Key strategic factors for stakeholders in the current global biosimilar market.
What are the strategies of success in the global biosimilar market? In general, originators have short-term options available, such as patent litigation, but should focus on sustainable long-term strategies such as development of biobetters or incorporating biosimilars as complements to existing products. For new entrants to the market, the learning curve will be steep and only biosimilars developed to compete with the best-selling biologics will be successful over the next decade. The attitudes of physicians, patients and payers will be crucial to the reception future biosimilars will receive and it will be essential that other players contribute to this debate.


Exploring education preferences of Australian women regarding long-term health after hypertensive disorders of pregnancy: a qualitative perspective.
Hypertensive disorders of pregnancy (HDP) affect 5-10% of pregnant women. Long-term health issues for these women include 2-3 times the risk of heart attacks, stroke and diabetes, starting within 10 years after pregnancy, making long-term health after HDP of major public health importance. Recent studies suggest this knowledge is not being transferred sufficiently to women and how best to transmit this information is not known. This study explored women's preferred content, format and access to education regarding long-term health after HDP. This was a qualitative study and framework analysis was undertaken. Women with a history of HDP who had participated in a survey on long-term health after HDP were invited to participate in this study. During telephone interviews women were asked about preferences and priorities concerning knowledge acquisition around long-term health after HDP. Thirteen women were interviewed. They indicated that they wanted more detailed information about long-term and modifiable risk factors. Their preference was to receive risk counselling from their healthcare provider (HCP) early after giving birth along with evidence-based, print or web-based information to take home. All women suggested more structured postnatal follow-up, with automated reminders for key appointments. Automated reminders should detail rationale for follow-up, recommended tests and discussion topics to be addressed at the appointment. Our findings show that most participants wanted information soon after birth with all women wanting information within 12 months post birth, complemented with detailed take-home evidence. Participants indicated preference for structured follow-up via their HCP with automated alerts about the appointment and recommended tests. This evidence can be used to guide the development of education programs for women on health after HDP which may enhance knowledge, preventive health management and more generally improve women's health trajectories.


Vertebrate GAGA factor associated insulator elements demarcate homeotic genes in the HOX clusters.
Hox genes impart segment identity to body structures along the anterior-posterior axis and are crucial for the proper development of all organisms. Multiple regulatory elements, best defined in Drosophila melanogaster, ensure that Hox expression patterns follow the spatial and temporal colinearity reflected in their tight genomic organization. However, the precise mechanisms that regulate colinear patterns of Hox gene expression remain unclear, especially in higher vertebrates where it is not fully determined how the distinct activation domains of the tightly clustered Hox genes are defined independently of each other. Here, we report the identification of a large number of novel cis-elements at mammalian Hox clusters that can help in regulating their precise expression pattern. We have identified DNA elements at all four murine Hox clusters that show poor association with histone H3 in chromatin immunoprecipitation (ChIP)-chip tiling arrays. The majority of these elements lie in the intergenic regions segregating adjacent Hox genes; we demonstrate that they possess efficient enhancer-blocking activity in mammalian cells. Further, we find that these histone-free intergenic regions bear GA repeat motifs and associate with the vertebrate homolog of the GAGA binding boundary factor. This suggests that they can act as GAGA factor-dependent chromatin boundaries that create independent domains, insulating each Hox gene from the influence of neighboring regulatory elements. Our results reveal a large number of potential regulatory elements throughout the murine Hox clusters. We further demarcate the precise location of several novel cis-elements bearing chromatin boundary activity that appear to segregate successive Hox genes. This reflects a pattern reminiscent of the organization of homeotic genes in Drosophila, where such regulatory elements have been characterized. Our findings thus provide new insights into the regulatory processes and evolutionarily conserved epigenetic mechanisms that control homeotic gene expression.


Genetic association between ADAM10 gene polymorphism and Alzheimer's disease in a Northern Han Chinese population.
The ADAM10 gene encodes a member of a disintegrin and metalloprotease family, which, after overexpression in Alzheimer's disease (AD), prevents amyloid pathology and improves long-term potentiation and memory. A common polymorphism (rs2305421) within ADAM10 has been recently associated with the risk of developing AD in Europeans. In order to assess the involvement of the ADAM10 polymorphism in the risk of developing late-onset AD (LOAD), we analyzed the genotype and allele distributions of the ADAM10 (rs2305421) polymorphism in 788 Northern Han Chinese subjects. The results revealed no significant differences in the distributions of allele or genotype between LOAD and control groups. However, when these data were stratified by the Apolipoprotein E (ApoE) ε4 status, in the subjects with ApoE ε4, there were significant differences in the allele (P=0.037) and genotype (P=0.035). Moreover, logistic regression analysis revealed that the rs2305421 polymorphism presented strong associations with LOAD in the recessive model (OR=0.611, 95% CI=0.408-0.931, P=0.023). This study suggests that the rs2305421 polymorphism in ADAM10 gene could modify the risk for LOAD in a Northern Han Chinese population.


Association between rising haemoglobin concentration and renal cyst formation in patients on long term regular haemodialysis treatment.
Seventeen of 20 (85%) patients on RDT for six to 13 years were found to have acquired renal cysts. There was a significant positive association between Hb and duration of RDT. The extent of cyst was positively and significantly correlated with the latest Hb and years on dialysis. There was also a significant positive correlation between size and years on dialysis only approached statistical significance. There was no correlation between kidney size and latest Hb. Complications in patients with acquired renal cysts appear to resemble those of familial polycystic disease with the added risk of neoplasia.


