Somatic and visceral nociceptive inputs from the orofacial area and the upper alimentary tract converge onto CB-containing neurons in interstitial nucleus of the spinal trigeminal tract in rats.
The interstitial nucleus of the spinal trigeminal tract (INV) contains many calbindin-D28k-containing neurons (CB-neurons) receiving convergence information from the somatic and visceral structures. The purpose of the present study was to confirm whether the primary afferent terminals from the inferior alveolar nerve (IAN) make close contact and synaptic connections with the same CB-neurons receiving visceral nociceptive signals in INV. Biotinylated dextran amine (BDA) and horseradish peroxidase (HRP) tracing combined with CB and Fos proteins immunohistochemistry were used. After injections of BDA and formalin into unilateral IAN and upper alimentary tract, respectively, the transganglionic labeled afferent fibers and terminals from IAN were observed in the ipsilateral INV, especially in its enlarged part. A large number of CB- and Fos-like immunoreactive (LI) neurons were found in bilateral INV. These CB- and Fos-LI neurons mostly overlapped with BDA-labeled terminals in the enlarged part of INV. About one half of the CB-LI neurons were double labeled with Fos-LI nuclei (74/153). The terminals from IAN were to made close contacts with many CB/Fos-double labeled or CB-single labeled neurons. After injection of HRP into IAN, HRP-labeled fibers and terminals in INV were similar to that labeled with BDA. Under the electron microscope, a large number of CB-LI dendrites and a few soma in the enlarged part of INV were found to form asymmetrical axo-dendritic and axo-somal synapses with the HRP-labeled axon terminals. These results indicate that the orofacial somatic inputs from IAN and the visceral nociceptive inputs from the upper alimentary tract converge onto the same CB-containing neurons in INV. These CB-containing neurons in INV probably play an important role in information integration as well as visceral and cardiovascular activity.


Orientation Invariant Sensorimotor Object Recognition Using Cortical Grid Cells.
Grid cells enable efficient modeling of locations and movement through path integration. Recent work suggests that the brain might use similar mechanisms to learn the structure of objects and environments through sensorimotor processing. This work is extended in our network to support sensor orientations relative to learned allocentric object representations. The proposed mechanism enables object representations to be learned through sensorimotor sequences, and inference of these learned object representations from novel sensorimotor sequences produced by rotated objects through path integration. The model proposes that orientation-selective cells are present in each column in the neocortex, and provides a biologically plausible implementation that echoes experimental measurements and fits in with theoretical predictions of previous studies.


Combined acellular pertussis vaccines: new indication. No tangible benefit in primary vaccination.
(1) Two acellular pertussis vaccines included in pentavalent combinations are available in France. Their use was initially restricted to booster injections. This restriction has now been lifted, meaning that the two products can be used for primary vaccination. (2) The initial assessment files, which mainly concerned primary vaccination, showed that the acellular pertussis vaccines had fewer mild side effects than the cellular vaccine, but there was no evidence that they were as effective. (3) Some epidemiological studies with fairly short follow-up (about 2 years), conducted in various countries, suggest that the acellular vaccines confer clinical protection. There are no data comparing the bi- and tri-antigenic acellular vaccines marketed in France. (4) For the time being, the whole-cell pertussis vaccine remains the standard.


The influence of breastfeeding on cortical and bio-behavioural indicators of procedural pain in newborns: Findings of a randomized controlled trial.
The objective of this study was to compare the influence of breastfeeding and 24% oral sucrose on pain-related electrophysiologic activity, bio-behavioural pain scores, physiologic recovery, and adverse events during heel lance. Single-blind randomized controlled trial. 39 full-term infants were randomized to receive breastfeeding or 0.24 mL of 24% oral sucrose plus offered non-nutritive sucking 2 min prior to heel lance. The primary outcome of pain-related potential was recorded on electroencephalogram. Secondary outcomes included Premature Infant Pain Profile - Revised (PIPP-R) score, physiologic recovery, and adverse events. Data were analyzed per protocol (ClinicalTrials.gov: NCT03272594). Between November 2017 and January 2019, 20 infants were randomized to breastfeeding and 19 infants to receive oral sucrose. Infants who were breastfeeding had an appreciably smaller, yet not statistically different (F[1,15.9] = 0.58, p = 0.64, SE = 11.79), amplitude pain-related potential (peak amplitude 0.29 μV) following heel lance compared to infants who received oral sucrose (peak amplitude 8.97 μV). Mean PIPP-R scores were not statistically significantly different between groups following heel lance, however, they were indicative of low pain across groups. Mean time in seconds to physiologic recovery was faster in breastfeeding infants (M = 17.5, SD = 31.1) compared to oral sucrose (M = 70.8, SD = 144.3). There were no safety concerns. Breastfeeding and oral sucrose both reduce bio-behavioural responses to pain, however, may differentially modulate pain response in the infant brain. Further research to understand the neurophysiologic effects of these interventions during acute painful procedures is needed.


Progressive accumulation of the abnormal conformer of the prion protein and spongiform encephalopathy in the obex of nonsymptomatic and symptomatic Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease.
The purpose of our study was to describe the progressive accumulation of the abnormal conformer of the prion protein (PrP(CWD)) and spongiform degeneration in a single section of brain stem in Rocky Mountain elk (Cervus elaphus nelsoni) with chronic wasting disease (CWD). A section of obex from 85 CWD-positive elk was scored using the presence and abundance of PrP(CWD) immunoreactivity and spongiform degeneration in 10 nuclear regions and the presence and abundance of PrP(CWD) in 10 axonal tracts, the subependymal area of the fourth ventricle, and the thin subpial astrocytic layer (glial limitans). Data was placed in a formula to generate an overall obex score. Data suggests that PrP(CWD) immunoreactivity and spongiform degeneration has a unique and relatively consistent pattern of progression throughout a section of obex. This scoring technique utilizing a single section of obex may prove useful in future work for estimating the presence and abundance of PrP(CWD) in peripheral tissues and the nervous system in elk with CWD.


A novel pheromone quorum-sensing system controls the development of natural competence in Streptococcus thermophilus and Streptococcus salivarius.
In streptococcal species, the key step of competence development is the transcriptional induction of comX, which encodes the alternative sigma factor sigma(X), which positively regulates genes necessary for DNA transformation. In Streptococcus species belonging to the mitis and mutans groups, induction of comX relies on the activation of a three-component system consisting of a secreted pheromone, a histidine kinase, and a response regulator. In Streptococcus thermophilus, a species belonging to the salivarius group, the oligopeptide transporter Ami is essential for comX expression under competence-inducing conditions. This suggests a different regulation pathway of competence based on the production and reimportation of a signal peptide. The objective of our work was to identify the main actors involved in the early steps of comX induction in S. thermophilus LMD-9. Using a transcriptomic approach, four highly induced early competence operons were identified. Among them, we found a Rgg-like regulator (Ster_0316) associated with a nonannotated gene encoding a 24-amino-acid hydrophobic peptide (Shp0316). Through genetic deletions, we showed that these two genes are essential for comX induction. Moreover, addition to the medium of synthetic peptides derived from the C-terminal part of Shp0316 restored comX induction and transformation of a Shp0316-deficient strain. These peptides also induced competence in S. thermophilus and Streptococcus salivarius strains that are poorly transformable or not transformable. Altogether, our results show that Ster_0316 and Shp0316, renamed ComRS, are the two members of a novel quorum-sensing system responsible for comX induction in species from the salivarius group, which differs from the classical phosphorelay three-component system identified previously in streptococci.


Effect of the scaffold microenvironment on cell polarizability and capacitance determined by probabilistic computations.
In living systems, it is frequently stated that form follows function by virtue of evolutionary pressures on organism development, but in the study of how functions emerge at the cellular level, function often follows form. We study this chicken versus egg problem of emergent structure-property relationships in living systems in the context of primary human bone marrow stromal cells cultured in a variety of microenvironments that have been shown to cause distinct patterns of cell function and differentiation. Through analysis of a publicly available catalog of three-dimensional (3D) cell shape data, we introduce a family of metrics to characterize the 'form' of the cell populations that emerge from a variety of diverse microenvironments. In particular, measures of form are considered that are expected to have direct significance for cell function, signaling and metabolic activity: dimensionality, polarizability and capacitance. Dimensionality was assessed by an intrinsic measure of cell shape obtained from the polarizability tensor. This tensor defines ellipsoids for arbitrary cell shapes and the thinnest dimension of these ellipsoids, P 1, defines a reference minimal scale for cells cultured in a 3D microenvironment. Polarizability governs the electric field generated by a cell, and determines the cell's ability to detect electric fields. Capacitance controls the shape dependence of the rate at which diffusing molecules contact the surface of the cell, and this has great significance for inter-cellular signaling. These results invite new approaches for designing scaffolds which explicitly direct cell dimensionality, polarizability and capacitance to guide the emergence of new cell functions derived from the acquired form.


Synthesis of nucleotidylated poliovirus VPg proteins.
Phosphitylation of the side chain hydroxyl function of Fmoc protected tyrosine with 5'-phosphoramidites of suitably protected cytidine, adenosine, and guanosine, followed by oxidation gave three novel nucleotidylated amino acid building blocks. After protective group manipulation, these building blocks were used in a solid phase peptide synthesis to afford the nucleotidylated poliovirus proteins VPgpC, VPgpA, and VPgpG.


