was 1 (SMV)/2 (MV-rep)/5 (MVR) patients (p<0.05). During follow-up, repeat surgical interventions were required in 6 (SMV)/2 (MV-rep)/3 (MVR) patients. 5-year survival was 80.5+/-4.4% (SMV)/82.6+/-5.6% (MV-rep)/80.2+/-5.5% (MVR; not significant); this was comparable to an age-matched normal population. At 5 years, the SMV compares favorably with conventional standards when taking the patients' risk profile into account. The SMV with its reliable functional and hemodynamic outcome may be the mitral prosthesis of choice in future.


Diet-induced hyperinsulinemia differentially affects glucose and protein metabolism: a high-throughput metabolomic approach in rats.
Metabolomics is a high-throughput tool that quantifies and identifies the complete set of biofluid metabolites. This "omics" science is playing an increasing role in understanding the mechanisms involved in disease progression. The aim of this study was to determine whether a nontargeted metabolomic approach could be applied to investigate metabolic differences between obese rats fed a high-fat sucrose (HFS) diet for 9 weeks and control diet-fed rats. Animals fed with the HFS diet became obese, hyperleptinemic, hyperglycemic, hyperinsulinemic, and resistant to insulin. Serum samples of overnight-fasted animals were analyzed by (1)H NMR technique, and 49 metabolites were identified and quantified. The biochemical changes observed suggest that major metabolic processes like carbohydrate metabolism, β-oxidation, tricarboxylic acid cycle, Kennedy pathway, and folate-mediated one-carbon metabolism were altered in obese rats. The circulating levels of most amino acids were lower in obese animals. Serum levels of docosahexaenoic acid, linoleic acid, unsaturated n-6 fatty acids, and total polyunsaturated fatty acids also decreased in HFS-fed rats. The circulating levels of urea, six water-soluble metabolites (creatine, creatinine, choline, acetyl carnitine, formate, and allantoin), and two lipid compounds (phosphatidylcholines and sphingomyelin) were also significantly reduced by the HFS diet intake. This study offers further insight of the possible mechanisms implicated in the development of diet-induced obesity. It suggests that the HFS diet-induced hyperinsulinemia is responsible for the decrease in the circulating levels of urea, creatinine, and many amino acids, despite an increase in serum glucose levels.


Effects of exercise training intensity on cardiac autonomic regulation in habitual smokers.
The sympathoexcitatory effects of cigarette smoking cause an autonomic imbalance that may lead to cardiovascular disease. Aerobic training improves autonomic function by developing cardiorespiratory fitness; however, it is still uncertain whether aerobic training ameliorates the compromised autonomic modulation in smokers. This study aimed to investigate the effects of 8 weeks' aerobic training at different exercise intensities on autonomic regulation in habitual smokers. Healthy males (n = 34) were randomly assigned to a moderate-intensity aerobic training (MAT, 60% of heart rate reserve [HRR]), a high-intensity training group (HAT, 75% HRR), or a control group (CG). Training groups performed 8 weeks' aerobic training on a treadmill (3 times/week), but all subjects continued to smoke cigarettes as usual. Heart rate variability was monitored to evaluate the effect of aerobic training on autonomic regulation. Aerobic training improved autonomic balance despite the continued smoking. In the time domain, rMSSD and pNN50 were significantly increased in HAT than in CG. On spectral analysis, the absolute and normalized units of high frequency (HF) were significantly increased in HAT, whereas the LF/HF ratio and the normalized unit of LF were significantly decreased compared to that in CG. SD1 and the SD1/SD2 ratio of the Poincaré plot analysis were significantly increased compared to CG. Although MAT showed a similar tendency to HAT in nonlinear indexes, there were no significant differences compared to CG. Aerobic training, particularly high-intensity training, increases the parasympathetic contribution to the sympathovagal system, leading to an improvement in autonomic balance despite continued cigarette smoking.


Design and control of patterns in reaction-diffusion systems.
We discuss the design of reaction-diffusion systems that display a variety of spatiotemporal patterns. We also consider how these patterns may be controlled by external perturbation, typically using photochemistry or temperature. Systems treated include the Belousov-Zhabotinsky (BZ) reaction, the chlorite-iodide-malonic acid and chlorine dioxide-malonic acid-iodine reactions, and the BZ-AOT system, i.e., the BZ reaction in a water-in-oil reverse microemulsion stabilized by the surfactant sodium bis(2-ethylhexyl) sulfosuccinate (AOT).


Referred Pain and Sensations Evoked by Standardized Palpation of the Masseter Muscle in Healthy Participants.
To determine if standardized palpation of the masseter muscle can evoke referred pain and/or sensations in healthy individuals and to compare the mechanical sensitivities in response to three different levels of palpation force. A total of 32 pain-free individuals participated. The right masseter muscle was divided into 15 test sites. Mechanical sensitivity of the masseter was assessed with three mechanical stimuli (0.5 kg, 1.0 kg, or 2.0 kg) applied by palpometers to the 15 test sites for 5 seconds each site. Participants scored the perceived intensity of pain and unpleasantness of each of the three mechanical stimuli on 0-100 numeric rating scales (NRS). After each stimulus, the duration of aftersensation was measured, and the participants were also asked to indicate areas within the orofacial region with referred pain/sensations. Data were tested using analysis of variance, Tukey post hoc, and McNemar's tests with a 5% level of significance. Referred pain/sensations were most commonly evoked with the 2.0-kg stimulus (34.4% of participants; P < .05) compared to the 1.0-kg (12.5%) and 0.5-kg stimuli (3.1%). There were significant effects of stimulus intensity on NRS scores for pain and unpleasantness, as well as for aftersensation (P < .05). There were significant effects on NRS scores for pain and unpleasantness for the 1.0- and 2.0-kg stimuli (P < .05) and on aftersensation for the 2.0-kg stimulus (P < .05). These results indicate that referred pain/sensations in the orofacial region are frequent phenomena among healthy individuals during standardized palpation of the masseter muscle.


Correlation between Macular Thickness and Visual Field in Early Open Angle Glaucoma: A Cross-Sectional Study.
The aim of this study was to correlate macular thickness and visual field parameters in early glaucoma. A total of 104 eyes affected with early glaucoma were examined in a cross-sectional, prospective study. Visual field testing using both standard automated perimetry (SAP) and shortwave automated perimetry (SWAP) was performed. Global visual field parameters, including mean deviation (MD) and pattern standard deviation (PSD), were recorded and correlated with spectral domain optical coherence tomography (SD-OCT)-measured macular thickness and asymmetry. Average macular thickness correlated significantly with all measures of visual field including MD-SWAP (r = 0.42), MD-SAP (r = 0.41), PSD-SWAP (r = -0.23), and PSD-SAP (r = -0.21), with P-values <0.001 for all correlations. The mean MD scores (using both SWAP and SAP) were significantly higher in the eyes with thin than in those with intermediate average macular thickness. Intraeye (superior macula thickness - inferior macula thickness) asymmetries correlated significantly with both PSD-SWAP (r = 0.63, P < 0.001) and PSD-SAP (r = 0.26, P = 0.01) scores. This study revealed a significant correlation between macular thickness and visual field parameters in early glaucoma. The results of this study should make macular thickness measurements even more meaningful to glaucoma specialists.