Electrocardiographic and electrophysiologic effects of pirmenol in ventricular tachycardia.
Twenty patients with ventricular tachycardia refractory to drug treatment underwent electrophysiologic study with pirmenol. Patients ranged in age from 39 to 84 years (mean 61); the presenting arrhythmia was sustained ventricular tachycardia in 15, nonsustained ventricular tachycardia in 3 and ventricular fibrillation in 2. After discontinuation of all antiarrhythmic drugs (for at least 5 half-lives) and assessment of electrocardiographic and electrophysiologic parameters in the drug-free state, patients underwent comprehensive intracardiac electrophysiologic evaluation with intravenous pirmenol (mean dose 195 +/- 46 mg). Programmed ventricular stimulation began at least 30 minutes after pirmenol infusion was started in each patient. There was significant shortening of sinus cycle length in all patients, from 746 +/- 155 to 683 +/- 107 ms (mean +/- standard deviation). In 7 patients in whom ventricular tachycardia could not be induced after intravenous pirmenol, an oral pirmenol regimen was begun. The dosage was 200 or 250 mg (both 3 times/day) in 2 and 5 patients, respectively. Seven hours after the third dose of oral drug was given, these patients underwent repeat electrophysiologic testing. Intravenous and oral pirmenol significantly prolonged the PR, QT, QTc and JT intervals compared with baseline. Intravenous pirmenol also significantly prolonged the QRS interval compared with baseline. Oral pirmenol significantly prolonged the sinus node recovery time compared with intravenous pirmenol. Intravenous pirmenol significantly increased the HV interval compared with control; oral pirmenol did not demonstrate a significant prolongation of the HV interval, but this is due to the smaller number of patients studied while taking oral drug.(ABSTRACT TRUNCATED AT 250 WORDS)


CT perfusion to measure venous outflow in acute ischemic stroke in patients with a large vessel occlusion.
Robust venous outflow (VO) profiles, measured by degree of venous opacification on pre-thrombectomy CT angiography (CTA) studies, are strongly correlated with favorable outcomes in patients with large vessel occlusion acute ischemic stroke treated by thrombectomy. However, VO measurements are laborious and require neuroimaging expertise. To develop a semi-automated method to measure VO using CTA and CT perfusion imaging studies. We developed a graphical interface using The Visualization Toolkit, allowing for voxel selection at the confluence and bilateral internal cerebral veins on CTA along with arterial input functions (AIFs) from both internal carotid arteries. We extracted concentration-time curves from the CT perfusion study at the corresponding locations associated with AIF and venous output function (VOF). Outcome analyses were primarily conducted by the Mann-Whitney U and Jonckheere-Terpstra tests. Segmentation at the pre-selected AIF and VOF locations was performed on a sample of 97 patients. 65 patients had favorable VO (VO+) and 32 patients had unfavorable VO (VO-). VO+ patients were found to have a significantly shorter VOF time to peak (8.26; 95% CI 7.07 to 10.34) than VO- patients (9.44; 95% CI 8.61 to 10.91), P=0.007. No significant difference was found in VOF curve width and the difference in time between AIF and VOF peaks. Time to peak of VOF at the confluence of sinuses was significantly associated with manually scored venous outflow. Further studies should aim to understand better the association between arterial inflow and venous outflow, and capture quantitative metrics of venous outflow at other locations.


Repeat Minimally Invasive Mitral Valve Replacement for Recurrent Mitral Stenosis after OMC in Patients Who Decline Blood Product Transfusion for Religious Reasons.
Cardiac surgery for Jehovah's Witness (JW) patients is considered to be high risk because of patients' refusal to receive blood transfusion. We report a successful mitral valve replacement for recurrent mitral stenosis after OMC with minimally invasive right thoracotomy, without any transfusion of allogeneic blood or blood products. This minimally invasive mitral valve replacement through right thoracotomy was an excellent approach for JW patients.


Efficient determination of equivalence for encrypted data.
Secure computation of equivalence has fundamental application in many different areas, including health-care. We study this problem in the context of matching an individual's identity to link medical records across systems under the socialist millionaires' problem: Two millionaires wish to determine if their fortunes are equal without disclosing their net worth (Boudot, et al. 2001). In Theorem 2, we show that when a "greater than" algorithm is carried out on a totally ordered set it is easy to achieve secure matching without additional rounds of communication. We present this efficient solution to assess equivalence using a set intersection algorithm designed for "greater than" computation and demonstrate its effectiveness on equivalence of arbitrary data values, as well as demonstrate how it meets regulatory criteria for risk of disclosure.


Associations of systemic inflammation markers with identification of pulmonary nodule and incident lung cancer in Chinese population.
Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII), easily accessible systemic inflammation response parameters, were reported to associate with poor lung cancer prognosis. However, research on the effects of these markers on the risk of positive nodules (PNs) and lung cancer is limited. Participants in this retrospective study were those who had their first computed tomography (CT) screening at Jiangsu Province Hospital's Health Promotion Center between January 1, 2017 and December 31, 2020. We identified PNs (≥6 mm in diameter) from free text of CT reports and lung cancer from medical records. Multivariate logistic analysis was used to assess the association between NLR, PLR, or SII and PNs or lung cancer. The detected rate of PNs was 9.60% among the 96,476 participants. Age, smoking and body mass index were possible influencing factors for PNs. We observed linear dose-effect relationship between NLR, PLR, or SII and PNs (pnon-linear > 0.05). Compared with low quintile, participants with top quintiles of NLR, PLR or SII had an increased risk of PNs, with the adjusted ORs of 1.19 (1.11-1.28), 1.11 (1.04-1.19) or 1.11 (1.03-1.18), respectively. Meanwhile, NLR showed the U-shaped relationship with lung cancer, with adjusted ORs of 1.40 (1.08-1.81) comparing highest NLR quintile to the third quintile. The high PLR and SII showed significantly associated with lung cancer with adjusted ORs of 1.29 (0.99-1.68) and 1.35 (1.04-1.74) comparing to the lowest quintile. The high levels of systemic inflammation markers were associated with the risk of positive pulmonary nodules and lung cancer, which suggested systemic immune response may be an important pre-clinical feature for the early identification of diseases.


Decreased levels of procoagulant phospholipids in bleeding patients treated by vitamin K antagonists.
International Normalized Ratio (INR) is currently used to monitor vitamin K antagonist therapy, and the bleeding incidence becomes exponential for INR>4.5. Inversely, more than 50% of patients with a supratherapeutic INR are asymptomatic. Therefore it could be of interest to identify patients with a higher bleeding risk. Microparticles derived from different cell types express procoagulant phospholipids (PPL) which can be evaluated by a chronometric coagulation assay where a shortening of the clotting times is associated with increased levels of PPL. In a series of 174 consecutive patients referred to our Emergency Department with an INR>5, median level of PPL was significantly (p=0.004) lower (38.2s) in the 119 asymptomatic patients than in patients with nonmajor (43.6s, n=35) or major bleeding (46.6s, n=19), indicating higher levels of procoagulant phospholipids in asymptomatic patients. By receiver operating characteristic curve analysis, a cut-off of 43.5s discriminated patients with higher haemorrhagic risk (area under the curve=0.648). In contrast, thrombomodulin levels, quantified either by immunological or functional assays were not significantly different between both groups. In conclusion, evaluation of PPL could be of interest to define the haemorrhagic risk of VKA- treated patients.