Contraceptive Decision-Making and the Importance of Side Effect Information Among a Sample of Latinas.
Context: U.S. Latinas have lower rates of contraceptive use and report more negative counseling experiences compared to non-Latina white women. Patient-centered approaches to contraceptive counseling are desired among Latinas and are also associated with patient satisfaction; yet, clinicians may not always use counseling methods that best support decision-making among marginalized groups. Objective: To examine Latinas' expectations of physician communication about contraceptive side effects, reported importance of personal knowledge about side effects, and the association of these with contraceptive use and use consistency. Materials and Methods: One hundred three self-identified Latinas aged 15-29 years at two urban federally qualified health centers completed a survey measuring factors associated with contraceptive use and consistency. Bivariate analysis was used to assess demographic and contraceptive information preferences. Associations between categorical variables were assessed using two-sided Fisher's exact tests. Continuous variables were compared using two-sided t-test. Results: The majority of respondents (85%) expected physicians to tell them about birth control side effects and reported that this information is important to use contraception, regardless of current contraceptive use. Among inconsistent and nonusers, importance of knowledge of side effects depended on expectations of information-sharing from physicians (p < 0.05). Conclusions: Expectations regarding side effect information-sharing by physicians and patient knowledge of side effects are important for the contraceptive decision-making process of this Latina group, regardless of contraceptive use. Clinicians engaging in contraceptive counseling should focus on providing clear and accurate information about side effects of discussed methods to facilitate informed decision-making and equitable, patient-centered contraceptive care for this vulnerable population.


p300 gene alterations in colorectal and gastric carcinomas.
Colorectal tumors frequently have loss of heterozygosity on chromosome 22q, suggesting that inactivation of tumor suppressor gene(s) on 22q participates in the tumor development. Neurofibromatosis 2 (NF2) gene and E1A binding protein p300 gene, recently identified on 22q, are thought to be candidates for tumor suppressor genes. In this study, mutation of the NF2 gene in 59 colorectal carcinomas, and mutation of the p300 gene in 27 colorectal and two gastric carcinomas, were analysed using PCR-SSCP, RT-PCR-SSCP and direct sequencing methods. Missense mutations of p300 gene were detected in a colorectal carcinoma, and in a gastric carcinoma, though no mutation of NF2 gene was detected. Both p300 mutations were somatic and coupled to deletion of the second allele of the gene, which suggests inactivation of the p300 gene, in these carcinomas. The mutations are located within the Cys/His-rich regions, which are assumed to play important roles in the function of p300. These are the first cases in which p300 gene has been found to be altered in both alleles, suggesting that inactivation of the p300 gene may be involved in the development of carcinomas, and that this gene may be the target of loss of 22q in carcinomas of the digestive tract.


Meta-analytical definition and functional connectivity of the human vestibular cortex.
Contrary to most other sensory systems, no consensus has been reached within the scientific community about the exact locations and functions of human cortical areas processing vestibular information. Metaanalytical modelling using activation likelihood estimation (ALE) for the integration of neuroimaging results has already been successfully applied to several distinct tasks, thereby revealing the cortical localization of cognitive functions. We used the same algorithm and technique with all available and suitable PET and fMRI studies employing a vestibular stimulus. Most consistently across 28 experiments vestibular stimuli evoked activity in the right hemispheric parietal opercular area OP 2 implicating it as the core region for vestibular processing. Furthermore, we took our primary results as a seeding point and fed them into a functional connectivity analysis based on resting-state oscillations in 100 healthy subjects. This subsequent calculation confirmed direct connections of the area OP 2 with every other region found in the meta-analysis, in particular temporo-parietal regions, premotor cortex, and the midcingulate gyrus. Thus revealing a joint vestibular network in accordance with a concept from animal literature termed the inner vestibular circle. Moreover, there was also a significant vestibular connectivity overlap with frontal but not parietal cortical centres responsible for the generation of saccadic eye movements, likely to be involved in nystagmus fast phase generation. This was shown in an additional ocular motor meta-analysis. We conclude that the cytoarchitectonic area OP 2 in the parietal operculum, embedded in a joint vestibular network, should be the primary candidate for the human vestibular cortex. This area may represent the human homologue to the vestibular area PIVC as proposed by Guldin and Grüsser in non-human primates.


Enhanced levels in neonatal rat liver of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxydeoxyguanosine), a major mutagenic oxidative DNA lesion.
The purpose of this study was to determine whether the level of 7,8-dihydro-8-oxo-2'-deoxyguanosine (8-hydroxy-2'-deoxyguanosine) (8-oxo-dG), a major mutagenic DNA oxidation product, is enhanced in newborn rat liver DNA as a consequence of oxidative stress incurred during the early postnatal period. 32P-postlabeling showed this adduct to increase approximately 2-fold from the 20th day of gestation (2 days before birth) to a peak level at 50-53 h after birth. Postnatal levels exceeded fetal levels at all time points investigated, i.e. 0.5-1, 8, 24, 50-53, 100, 216 and 432 h after birth. Increased formation of this mutagenic DNA lesion during the critical postnatal phase when there is rapid cell proliferation in all tissues is proposed to contribute to carcinogenesis in susceptible tissues later in life.


Disinvestment for re-allocation: a process to identify priorities in healthcare.
Resource scarcity and increasing service demand lead health systems to cope with choices within constrained budgets. The aim of the paper is to describe the study carried out in the Tuscan Health System in Italy on how to set priorities in the disinvestment process for re-allocation. The analysis was based on 2007 data benchmarking of the Tuscan Health System with an impact on the level of resources used. For each indicator, the first step was to estimate the gap between the performance of each Health Authority (HA) and the best performance or the regional average. The second step was to measure this gap in terms of financial value. The results of the analysis demonstrated that, at the regional level, 2-7% of the healthcare budget can be re-allocated if all the institutions achieve the regional average or the best practice. The implications of this study can be useful for policy makers and the HA top management. In the context of resource scarcity, it allows managers to identify the areas where the institutions can achieve a higher level of efficiency without negative effects on quality of care and instead re-allocate resources toward services with more value for patients.


A proteomic analysis of p53-independent induction of apoptosis by bortezomib in 4T1 breast cancer cell line.
The 26S proteasome is a proteolytic enzyme found in both cytoplasm and nucleus. In this study, we examined the differential expression of proteasome inhibitor bortezomib-induced proteins in p53-deficient 4T1 cells. It was found that GRP78 and TCEB2 were over-expressed in response to treatment with bortezomib for 24h. Next, we analyzed the expression of intracellular proteins in response to treatment with 100nM bortezomib for 24h by label-free LC-MS/MS. These analyses showed that Hsp70, the 26S proteasome non-ATPase regulatory subunit 14 and sequestosome 1 were increased at least 2 fold in p53-deficient 4T1 cells. The proteins identified by label-free LC-MS/MS were then analyzed by Ingenuity Pathway Analysis (IPA) Tool to determine biological networks affected by inhibition of the 26S proteasome. The analysis results showed that post-translational modifications, protein folding, DNA replication, energy production and nucleic acid metabolism were found to be among the top functions affected by the 26S proteasome inhibition. The biological network analysis indicated that ubiquitin may be the central regulator of the pathways modulated after bortezomib-treatment. Further investigation of the mechanism of the proteins modulated in response to the proteasomal inhibition may lead to the design of more effective and novel therapeutic strategies for cancer. Although the proteasome inhibitor bortezomib is approved and used for the treatment of human cancer (multiple myeloma), the mechanism of action is not entirely understood. A number of studies showed that proteasome inhibitors induced apoptosis through upregulation of tumor suppressor protein p53. However, the role of tumor suppressor protein p53 in bortezomib-induced apoptosis is controversial and not well-understood. The tumor suppressor p53 is mutated in at least 50% of human cancers and is strongly induced by proteasomal inhibition. Some also reported that the proteasome inhibitor can induce apoptosis in a p53-independent manner. Also, it is reported that Noxa, a target of p53, is induced in response to proteasomal inhibition in a p53-independent manner. However, we have also previously reported that neither Puma nor Noxa are induced by proteasomal inhibition in p53-null 4T1 breast cancer cells, which is commonly used for in vivo breast cancer tumor models. The current results provided additional targets of proteasome inhibitor bortezomib and may therefore help in understanding the p53-independent mechanism of apoptosis induction by proteasome inhibitors. In addition, the results presented in this current study report for the first time that proteasomal subunit Psmd14, anti-apoptotic GRP78, anti apoptotic protein Card10, Dffb, Traf3 and Trp53bp2 are regulated and overexpressed in response to proteasome inhibitor bortezomib in p53-deficient 4T1 cells. Therefore, novel therapeutic strategies targeting these anti-apoptotic or pro-apoptotic proteins as well as inhibiting the proteasome simultaneously may be more effective against cancer cells. The proteins identified here present new avenues for the development of anti-cancer drugs.


[Influence of a combination of environmental factors on elementary school children].
Three-year ecological, hygienic, and physiological studies of the influence of a combination of environmental factors on the functional status in 510 junior schoolchildren have established that the leading determinants of the formation of the habitat of junior schoolchildren from the educational establishments under study are the irrational organization of a learning process, poor educational conditions, sociohygienic living conditions and lifestyle in the family, the level of environmental pollution. Dispersion and factorial analyses have established that there is a relationship between the quantitative and qualitative characteristics of these factors, as well as between the performance of the central nervous and cardiovascular systems and the increase in the incidence of diseases in the pupils. The findings may be used to draw up research-and-practical recommendations on the optimization of training of junior pupils on organizing gymnasium-type education and on their health promotion whose introduction will increase the reserve capacities of the children and preserve their health.


Intra-arterial abciximab for the treatment of thrombus formation during coil embolization of intracranial aneurysms.
Thrombus formation during endovascular embolization of intracranial aneurysms occurs in 2.9%-6% of patients. Use of IIb/IIIA inhibitors such as abciximab or eptifibatide intravenously has been reported in management of this complication. Because the intra-arterial infusion of IIb/IIIA inhibitors may require lower doses to achieve thrombolysis, it may reduce the risk of haemorrhage. Therefore, we retrospectively analyze our database and review the literature. This is a retrospective analysis of a prospectively acquired database of patients with ruptured or unruptured aneurysm treated intra-arterially for thrombus formation during endovascular coil embolization between July 2005 and August 2008. Patient demographics, aneurysmal characteristics, procedural, clinical outcome and complications were recorded. From July 2005 to August 2008, out of 184 patients who underwent coil embolization, 19 patients (15 smokers, 14 female, mean age 52) developed intraprocedural thrombus formation and received intra-arterial abciximab treatment. Mean aneurysm size was 6.6 mm±4.9 mm; neck size was 3.8 mm±2.1 mm. Eight (42.1%) aneurysms were ruptured. Most aneurysms (63.1%) were in anterior communicating and middle cerebral arteries. Thrombus was visualized in all cases by angiogram and treated intra-arterially with a mean dose of 10.5 mg±4.2. There were no periprocedural hemorrhagic complications. No deaths or other complications occurred during follow-up. Thrombus formation during coil embolization of intracranial aneurysms occurred more in women and smokers. Low doses of intra-arterial abciximab may be effective in the thromboembolic complications occurring during endovascular embolization of intracranial aneurysms.