The Impact of Total Variation Regularized Expectation Maximization Reconstruction on 68Ga-DOTA-TATE PET/CT Images in Patients With Neuroendocrine Tumor.
The aim of this study was to investigate the effects of the total variation regularized expectation maximization (TVREM) reconstruction on improving 68Ga-DOTA-TATE PET/CT images compared to the ordered subset expectation maximization (OSEM) reconstruction. A total of 17 patients with neuroendocrine tumors who underwent clinical 68Ga-DOTA-TATE PET/CT were involved in this study retrospectively. The PET images were acquired with either 3 min-per-bed (min/bed) acquisition time and reconstructed with OSEM (2 iterations, 20 subsets, and a 3.2-mm Gaussian filter) and TVREM (seven penalization factors = 0.01, 0.07, 0.14, 0.21, 0.28, 0.35, and 0.42) for 2 and 3 min-per-bed (min/bed) acquisition time using list-mode. The SUVmean of the liver, background variability (BV), signal-to-noise ratios (SNR), SUVmax of the lesions and tumor-to-background ratios (TBR) were measured. The mean percentage difference in the SNR and TBR between TVREM with difference penalization factors and OSEM was calculated. Qualitative image quality was evaluated by two experienced radiologists using a 5-point score scale (5-excellent, 1-poor). In total, 63 lesions were analyzed in this study. The SUVmean of the liver did not differ significantly between TVREM and OSEM. The BV of all TVREM groups was lower than OSEM groups (all p < 0.05), and the BV of TVREM 2 min/bed group with penalization factor of 0.21 was considered comparable to OSEM 3 min/bed group (p = 0.010 and 0.006). The SNR, SUVmax and TBR were higher for all TVREM groups compared to OSEM groups (all p < 0.05). The mean percentage difference in the SNR and TBR was larger for small lesions (<10 mm) than that for medium (≥10 mm but < 20 mm) and large lesions (≥20 mm). The highest image quality score was given to TVREM 2 min/bed group with penalization factor of 0.21 (3.77 ± 0.26) and TVREM 3 min/bed group with penalization factor of 0.35 (3.77 ± 0.26). TVREM could reduce image noise, improve the SNR, SUVmax and TBR of the lesions, and has the potential to preserves the image quality with shorter acquisition time.


Evaluation of gene-finding algorithms by a content-balancing accuracy index.
A content-balancing accuracy index, called q(9), to evaluate gene-finding algorithms has been proposed. Here the concept of content-balancing means that the evaluation by this index is independent of the coding and non-coding composition of the sequence being evaluated. Since the coding and non-coding compositions are severely unbalanced in eukaryotic genomes, the performance of gene-finding algorithms is either over- or under-evaluated by the widely used accuracy indices, e.g., the correlation coefficient, due to the lack of content-balancing ability. Using the new accuracy index q(9), seven gene-finding algorithms, FGENES; Gene-Mark.hmm; Genie; Genescan; HMMgene; Morgan and MZEF, were compared and evaluated. It is shown that Genescan is still the best one, but with q(9)= 89%, averaged over the prediction for 195 sequences. In addition to the content-balancing ability, q(9) has the merit of having definition in all possible cases. It is also shown that the traditional specificity s(p) carries important information on the performance of the algorithm being evaluated. The set of sensitivity s(n), specificity s(p) and the accuracy q(9) constitutes a complete kit to evaluate gene-finding algorithms at nucleotide level. In addition, a graphic method to compare and evaluate gene-finding algorithms has been proposed, too. Its major advantage is that the overall performance of algorithms can be grasped quickly in a perceivable form. Additionally, the new accuracy index q(9) may be applied to evaluate the performance of weather forecast, clinical diagnosis, psychological examination and protein secondary structure prediction etc.


Burkholderia multivorans acts as an antagonist against the growth of Burkholderia pseudomallei in soil.
In this study, it was demonstrated, by using agar diffusion tests and a Transwell system, that Burkholderia multivorans NKI379 has an antagonistic effect against the growth of B. pseudomallei. Bacterial representatives were isolated from agricultural crop soil and mixed to construct a partial bacterial community structure that was based on the results of reproducible patterns following PCR-denaturing gradient gel electrophoresis analysis of total soil chromosomes. The antagonistic effect of B. multivorans on B. pseudomallei was observed in this imitate community. In a field study of agricultural crop soil, the presence of B. pseudomallei was inversely related to the presence of the antagonistic strains B. multivorans or B. cenocepacia. B. multivorans NKI379 can survive in a broader range of pH, temperatures and salt concentrations than B. pseudomallei, suggesting that B. multivorans can adapt to extreme environmental changes and therefore predominates over B. pseudomallei in natural environments.


Geriatric Cooperatives in Southwestern Ontario: A novel way of increasing inter-sectoral partnerships in the care of older adults with responsive behaviours.
Established in 2010, Geriatric Cooperatives support the evolving Behavioural Supports Ontario (BSO) programme in the South West Local Health Integration Network. Geriatric Cooperatives bring together members representing relevant cross-sectoral services and are tasked with identifying system gaps associated with the BSO target population as well as developing work plans specific to their local area, leveraging local capacity, and co-ordinating and improving linkages between sectors and services. The purpose of this study was to evaluate the partnerships formed over time within these Cooperatives in order to inform their ongoing development and sustainability. In 2012 and in 2015, Geriatric Cooperative members were invited to complete the Partnership Self-Assessment Tool (PSAT), a valid and reliable tool for evaluating collaborative processes and identifying areas in need of improvement. Scoring the PSAT involves the calculation of mean scores (ranging from 1 to 5) for each of six dimensions describing effective collaboration; higher mean scores reflect better functioning. Two psychometrically sound versions of the PSAT exist; the shorter version (PSAT-S) scores fewer items in three dimensions. Survey response rates for the three Cooperatives that were evaluated in both 2012 and 2015 were 70% in 2012 and 36% in 2015; 57% of members who completed the survey in 2015 were new Cooperative members. Both years, more than 25% of respondents selected "don't know" for three of the nine items used to score the administration and management dimension. Both PSAT and PSAT-S mean dimension scores across both years reflected that more effort is needed to maximise collaborative potential. Use of the PSAT has promoted a better understanding of how partnerships are functioning. Knowledge of where more work is required along with effective strategies to overcome weak areas and gaps in functioning has the potential to ensure that these Cooperatives are successful.