Disease-related animal models for optimising oral rehydration solution composition.
To optimise the composition of oral rehydration solutions (ORS) for European children is not a simple task. Although controlled clinical trial is ultimately the only way to determine whether a new solution is superior to an established ORS, testing many different formulations is neither feasible nor ethical. Several groups of investigators have evolved the concept of using animal models to test new ORS formulations. Disease-related animal models using perfusion of cholera toxin-treated rat small intestine or experimental rotavirus infection of neonatal rats suggest that optimal water absorption will be obtained by using a hypotonic ORS with a sodium concentration of 50-60 mmol/l and a glucose concentration of 50-100 mmol/l. Addition of citrate or bicarbonate had no benefit with respect to the promotion of water absorption.


ApoE epsilon4 genotype is accompanied by lower metabolic activity in nucleus basalis of Meynert neurons in Alzheimer patients and controls as indicated by the size of the Golgi apparatus.
We previously found apolipoprotein (apoE) epsilon4-dependent lower metabolic activity in nucleus basalis of Meynert (NBM) neurons in Alzheimer disease (AD). In the present study we examined the metabolic activity in the NBM of 39 mentally intact control subjects with different APOE genotype. The control subjects had either no AD pathology (Braak stage 0) or the very beginning of AD pathology (Braak stage I-II). We used the Golgi apparatus (GA) size as a measure of neuronal metabolic activity. Control subjects carrying an apoE epsilon4 allele showed reduced neuronal metabolism; they had significantly more neurons with smaller GA sizes compared to control subjects not carrying an apoE epsilon4 allele. Only control subjects not carrying an apoE epsilon4 allele had increased neuronal metabolism in Braak I-II subjects. They had more neurons with larger GA sizes compared to Braak 0 subjects, which may reflect a compensatory mechanism. Our data indicate that APOE epsilon4 may act by a lower neuronal metabolism as a risk factor for cognitive impairment in normal aging and early prodromal AD. As the disease progresses into later stages of AD (Braak V-VI) neuronal metabolism strongly diminishes, resulting in neurons with extremely small GA sizes, irrespective of APOE genotype.


Persistence and recurrence in tumor-induced osteomalacia: A systematic review of the literature and results from a national survey/case series.
Tumor induced osteomalacia (TIO) is a rare disease of mineral metabolism, whose clinical picture is dominated by hypophosphatemia usually due to an excess of circulating FGF23 produced by small mesenchymal tumors. Data on the real prevalence of the disease are lacking, with the knowledge of the disease mainly relying on case reports and small case series. No estimate is available on the prevalence of uncured TIO. National multi-center, cross-sectional and retrospective study on persistent or recurrent cases of TIO followed in referral centers for bone diseases; systematic review of the published persistent and recurrent cases of TIO. Data from patients consecutively evaluated in referral Italian centers for bone diseases were collected; a PubMed search on persistent, recurrent and unoperable cases of TIO was carried out. Sixteen patients (mean age at diagnosis 52.5 ± 10.6 years) with persistent (n = 6, 37,5%), recurrent (n = 7, 43.7%) or not operable (n = 3, 18.8%) TIO were described. Delay in diagnosis (2.5 ± 1.3 years) was demonstrated. All patients experienced fragility fractures or pseudofractures and disabling bone and muscle pain. BMD was significantly reduced (mean T-score -2.7 ± 1.7 and -2.7 ± 0.9 at lumbar spine and femoral neck, respectively). Fourteen patients were maintained under therapy with phosphate salts and calcitriol, while in 2 patients therapy with burosumab, an anti-FGF23 antibody, was commenced. A significant number of patients with TIO remain either undiagnosed for tumor localization or tumor recur or persist after surgery. These patients with active disease represent possible candidates for burosumab treatment.


Elevated DNA polymerase beta activity in a cis-diamminedichloroplatinum(II) resistant P388 murine leukemia cell line.
The activity of DNA polymerase beta, which is an enzyme involved in repair of DNA damage, was assessed in P388 murine leukemia cell lines sensitive and resistant to cis-diamminedichloroplatinum(II) (cis-Pt). The resistant line was selected with cis-Pt and showed cross-resistance to a number of alkylating agents, but not to an anthracycline. The DNA polymerase beta activity was found to be elevated 5-fold in the resistant line based upon activity per mg cell protein and elevated 4-fold based upon activity per 10(7) cells. The characterization of elevated activity of an enzyme active in DNA repair in a cell line resistant to DNA damaging agents describes a possible mechanism of resistance in addition to those previously found.


The use of agarose in the determination of anchorage-independent growth.
At the present time, growth in agar suspension is one of the best in vitro correlates of tumorigenicity. Growth in agarose, however, has not been evaluated extensively as an in vitro criterion for tumorigenicity. In the present study we have tested 19 cell lines, including six mouse-human hybrids, for growth in agarose and agar in the presence and absence of exogenous hypoxanthine. None of the six nontumorigenic cell lines grew in agar or agarose. Ten of the 13 tumorigenic cell lines grew in both agar and agarose with about equal efficiency. The remaining three tumorigenic cell lines grew well in agarose but poorly or not at all in agar. Hypoxanthine did not stimulate the growth in agar or agarose of any of the cell lines except BHK. We conclude that growth in agarose may be a more sensitive marker for tumorigenicity than growth in agar and that BHK is exceptional in its sensitivity to supplemental purines.


Off-resonance rf fields in heteronuclear NMR: Application to the study of slow motions.
The advantages of using off-resonance rf fields in heteronuclear self-relaxation experiments are explored on a fully (15)N-enriched protein. It is firstly shown that in the absence of slow motions the longitudinal and transverse (15)N self-relaxation rate values derived with this method are in agreement with the ones measured by the classical inversion-recovery and Carr-Purcell-Meiboom-Gill (CPMG) sequences, respectively. Secondly, by comparing the (15)N transverse self-relaxation rates obtained by the proposed off-resonance sequence and by the CPMG sequence, 11 residues out of the 61 of toxin α are shown to exhibit a chemical exchange phenomenon in water on a time scale ranging from 1 µs to 100 ms. By varying the effective field amplitude, chemical exchange processes involving these residues are measured and the corresponding correlation times are evaluated without having assumed any motion model. Similar, though less precise, results are given by the analysis of the (15)N off-resonance self-relaxation rates on the basis of the Lipari-Szabo model to describe the fast internal dynamics of toxin α.