Potential modulation of cancer progression by oxysterols.
At least with regard to promotion and progression of cancer, oxysterols actually appear as typical Janus molecules, by inducing early inflammatory reaction against cancer expansion and apoptotic death of cancer cells, but on the other hand sustaining a complex survival signaling pathway that eventually turns in favor of the neoplastic process itself. The pro-tumoral and anti-tumoral properties of this class of compounds is mediated by both LXR-dependent and independent mechanisms. The extent of oxidative redox imbalance, moderate or extensive, likely plays a key role in determining the actual effects operated by oxysterols along the various steps of carcinogenesis.


Medical Comorbidities Associated With Outcomes in Patients With Traumatic Epidural Hematomas.
Background Traumatic brain injury (TBI) is a frequently encountered neurosurgical pathology with significant morbidity and mortality. One such subtype is the epidural hematoma. Literature regarding the effects of comorbidities in TBI and epidural hematomas is limited. Methodology This was a single-center retrospective review of 50 consecutive patients admitted to a level two trauma center with epidural hematomas. Patients were identified using an internal trauma database. Patients were included if they were 18 years of age with a diagnosed epidural hematoma. Outcome variables of Glasgow coma scale (GCS), length of stay in the intensive care unit (ICU) and hospital, and requirement of a neurosurgical procedure were analyzed. Identification of the presence of diagnosed comorbidities was performed including common comorbidities such as obesity, diabetes, hypertension, hyperlipidemia, drug use, tobacco use, cancer, psychiatric disease, and renal disease. Correlations were evaluated using two-sided bivariate analysis (p < 0.05). Results A total of 50 patients were included for analysis. Significant correlations with a p-value less of than 0.05 were noted in initial GCS and cancer (r = -0.357, p = 0.011), requirements of an intracranial procedure with a history of gastrointestinal disease (r = 0.377, p = 0.007), and younger age (r = -0.306, p = 0.031). Increased ICU length of stay was related to a history of cancer (r = 0.494, p < 0.001), a history of respiratory disease (r = 0.427, p = 0.002), and a history of psychiatric disease (r = 0.297, p = 0.036). Increased hospital length of stay was related to psychiatric disorders (r = 0.285, p = 0.045). Discharge GCS was negatively associated with a history of hypertension (r = -0.374, p = 0.008), tobacco use (r = -0.417, p = 0.003), drug use (r = -0.294, p = 0.037), and history of cancer (r = -0.303, p = 0.032). Discussion and Conclusions In our 50 consecutive patient subset, selected comorbidities demonstrated significant relationships with outcome measures of GCS, need for a procedure, and lengths of stay in the hospital and ICU. Obtaining comorbidity information when available from families can better allow the clinician to optimize treatment and educate loved ones about the potential effects of these comorbidities on the overall health of the patient. Understanding these correlations may allow for a better understanding of the systemic effects of the pathophysiology of injury in epidural hematomas.


Tools for precision enhancement in minimally invasive cardiac surgery: three dimensional visualization, computer enhancement and robotics.
This article is a current update of the rationale for development of new enabling technologies in minimally invasive cardiac surgery. Specifically the potential advantages of three dimensional visualization, computer enhancement technology and robotics in performance of totally endoscopic coronary artery bypass grafts will be addressed.


Theory of mind and conceptual change.
We agree with the commentaries by Scholl and Leslie, and also by Moses, that the meta-analytic findings do not definitively rule out early competence accounts. But they do make extant versions of such accounts increasingly unlikely. In particular, the meta-analytic findings argue against executive function expression accounts, including the Theory-of-Mind Mechanism/Selection Processor account advocated by Scholl and Leslie. Specifically, Scholl and Leslie articulate two explicit predictions of their account: that task manipulations that attenuate inhibitory demands should differentially advantage older children, and that theory-of-mind developments should occur with consistent timetables. Both of these specific predictions are clearly contradicted, not supported, by the meta-analytic findings.


The severity of functional mitral regurgitation depends on the shape of the mitral apparatus: a three-dimensional echo analysis.
The relationship between structural abnormalities of the mitral apparatus and severity of functional mitral regurgitation (MR) was examined in patients with non-ischemic dilated cardiomyopathy. Three-dimensional (3D) echocardiography was performed in 13 cardiomyopathy patients with mild (n = 5) or moderate to severe (n = 8) MR, and in eight normal volunteers using freehand scanning. The size, shape and function of the left ventricle, and the dimensions of the mitral annulus, chordae tendineae and papillary muscles, were measured. Virtually all parameters differed significantly between normal subjects and cardiomyopathy patients. Annular size, the central angle between the anterior and posterior chordae, and dilatation of the anterior and anterolateral left ventricular (LV) wall were greater in patients with moderate to severe MR than in those with trace to mild MR. Anterior wall dilatation was associated with greater outward displacement of the anterior papillary muscle, and correlated with widening of the central chordal angle, apical displacement of the mitral leaflet coaptation point, and mitral annular dilatation. In non-ischemic dilated cardiomyopathy, functional MR is related to both annular dilatation and to dilatation of the anterior and anterolateral LV wall. The latter results in displacement of the anterior papillary muscle, narrowing of the angle of the anterior chorda to the mitral annulus, and widening of the central angle between the anterior and posterior chordae.


Impact of human immunodeficiency virus type-1 sequence diversity on antiretroviral therapy outcomes.
Worldwide circulating HIV-1 genomes show extensive variation represented by different subtypes, polymorphisms and drug-resistant strains. Reports on the impact of sequence variation on antiretroviral therapy (ART) outcomes are mixed. In this review, we summarize relevant published data from both resource-rich and resource-limited countries in the last 10 years on the impact of HIV-1 sequence diversity on treatment outcomes. The prevalence of transmission of drug resistant mutations (DRMs) varies considerably, ranging from 0% to 27% worldwide. Factors such as geographic location, access and availability to ART, duration since inception of treatment programs, quality of care, risk-taking behaviors, mode of transmission, and viral subtype all dictate the prevalence in a particular geographical region. Although HIV-1 subtype may not be a good predictor of treatment outcome, review of emerging evidence supports the fact that HIV-1 genome sequence-resulting from natural polymorphisms or drug-associated mutations-matters when it comes to treatment outcomes. Therefore, continued surveillance of drug resistant variants in both treatment-naïve and treatment-experienced populations is needed to reduce the transmission of DRMs and to optimize the efficacy of the current ART armamentarium.


Medicaid expenditures for the disabled under a work incentive program.
Congress enacted Section 1619 of the Social Security Act to enable the disabled receiving Supplemental Security Income (SSI) to obtain jobs and still retain Medicaid health benefits. Congress intended this work incentive to remove the fear of the severely disabled that by obtaining employment they would lose Medicaid benefits. Based on data from 11 States, our analysis found that Medicaid expenditures for Section 1619 enrollees were relatively small and only one-half the average Medicaid expenditure for the disabled. Retaining Medicaid appears to provide a significant work incentive because Medicaid expenditures represent 13 percent of Section 1619 enrollees' earnings.


Evaluation of commercial von Willebrand factor collagen binding assays to assist the discrimination of types 1 and 2 von Willebrand disease.
This study reports on the evaluation of seven commercial von Willebrand factor (VWF) collagen binding (VWF:CB) assays to potentially assist the discrimination of types 1 and 2 von Willebrand disease (VWD). Samples from 25 patients with type 1 VWD, of varying severity, were co-tested with 16 samples from patients with types 2A or 2B VWD, plus various control samples, using each commercial VWF:CB assay assessed against our standard (reference) in-house VWF:CB assay, as well as our in-house VWF antigen (VWF:Ag) and ristocetin cofactor (VWF:RCo) assays. Commercial VWF:CB assays varied in their ability to discriminate types 1 and 2A/2B VWD. The optimal VWF:CB/VWF:Ag ratio at which optimal discrimination occurred also differed between assays, with some improvements observed with some (but not all) assays following a harmonisation process that aimed to correct for different calibrator effects. Assay variability also compromised assay utility in some test occasions. Future standardisation and improvements in some commercial VWF:CB assays are needed before the VWF:CB assay can be more fully and globally utilised for discrimination of VWD types in diagnostic laboratories.


Adenovirus pneumonia in guineapigs: an experimental reproduction of the disease.
The recently described virus-induced pneumonia in guineapigs (Naumann et al., 1981) was experimentally reproducible in newborn animals, though not in preadult animals. Baby hamsters and newborn rats were also not susceptible to infection. 10 of 11 infected newborn guineapigs developed pathological changes identical with those found in spontaneous cases. The incubation period was from 5 to 10 days. The agent could not be cultivated in vitro, and therefore no applicable serological tests could be established. The morphology of the virus, its intranuclear location, the course of the disease and the histopathological and ultrastructural changes strongly suggest that the virus is an adenovirus specific for guineapigs. The virus did not cross-react with human or fowl adenoviruses. It was ether resistant and non-oncogenic in baby rats and hamsters. During a 5-year period we registered a total of 51 spontaneous death cases diagnosed as adenovirus pneumonia in our experimental guineapigs, 4 from own breeding colony.


Brain tissue penetration of ciprofloxacin following a single intravenous dose.
Ciprofloxacin distribution was assessed in cerebral tissues in 14 patients undergoing craniotomy. The study objective was to determine the brain tissue/serum concentration ratio of ciprofloxacin. Patients received a single intravenous (iv) 200 mg dose of ciprofloxacin. Mean (+/- S.D.) tissue/serum concentration ratios were (mg/kg): parietal fat during opening 1.40 +/- 1.05, during closure 1.34 +/- 1.17, in the dura mater 2.26 +/- 1.36, in skull bone during opening 0.44 +/- 0.29, during closure 0.97 +/- 1.57 and in brain tissue 0.88 +/- 0.99. Mean (+/- S.D.) concentrations of ciprofloxacin in brain tissue were 0.87 +/- 0.08 mg/kg, suggesting that a dose >200 mg iv ciprofloxacin is required to ensure therapeutic concentrations in brain tissue.