Detection of cytomegalovirus, Epstein-Barr virus, and Torque Teno virus in subgingival and atheromatous plaques of cardiac patients with chronic periodontitis.
Periodontitis and atherosclerosis represent a chronic inflammatory process. The incidence of periodontitis in cardiac patients with atherosclerosis is a well-established fact. The role of viruses in the etiopathogenesis of both has been proposed. The aim of the study was to evaluate the prevalence of Torque Teno virus (TTV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) in cardiac patients with atherosclerosis and coexisting chronic periodontitis (CP). Thirty patients (17 males and 13 females) with atherosclerotic plaques and coexisting periodontitis were recruited for this cross-sectional study. Viral DNA was extracted from the subgingival and atheromatous plaque. The presence of CMV, EBV, and TTV in the plaque samples was identified using polymerase chain reaction. The collected data were statistically analyzed for the prevalence of the viruses and Chi-squared test was performed to find out its association with atheroma and CP. The prevalence of CMV, EBV, and TTV in atheromatous plaque was 63.3%, 56.7%, and 46.7%, respectively, as compared to rates of 80%, 63.3%, and 53.3% in subgingival plaque. Results also indicated no significant association of CMV, EBV, and TTV in both samples (P = 0.08, 0.346, and 0.261, respectively). There was no significant association of CMV, EBV, and TTV between subgingival and atheromatous plaque. The prevalence of CMV, EBV, and TTV was high in atheromatous plaque. TTV was isolated from more than 50% of participants in atheromatous plaque, which is a significant finding.


Preference of Arabidopsis thaliana GH3.5 acyl amido synthetase for growth versus defense hormone acyl substrates is dictated by concentration of amino acid substrate aspartate.
The GH3 family of adenylating enzymes conjugate acyl substrates such as the growth hormone indole-3-acetic acid (IAA) to amino acids via a two-step reaction of acyl substrate adenylation followed by amino acid conjugation. Arabidopsis thaliana GH3.5 was previously shown to be unusual in that it could adenylate both IAA and the defense hormone salicylic acid (SA, 2-hydroxybenzoate). Our detailed studies of the kinetics of GH3.5 on a variety of auxin and benzoate substrates provides insight into the acyl preference and reaction mechanism of GH3.5. For example, we found GH3.5 activity on substituted benzoates is not defined by the substitution position as it is for GH3.12/PBS3. Most importantly, we show that GH3.5 strongly prefers Asp as the amino acid conjugate and that the concentration of Asp dictates the functional activity of GH3.5 on IAA vs. SA. Not only is Asp used in amino acid biosynthesis, but it also plays an important role in nitrogen mobilization and in the production of downstream metabolites, including pipecolic acid which propagates defense systemically. During active growth, [IAA] and [Asp] are high and the catalytic efficiency (kcat/Km) of GH3.5 for IAA is 360-fold higher than with SA. GH3.5 is expressed under these conditions and conversion of IAA to inactive IAA-Asp would provide fine spatial and temporal control over local auxin developmental responses. By contrast, [SA] is dramatically elevated in response to (hemi)-biotrophic pathogens which also induce GH3.5 expression. Under these conditions, [Asp] is low and GH3.5 has equal affinity (Km) for SA and IAA with similar catalytic efficiencies. However, the concentration of IAA tends to be very low, well below the Km for IAA. Therefore, GH3.5 catalyzed formation of SA-Asp would occur, fine-tuning localized defensive responses through conversion of active free SA to SA-Asp. Taken together, we show how GH3.5, with dual activity on IAA and SA, can integrate cellular metabolic status via Asp to provide fine control of growth vs. defense outcomes and hormone homeostasis.


Expenditure of hospital care on cancer in China, from 2011 to 2015.
A solid understanding of levels and trends of spending on cancer is important to evaluate whether our healthcare resources were wisely spent and to prioritize future resources for cancer treatment and prevention. However, studies on economic burden of cancers in China are scant and the results are inconsistent. The Chinese hospital information database and nearly 350 million inpatient medical record data were used. As the ratios of cancer inpatient payments to total inpatient payments were mainly influenced by the grades and sites of hospitals, the estimates of payments of cancer inpatients in this study were stratified by hospital grades and provinces. Only the payments of cancer inpatients happened in grade 2, grade 3 and specialized cancer hospitals were included in the analyses. The total medical payments of cancers in China were estimated based on the ratios of outpatient payments to inpatient payments in specialized cancer hospitals. From 2011 to 2015, the payments of cancer inpatients in China have increased by 84.1% and the total inpatient payments reached 177.1 billion RMB in 2015, accounting for 4.3% of the total health expenditure in China. Based on the ratio of outpatient payments to inpatient payments, the total payments on cancer treatments in China were estimated to be 221.4 billion RMB in 2015. Among different cancer types, the highest payments were the treatment of trachea, bronchus and lung cancer. The major cancer inpatient payments (67.1% in 2015) spent in grade 3 general hospitals and this ratio increased continually from 2011 to 2015. The expenditure of cancer treatments also varies by region with the major expenditure in the eastern region of China. This study estimated the total payments of cancer treatments in China and analyzed how the money was spent on cancer treatments in the recent 5 years, which would provide information for decision makings on the allocation of resources to service provisioning, prevention strategies, research funding, and assessing whether the economic burden of cancer is affordable to the governments.


Ethical position of medical practitioners who refuse to treat unvaccinated children.
Recent reports in Australia have suggested that some medical practitioners are refusing to treat children who have not been vaccinated, a practice that has been observed in the USA and parts of Europe for some years. This behaviour, if it is indeed occurring in Australia, has not been supported by the Australian Medical Association, although there is broad support for medical practitioners in general having the right to conscientious objection. This paper examines the ethical underpinnings of conscientious objection and whether the right to conscientious objection can be applied to the refusal to treat unvaccinated children. The implications of such a decision will also be discussed, to assess whether refusal to treat unvaccinated children is ethically justifiable. The best interests of both existing and new patients are crucially important in a doctor's practice, and the tension between these two groups of patients are contemplated in the arguments below. It is argued that on balance, the refusal to treat unvaccinated children constitutes unjustified discrimination.


Basic organization principles of the VOR: lessons from frogs.
Locomotion is associated with a number of optical consequences that degrade visual information processing in the absence of appropriate compensatory movements. The resulting retinal image flow is counteracted by coordinated eye-head reflexes that are initiated by optokinetic and vestibular inputs. The contribution of the vestibulo-ocular reflex (VOR) for stabilizing retinal images is relatively small in amplitude in frogs but important in function by compensating for the non-linearities of the neck motor system. The spatial tuning of the VOR networks underlying the angular (AVOR) and linear (LVOR) with respect to canal and extraocular motor coordinates is organized in a common, canal-related reference frame. Thereby, the axes of head and eye rotation are aligned, principle and auxiliary VOR connections transform vestibular into motor signals and parallel AVOR and LVOR circuits mediate vergence and version signals separately. Comparison of these results with data from other vertebrates demonstrates a number of fundamental organization principles common to most vertebrates. However, the fewer degrees of behavioral freedom of frogs are reflected by the absence of, e.g. a functioning velocity storage network or of a fixation suppression of the VOR. In vitro experiments with the isolated brainstem and branches of N.VIII attached were used to study the putative transmitters of vestibular nerve afferent inputs, the postsynaptic receptor subtypes of second-order vestibular neurons and their dynamic response properties. Evidence is presented that suggests that afferent vestibular nerve fibers with different dynamic response properties activate different subtypes of glutamate receptors. The convergence pattern of monosynaptic afferent nerve inputs from different labyrinthine organs onto second-order vestibular neurons is remarkably specific. As a rule, second-order vestibular neurons receive converging afferent nerve inputs from one semicircular canal and from a specific sector of hair cells on one otolith organ. This convergence pattern remains malleable even in adulthood and reorganization is initiated by activity-related changes in vestibular nerve afferent fibers. The output of second-order vestibular neurons is modified by at least three inhibitory control loops. Uncrossed inhibitory vestibular side loops appear to control specifically the dynamic response tuning, whereas coplanar commissural inhibitory inputs improve mainly the spatial tuning and the cerebellar feedback loop controls the response gain. Among the targets of second-order vestibular projection neurons are extraocular motoneurons and internuclear neurons. Extraocular motoneurons differ among each other by the presence of very different response dynamics. These differences may represent a co-adaptation to the response dynamics of twitch and non-twitch extraocular muscle fibers. Different dynamical properties are required for a rapid acceleration of the globe at the one end and for the maintenance of a stable eccentric eye position over long periods of time at the other end of a continuum of variations in dynamic response properties. The maintenance of a given eccentric eye position over long periods of time is especially well developed in frogs and assists visual surveillance during lurking in the absence of saccades.