Tianeptine and its main metabolite pharmacokinetics in chronic alcoholism and cirrhosis.
The effect of chronic alcoholism (with or without associated moderate cirrhosis) on the disposition of the antidepressant tianeptine, which is devoid of substantial first-pass metabolism, was examined in 21 patients and 11 age-matched controls. Pharmacokinetic parameters for tianeptine and its C5 acid analogue metabolite (MC5 metabolite) were estimated by non-compartmental analysis. The area under the curve (AUC) for tianeptine, following a 12.5mg single oral dose, was decreased by 31% in chronic alcoholics and increased by only 14% in cirrhotics, compared to controls. These changes did not attain statistical significance. The trend of changes in the AUC for the MC5 metabolite was similar to that observed for the parent drug. No statistical difference was found in the terminal half-life for both tianeptine and its MC5 metabolite between patients and controls. On the basis of this study, it appears unnecessary to modify the proposed dosage regimen used in clinical trials (tianeptine sodium salt 12.5mg 3 times daily) in chronic alcoholics with or without associated moderate cirrhosis.


Medical students' opinions on professional behaviours: The Professionalism of Medical Students' (PoMS) study.
Introduction: The Professionalism of Medical Students (PoMS) study aimed to develop a comprehensive understanding of Australian and New Zealand (Aus/NZ) medical students' opinions and experience with professionalism dilemmas.Methods: A confidential, online survey for medical students was developed and distributed to all Aus/NZ medical schools. Students submitted de-identified demographic information, gave opinions on the acceptability of a range of student behaviours for professionally challenging situations, and whether they had encountered similar situations.Results: 3171 medical students participated from all 21 Aus/NZ medical schools (16% of the total student population). Medical students reported encountering many of the professionally challenging situations and had varying opinions on what was acceptable behaviour for the scenarios. In general, students' opinions were not influenced by the seniority, gender or the type of health professional involved in the scenario. Participant demographic factors appeared to have significant effects on professional opinions - particularly male gender and being a student in the latter stages of the course.Discussion: Medical students' professional opinions are a complex area. The PoMS data provides a reference point for students, their educators and other health professionals in identifying current student professional behaviour norms, determining the effects of demographic factors on their decision making, and where important gaps exist in medical students' approaches to professionalism.


MRI detection of myocardial perfusion changes by gadolinium-DTPA infusion during dipyridamole hyperemia.
To detect abnormal regional myocardial coronary flow reserve, serial spin-echo MR tomograms of four control dogs and six with a partial balloon occlusion of the left anterior descending (LAD) coronary artery were acquired before and after dipyridamole infusion and during the paramagnetic effect of a bolus plus infusion of gadolinium-DTPA. Microsphere myocardial blood flow was measured for correlation with serial regional changes in MR signal intensity. Significant difference in gadolinium-enhanced MR signal intensity existed between the hypoperfused LAD and the hyperemic left circumflex perfusion beds (46 +/- 22% vs 78 +/- 29% above baseline, respectively; P less than 0.05). The percentage changes in gadolinium-enhanced MR signal and microsphere myocardial blood flow were significantly correlated (r2 = 0.93).


Carcinoma of the gallbladder presenting as scalp tumour.
Carcinoma of the gallbladder is characterized by rapid tumour growth associated with lymphatic and local tumour invasion. The peritoneum, GIT and lungs are common sites of seeding. Distant metastasis to bone rarely occurs. Here we document a case of silent gallbladder carcinoma presenting as scalp tumour with improved survival.


Do cell culture conditions influence the carrier-mediated transport of peptides in Caco-2 cell monolayers?
Despite the fact that different laboratories have reported large differences in permeability for actively transported substrates, Caco-2 cell monolayers are widely used as in vitro model to study small intestinal drug transport. Therefore, we investigated the effect of cell culture conditions, such as time in culture, membrane support, seeding density and supplements to the medium, on the morphology, the formation of tight junctions, as well as the expression of two peptide transporters (PepT1, HPT1) and the efflux pump, P-glycoprotein (Pgp), in Caco-2 cell monolayers. Tight junction formation was assessed by transepithelial electrical resistance measurements; multi-cell layer formation by confocal laser scanning microscopy, the expression of transporters by RT-PCR and the permeability of the PepT1 substrate, cephradine. Both morphology and the expression of carrier-mediated transporters, varied strongly as a function of culture conditions. An increase of differentiation, as documented by tight, homogeneous cell monolayer formation displaying a strong expression of all carrier-mediated transporters, was found up to 3 weeks post seeding. One week later, multi-layer structures were observed and the expression of Pgp decreased. Polyester and polyethylene terephthalate membrane supports decreased the paracellular transport rates substantially, while collagen-coating of PC inserts showed no influence on the morphology and even increased carrier-mediated transporter expression. An average seeding density of 6x10(4) cells/cm(2) seemed to be most favorable, since lower seeding densities led to thin monolayers with altered tight junctions and higher seeding densities to the formation of multilayers. In summary, the expression of carrier-mediated transporters was strongly affected by the culture conditions. The full differentiation was reached after 21 days on collagen-coated polycarbonate inserts at an initial seeding density of 6x10(4) cells/cm(2).


[Ammonia release and binding processes and the activity of acid proteinase and glycolysis enzymes in the dynamics of experimental toxic adrenal encephalopathy].
The content of ammonium, glutamine, glutamate, aspartate and GABA, glutamine synthetase activity, acid proteinase, hexonase, phosphohexoisomerase and dehydrogenase glucose-6-phosphate were studied in dog brain homogenates after individual injections of Bacillus coli endotoxin (10 micrograms/kg) and adrenaline (75 micrograms/kg) into veins and their combined injections into the carotid artery. Isolated injections of endotoxin and adrenaline were shown to cause transient metabolic compensatory changes. Combined injections caused stable progressing brain metabolic disorders. It is suggested that neurochemical changes influence endogenous development of toxic adrenal encephalopathy.