Genome-wide association studies of cancer predisposition.
Genome-wide association studies (GWAS) have now been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer. For most discovered germline risk variants, the per allele effect size is small (<1.5) and the biologic mechanism of the detected association remains unexplained. Exceptions are the risk variants identified in JAK2 in myeloproliferative neoplasm and in the KITLG gene in testicular cancer, which are each associated with nearly a 3-fold increased risk of disease. GWAS have provided an efficient approach to identifying common, low-penetrance risk variants, and have implicated several novel cancer susceptibility loci. However, the identified low-penetrance risk variants explain only a small fraction of the heritability of cancer and the clinical usefulness of using these variants for cancer-risk prediction is to date limited. Studies involving more heterogeneous populations, determination of the causal variants, and functional studies are now necessary to further elucidate the potential biologic and clinical significance of the observed associations.


Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.
Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.


Postoperative spinal cord ischaemia: magnetic resonance imaging and clinical features.
Ischaemic spinal cord injury (SCI) is one of the most serious complications of aortic surgery. Ischaemic SCIs occur due to various aetiologies, and prediction of the risk is difficult. Magnetic resonance imaging (MRI) is useful to detect the details of spinal cord infarction. There are few studies about MRI for evaluating ischaemic SCI after cardiovascular surgery and aortic events. We report 9 cases of postoperative ischaemic SCI and analyse their MRI features. T2-weighted MRI scans of 9 patients who developed ischaemic SCI due to cardiovascular surgery and aortic events between 2012 and 2017 were evaluated. In all patients, high-intensity areas were observed on T2-weighted magnetic resonance images. The site of infarction was the thoracic spinal cord level (9 cases) and additionally at the lumbar spinal cord level (5 cases). The area of infarction area was categorized based on the arterial territory: anterior spinal artery territory (3 cases), posterior spinal artery territory (2 cases), spinal sulcal artery territory (1 case) and artery of Adamkiewicz territory (3 cases). MRI revealed the infarction sites in all cases and the differences in the infarction patterns in each case. MRI could thus be useful for investigating the aetiology of ischaemic SCI following aortic surgeries and events.


Lipid metabolic pathways as lung cancer therapeutic targets: a computational study.
Inhibitors of lipid metabolic pathways, particularly drugs targeting the mevalonate pathway, have been suggested to be valuable in enhancing the effectiveness of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and these compounds may also be effective in patients with inherent or acquired resistance to EGFR-TKIs. The present study examined gene expression profiles in lung adenocarcinoma to characterize the interaction between growth factor signals and lipid metabolic pathways at the transcriptional level. Gene expression correlation analysis showed that genes involved in the mevalonate pathway and unsaturated fatty acid synthesis were negatively correlated with the expression of EGFR, MET and other growth factor receptor genes, as well as with the expression of genes involved in cell migration and adhesion. On the other hand, the expression of genes related to cell cycle progression, DNA repair and DNA replication were positively correlated with the metabolic pathway genes mentioned above, and a significant number of such genes had promoter domains for nuclear factor Y (NFY). Genes whose expression showed a positive correlation with NFY expression and mevalonate pathway genes were found to exhibit protein-protein interactions with several 'hub' genes, including BRCA1, that have been associated with both lung cancer and cell division. These results support the idea that inhibition of lipid metabolic pathways may be valuable as an alternative therapeutic option for the treatment of lung adenocarcinoma, and suggest that NFY is a possible molecular target for such efforts.


Anisotropic effective interactions and stack formation in mixtures of semiflexible ring polymers.
By means of extensive computer simulations, we investigate the formation of columnar structures (stacks) in concentrated solutions of semiflexible ring polymers. To characterize the stacks we employ an algorithm that identifies tube-like structures in the simulation cell. Stacks are found both in the real system and in the fluid of soft disks interacting through the effective anisotropic pair potential derived for the rings [P. Poier et al., Macromolecules, 2015, 48, 4983-4997]. Furthermore, we investigate binary mixtures of cluster-forming and non-cluster-forming rings. We find that monodispersity is not a requirement for stack formation. The latter is found for a broad range of mixture compositions, though the columns in the mixtures exhibit important differences to those observed in the monodisperse case. We extend the anisotropic effective model to mixtures. We show that it correctly predicts stack formation and constitutes a significant improvement with respect to the usual isotropic effective description based only on macromolecular centers-of-mass.


[Determination of melamine in milk and milk-containing products by capillary zone electrophoresis].
For determination of melamine methods of reversed phase and ion-pair high-performance liquid chromatography, and also immune-enzyme analysis are used. The purpose of our work was working out of a technique of determination melamine in milk and lactiferous products method CZE. As a result of researches determination conditions melamine in foodstuff by method CZE (sensitivity from 0.8-1.0 mg/l) are developed, and also conditions of its isolation from objects of research are adapted.


Effect of Topical Anesthesia with Lidocaine-prilocaine (EMLA) Cream and Local Pressure on Pain during Infiltration Injection for Maxillary Canines: A Randomized Double-blind clinical trial.
This study compared the effect of local pressure and topical lidocaine-prilocaine (EMLA) cream on pain during infiltration injection for maxillary canine teeth. A total of 140 volunteer students participated in this split-mouth design randomized clinical trial. The subjects were randomly divided into four groups (n = 35). Before administration of anesthesia, in each group, one side was randomly selected as the experimental and the opposite side as the control. In group 1, finger pressure was applied on the alveolar mucosa on the experimental side and on the tooth crown on the control side. In group 2, 5% EMLA cream and placebo; in group 3, finger pressure and 5% EMLA cream; and in group 4, 5% EMLA cream and 20% benzocaine gel were applied. In all the groups, a buccal infiltration procedure was carried out. Pain during injection was recorded with visual analog scale (VAS). Wilcoxon and McNemar tests were used for statistical analysis of the results. Statistical significance was set at p < 0.05. The results showed that EMLA reduced the injection pain significantly more than benzocaine (p = 0.02). Also, injection pain was significantly lower with the use of EMLA in comparison to placebo (p = 0.00). Application of local pressure reduced the injection pain, but the difference from the control side was not significant (p = 0.05). Furthermore, the difference between application of local pressure and EMLA was not statistically significant (p = 0.08). Topical anesthesia of 5% EMLA was more effective than 20% benzocaine in reducing pain severity during infiltration injection. However, it was not significantly different in comparison to the application of local pressure.


Factors associated with larval control practices in a dengue outbreak prone area.
In order to reduce the risk of dengue outbreak recurrence in a dengue outbreak prone area, the members of the community need to sustain certain behavior to prevent mosquito from breeding. Our study aims to identify the factors associated with larval control practices in this particular community. A cross-sectional study involves 322 respondents living in a dengue outbreak prone area who were interviewed using a pretested questionnaire. The level of knowledge about Aedes mosquitoes, dengue transmission, its symptoms, and personal preventive measures ranges from fair to good. The level of attitude towards preventive measures was high. However, reported level of personal larval control practices was low (33.2%). Our multiple logistic regression analysis showed that only those with a good level of attitude towards personal preventive measure and frequent attendance to health campaigns were significantly associated with the good larval control practices. We conclude that, in a dengue outbreak prone area, having a good attitude towards preventive measures and frequent participation in health campaigns are important factors to sustain practices on larval control.


Glycerol-3-phosphate acyltransferase 6 controls filamentous pathogen interactions and cell wall properties of the tomato and Nicotiana benthamiana leaf epidermis.
The leaf outer epidermal cell wall acts as a barrier against pathogen attack and desiccation, and as such is covered by a cuticle, composed of waxes and the polymer cutin. Cutin monomers are formed by the transfer of fatty acids to glycerol by glycerol-3-phosphate acyltransferases, which facilitate their transport to the surface. The extent to which cutin monomers affect leaf cell wall architecture and barrier properties is not known. We report a dual functionality of pathogen-inducible GLYCEROL-3-PHOSPHATE ACYLTRANSFERASE 6 (GPAT6) in controlling pathogen entry and cell wall properties affecting dehydration in leaves. Silencing of Nicotiana benthamiana NbGPAT6a increased leaf susceptibility to infection by the oomycetes Phytophthora infestans and Phytophthora palmivora, whereas overexpression of NbGPAT6a-GFP rendered leaves more resistant. A loss-of-function mutation in tomato SlGPAT6 similarly resulted in increased susceptibility of leaves to Phytophthora infection, concomitant with changes in haustoria morphology. Modulation of GPAT6 expression altered the outer wall diameter of leaf epidermal cells. Moreover, we observed that tomato gpat6-a mutants had an impaired cell wall-cuticle continuum and fewer stomata, but showed increased water loss. This study highlights a hitherto unknown role for GPAT6-generated cutin monomers in influencing epidermal cell properties that are integral to leaf-microbe interactions and in limiting dehydration.


Link between traditional cardiovascular risk factors and inflammation in patients with early arthritis: results from a French multicenter cohort.
To compare the characteristics of traditional cardiovascular risk factors for untreated patients with early arthritis (EA) and healthy subjects, and to look for a link between cardiovascular risk factors and inflammation in EA patients. This multicenter case-control study enrolled 607 patients with EA (ESPOIR cohort) and 1,821 age- and sex-matched controls (World Health Organization MONICA survey). Lipid levels, blood pressure, glucose levels, and exposure to smoking were characterized in patients and controls. Systemic inflammation was quantified in EA patients. Traditional cardiovascular risk factor characteristics were compared between patients with EA and controls. The link between cardiovascular risk factors and inflammation was assessed in EA patients. Mean ± SEM total cholesterol (2.14 ± 0.022 versus 2.34 ± 0.017 gm/liter; P < 0.001), high-density lipoprotein (HDL) cholesterol (0.60 ± 0.011 versus 0.63 ± 0.007 gm/liter; P = 0.020), and low-density lipoprotein (LDL) cholesterol (1.28 ± 0.025 versus 1.51 ± 0.016 gm/liter; P < 0.001) were lower in EA patients than in controls. Triglycerides, triglycerides/HDL ratio, and pulse pressure were higher in patients with EA. Diastolic blood pressure and glucose levels were lower in EA patients. Former or current smokers were more frequent in patients with EA. Total and HDL cholesterol levels were negatively associated with C-reactive protein or serum interleukin-6 levels. Total, HDL, and LDL cholesterol, triglycerides, diastolic blood pressure, pulse pressure, glucose, and triglycerides/HDL ratio differ between patients with EA and controls. Some of these risk factors appear to be linked to systemic inflammation. Such initial differences could modulate the risk of cardiovascular events later in the course of arthritis.