Classification of highly similar crude oils using data sets from comprehensive two-dimensional gas chromatography and multivariate techniques.
Comprehensive two-dimensional gas chromatography (GCxGC) has proven to be an extremely powerful separation technique for the analysis of complex volatile mixtures. This separation power can be used to discriminate between highly similar samples. In this article we will describe the use of GCxGC for the discrimination of crude oils from different reservoirs within one oil field. These highly complex chromatograms contain about 6000 individual, quantified components. Unfortunately, small differences in most of these 6000 components characterize the difference between these reservoirs. For this reason, multivariate-analysis (MVA) techniques are required for finding chemical profiles describing the differences between the reservoirs. Unfortunately, such methods cannot discern between 'informative variables', or peaks describing differences between samples, and 'uninformative variables', or peaks not describing relevant differences. For this reason, variable selection techniques are required. A selection based on information between duplicate measurements was used. With this information, 292 peaks were used for building a discrimination model. Validation was performed using the ratio of the sum of distances between groups and the sum of distances within groups. This step resulted in the detection of an outlier, which could be traced to a production problem, which could be explained retrospectively.


The neuropathology of the autism spectrum disorders: what have we learned?
Autism is a behaviourally defined disorder, initially described by Kanner in 1943. By definition, symptoms are manifested by 36 months of age and are characterized by delayed and disordered language, impaired social interaction, abnormal responses to sensory stimuli, events and objects, poor eye contact, an insistence on sameness, an unusual capacity for rote memory, repetitive and stereotypic behaviour and a normal physical appearance. Relatively few neuropathological studies have been performed on the brains of autistic subjects. Of those reported, abnormalities have been described in the cerebral cortex, the brainstem, the limbic system and the cerebellum. Although those with the disorder present with a specific set of core characteristics, each individual patient is somewhat different from another. Thus, it should not be surprising that the brains of these subjects should show a wide range of abnormalities. However, it is important to delineate the anatomic features, which are common to all cases, regardless of age, sex and IQ, in order to begin to understand the central neurobiological profile of this disorder. The results of our systematic studies indicate that the anatomic features that are consistently abnormal in all cases include reduced numbers of Purkinje cells in the cerebellum, and small tightly packed neurons in the entorhinal cortex and in the medially placed nuclei of the amygdala. It is known that the limbic system is important for learning and memory, and that the amygdala plays a role in emotion and behaviour. Research in the cerebellum indicates that this structure is important as a modulator of a variety of brain functions and impacts on language processing, anticipatory and motor planning, mental imagery and timed sequencing. Defining the differences and similarities in brain anatomy in autism and correlating these observations with detailed clinical descriptions of the patient may allow us greater insight into the underlying neurobiology of this disorder.


A Vasopressin-Induced Change in Prostaglandin Receptor Subtype Expression Explains the Differential Effect of PGE2 on AQP2 Expression.
Arginine vasopressin (AVP) stimulates the concentration of renal urine by increasing the principal cell expression of aquaporin-2 (AQP2) water channels. Prostaglandin E2 (PGE2) and prostaglandin2α (PGF2α) increase the water absorption of the principal cell without AVP, but PGE2 decreases it in the presence of AVP. The underlying mechanism of this paradoxical response was investigated here. Mouse cortical collecting duct (mkpCCDc14) cells mimic principal cells as they endogenously express AQP2 in response to AVP. PGE2 increased AQP2 abundance without desmopressin (dDAVP), while in the presence of dDAVP, PGE2, and PGF2α reduced AQP2 abundance. dDAVP increased the cellular PGD2 and PGE2 release and decreased the PGF2α release. MpkCCD cells expressed mRNAs for the receptors of PGE2 (EP1/EP4), PGF2 (FP), and TxB2 (TP). Incubation with dDAVP increased the expression of EP1 and FP but decreased the expression of EP4. In the absence of dDAVP, incubation of mpkCCD cells with an EP4, but not EP1/3, agonist increased AQP2 abundance, and the PGE2-induced increase in AQP2 was blocked with an EP4 antagonist. Moreover, in the presence of dDAVP, an EP1/3, but not EP4, agonist decreased the AQP2 abundance, and the addition of EP1 antagonists prevented the PGE2-mediated downregulation of AQP2. Our study shows that in mpkCCDc14 cells, reduced EP4 receptor and increased EP1/FP receptor expression by dDAVP explains the differential effects of PGE2 and PGF2α on AQP2 abundance with or without dDAVP. As the V2R and EP4 receptor, but not the EP1 and FP receptor, can couple to Gs and stimulate the cyclic adenosine monophosphate (cAMP) pathway, our data support a view that cells can desensitize themselves for receptors activating the same pathway and sensitize themselves for receptors of alternative pathways.


Mosaicplasty for osteochondral lesions of the talus: a report of two cases.
Two women (24 and 27 years old) noted pain in the affected ankle of several years' duration. Radiography and magnetic resonance imaging revealed osteochondral lesions of the talus in both patients. The lesion sites measured 1.3 × 1.0 × 0.4 cm (0.52 cm(3)) and 2.0 × 1.9 × 0.5 cm (1.9 cm(3)). Each patient received a medial malleolar osteotomy with mosaicplasty. Donor plugs were obtained from the ipsilateral knee in both patients. Surgery was performed successfully in both patients without complications. At 2-year follow-up, both patients had recovered good ankle function, with no donor site morbidity. American Orthopedic Foot and Ankle Society ankle/hindfoot scores improved in the affected ankles from 16 to 84 in case 1 and from 43 to 87 in case 2. Mosaicplasty is effective in treating stage III or IV osteochondral lesions of the talus and results in good-to-excellent recovery of function.