Effects of etoposide-induced blood-brain barrier disruption on brain water, intracranial pressure, and cerebral vasomotor tone.
This study investigated the effects of hypertension and water loading on etoposide-induced, reversible blood-brain barrier disruption in a rat model. Twenty-nine animals were divided into four groups: group 1--intracarotid (i.c.) injection of saline followed in 1 h by 5 ml i.c. water; group 2--i.c. etoposide followed by i.c. water; group 3--i.c. saline followed by i.v. metaraminol to increase systemic blood pressure; group 4--i.c. etoposide followed by i.v. metaraminol. Systemic blood pressure and intracranial pressure were monitored continuously. Evans blue staining of the brain was used as a monitor of blood-brain barrier disruption. Animals were killed 1 h after either aramine or water infusion, and the brains removed and inspected for the degree of disruption. After dehydration, brain water was calculated for each hemisphere. Two-thirds of the animals infused with etoposide had evidence of barrier disruption, whereas none of the control animals infused with saline were disrupted. Neither control groups 1 or 3 showed significant change in intracranial pressure after water loading or augmentation of systemic blood pressure, respectively. Group 4 animals failed to demonstrate any significant change in intracranial pressure despite marked barrier disruption and acute hypertension (within the limits of normal autoregulation). A small but statistically significant increase in intracranial pressure was noted in group 2 animals with the greatest degree of barrier disruption. A significant increase in brain water was observed ipsilateral to etoposide infusion in only those animals with the most marked barrier disruption. These results indicate that etoposide-induced blood-brain barrier disruption caused significant increases in brain water without significant alteration of cerebral vasomotor tone or increases in intracranial pressure after water loading except in the most severe disruption. The classic untoward consequences of vasogenic edema were not encountered in the present model.


Correction: Kutafina, E.; Laukamp, D.; Bettermann, R.; Schroeder, U.; Jonas, S.M. Wearable Sensors for eLearning of Manual Tasks: Using Forearm EMG in Hand Hygiene Training. Sensors 2016, 16, 1221.
The authors wish to make the following erratum to this paper [...].


ResNet and its application to medical image processing: Research progress and challenges.
Deep learning, a novel approach and subset of machine learning, has drawn a growing amount of attention from computer vision researchers in recent years. This method has drawn a lot of interest because of its extraordinary ability to interpret medical pictures, especially when combined with residual neural networks, which have helped to progress the field. In this paper, the following research is carried out on the residual network. First, the research status of ResNet in the medical field is introduced. The fundamental idea behind the residual neural network is then explained, along with the residual unit, its many structures, and the network architecture. Second, four aspects of the widespread use of residual neural networks in medical image processing are discussed: lung tumor, diagnosis of skin diseases, diagnosis of breast diseases, and diagnosis of diseases of the brain. Finally, the main issues and ResNet's future development in the area of processing medical images are discussed. In the area of medical graph processing, residual neural networks have made strides and have had success in the clinical auxiliary diagnosis of serious illnesses such as lung tumors, breast cancer, skin conditions, and cardiovascular and cerebrovascular diseases. We thoroughly sorted out the most recent developments in residual neural network research and their use in medical image processing, which serves as a crucial point of reference for this field of study. It offers a helpful reference for further promoting the application and research of the ResNet model in the field of medical image processing by summarising the application status and issues of the ResNet model in the field of medical image processing and putting forwards some future development directions.


Zymogenic latency in an ∼250-million-year-old astacin metallopeptidase.
The horseshoe crab Limulus polyphemus is one of few extant Limulus species, which date back to ∼250 million years ago under the conservation of a common Bauplan documented by fossil records. It possesses the only proteolytic blood-coagulation and innate immunity system outside vertebrates and is a model organism for the study of the evolution and function of peptidases. The astacins are a family of metallopeptidases that share a central ∼200-residue catalytic domain (CD), which is found in >1000 species across holozoans and, sporadically, bacteria. Here, the zymogen of an astacin from L. polyphemus was crystallized and its structure was solved. A 34-residue, mostly unstructured pro-peptide (PP) traverses, and thus blocks, the active-site cleft of the CD in the opposite direction to a substrate. A central `PP motif' (F35-E-G-D-I39) adopts a loop structure which positions Asp38 to bind the catalytic metal, replacing the solvent molecule required for catalysis in the mature enzyme according to an `aspartate-switch' mechanism. Maturation cleavage of the PP liberates the cleft and causes the rearrangement of an `activation segment'. Moreover, the mature N-terminus is repositioned to penetrate the CD moiety and is anchored to a buried `family-specific' glutamate. Overall, this mechanism of latency is reminiscent of that of the other three astacins with known zymogenic and mature structures, namely crayfish astacin, human meprin β and bacterial myroilysin, but each shows specific structural characteristics. Remarkably, myroilysin lacks the PP motif and employs a cysteine instead of the aspartate to block the catalytic metal.


Rapid identification of clinical isolates of Bacteroides species by matrix-assisted laser-desorption/ionization time-of-flight mass spectrometry.
The objective of this study was to compare MALDI-TOF MS and Rapid ID 32A with 16S rRNA gene sequencing, the reference method for identification of Bacteroides species. Results show that MALDI-TOF MS can be a good option for identification of Bacteroides species, especially if the database is expanded.


The reproductive toxicity and potential mechanisms of combined exposure to dibutyl phthalate and diisobutyl phthalate in male zebrafish (Danio rerio).
Dibutyl phthalate (DBP) and diisobutyl phthalate (DiBP) are phthalate compounds frequently detected in the environment. Despite increasing awareness of their toxicity in human and animals, the male reproductive toxicity of their combined exposure remains elusive. The purposes of this study were to investigate whether combined exposure to DBP and DiBP could induce male reproductive toxicity, and to explore the potential toxicological mechanisms. Adult male zebrafish were exposed to DBP (11, 113 and 1133 μg L-1), DiBP (10, 103 and 1038 μg L-1) and their mixtures (Mix) (11 + 10, 113 + 103, 1133 + 1038 μg L-1) for 30 days, and their effects on plasma hormone secretion, testis histology and transcriptomics were examined. Highest concentrations of Mix exposure caused greater imbalance ratio of T/E2 and more severe structural damage to testis than single exposure. These effects were consistent with the testis transcriptome analysis for which 4570 genes were differentially expressed in Mix exposure, while 2795 and 1613 genes were differentially expressed in DBP and DiBP, respectively. KEGG pathway analysis showed that both single and combined exposure of DBP and DiBP could affect cytokine-cytokine receptor interaction. The difference was that combined exposure could also affect steroid hormone synthesis, extracellular matrix receptor interaction, retinol metabolism, and PPAR signaling pathways. These results demonstrated that combined exposure to DBP and DiBP could disrupt spermatogenesis and elicit male reproductive toxicity in zebrafish.