[Trends in traffic accidents in Campinas, São Paulo State, Brazil: the increasing involvement of motorcyclists].
In order to describe trends in traffic accidents, mortality, vehicle types, fleet sizes, and victims' characteristics in Campinas, São Paulo State, Brazil, from 1995 to 2008, this study analyzed vehicle rates, traffic accident rates per inhabitant and per vehicle, case-fatality rates, proportional mortality, mortality rates, and rates ratios. The motorcycle fleet increased 241%. Although the case-fatality rate of motorcycle users from 2000 to 2008 decreased, in 2008 they accounted for 49.3% of fatal accidents on public byways in Campinas. Motorcycles were responsible for the highest run-over rate (66.7 pedestrians/1,000 accidents) and highest pedestrian fatality rate (4 deaths/1,000 accidents). Men showed much higher mortality rates than women. Pedestrian victims were mainly elderly; most vehicle occupants in traffic accidents were in the 15 to 29-year age bracket. From 2006 to 2008, nearly 80% of vehicle users 15 to 39 years of age were motorcyclists. Motorcycle accident prevention should be a priority, using multi-institutional measures.


[Transmural myocardial infarction and Prinzmetal's syndrome in an allergic reaction to glafenine. Physiopathological discussion. Apropos of a case].
The authors report the case of a 38 year old man who experienced at two month' interval, hypersensitivity reactions to the ingestion of 200 mg tablets of glafenine, complicated on the first occasion by a transmural anterior wall myocardial infarction as the first manifestation of coronary artery disease and on the second occasion by Prinzmetal angina due to posterior wall ischaemia. Coronary angiography was more or less normal. The timing of the symptoms in the context of an anaphylactic reaction and their repetition when the same molecule was reintroduced are strong arguments in favour of the pathogenic role of glafenine, even in the absence of biological criteria which are always variable. The mechanism of the coronary problems is discussed with reference to mediators released during the anaphylactic reaction: coronary vasoconstriction due to histamine and leukotriene release; inhibition of prostaglandin synthesis causing potentiation of the effects of histamine; lowering of the vasodilatory and antiaggregant prostacyclin enhancing the vasoconstrictor and platelet aggregant action of thromboxane A2. All the conditions favouring the initiation of coronary spasm with eventual coronary thrombosis, the one aggravating the other, are therefore present.


Hypoglossal nerve stimulation for treatment of obstructive sleep apnea (OSA): a primer for oral and maxillofacial surgeons.
The prevalence of obstructive sleep apnea (OSA) is estimated to be 1-5% of the adult population world-wide, and in Korea, it is reported at 4.5% of men and 3.2% of women (Age 40 to 69 years old). Active treatment of OSA is associated with decrease in insulin resistance, cardiovascular disease, psychosocial problems, and mortality. Surgical treatment of OSA has evolved in the era of neuromodulation with the advent of hypoglossal nerve stimulation (HGNS). We share this review of HGNS with our maxillofacial surgical colleagues to expand the scope of surgical care for OSA.


In vitro antimycobacterial and antilegionella activity of licochalcone A from Chinese licorice roots.
Licochalcone A, extracted and purified from Chinese licorice roots, showed in vitro inhibitory effect on human pathogenic Mycobacteria species and Legionella species. M. tuberculosis, M. bovis and BCG were inhibited by < 20 mg/l licochalcone A, whereas all non- M. tuberculosis complex species were resistant to > 20 mg/l Legionella pneumophila (serogroups 1 - 7) and L. bozemanii, L. dumoffii, L. feelei, L. longbeacheae and L. wadsworthii were inhibited by licochalcone A 1 - 4 mg/l, whereas L. gormanii and L. micdadei were inhibited by licochalcone A 500 - 1000 mg/l. These data indicate that licochalcone A might be of interest as a new class of antibacterial drug in the treatment of severe lung-infections.


[Surgical resection standard and prognostic analysis of non-small cell lung cancer].
To investigate the effect of complete resection standards on the prognosis of non-small cell lung cancer. Clinical data of 2 711 inpatient cases treated from January 2000 to December 2008 at our hospital were retrospectively reviewed. The relationship between surgical resection standard and the overall survival and other factors affecting the overall survival was analyzed. The overall 5-year survival rate was 44.6%. The overall 5-year survival rate of stage IA, IB, IIA, IIB, IIIA cases was 60.5%, 55.4%, 43.1%, 37.0% and 28.1%, respectively. The 5-year survival rate of patients who underwent complete resection was 50.3%, and that of patients who underwent incomplete resection was only 40.1% (P < 0.01). The main prognostic factors were operation type, resection margin, pathological type, T stage, N stage, TNM stage, the number of dissected lymph node (LN) stations (<6 and ≥ 6), the number of resected lymph nodes (1-10, 11-20, and >20), postoperative radiotherapy and complete resection (P < 0.05 for all). Cox regression suggested that TNM stage and complete resection were independent factors affecting the prognosis. Adjuvant chemotherapy affected the prognosis of stage II-IIIA patients. TNM stage and complete resection are independent factors affecting the prognosis of NSCLC patients. The 5-year survival rate of NSCLC has significantly increased through promoting the standard of operation, especially increasing the standard of lymph node dissection. The standard of complete resection should be recommended to be used in clinical practice. Adjuvant chemotherapy is beneficial for stage II-IIIA NSCLC patients.


Components of the multicatalytic proteinase complex.
The multicatalytic proteinase complex is a high molecular weight nonlysosomal proteinase. Kinetic studies of the proteolytic activities of the complex have shown that there are at least three distinct types of catalytic centre, each of which has a different specificity. All of the activities can be inhibited by the serine protease inhibitor 3,4-dichloroisocoumarin. Viewed under the electron microscope, the multicatalytic proteinase purified from rat liver appears to have a hollow cylindrical structure. It is composed of many different types of subunit and on two-dimensional polyacrylamide gels gives rise to a complex pattern of about 20 spots with pI values ranging between 5 and 8.5 and molecular masses between 22 and 34 kDa. Immunoblot analysis has shown that many of the major polypeptides are antigenically distinct. However, there are some relationships between the proteinase polypeptides. For example, although N-terminal sequences of five of the polypeptides are unique, they show considerable sequence similarity suggesting that these proteins are encoded by members of the same gene family. Also, there is some cross-reactivity between certain polypeptides when blots are probed with affinity purified, subunit-specific antisera. In addition to the variety of polypeptide components of the proteinase, a small RNA species (80 nucleotides) can be found associated with the complex even after purification by chromatographic procedures.


Arbuscular mycorrhizal fungi decrease Meloidogyne enterolobii infection of Guava seedlings.
Guava (Psidium guajava L.) production is prominent in the irrigated fruit growing area of Brazil. However, the parasite Meloidogyne enterolobii (a phytonematode) has caused a decrease in guava production. Arbuscular mycorrhizal fungi (AMF) are known to be beneficial to plants; however, their ability to protect plants against nematodes such as M. enterolobii remains poorly known. This study aimed to monitor M. enterolobii infection in guava seedlings inoculated with three AMF species. After AMF inoculation, the seedlings were grown in sterile soil for 60 days before inoculation with 2000 M. enterolobii eggs. Plant growth parameters, mycorrhizal colonization and the number of Meloidogyne in the roots were determined over time (30 and 60 days after Meloidogyne inoculation). The AMF enhanced guava seedling growth, and reduced the amount of Meloidogyne in the roots at 30 and 60 days after nematode inoculation, indicating that these AMF species could serve as biocontrol agents of M. enterolobii in guava cultivation.


Feminizing Adrenocortical Carcinoma with Distant Metastases: Can Surgery be Considered?
Functioning adrenocortical carcinomas are rare diseases with dismal prognosis. A 41-year-old man presenting with gynecomastia had a giant feminizing adrenocortical carcinoma at stage IV. Although surgical resection was controversial, we removed the primary tumor to reduce the mass effects. He lived for 12 months with an acceptable quality of life. Gynecomastia may be the first sign of feminizing adrenal malignancies. Surgery may ameliorate the quality of life in selected patients with metastatic disease.


Profiling Signal Transduction in Global Marine Biofilms.
Microbes use signal transduction systems in the processes of swarming motility, antibiotic resistance, virulence, conjugal plasmid transfer, and biofilm formation. However, the signal transduction systems in natural marine biofilms have hardly been profiled. Here we analyzed signal transduction genes in 101 marine biofilm and 91 seawater microbial metagenomes. The abundance of almost all signal transduction-related genes in biofilm microbial communities was significantly higher than that in seawater microbial communities, regardless of substrate types, locations, and durations for biofilm development. In addition, the dominant source microbes of signal transduction genes in marine biofilms were different from those in seawater samples. Co-occurrence network analysis on signal communication between microbes in marine biofilms and seawater microbial communities revealed potential inter-phyla interactions between microorganisms from marine biofilms and seawater. Moreover, phylogenetic tree construction and protein identity comparison displayed that proteins related to signal transductions from Red Sea biofilms were highly similar to those from Red Sea seawater microbial communities, revealing a possible biological basis of interspecies interactions between surface-associated and free-living microbial communities in a local marine environment. Our study revealed the special profile and enrichment of signal transduction systems in marine biofilms and suggested that marine biofilms participate in intercellular interactions of the local ecosystem where they were seeded.