[Essential pulmonary arterial hypertension].
Pulmonary arterial hypertension is defined by a pressure of at least 25 mmHg. Values can reach 50 mmHg in moderate cases and far more in severe cases. Some cases are secondary to cardiopulmonary disease, whereas primary forms can be due to collagen disorders (e.g scleroderma), viral infections (HIV, human herpes virus type 8, etc.). Numerous cases are induced by drugs, such as appetite suppressants. The recent discovery of BMPR2, a dominant gene with weak penetrance, has opened up several interesting possibilities in this setting. Likewise, pathophysiological research has identified a fall in vasodilatory substances and an increase in vasoconstrictive mediators, opening the way to medical treatments that can postpone the need for lung transplantation.


[Sir William Richard Gowers: author of the "bible of neurology"].
William Richard Gowers is one of the great pioneers in neurology and the author of the well-known neurology textbook, "A Manual of Diseases of the Nervous System." His concepts of neurology are based on meticulously and carefully accumulated knowledge of history, observations, and neurological examinations of patients with various neurological diseases. He is not only a great neurologist but also a great teacher who loves teaching students and physicians through well-prepared lectures. We can glean the essence of the field of neurology through his life story and numerous writings concerning neurological diseases.


Integrated Plastic Surgery Match: Trends in Research Productivity of Successful Candidates.
Plastic surgery continues to be one of the most competitive specialties in the residency match. Research productivity is a key component of the selection process. Nevertheless, potential applicants have a poor understanding of the strength of their research credentials in comparison to other applicants. The authors identified successful applicants from the 2012 to 2017 integrated plastic surgery residency application cycles. The authors performed a bibliometric analysis of these residents using Scopus, PubMed, and Google Scholar to identify published articles at the time of application. The authors then calculated the h-index of each applicant at the time of application. The authors included 829 integrated residents. The median h-index was 0 (interquartile range, 0 to 3) and the median number of publications was 2 (interquartile range, 0 to 5) for all applicants. The proportion of applicants with at least one publication at the point of application increased significantly over time (60 percent in 2012 versus 76 percent in 2017; p = 0.0072). In addition, the number of publications per applicant increased over time (one in 2012 versus two in 2017; p = 0.0005), as did h-index (0 in 2012 versus 1 in 2017; p = 0.0015). Strikingly, the number and percentage of review articles among applicants increased significantly over this time frame (9 percent versus 14 percent; p = 0.0299). The increasing level of academic productivity among applicants may reflect the increasing competitiveness of the integrated plastic surgery residency application process. As the pressure to compete for a training position increases, students may seek faster-to-publish articles to gain an edge.


Thermally stimulated exoelectron emission from solid neon.
In spite of the negative electron affinity of Ne atoms, appreciable concentrations of electrons can be trapped in solid neon layers formed by depositing the gas on a cold substrate with concurrent electron irradiation. These are trapped at defect sites, and can be promoted into the conduction band in an annealing experiment. They can then recombine with positive charges producing vacuum ultraviolet "thermoluminescence," but can also be extracted from the solid, and detected as an "exoelectron" current. The thermally stimulated exoelectron emission profiles of the electron current versus temperature reveal two broad features near 7.5 and 10 K. These are shown to correspond to two distributions of electron trapping sites with slightly differing activation energies. For the narrower, higher temperature maximum, an average activation energy of about 23 meV is deduced, in good agreement with predictions based on the theory of electronic defect formation.


Genetic method to optimize binary dithering technique for high-quality fringe generation.
The recently proposed dithering techniques could substantially improve measurement quality when fringes are wide, but offer limited improvement when fringes are narrow. This Letter presents a genetic algorithm to optimize the dithering technique for sinusoidal structured pattern representation. We believe both simulation and experimental results show that this proposed algorithm can substantially improve fringe quality for both narrow and wide fringe patterns.


Organization of primary visual cortex (area 17) in the ferret.
Anatomical and electrophysiological mapping techniques were used to determine topographic organization and arrangement of ocular dominance columns in the primary visual cortex of ferrets. From its border with area 18 on the posterior lateral gyrus, area 17 extends around the caudal pole of the hemisphere and over the splenial gyrus to the caudal bank of the splenial sulcus. The visuotopic map is oriented with the isoazimuth lines approximately parallel to the long axis of the posterior lateral gyrus and the isoelevation lines approximately perpendicular to the isoazimuths. Central azimuths are represented on the posterior lateral gyrus and peripheral azimuths are represented on the splenial gyrus; the inferior visual field maps medially and the superior visual field maps laterally. As in other species, the representation of the central visual field is expanded. The ferret has a considerable degree of binocular vision. Receptive fields driven through the ipsilateral eye extended more than 20 degrees into the contralateral visual field. Within the region of area 17 corresponding to the binocular portion of the visual field, tritiated proline injected into one eye transneuronally labelled an ipsilateral projection as a series of patchy bands roughly complementary to gaps in the labelled contralateral projection. Physiological ocular dominance columns were evident as well in that neurons and groups of neurons recorded in this region showed clustered ocular dominance preferences. Most single neurons studied were binocularly driven.


Reflective practice.
What was the nature of the CPD activity, practice-related feedback and/or event and/or experience in your practice? The CPD article provided a useful introduction to reflection, defined as a method of using experiential knowledge to enable professional and personal development, while reinforcing continuous learning.


Revisiting ESKAPE Pathogens: virulence, resistance, and combating strategies focusing on quorum sensing.
The human-bacterial association is long-known and well-established in terms of both augmentations of human health and attenuation. However, the growing incidents of nosocomial infections caused by the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter sp.) call for a much deeper understanding of these organisms. Adopting a holistic approach that includes the science of infection and the recent advancements in preventing and treating infections is imperative in designing novel intervention strategies against ESKAPE pathogens. In this regard, this review captures the ingenious strategies commissioned by these master players, which are teamed up against the defenses of the human team, that are equally, if not more, versatile and potent through an analogy. We have taken a basketball match as our analogy, dividing the human and bacterial species into two teams playing with the ball of health. Through this analogy, we make the concept of infectious biology more accessible.


Role of SPECT/CT in differentiated thyroid cancer.
Radioiodine scintigraphy and therapy has played a major role in the treatment and follow-up of thyroid cancer patients for decades. Single-photon emission computed tomography/computed tomography in this setting is emerging as a useful tool in accurately localizing sites of pathological uptake and physiological mimics of disease, thus providing more accurate staging prognostic information for risk stratification, which in turn tailors management and follow-up regimes. This review presents the current evidence and potential indications of single-photon emission computed tomography/computed tomography in thyroid cancer.


APP717, APP693, and PRIP gene mutations are rare in Alzheimer disease.
The amyloid precursor protein (APP) gene codes for the precursor to the beta-protein found in the amyloid deposits of Alzheimer disease (AD). Recently Goate et al. identified in codon 717 of this gene a missense mutation which segregates with AD in a familial AD (FAD) kindred. The same mutation was also found in affected subjects from a second FAD family but not in other FAD families or in normal controls. The following work was undertaken to determine the frequency of the codon 717 mutation in FAD and nonfamilial AD cases and in normal controls. We tested 76 FAD families, 127 "sporadic" AD subjects, 16 Down syndrome cases, and 256 normal controls for this mutation, and none were positive. We also tested for the APP codon 693 mutation associated with hereditary cerebral hemorrhage with amyloidosis-Dutch type, for PRIP gene missense mutations at codons 102, 117, and 200, and for the PRIP insertion mutations which are associated with Creutzfeld-Jakob disease and Gerstmann-Straussler Scheinker syndrome. No examples of these mutations were found in our population. Thus these APP and PRIP mutations are rare in both FAD and nonfamilial AD.