Job satisfaction of public and private primary care physicians in Malaysia: analysis of findings from QUALICO-PC.
Job satisfaction of doctors is an important factor determining quality and performance of a health system. The aim of this study was to assess job satisfaction among doctors of the public and private primary care clinics in Malaysia and evaluate factors that could influence the job satisfaction rating. This study was part of the Quality and Costs of Primary Care (QUALICOPC) Malaysia, a cross-sectional survey conducted between August 2015 and June 2016 in Malaysia. Data was collected from doctors recruited from public and private primary care clinics using a standardised questionnaire. Comparisons were made between doctors working in public and private clinics, and logistic regression analysis was used to determine factors influencing the likelihood of job satisfaction outcomes. A total of 221 doctors from the public and 239 doctors from the private sector completed the questionnaire. Compared to private doctors, a higher proportion of public doctors felt they were being overloaded with the administrative task (59.7% vs 36.0%) and part of the work does not make sense (33.9% vs 18.4%). Only 62.9% of public doctors felt that there was a good balance between effort and reward while a significantly higher proportion (85.8%) of private doctors reported the same. Over 80% of doctors in both sectors indicated continued interest in their job and agreed that being a doctor is a well-respected job. Logistic regression analysis showed public-private sector and practice location (urban-rural) to be significantly associated with work satisfaction outcomes. A higher proportion of public doctors experienced pressure from administrative tasks and felt that part of their work does not make sense than their colleague in the private sector. At the same time, the majority of private doctors reported positive outcome on effort-and-reward balance compared to only one third of public doctors. The finding suggests that decreasing administrative workload and enhancing work-based supports might be the most effective ways to improve job satisfaction of primary care doctors because these are some of the main aspects of the job that doctors, especially in public clinics, are most unhappy with.


Evolving trauma and orthopedics training in the UK.
The ever-growing population of the UK has resulted in increasing demands on its healthcare service. Changes have been introduced in the UK medical training system to avoid loss of training time and make it more focused and productive. Modernizing medical careers (MMC) was introduced in 2005. This promised to reduce the training period for a safe trauma specialist, in trauma and orthopedics, to 10 years. At around the same time, the European Working Time Directive (EWTD) was introduced to reduce the working hours for junior doctors in training, to improve patient safety and also work-life balance of junior doctors. Introduction of the assessment tools from Orthopedic Competency assessment project (OCAP) will help tailor the training according to the needs of the trainee. The aim of this article is to review the changes in the UK orthopedic surgical training over the past two decades.


Patient demographics, insurance status, race, and ethnicity as predictors of morbidity and mortality after spine trauma: a study using the National Trauma Data Bank.
Predictors of complications and mortality after spine trauma are underexplored. At present, no study exists capable of predicting the impact of demographic factors, injury-specific predictors, race, ethnicity, and insurance status on morbidity and mortality after spine trauma. This study endeavored to describe the impact of patient demographics, comorbidities, injury-specific factors, race/ethnicity, and insurance status on outcomes after spinal trauma using the National Sample Program (NSP) of the National Trauma Data Bank (NTDB). The weighted sample of 75,351 incidents of spine trauma in the NTDB was used to develop a predictive model for important factors associated with mortality, postinjury complications, length of hospital stay, intensive care unit (ICU) days, and time on a ventilator. A weighted sample of 75,351 incidents of spine trauma as contained in the NTDB. Mortality, postinjury complications, length of hospital stay, ICU days, and time on a ventilator as reported in the NTDB. The 2008 NSP of the NTDB was queried to identify patients sustaining spine trauma. Patient demographics, race/ethnicity, insurance status, comorbidities, injury-specific factors, and outcomes were recorded, and a national estimate model was derived. Unadjusted differences in baseline characteristics between racial/ethnic groups and insurance status were evaluated using the t test for continuous variables and Wald chi-square analysis for categorical variables with Bonferroni correction for multiple comparisons. Weighted logistic regression was performed for categorical variables (mortality and risk of one or more complications), and weighted multiple linear regression analysis was used for continuous variables (length of hospital stay, ICU days, and ventilator time). Initial determinations were checked against a sensitivity analysis using imputed data. The weighted sample contained 75,351 incidents of spine trauma. The average age was 45.8 years. Sixty-four percent of the population was male, 9% was black/African American, 38% possessed private/commercial insurance, and 12.5% lacked insurance. The mortality rate was 6% and 16% sustained complications. Increased age, male gender, Injury Severity Score (ISS), and blood pressure at presentation were significant predictors of mortality, whereas age, male gender, other mechanism of injury, ISS, and blood pressure at presentation influenced the risk of one or more complications. Nonwhite and black/African American race increased risk of mortality, and lack of insurance increased mortality and decreased the number of hospital days, ICU days, and ventilator time. This is the first study to postulate predictors of morbidity and mortality after spinal trauma in a national model. Race/ethnicity and insurance status appear to be associated with greater risk of mortality after spine trauma.


The dysphonic videolaryngoscopy with stroboscopy paradox and challenge of acquired subglottic stenosis after laryngotracheal reconstruction.
There's no greater challenge in pediatric laryngology than diagnosis and treatment of chronic dysphonia following laryngotracheal reconstruction of acquired subglottic stenosis. Videolaryngoscopy with stroboscopy provides incomparable diagnostic information to fiberoptic endoscopy. Unfortunately, this pediatric subpopulation which would benefit the most from videolaryngoscopy with stroboscopy infrequently does. We present the unique videolaryngostroboscopic patterns with their diagnostic and treatment implications in this complex population. From a total database of 113 children with histories of subglottic stenosis and/or airway reconstruction between January 1, 2000 and September 30, 2011, successive frames of recorded videolaryngostroboscopies in twenty-three dysphonic children were reviewed. These stroboscopies were compared to age and gender matched controls with dysphonia due to vocal nodules consecutively analyzed from the time period 2009-2011. To validate the similarity of our patient population to others previously reported, we also collected the standardized perceptual, acoustic, and aerodynamic measures of voice analysis and parent/patient reported quality of life. The voices of patients' pre- and post-airway reconstruction are typically moderately breathy and harsh in voice quality with the majority exhibiting a restricted pitch range and vocal strain. Reduced vocal volume intensity and low habitual speaking pitch were common. Overall, the severity of voice fell within the moderately dysphonic range. Despite universal glottic aperture incompetence, muscle tension dysphonia of the true vocal cords was seen. The glottic muscle tension was confirmed indirectly by noting a consistent "posterior cricoarytenoid bulge." In addition, our group termed a unique pattern of "circumferential supraglottic squeeze" which included both lateral plica ventricularis (false vocal folds) and anteroposterior squeeze opposing the arytenoids to the epiglottic petiole (termed by our group as "arytenoid hooding"). In no patients were the true vocal cords fully visualized. While superficially appearing as hyperfunction, these findings paradoxically represented compensation for laryngeal hypofunction marking the hyperfunction not the problem but a symptom. Actual "mucosal waves" were seen involving the false vocal cords. Videolaryngoscopy with stroboscopy results in patterns that are not only unique to patients after airway reconstruction for subglottic stenosis but are also critical for both surgical and non-surgical treatment of chronic dysphonia in these children.