Secondary total hip replacement after fractures of the femoral neck.
We studied the rate of revision in 84 consecutive total hip replacements performed for failed osteosynthesis of femoral neck fractures and compared it with that for primary arthroplasty for osteoarthritis. The age and sex adjusted risk of prosthetic failure was 2.5 times higher after failure of fixation, but all the excess risk was in patients over 70 years of age. There were radiographic signs of loosening of the femoral component at five to 12 years after secondary arthroplasty in six of 33 survivors. In general, the results of secondary replacement were no worse than those obtained after primary arthroplasty for femoral neck fracture. We consider that internal fixation should be the primary procedure: total hip replacement is a safe secondary procedure when osteosynthesis fails.


Myasthenia gravis--an unexpected cause of respiratory failure and reversible left ventricular dysfunction after cardiac surgery.
We report a case of postpericardiotomy myasthenia gravis. A 68-year-old male patient without prior history of neuromuscular or autoimmune disorders presented with respiratory failure and severe left ventricular dysfunction four weeks after mitral valve replacement. Markedly elevated acetylcholine receptor antibodies were noted, and the patient responded promptly to immunologic therapy. Awareness of this rare but potentially fatal consequence of cardiac surgery may allow the early institution of specific treatment.


Effect of chronic administration of hydrocortisone on the induction and evolution of acute pancreatitis induced by cerulein.
The effects of chronic administration of hydrocortisone (10 mg/kg/day) on the development and evolution of acute pancreatitis induced by supramaximal stimulation with cerulein were examined in the rat. In these circumstances the potentially therapeutic effect of L-364,718, a CCK-receptor antagonist, was assayed. Administration of hydrocortisone over 7 days did not increase the severity of edematous acute pancreatitis induced by cerulein, since the reduction in pancreatic secretion, the hyperamylasemia and the increase in the levels of hematocrit and fluid in the pancreatic tissue were similar in rats with acute pancreatitis treated and untreated with hydrocortisone previously. When hydrocortisone was administered chronically, before administration of supramaximal doses of cerulein, a spontaneous regression of acute pancreatitis occurred. However, when hydrocortisone administration was continued after inducing pancreatitis, pancreatic recovery was prevented, observing a significantly depressed acinar secretion and elevated values of hematocrit and tissue fluid (edema). L-364,718 administration proved to be detrimental in the evolution of edematous acute pancreatitis when the rats had been treated chronically with hydrocortisone because the blockade exerted on secretion prevented the draining of enzymes stored in excess by hydrocortisone administration.


Rotigotine adverse effects affecting patient's sexual partner.
Somnolence is one of the most common adverse effects of a dopaminergic agonist, rotigotine. We report putative adverse effects experienced by a spouse of a man treated with this compound because of advanced Parkinson disease. We propose the exposure to rotigotine through the seminal fluid because protected sexual intercourse eliminated her postcoital symptoms. This previously unrecognized mechanism may be more common and associated with other psychoactive compounds penetrating the blood-testis barrier, and it may account for otherwise unexplained postcoital somnolence or fatigue.


Early prednisone therapy in Henoch-Schönlein purpura: a randomized, double-blind, placebo-controlled trial.
To evaluate the efficacy of early prednisone therapy in preventing renal and treating extrarenal and renal symptoms in Henoch-Schönlein purpura (HSP) in a placebo-controlled trial. A total of 171 patients (84 treated with prednisone and 87 receiving placebo) were included and followed up for 6 months. The endpoints were renal involvement at 1, 3, and 6 months and healing of extrarenal symptoms. The analyses were performed on an intent-to-treat basis. Prednisone (1 mg/kg/day for 2 weeks, with weaning over the subsequent 2 weeks) was effective in reducing the intensity of abdominal pain (pain score, 2.5 vs 4.8; P = .029) and joint pain (4.6 vs 7.3; P = .030). Prednisone did not prevent the development of renal symptoms but was effective in treating them; renal symptoms resolved in 61% of the prednisone patients after treatment, compared with 34% of the placebo patients (difference = 27%; 95% confidence interval = 3% to 47%; P = .024). The general use of prednisone in HSP is not supported, but patients with disturbing symptoms may benefit from early treatment, because prednisone reduces extrarenal symptoms and is effective in altering (but not preventing) the course of renal involvement.


Direct measurement of uranium in seawater by inductively coupled plasma mass spectrometry.
A simple method for direct measurement of uranium (238U) in seawater using triple quadrupole inductively coupled plasma mass spectrometry (ICP-MS) was established. The method provides a good analytical performance with respect to detection limit, accuracy, precision and sample throughput. During the method development and application, several interesting facts were observed: 1) Comparison results for reference material using different quantitation approaches indicate that isotope dilution (using 233U) is the most reliable to achieve accurate 238U measurement. The results obtained for direct 238U measurement in 50-fold diluted seawater samples (n = 112) also underline the difference between isotope dilution and internal (or external) standardization. 2) Appropriate dilution of seawater is important to minimize the matrix effect on the ICP-MS measurement and 20-50 dilution is recommended for natural seawater samples. 3) The sensitivity of ICP-MS was observed to increase in the beginning of sample measurement, and then decrease with the continuous injection of samples, which is believed as a consequence of matrix effect from the seawater to the ionization efficiency in the plasma. 4) When measuring samples taken from large volume of seawater stored in immovable containers for relatively long period (i.e., several months), the uranium concentration and salinity data showed slightly increasing trends with the increase of water depth in the container. Therefore, cautions need to be paid in sampling representativeness when performing 238U measurement for such long-term stored large volume samples.


Streptomyces dysideae sp. nov., isolated from a marine Mediterranean sponge Dysidea tupha.
A Gram-stain-positive bacterium, strain RV15T, forming an extensively branched substrate mycelium and aerial hyphae that differentiate into spiral chains of spores, was isolated from a marine sponge Dysidea tupha collected from Rovinj (Croatia). Comparison of 16S rRNA gene sequences showed that strain RV15T is a member of the genus Streptomyces with highest sequence similarity to the type strains of Streptomyces caeruleatus (98.8 %), Streptomyces cyaneochromogenes (98.6 %) and Streptomyces shaanxiensis (98.5 %). Sequence similarities to all other Streptomyces types strains were below 98.5 %. The multilocus sequence analysis-based evolutionary distance, the average nucleotide identity value and the genome-to-genome distance of strain RV15T and the type strain of S. caeruleatus were clearly below the species cut-off values. Strain RV15T exhibited a quinone system composed of the major menaquinones MK-9(H4), MK-9(H6) and MK-9(H2), typical for the genus Streptomyces. The polar lipid profile of strain RV15T consisted of the predominant compounds diphosphatidylglycerol and phosphatidylethanolamine, moderate amounts of phosphatidylinositol, phosphatidylinositol mannoside, an unidentified lipid and an unidentified phospholipid. Major polyamines were spermine and spermidine. The diagnostic diaminoacid of the peptidoglycan was meso-diaminopimelic acid. The major fatty acids were iso C16 : 0, anteiso C17 : 1 ω9c and anteiso C17 : 0. The results of physiological and biochemical tests allowed further phenotypic differentiation of strain RV15T from its most-related species and hence clearly merits species status. We propose the name Streptomyces dysideae sp. nov. with the type strain RV15T (=DSM 42110T=LMG 27702T).


Review of clinical trials and benefit/risk ratio of meloxicam.
Meloxicam is a new once daily non-steroidal anti-inflammatory drug (NSAID). Double-blind trials in over 5000 patients with osteoarthritis and rheumatoid arthritis have shown that meloxicam 7.5 mg and 15 mg are significantly more effective than placebo and comparable in efficacy to standard NSAIDs such as naproxen 750-1000 mg, piroxicam 20 mg and diclofenac 100 mg slow release. In a global safety analysis, both meloxicam doses produced significantly fewer gastrointestinal (GI) side effects than the comparators (p < 0/05). Severe GI side effects, discontinuations due to GI side effects and less serious events such as dyspepsia and abdominal pain were also significantly less frequent with meloxicam. Perforations, ulcerations and bleedings occurred in 0.1%, 0.2%, 1.2%, 0.6% and 2.1% of meloxicam 7.5 mg, 15 mg, piroxicam, diclofenac and naproxen patients respectively (p < 0.05 for piroxicam and naproxen compared with meloxicam). This improved safety profile is likely to be due to meloxicam's selective inhibition of COX-2 relative to COX-1.


Automated pelvic anatomical coordinate system is reproducible for determination of anterior pelvic plane.
Most of computer-assisted planning systems need to determine the anatomical axis based on the anterior pelvic plane (APP). We analysed that our new system is more reproducible for determination of APP than previous methods. A pelvic model bone and two subjects suffering from hip osteoarthritis were evaluated. Multidetector-row computed tomography (MDCT) images were scanned with various rotations by MDCT scanner. The pelvic rotation was calibrated using silhouette images. APP was determined by an optimisation technique. The values of variation of APP caused by pelvic rotation were analysed with statistical analysis. APP determination with calibration and optimisation was most reproducible.The values of variance of APP were within 0.05° in model bone and 0.2° even in patient pelvis. Furthermore, the values of variance of APP with calibration/optimisation were significantly lower in comparison without calibration/optimisation. Both calibration and optimisation are actually required for determination of APP. This system could contribute to the evaluation of hip joint kinematics and computer-assisted surgery.


Recent Advances in the Design of Water Based-Flame Retardant Coatings for Polyester and Polyester-Cotton Blends.
Over the last ten years a new trend of research activities regarding the flame retardancy of polymeric materials has arisen. Indeed, the continuous search for new flame retardant systems able to replace the traditional approaches has encouraged alternative solutions, mainly centred on nanotechnology. In this context, the deposition of nanostructured coatings on fabrics appears to be the most appealing and performance suitable approach. To this aim, different strategies can be exploited: from the deposition of a single monolayer consisting of inorganic nanoparticles (single-step adsorption) to the building-up of more complex architectures derived from layer by layer assembly (multi-step adsorption). The present paper aims to review the application of such systems in the field of polyester and polyester-cotton blend fabrics. The results collated by the authors are discussed and compared with those published in the literature on the basis of the different deposition methods adopted. A critical analysis of the advantages and disadvantages exhibited by these approaches is also presented.