Evolutionary, structural and functional relationships revealed by comparative analysis of syntenic genes in Rhizobiales.
Comparative genomics has provided valuable insights into the nature of gene sequence variation and chromosomal organization of closely related bacterial species. However, questions about the biological significance of gene order conservation, or synteny, remain open. Moreover, few comprehensive studies have been reported for rhizobial genomes. We analyzed the genomic sequences of four fast growing Rhizobiales (Sinorhizobium meliloti, Agrobacterium tumefaciens, Mesorhizobium loti and Brucella melitensis). We made a comprehensive gene classification to define chromosomal orthologs, genes with homologs in other replicons such as plasmids, and those which were species-specific. About two thousand genes were predicted to be orthologs in each chromosome and about 80% of these were syntenic. A striking gene colinearity was found in pairs of organisms and a large fraction of the microsyntenic regions and operons were similar. Syntenic products showed higher identity levels than non-syntenic ones, suggesting a resistance to sequence variation due to functional constraints; also, an unusually high fraction of syntenic products contained membranal segments. Syntenic genes encode a high proportion of essential cell functions, presented a high level of functional relationships and a very low horizontal gene transfer rate. The sequence variability of the proteins can be considered the species signature in response to specific niche adaptation. Comparatively, an analysis with genomes of Enterobacteriales showed a different gene organization but gave similar results in the synteny conservation, essential role of syntenic genes and higher functional linkage among the genes of the microsyntenic regions. Syntenic bacterial genes represent a commonly evolved group. They not only reveal the core chromosomal segments present in the last common ancestor and determine the metabolic characteristics shared by these microorganisms, but also show resistance to sequence variation and rearrangement, possibly due to their essential character. In Rhizobiales and Enterobacteriales, syntenic genes encode a high proportion of essential cell functions and presented a high level of functional relationships.


The variability of the 16S rRNA gene in bacterial genomes and its consequences for bacterial community analyses.
16S ribosomal RNA currently represents the most important target of study in bacterial ecology. Its use for the description of bacterial diversity is, however, limited by the presence of variable copy numbers in bacterial genomes and sequence variation within closely related taxa or within a genome. Here we use the information from sequenced bacterial genomes to explore the variability of 16S rRNA sequences and copy numbers at various taxonomic levels and apply it to estimate bacterial genome and DNA abundances. In total, 7,081 16S rRNA sequences were in silico extracted from 1,690 available bacterial genomes (1-15 per genome). While there are several phyla containing low 16S rRNA copy numbers, in certain taxa, e.g., the Firmicutes and Gammaproteobacteria, the variation is large. Genome sizes are more conserved at all tested taxonomic levels than 16S rRNA copy numbers. Only a minority of bacterial genomes harbors identical 16S rRNA gene copies, and sequence diversity increases with increasing copy numbers. While certain taxa harbor dissimilar 16S rRNA genes, others contain sequences common to multiple species. Sequence identity clusters (often termed operational taxonomic units) thus provide an imperfect representation of bacterial taxa of a certain phylogenetic rank. We have demonstrated that the information on 16S rRNA copy numbers and genome sizes of genome-sequenced bacteria may be used as an estimate for the closest related taxon in an environmental dataset to calculate alternative estimates of the relative abundance of individual bacterial taxa in environmental samples. Using an example from forest soil, this procedure would increase the abundance estimates of Acidobacteria and decrease these of Firmicutes. Using the currently available information, alternative estimates of bacterial community composition may be obtained in this way if the variation of 16S rRNA copy numbers among bacteria is considered.


Real-Time Magnetic Resonance Imaging: Radial Gradient-Echo Sequences With Nonlinear Inverse Reconstruction.
The aim of this study is to evaluate a real-time magnetic resonance imaging (MRI) method that not only promises high spatiotemporal resolution but also practical robustness in a wide range of scientific and clinical applications. The proposed method relies on highly undersampled gradient-echo sequences with radial encoding schemes. The serial image reconstruction process solves the true mathematical task that emerges as a nonlinear inverse problem with the complex image and all coil sensitivity maps as unknowns. Extensions to model-based reconstructions for quantitative parametric mapping further increase the number of unknowns, for example, by adding parameters for phase-contrast flow or T1 relaxation. In all cases, an iterative numerical solution that minimizes a respective cost function is achieved with use of the iteratively regularized Gauss-Newton method. Convergence is supported by regularization, for example, to the preceding frame, whereas temporal fidelity is ensured by downsizing the regularization strength in comparison to the data consistency term in each iterative step. Practical implementations of highly parallelized algorithms are realized on a computer with multiple graphical processing units. It is "invisibly" integrated into a commercial 3-T MRI system to allow for conventional usage and to provide online reconstruction, display, and storage of regular DICOM image series. Depending on the application, the proposed method offers serial imaging, that is, the recording of MRI movies, with variable spatial resolution and up to 100 frames per second (fps)-corresponding to 10 milliseconds image acquisition times. For example, movements of the temporomandibular joint during opening and closing of the mouth are visualized with use of simultaneous dual-slice movies of both joints at 2 × 10 fps (50 milliseconds per frame). Cardiac function may be studied at 30 to 50 fps (33.3 to 20 milliseconds), whereas articulation processes typically require 50 fps (20 milliseconds) or orthogonal dual-slice acquisitions at 2 × 25 fps (20 milliseconds). Methodological extensions to model-based reconstructions achieve improved quantitative mapping of flow velocities and T1 relaxation times in a variety of clinical scenarios. Real-time gradient-echo MRI with extreme radial undersampling and nonlinear inverse reconstruction allows for direct monitoring of arbitrary physiological processes and body functions. In many cases, pertinent applications offer hitherto impossible clinical studies (eg, of high-resolution swallowing dynamics) or bear the potential to replace existing MRI procedures (eg, electrocardiogram-gated cardiac examinations). As a consequence, many novel opportunities will require a change of paradigm in MRI-based radiology. At this stage, extended clinical trials are needed.


The taming of a transposon: V(D)J recombination and the immune system.
The genes that encode immunoglobulins and T-cell receptors must be assembled from the multiple variable (V), joining (J), and sometimes diversity (D) gene segments present in the germline loci. This process of V(D)J recombination is the major source of the immense diversity of the immune repertoire of jawed vertebrates. The recombinase that initiates the process, recombination-activating genes 1 (RAG1) and RAG2, belongs to a large family that includes transposases and retroviral integrases. RAG1/2 cleaves the DNA adjacent to the gene segments to be recombined, and the segments are then joined together by DNA repair factors. A decade of biochemical research on RAG1/2 has revealed many similarities to transposition, culminating with the observation that RAG1/2 can carry out transpositional strand transfer. Here, we discuss the parallels between V(D)J recombination and transposition, focusing specifically on the assembly of the recombination nucleoprotein complex, the mechanism of cleavage, the disassembly of post-cleavage complexes, and aberrant reactions carried out by the recombinase that do not result in successful locus rearrangement and may be deleterious to the organism. This work highlights the considerable diversity of transposition systems and their relation to V(D)J recombination.