[Inhibit affection of resveratrol on the growth of Hep-2 cell line].
To study the inhibitory effect of resveratrol on growth of human laryngeal cancer cell line, Hep-2. Count cell number under microscope, MTT assay was used to determine the cell growth inhibitory rate. Soft agar colony forming experiment was performed to observe the proliferation ability, before or after resveratrol treatment. Resveratrol was able to depress cell growth and inhibit cell proliferation. Resveratrol strongly inhibit Hep-2 cell proliferation in a time- and dose-dependent manner.


Pantanal yacare (Caiman yacare) tail fillets subjected to traditional hot smoking and liquid smoke.
The present study aimed to evaluate the effects of hot smoking and liquid smoke on process yield, physicochemical properties, microbiological parameters, fatty acid profile, benzo(a)pyrene levels, and sensory profile of Pantanal yacare tail fillets. The fillets were subjected to two types of smoking processes: hot smoking and liquid smoke flavoring. The process yield of liquid-smoked fillets was higher (69.8%) compared to hot-smoked fillets (58.0%). All fillets were with good microbiological quality and low benzo(a)pyrene levels and were well accepted by consumers. The hot-smoked fillets and the liquid-smoked fillets presented 456.2 and 589.7 g kg-1 moisture, 262.3 and 263.7 g kg-1 crude protein, 218 and 85 g kg-1 total lipids, and 26.0 and 20.9 g kg-1 ash, respectively. The major fatty acids identified in the smoked tail fillets were palmitic, stearic, oleic, and linoleic acids. The liquid-smoked fillets had lower lipid content, and higher process yield because of lower losses; thus, they proved to be more advantageous and practical to obtain than the hot-smoked fillets. © 2022 Society of Chemical Industry.


Predicting energy intake in adults who are dieting and exercising.
When a lifestyle intervention combines caloric restriction and increased physical activity energy expenditure (PAEE), there are two components of energy balance, energy intake (EI) and physical activity energy expenditure (PAEE), that are routinely misreported and expensive to measure. Energy balance models have successfully predicted EI if PAEE is known. Estimating EI from an energy balance model when PAEE is not known remains an open question. The objective was to evaluate the performance of an energy balance differential equation model to predict EI in an intervention that includes both calorie restriction and increases in PAEE. The Antonetti energy balance model that predicts body weight trajectories during weight loss was solved and inverted to estimate EI during weight loss. Using data from a calorie restriction study that included interventions with and without prescribed PAEE, we tested the validity of the Antonetti weight predictions against measured weight and the Antonetti EI model against measured EI using the intake-balance method at 168 days. We then evaluated the predicted EI from the model against measured EI in a study that prescribed both calorie restriction and increased PAEE. Compared with measured body weight at 168 days, the mean (±SD) model error was 1.30 ± 3.58 kg. Compared with measured EI at 168 days, the mean EI (±SD) model error in the intervention that prescribed calorie restriction and did not prescribe increased PAEE, was -84.9 ± 227.4 kcal/d. In the intervention that prescribed calorie restriction combined with increased PAEE, the mean (±SD) EI model error was -155.70 ± 205.70 kcal/d. The validity of the newly developed EI model was supported by experimental observations and can be used to determine EI during weight loss.


Computer generated scatter dose distributions for 6-MV radiotherapy photon beams.
The time required for accurate computer dose distributions is of major concern in radiation therapy. Isodose distributions were obtained by calculating the primary and scatter radiation reaching a point. A description of the primary dose distribution, especially at the edge of the beam, requires the calculation of the dose on a finely spaced grid. However, the scatter dose distributions can be described on a much coarser grid. The primary and scatter dose distribution calculations were separated into two computer subroutines which permitted choosing the appropriate grid spacing for each dose component. A more rational partition of the computing time for the primary and scatter dose was obtained. In addition, the separation of the calculation of the scatter dose from the total dose allows one to examine the calculated scatter dose distribution as the radial and angular increments used in the Clarkson-Cunningham summation are varied. Accurate scatter dose distributions were generated with a tenfold time reduction by optimization of grid spacing and radial and angular increments.


Radiological evidence of early cerebral microvascular disease in young children with Fabry disease.
We report on 2 children with Fabry disease who had radiologic evidence of microvascular central nervous system involvement despite the clinical absence of renal, cardiac, or cerebral manifestations. This suggests that treatment with enzyme replacement therapy may be necessary early in the disease to avoid irreversible complications.


The ICAM-1 ligand HRV-A89 is internalized independently of clathrin-mediated endocytosis and its capsid reaches late endosomes.
The human rhinovirus (HRV) A2 is endocytosed by clathrin-mediated endocytosis (CME) bound to the classical LDL receptor and releases its RNA during its transport to late endosomes. Here it is shown that - presumably due to an effect on virus recycling - a low concentration of the CME inhibitor chlorpromazine present during virus internalization (30 min) did not reduce HRV-A2 infection, but strongly inhibited short-time (5 min) endocytosis of HRV-A2. Chlorpromazine had no effect on the colocalization of the ICAM-1 ligand HRV-A89 with early endosomes, excluding CME as the main endocytosis pathway of this virus. As published for HRV-A2 and HRV-A14, HRV-A89 partially colocalized with lysosome-associated membrane protein 2 and the microtubule inhibitor nocodazole did not reduce virus infection when present only during virus internalization. Together with previous work these data suggest that there are no principal differences between endocytosis pathways of ICAM-1-binding rhinoviruses in different cell types.