Relevance of the cranioaxial angle in the occipitocervical stabilization using an original construct: a retrospective study on 50 patients.
We present a retrospective study on a series composed of 50 patients, treated between 1992 and 2006, affected by pathologies of the craniocervical junction. All the patients were treated using an innovative procedure based on a cranial claw made up of low profile hooks, conceived by one of the authors. Advantages of this technique are, to our point of view, a higher resistance to cranial hooks dislodgment, when compared with screw fixation instrumentation, especially in pathological conditions, such as rheumatoid arthritis that leads to a qualitative deterioration of the bone stock and to the reduction of the occipital wall thickness. Occipitoaxial alignment was assessed radiographically using the McGregor line. We observed an improvement in the subjective evaluation of pain in all treated patients with a 46% improvement from the initial values. Moreover, patient stabilized with an occipitoaxial angle included in the physiological range showed better results either for the survival of the instrumentation or the onset of junctional pathology. Patients have been followed up afterwards and evaluated by the visual analogue scale for the assessment of pain and by the Nurick scale for the cases associated with myelopathy. We believe that cranial anchorage with a hook claw allows for an instrumentation provided with high stability, particularly useful in revision surgery and major instabilities. The study of the occipitoaxial angles showed that the better results and the long-lasting stability of the implant are correlated to a fusion angle included in the physiological range.


Measuring the Tibia: Trotter's Error Revisited.
In Trotter and Gleser's (Am J Phys Anthropol 1952;10:463) classic study of stature estimation, a definition of the tibia length measurement is given that agrees with the standard condylar-malleolar length. That Trotter did not in fact measure according to her definition, but rather omitted the malleolus, has been well documented by Jantz et al. (J Forensic Sci 1995;40:758). Both the Terry collection and the World War 2 (WW2) samples were affected, although questions remain about the latter that cannot be resolved directly because it is no longer available for examination. Trotter's data from hundreds of servicemen are especially important because the statures were measured by technicians, rather than based on cadaver lengths or forensic statures. The questions examined in this note are as follows: Was WW2 measured uniformly in the same way as Terry; are there differences between Terry and WW2 that could influence estimation of the adjustment; and is the 10 millimeter (mm) adjustment proposed by Jantz et al. (J Forensic Sci 1995;40:758) still appropriate. Our analysis relies on a measurement taken by Trotter that is clearly and uniquely defined, what she called "ordinary length". This measurement was used to create expectations about how Trotter measured what she called maximum length of the tibia. Results provide no evidence that WW2 was measured any differently than Terry, with the exception of one small series. They also show slight morphological differences on the distal and/or proximal end of the tibia between Terry and WW2. Despite the slight difference, the adjustment to account for the malleolus is still valid.


Two new potent inhibitors of xanthine oxidase from leaves of Perilla frutescens Britton var. acuta Kudo.
A known and a new caffeic ester (1 and 2), new inhibitors of xanthine oxidase (XO), were isolated from leaves of Perilla frutescens var. acuta and their structures have been established as (Z,E)-2-(3,4-dihydroxyphenyl)ethenyl ester (1) and (Z,E)-2-(3,5-dihydroxyphenyl)ethenyl ester (2) of 3-(3,4-dihydroxyphenyl)-2-propenoic acid, respectively, based on detailed spectral studies, including 2D COSY, long range COSY, difference NOE, etc. Both caffeic esters strongly inhibited XO in vitro and especially, the inhibition by 1 was as potent as that by allopurinol. The inhibition mode of 1 was also shown to be non-competitive.


A templateless, surfactantless, simple electrochemical route to a dendritic gold nanostructure and its application to oxygen reduction.
A templateless, surfactantless, simple electrochemical route to prepare dendritic gold nanostructure is reported. The morphology, composition, and structure of as-prepared dendritic gold nanostructure were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray spectroscopy (EDX), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), respectively. The whole nanostructure was constructed by pristine metallic gold. The formation mechanism related to experimental conditions was discussed. The synthesis promises indium tin oxide (ITO) electrode can be easily modified with the dendritic pristine gold nanostructure. The as-prepared modified ITO electrode has excellent catalytic activity to oxygen reduction in neutral KCl solution.


Prevalence of undetected cognitive impairment and depression in residents of an elderly care home.
The elderly population in Malaysia is growing rapidly. Some of the most vulnerable are in residential care. Research is needed into the characteristics of this population to aid clinicians and policy makers in addressing the needs of this group. This observational, cross-sectional study aims to determine prevalence of undetected cognitive impairment and depression in elderly care home residents in Malaysia. One hundred and sixty-seven people over 60 years of age living in a state run residential home were interviewed. Validated assessment tools were used to measure dependency, cognitive impairment and depression. The prevalence of probable dementia is 36.5%, with increasing prevalence with age and level of dependence. Prevalence of depression is 67.0% (major depression 13.2%), with more depression in males and in the Indian population. None of the identified cases had been previously investigated or treated for dementia or depression.


131I effective half-life and dosimetry in thyroid cancer patients.
(131)I treatment in thyroid cancer patients may induce side effects, including extrathyroidal cancer and leukemia. There are still some uncertainties concerning parameters that may influence the effective half-life of (131)I and the absorbed doses by extrathyroidal organs. Whole-body retention of radioiodine was measured in 254 patients, and repeated quantitative whole-body scans and measurements of the urinary excretion of (131)I were performed on 30 of these patients. The mean effective half-life (10.5 h) was shorter by 31%, with little difference between patients, in the 36 patients who received recombinant human thyroid-stimulating hormone than in the 218 patients who underwent thyroid hormone withdrawal (15.7 h). The residence times in the stomach and in the rest of the body were significantly shorter in patients who received recombinant human thyroid-stimulating hormone than in patients who underwent withdrawal, but the residence times were similar in the colon and bladder. In patients who undergo thyroid hormone withdrawal, the longer mean effective half-life is mainly due to delayed renal excretion of (131)I and results in dose estimates higher than the data in report 53 of the International Commission on Radiological Protection, which were obtained from healthy, euthyroid subjects.


Ferroptosis as a novel therapeutic target for cardiovascular disease.
Cell death is an important component of the pathophysiology of cardiovascular disease. An understanding of how cardiomyocytes die, and why regeneration of cells in the heart is limited, is a critical area of study. Ferroptosis is a form of regulated cell death that is characterized by iron overload, leading to accumulation of lethal levels of lipid hydroperoxides. The metabolism of iron, lipids, amino acids and glutathione tightly controls the initiation and execution of ferroptosis. Emerging evidence shows that ferroptosis is closely associated with the occurrence and progression of various diseases. In recent years, ferroptosis has been found to play critical roles in cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and heart failure. This article reviews the mechanisms by which ferroptosis is initiated and controlled and discusses ferroptosis as a novel therapeutic target for various cardiovascular diseases.


An abbreviated phase II trial of thalicarpine.
Thalicarpine, a plant alkaloid of novel structure, was evaluated in a phase II clinical trial. Fourteen previously treated patients with advanced malignant disease were given thalicarpine at a dose of 1100 mg/m2 weekly as a constant 2-hour iv infusion. Common toxic effects included nausea, ECG changes, arm pain, and lethargy; less frequent effects included vomiting, tachycardia, hypotension, pain distant from infusion site, urticaria, chills, diarrhea, and mydriasis. There was no hematologic, hepatic, or renal toxicity. There were no complete or partial objective responses. Although the drug's true response rate in any given tumor type cannot be determined, its absence of activity in man, to date, and the recent closing of its IND, make further clinical investigation with thalicarpine unlikely.


The microtubule-severing protein Spastin is essential for axon outgrowth in the zebrafish embryo.
Hereditary spastic paraplegia (HSP) is a collection of neurological disorders characterized by developmental failure or degeneration of motor axons in the corticospinal tract and progressive lower limb spasticity. SPG4 mutations are the most common cause of autosomal dominant HSP and Spastin (the SPG4 gene product) is a microtubule severing protein that shares homology with katanin, the microtubule severing activity of which promotes axon growth in cultured neurons. Given the sequence and functional similarity between spastin and katanin, we hypothesized that spastin promotes the dynamic disassembly and remodelling of microtubules required for robust, properly directed motor axon outgrowth. To investigate this hypothesis, we cloned the zebrafish spg4 orthologue and used morpholino antisense oligonucleotides directed against the translation start site and the intron 7-8 splice donor site to knock down spastin function in the developing zebrafish embryo. Reduced spg4 function caused dramatic defects in motor axon outgrowth without affecting the events driving the initial specification of motor neurones. Other neuronal subtypes also exhibited a requirement for spg4 function, since spg4 knock down caused both widespread defects in neuronal connectivity and extensive CNS-specific apoptosis. Our results reveal a critical requirement for spastin to promote axonal outgrowth during embryonic development, and they validate the zebrafish embryo as a novel model system to dissect the pathogenetic mechanisms underlying HSP. Taken together with other recent studies, our findings suggest that axon outgrowth defects may be a common feature of childhood SPG3A and SPG4 cases.


Pulmonary malakoplakia diagnosed by fine needle aspiration. A case report.
Pulmonary malakoplakia is an uncommon disorder, with 24 previously reported cases, only 4 of which were diagnosed by bronchial washings, bronchial brushings or aspiration cytology. We report a case that was diagnosed initially by computed tomography (CT)-guided fine needle aspiration (FNA) cytology. A 56-year-old male with follicular small cleaved cell lymphoma had a 10-cm left lower lobe mass compressing the main bronchus to that lobe. A transthoracic, CT-guided FNA specimen consisted predominantly of foamy macrophages, many of which contained typical Michaelis-Gutmann bodies. Microbiologic cultures identified Rhodococcus equi. A subsequent transbronchial biopsy and left pneumonectomy specimen confirmed the cytologic diagnosis. Pulmonary malakoplakia associated with R equi pneumonia is a rare lesion that is essentially limited to immunocompromised hosts. Awareness of the FNA cytomorphology of this lesion permits resolution of the typical clinical differential diagnosis of pulmonary masses in the immunocompromised host and can facilitate treatment.