Loss of MeCP2 causes subtle alteration in dendritic arborization of retinal ganglion cells.
Methyl-CpG-binding protein (MeCP2) is highly expressed in neurons. It plays an important role in the development of synapses and the formation of circuits in the central nervous system (CNS). Mutations in MECP2 cause neurodevelopmental disorders and mental retardation in humans. Therefore, it has become important to determine the distribution and function of MeCP2 in vivo. The retina consists of three nuclear cell layers and two layers of synapses; neurons in each layer are connected to form fine circuits necessary for visual signal transduction. Using immunohistochemical analysis, we found that MeCP2 was expressed in all nuclear cell layers, with differences in the levels of MeCP2 expression observed among the layers. To understand the structural defects in the retina due to the loss of MeCP2, we sought to elucidate the organization of the retinal structure in the Mecp2 knockout (KO) mouse. Overall, we found a normal retinal structure in Mecp2 KO mice. However, because Mecp2 mutations have a highly variable effect on neuronal architecture, we analyzed morphological changes in a subset of retinal ganglion cells of Mecp2 KO mice. In Thy1-GFP mice crossed with Mecp2 mutant mice, Sholl intersections analyses showed a subtle increase in number of intersections due to increased branching proximal to the soma in Mecp2 KO mice. Our results demonstrate that the expression of MeCP2 and the effects of Mecp2 mutations are highly specific to tissue and cell types.


Selective regulation of 14-3-3eta in primary culture of cerebral cortical neurons and astrocytes during development.
The 14-3-3 proteins exist predominantly in the brain and may play regulatory roles in cellular processes of growth, differentiation, survival, and apoptosis. The biological functions, however, of the various 14-3-3 isoforms (beta, epsilon, eta, gamma, and zeta) in the brain remain unclear. We have reported previously upregulation of 14-3-3gamma in ischemic astrocytes. In the present study, we report selective regulation of 14-3-3eta in cultured cerebral cortical neurons and astrocytes during in vitro development. In cultured neurons, gene expression levels of 14-3-3eta increase with culture age (0-10 days). Brain-derived neurotrophic factor and neurotrophin-3 upregulate 14-3-3eta gene expression. In cultured astrocytes, 14-3-3eta is downregulated with culture age (1-5 weeks). The gene expression level of 14-3-3eta is not affected by scratch injury in astrocytes or by ischemia in neurons. These data suggest a possible role of 14-3-3eta in growth and differentiation of neurons and astrocytes, indicating an intricate mechanism governing coordinated and well-controlled developmental events in the brain to ensure normal neural functions.


Pharmacokinetic/Pharmacodynamic Modeling of Tulathromycin against Pasteurella multocida in a Porcine Tissue Cage Model.
Tulathromycin, a macrolide antibiotic, is used for the treatment of respiratory disease in cattle and swine. The aim of our study was to investigate the in vitro and ex vivo activities of tulathromycin in serum, (non-inflamed) transudate, and (inflamed) exudate against Pasteurella multocida in piglets. The pharmacokinetics properties of tulathromycin were studied for serum, transudate, and exudate using a tissue cage model. In vitro antibiotic susceptibility of P. multocida and dynamic time-kill curve experiments over eight tulathromycin concentrations were determined. The ratio of 24-h area under the concentration-time curve to minimum inhibitory concentration [AUC(0-24 h)/MIC] was recognized as an important pharmacokinetic/pharmacodynamic (PK/PD) parameter of tulathromycin for antibacterial efficiency (R2 = 0.9969). In serum ex vivo, for bacteriostatic, bactericidal activity, and virtual bacterial eradication AUC(0-24 h)/MIC values for tulathromycin were 44.55, 73.19, and 92.44 h by using sigmoid Emax model WinNonlin software, respectively, and lower values were obtained for exudate and transudate. In conjunction with the data on MIC90, the dose of tulathromycin for a bacteriostatic effect and virtual elimination of P. multocida as computed using the value of the PK/PD breakpoint obtained in serum were 6.39 and 13.25 mg/kg. However, it would be preferable to calculate a dose combined with population pharmacokinetics data to optimize the dosage regimen for bacteriological and clinical cure.


CHX10 mutations cause non-syndromic microphthalmia/ anophthalmia in Arab and Jewish kindreds.
Microphthalmia/anophthalmia is a clinically heterogeneous disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. The genetic defect underlying isolated autosomal recessive microphthalmia/anophthalmia is yet unclear. We studied four families (two of Arab origin, one of Bedouin origin, and one of Persian-Jewish origin) with autosomal recessive microphthalmia/anophthalmia and no associated eye anomalies, and one Syrian-Jewish family with associated colobomas. Assuming a founder effect in each of the families, we performed homozygosity mapping using polymorphic markers adjacent to human homologues of genes known to be associated with eye absence in various species, namely EYA1, EYA2, EYA3, SIX4, SIX6, PAX6 and CHX10. No association was found with EYA1, EYA2, EYA3, SIX6 or PAX6. In two families, linkage analysis was consistent with possible association with SIX4, but no mutations were found in the coding region of the gene or its flanking intron sequences. In three of the five families, linkage analysis followed by sequencing demonstrated that affected individuals in each family were homozygous for a different CHX10 aberration: a mutation in the CVC domain and a deletion of the homeobox domain were found in two Arab families, and a mutation in the donor-acceptor site in the first intron in the Syrian-Jewish family. There was phenotypic variation between families having different mutations, but no significant phenotypic variation within each family. It has been previously shown that mutations in a particular nucleotide in CHX10 are associated with an autosomal recessive syndrome of microphthalmia/anophthalmia with iris colobomas and cataracts in two families. We now show that different mutations in other domains of the same gene underlie isolated microphthalmia/anophthalmia.


An investigation into the usefulness of generalized regression neural network analysis in the development of level A in vitro-in vivo correlation.
Quantitative correlations between in vivo and in vitro data (IVIVC) reduce the number of human in vivo studies, thus decreasing the overall time and expenses necessary for the development of optimal drug product formulation. Although linear regression analysis represents the simplest relationship, it is recognized that IVIVC should not be limited to linear relationship. With regards to the implementation of non-linear IVIVC models and the ability of artificial neural network (ANN) computing to cope with non-linear relationships, the usefulness of ANN analysis in the development of IVIVC merits further evaluation. The present paper is an attempt to develop an IVIVC for model sustained release paracetamol matrix tablet formulations employing various correlation approaches based on linear and non-linear modeling of in vitro and in vivo data. Currently accepted compendial methodology was compared with the alternative approaches, involving general mixed effects model and generalized regression neural network (GRNN) analysis, in order to evaluate their usefulness for predicting the in vivo behavior of drug products. Although based on analogous approaches, data generated by GRNN were closer to those observed in vivo, leading to the higher level of IVIVC than obtained by convolution. It can be assumed that GRNN analysis was able to generalize complex relations between the output and input parameters and could account for the differences in drug release kinetics observed under various conditions in vitro, thus offering potential as a reliable and robust estimate of drug products in vivo behavior.


Bisphenol A-mediated suppression of LPL gene expression inhibits triglyceride accumulation during adipogenic differentiation of human adult stem cells.
The endocrine disrupting chemical, bisphenol A (BPA), has been shown to accelerate the rate of adipogenesis and increase the amount of triglyceride accumulation during differentiation of 3T3-L1 preadipocytes. The objective of this study was to investigate if that observation is mirrored in human primary cells. Here we investigated the effect of BPA on adipogenesis in cultured human primary adult stem cells. Continuous exposure to BPA throughout the 14 days of differentiation dramatically reduced triglyceride accumulation and suppressed gene transcription of the lipogenic enzyme, lipoprotein lipase (LPL). Results presented in the present study show for the first time that BPA can reduce triglyceride accumulation during adipogenesis by attenuating the expression of LPL gene transcription. Also, by employing image cytometric analysis rather than conventional Oil red O staining techniques we show that BPA regulates triglyceride accumulation in a manner which does not appear to effect adipogenesis per se.


PHYLOGENIES FROM RESTRICTION SITES: A MAXIMUM-LIKELIHOOD APPROACH.
Restriction sites data can be analyzed by maximum likelihood to obtain estimates of phylogenies. The likelihood methods of Smouse and Li, who were able to compute likelihoods for up to four species under a simplified model of base change, can be extended numerically to deal with any number of species. The computational methods for doing so are outlined. The resulting algorithms are slow but take multiple gains and losses of restriction sites fully into account, unlike parsimony methods. They allow for the failure to observe potential sites that are absent from all species. Analysis of the five-species hominoid data of Ferris and coworkers confirms the pattern found by Smouse and Li with four species-that a chimpanzee-gorilla clade is favored, but not statistically significantly over other tree topologies. A large data set produced by computer simulation has also been analyzed to confirm that the method works properly. The methods used here do not allow for different rates of transitions and transversions. They can be extended to do so, but only at a cost of considerably slower computations. The present method is available in a computer program.


Comparison between Simple Radiographic and Computed Tomographic Three-Dimensional Reconstruction for Evaluation of the Distal Metatarsal Articular Angle.
The hallux valgus is a pathologic condition in the forefoot that often causes pain and functional limitations. Assessing all deformity components, such as the distal metatarsal articular angle (DMAA) is essential to hallux valgus treatment. Nevertheless, interobserver agreement of DMAA is poor on plain radiographs. The present study compared computed tomographic (CT) 3-dimensional (3D) reconstruction with plain radiographic measurements for measuring the DMAA. We included 43 consecutive patients (77 feet), diagnosed with hallux valgus at the orthopedic outpatient clinic at Hospital de Clínicas de Porto Alegre (Porto Alegre, Brazil) from April 2014 to June 2015 in our prospective study. The DMAAs were measured by 2 observers using CT 3D reconstruction. The results were compared between observers and with the plain radiographic measurements using the concordance correlation coefficient and the Bland-Altman plot to determine the agreement between the 2 methods. The interobserver agreement of the CT 3D measurements was high (concordance correlation coefficient 0.90; p < .001). Significant agreement was found between the plain radiographic and CT measurements (concordance correlation coefficient 0.667; p < .001). The Bland-Altman plot showed that the difference between the plain radiographic and CT measurements increased when greater DMAA values were associated with the presence of metatarsal rotation. The interobserver agreement of DMAA measurements was greater on CT 3D reconstruction than on plain radiography. The poor interobserver agreement of the radiographic DMAA might have resulted from metatarsal rotation.


[Effects of starvation and refeeding in winter on the growth, survival, and biochemical composition of different size Ruditapes philippinarum].
From December 2007 to April 2008, a laboratory experiment was conducted to study the effects of various starvation periods followed by the same refeeding period on the growth, survival, and biochemical composition of different size Ruditapes philippinarum at water temperature 3.0 degrees C-4.2 degrees C, salinity 25-27, and pH 7.90-8.16. No significant differences in the growth characteristics of R. philippinarum at low temperatures were observed among different size groups. The tolerance to starvation increased with increasing size, while the survival rate decreased with increasing starvation period, point-of-no return (PNR50) was not observed during the study period. For the larger size group (7 mm), the body moisture and lipid concentrations generally decreased with increasing starvation period. During starvation, the body protein content increased initially as a result of lipid being utilized for energy, but decreased thereafter when the lipid was depleting. Ash content remained unchanged during the study period, and was not affected by starvation or refeeding.


Influence of sex on the functional assessment of myocardial ischemia.
Fractional flow reserve (FFR) and non-hyperemic resting pressure ratios, such as instantaneous wave-free ratio (iFR) and resting full-cycle ratio (RFR), are recommended for evaluating the significance of angiographically intermediate coronary stenoses. Despite their usefulness, approximately 20% of assessed lesions exhibit discordance between FFR and iFR/RFR. The role of sex in this discrepancy remains uncertain; thus, we aimed to investigate its impact on the discordance between FFR and iFR/RFR. We reviewed 417 consecutive intermediate stenotic lesions from 381 patients, stratified by sex and assessed with both FFR and iFR/RFR. FFR ≤0.80 and iFR/RFR ≤0.89 were considered positive for ischemia. Of the 381 patients, 92 (24.1%) were women. Women were older, had a lower estimated glomerular filtration rate (eGFR), higher ejection fraction, and were more likely to have peripheral artery disease than men. Median FFR and iFR/RFR values were lower in men than in women (FFR 0.86 vs. 0.80; P <0.001; iFR 0.92 vs. 0.90; P = 0.049). However, overall discordance prevalence was similar for both sexes (20.6% vs. 15.1%; P = 0.22). In men, eGFR, insulin-treated diabetes mellitus, and arterial hypertension were predictors of positive FFR | negative iFR/RFR discordance, while eGFR, insulin-treated diabetes mellitus, atrial fibrillation, and chronic obstructive pulmonary disease were predictors of negative FFR | positive iFR/RFR discordance. No factors associated with either discordance were identified in women. FFR and iFR/RFR results indicating significant ischemia were more common in men than women when assessing intermediate coronary stenoses. Nevertheless, sex did not predict discordant results.


Systems for the provision of oral health care in the Black Sea countries. Part 11: Serbia.
This paper gives an overview of the provision of health care in the Republic of Serbia. It then gives details of the system for the provision of oral health care, the education of dentists and dental staff, epidemiological data, and costs. It includes details of the state (public) and private sectors of health and dental care in Serbia. Private health and oral health care is based mainly on a number of practices that provide medical and dental care to the population. The state sector has a wider range of types of provision, including complex health care institutions. The number of employees in the private health and dental sector is much smaller than the number of employees in the public sector. Far fewer patients seek private medical and dental care than visit a doctor and dentist in the state sector, which still provides the bedrock for the health system in Serbia.