Characterization of a subunit of the outer dynein arm docking complex necessary for correct flagellar assembly in Leishmania donovani.
In order to proceed through their life cycle, Leishmania parasites switch between sandflies and mammals. The flagellated promastigote cells transmitted by the insect vector are phagocytized by macrophages within the mammalian host and convert into the amastigote stage, which possesses a rudimentary flagellum only. During an earlier proteomic study of the stage differentiation of the parasite we identified a component of the outer dynein arm docking complex, a structure of the flagellar axoneme. The 70 kDa subunit of the outer dynein arm docking complex consists of three subunits altogether and is essential for the assembly of the outer dynein arm onto the doublet microtubule of the flagella. According to the nomenclature of the well-studied Chlamydomonas reinhardtii complex we named the Leishmania protein LdDC2. This study features a characterization of the protein over the life cycle of the parasite. It is synthesized exclusively in the promastigote stage and localizes to the flagellum. Gene replacement mutants of lddc2 show reduced growth rates and diminished flagellar length. Additionally, the normally spindle-shaped promastigote parasites reveal a more spherical cell shape giving them an amastigote-like appearance. The mutants lose their motility and wiggle in place. Ultrastructural analyses reveal that the outer dynein arm is missing. Furthermore, expression of the amastigote-specific A2 gene family was detected in the deletion mutants in the absence of a stage conversion stimulus. In vitro infectivity is slightly increased in the mutant cell line compared to wild-type Leishmania donovani parasites. Our results indicate that the correct assembly of the flagellum has a great influence on the investigated characteristics of Leishmania parasites. The lack of a single flagellar protein causes an aberrant morphology, impaired growth and altered infectiousness of the parasite.


Proteomic identification of common SCF ubiquitin ligase FBXO6-interacting glycoproteins in three kinds of cells.
FBOX6 ubiquitin ligase complex is involved in the endoplasmic reticulum-associated degradation pathway by mediating the ubiquitination of glycoproteins. FBXO6 interacts with the chitobiose in unfolded N-glycoprotein, pointing glycoproteins toward E2 for ubiquitination. Although the glycoprotein-recognizing mechanism of FBXO6 is well documented, its bona fide interacting glycoproteins are largely unknown. Here we utilized a protein purification approach combined with LC-MS to systematically identify the FBXO6-interacting glycoproteins. Following identification of 39 proteins that specifically interact with FBXO6 in all three different cell lines, 293T, HeLa and Jurkat cells, we compared the protein complex organization between wild-type FBXO6 and its mutant, which fails to recognize glycoproteins. Combining these databases, 29 highly confident glycoproteins that interact with FBXO6 in an N-glycan dependent manner are identified. Our data provide valuable information for the discovery of the interacting glycoproteins of FBXO6 and also demonstrate the potential of these approaches as general platforms for the global discovery of interacting glycoproteins of other FBAs (F-box associated regions) containing F-box proteins.


A novel mechanism in recessive nephrogenic diabetes insipidus: wild-type aquaporin-2 rescues the apical membrane expression of intracellularly retained AQP2-P262L.
Vasopressin regulates water homeostasis through insertion of homotetrameric aquaporin-2 (AQP2) water channels in the apical plasma membrane of renal cells. AQP2 mutations cause recessive and dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin. Until now, all AQP2 mutants in recessive NDI were shown to be misfolded, retained in the endoplasmic reticulum (ER) and unable to interact with wild-type (wt)-AQP2, whereas AQP2 mutants in dominant NDI are properly folded and interact with wt-AQP2, but, due to the mutation, cause missorting of the wt-AQP2/mutant complex. Here, patients of two families with recessive NDI appeared compound heterozygotes for AQP2-A190T or AQP2-R187C mutants, together with AQP2-P262L. As mutations in the AQP2 C-tail, where P262 resides, usually cause dominant NDI, the underlying cell-biological mechanism was investigated. Upon expression in oocytes, AQP2-P262L was a properly folded and functional aquaporin in contrast to the classical mutants, AQP2-R187C and AQP2-A190T. Expressed in polarized cells, AQP2-P262L was retained in intracellular vesicles and did not localize to the ER. Upon co-expression, however, AQP2-P262L interacted with wt-AQP2, but not with AQP2-R187C, resulting in a rescued apical membrane expression of AQP2-P262L. In conclusion, our study reveals a novel cellular phenotype in recessive NDI in that AQP2-P262L acts as a mutant in dominant NDI, except for that its missorting is overruled by apical sorting of wt-AQP2. Also, it demonstrates for the first time that the recessive inheritance of a disease involving a channel can be due to two cell-biological mechanisms.


Titanium allergy in dental implant patients: a clinical study on 1500 consecutive patients.
In dentistry, allergic reactions to Ti implants have not been studied, nor considered by professionals. Placing permanent metal dental implants in allergic patients can provoke type IV or I reactions. Several symptoms have been described, from skin rashes and implant failure, to non-specific immune suppression. Our objective was to evaluate the presence of titanium allergy by the anamnesis and examination of patients, together with the selective use of cutaneous and epicutaneous testing, in patients treated with or intending to receive dental implants of such material. Thirty-five subjects out of 1500 implant patients treated and/or examined (2002-2004) were selected for Ti allergy analysis. Sixteen presented allergic symptoms after implant placement or unexplained implant failures [allergy compatible response group (ACRG)], while 19 had a history of other allergies, or were heavily Ti exposed during implant surgeries or had explained implant failures [predisposing factors group (PFG)]. Thirty-five controls were randomly selected (CG) in the Allergy Centre. Cutaneous and epicutaneous tests were carried out. Nine out of the 1500 patients displayed positive (+) reactions to Ti allergy tests (0.6%): eight in the ACRG (50%), one in the PFG (5.3%)(P=0.009) and zero in the control group. Five positives were unexplained implant failures (five out of eight). Ti allergy can be detected in dental implant patients, even though its estimated prevalence is low (0.6%). A significantly higher risk of positive allergic reaction was found in patients showing post-op allergy compatible response (ACRG), in which cases allergy tests could be recommended.


Exploring biological motion perception in two-stream convolutional neural networks.
Visual recognition of biological motion recruits form and motion processes supported by both dorsal and ventral pathways. This neural architecture inspired the two-stream convolutional neural network (CNN) model, which includes a spatial CNN to process appearance information in a sequence of image frames, a temporal CNN to process optical flow information, and a fusion network to integrate the features extracted by the two CNNs and make final decisions about action recognition. In five simulations, we compared the CNN model's performance with classical findings in biological motion perception. The CNNs trained with raw RGB action videos showed weak performance in recognizing point-light actions. Additional transfer training with actions shown in other display formats (e.g., skeletal) was necessary for CNNs to recognize point-light actions. The CNN models exhibited largely viewpoint-dependent recognition of actions, with a limited ability to generalize to viewpoints close to the training views. The CNNs predicted the inversion effect in the presence of global body configuration, but failed to predict the inversion effect driven solely by local motion signals. The CNNs provided a qualitative account of some behavioral results observed in human biological motion perception for fine discrimination tasks with noisy inputs, such as point-light actions with disrupted local motion signals, and walking actions with temporally misaligned motion cues. However, these successes are limited by the CNNs' lack of adaptive integration for form and motion processes, and failure to incorporate specialized mechanisms (e.g., a life detector) as well as top-down influences on biological motion perception.


In vivo inhibition of nitric oxide synthase by bisisothiouronium and bisguanidinium salts.
The ability of two S,S'-(alkane-1,omega-diyl) bisisothiouronium dibromides, three N,N'-(alkane-1, omega-diyl) bis guanidinium dinitrates and N,N'-bis (3-guanidinopropyl)piperazine dinitrate to inhibit constitutive (i.e. endothelial and neuronal forms) and inducible forms of nitric oxide synthases has been evaluated in vivo. These compounds, synthesized by two of us (J. C. L. and C. S.), have been tested in vivo; they were administered simultaneously with an irritant (carrageenan lambda) into the pleural cavity. The amount of nitrites collected 0.5 and 7 hours after this injection can be considered as an indicator of nitric oxide (NO) production. According to previous data, the first harvesting time can be related to activation of constitutive NO synthases and the second to activation of inducible NO synthases. These substances significantly inhibited nitrite production as did 2-methyl-2-thiopseudourea sulphate, previously described as a potent inhibitor of NO synthases and considered as the reference compound. The inhibiting effect varied according to the chemical structure of the compounds. Results were significantly different from controls at 0.5 h only with the S,S'-(octane-1,8-diyl) bisisothiouronium dibromide and the S,S'-(nonane-1,9-diyl) bisisothiouronium dibromide at the highest concentration, N,N'-(heptane-1,7-diyl) bisguanidinium dinitrate and N,N'-bis (3-guanidinopropyl)piperazine dinitrate. At 7 h, all the results were significantly different from controls, with a major effect observed with N,N'-(heptane-1,7-diyl) bisguanidinium dinitrate. The most active substances exerted similar effects to the reference substance.


Serotonin localization and its functional significance during mouse preimplantation embryo development.
Serotonin is a neurotransmitter functioning also as a hormone and growth factor. To further investigate the biological role of serotonin during embryo development, we analysed serotonin localization as well as the expression of specific serotonin 5-HT1D receptor mRNA in mouse oocytes and preimplantation embryos. The functional significance of serotonin during the preimplantation period was examined by studying the effects of serotonin on mouse embryo development. Embryo exposure to serotonin (1 microM) highly significantly reduced the mean cell number, whereas lower concentrations of serotonin (0.1 microM and 0.01 microM) had no significant effects on embryo cell numbers. In all serotonin-treated groups a significant increase in the number of embryos with apoptotic and secondary necrotic nuclei was observed. Expression of serotonin 5-HT1D receptor mRNA in mouse oocytes and preimplantation embryos was confirmed by in situ hybridization showing a clearly distinct punctate signal. Immunocytochemistry results revealed the localization of serotonin in oocytes and embryos to the blastocyst stage as diffuse punctate cytoplasmic labelling. It appears that endogenous and/or exogenous serotonin in preimplantation embryos could be involved in complex autocrine/paracrine regulations of embryo development and embryo-maternal interactions.