Cytogenetic analysis in melanoma and nevi.
We have presented data from the cytogenetic analysis of melanocytes derived from four dysplastic nevi and 14 melanomas. We have confirmed previous results from melanomas, including the loss of chromosome 6q and duplication of 1q and 7p. We did not observe an excess of rearrangements involving chromosomes 2 and 3, but we found frequent deletion of chromosomes 9p, 10p, 10q, and 11q. We observed the loss of chromosome 9 in 2 of 4 dysplastic nevi, and combining this observation with that from the melanomas suggests that deletion or inactivation of a gene on 9p may be a primary event in melanocyte transformation. Other tumor suppressor genes are likely to be involved in the transformation process, and these are most likely located on 10p, 10q, 11q, and 6q. We observed many rearrangement involving chromosome band 1p13 and suggest that activation of a gene in that band may also contribute to the transformation process.


Intoxication with massive doses of amlodipine and candesartan requiring venoarterial extracorporeal membrane oxygenation.
Calcium channel blockers and angiotensin II receptor blockers are commonly prescribed to treat hypertension. Massive overdoses can cause both distributive and cardiogenic shock because of their effects on vascular smooth muscles and severe myocardial depression. We present the case of a 46-year-old man who was brought to our emergency department after ingesting 1210 mg amlodipine and 936 mg candesartan. The patient's hemodynamic status deteriorated despite treatment with vasopressors, calcium gluconate, and hyperinsulinemia-euglycemia therapy with mechanical ventilation. Venoarterial extracorporeal membrane oxygenation was initiated for refractory shock. The patient was weaned off extracorporeal membrane oxygenation on day 5 and discharged on day 18 of hospitalization. When medical therapies are ineffective, aggressive venoarterial extracorporeal membrane oxygenation should be considered for the management of refractory shock in the setting of calcium channel blocker with angiotensin II receptor blocker overdose.


Cysticercosis in cattle in Senegal.
The hearts of 51, and the masticatory muscles of another 51 cattle from the slaughter-house in Dakar, were examined by careful dissection. Cysticerci and/or cystic lesions were found in 13.7% of the hearts and in 25.5% of the masticatory muscles. The cystic lesions were examined histologically in an attempt to identify Taenia saginata cysticerci. A final infection rate of 5.8% in hearts and 15.7% in masticatory muscles was thus obtained. Lower percentages were recorded after inspecting 2088 slaughtered cattle by the routine meat inspection technique.


Ethical dilemmas in providing nutrition.
The decisions involved in the institution of artificial feeding in patients with chronic and/or terminal illness are difficult. They are more complex when one is deciding if nutrition and hydration are to be withdrawn. In both instances the decision must be based on a combination of factors: the patient's right to self-determination; documented medical evidence demonstrating the need for artificial feeding, combined with a risk/benefit analysis if alternative alimentation is recommended; and an appreciation of prior legal decisions as they relate to the implementation of alternative forms of nutrients to sustain life.


SOD1 mutations cause hypersensitivity to high-pressure-induced oxidative stress in Saccharomyces cerevisiae.
Living organisms are subject to various mechanical stressors, such as high hydrostatic pressure. Empirical evidence shows that under high pressure, the oxidative stress response is activated in Saccharomyces cerevisiae. However, the mechanisms involved in its antioxidant systems are unclear. Here, we demonstrate that superoxide dismutase 1 (Sod1) plays a role in resisting high pressure for cell growth. Mutants lacking Sod1 or Ccs1, the copper chaperone for Sod1, displayed growth defects under 25 MPa. Of the various SOD1 mutations associated with familial amyotrophic lateral sclerosis, H46Q and S134N substitutions diminished SOD activity to levels comparable to those of catalytically deficient H63A and null mutants. When these mutant cells were cultured under 25 MPa, their intracellular O2•- levels increased while sod1∆ mutant genome stability was unaffected. The high-pressure sensitive sod1 mutants were also susceptible to sublethal levels of the O2•- generator paraquat. The sod1∆ mutant is known to exhibit methionine and lysine auxotrophy. However, excess methionine addition or overexpression of the lysine permease gene LYP1 did not counteract high-pressure sensitivity in the sod1 mutants, suggesting that their amino acid availability might be intact under 25 MPa. Interestingly, an exclusive localization of Sco2-Sod1 to the intermembrane space (IMS) of mitochondria appeared to partially restore the high-pressure growth ability in the sod1 mutants. Taken these results together, we suggest that high pressure enhances O2•- production and Sod1 within the IMS plays a role in scavenging O2•- allowing the cells to grow under high pressure. Empirical evidence shows that under high hydrostatic pressure, the oxidative stress response is activated in Saccharomyces cerevisiae. However, the mechanisms involved in its antioxidant systems are unclear. In the current study, we aimed to explore the role of superoxide dismutase 1 (Sod1) in yeast able to grow under high pressure. Wild type and sod1 mutant cells were cultured in high-pressure chambers under 25 MPa (~250 kg/cm2). The SOD activity in whole cell extracts and 6His-tagged Sod1 recombinant proteins was analyzed using an SOD assay kit. The O2•- generation in cells was estimated by fluorescence staining. Mutants lacking Sod1 or Ccs1, the copper chaperone for Sod1, displayed growth defects under 25 MPa. Of the various SOD1 mutations associated with familial amyotrophic lateral sclerosis, H46Q and S134N substitutions diminished SOD activity to levels comparable to those of catalytically deficient H63A and null mutants. The high-pressure sensitive sod1 mutants were also susceptible to sublethal levels of the O2•- generator paraquat. Exclusive localization of Sco2-Sod1 to the intermembrane space (IMS) of mitochondria partially restored the high-pressure growth ability in the sod1 mutants. High pressure enhances O2•- production and Sod1 within the IMS plays a role in scavenging O2•- allowing the cells to grow under high pressure. Unlike external free radical-generating compounds, high-pressure treatment appeared to increase endogenous O2•- levels in yeast cells. Our experimental system offers a unique approach to investigating the physiological responses to mechanical and oxidative stresses in human body.


Impact of RSV Coinfection on Human Bocavirus in Children with Acute Respiratory Infections.
The objective of this study was to assess epidemiological and clinical features of human bocavirus (HBoV) coinfection with other viruses. Children coinfected with HBoV between January 2012 and December 2014 were enrolled and retrospectively reviewed. A total of 984 patients were stratified into five groups: HBoV infection alone (n = 249), respiratory syncytial virus (RSV) infection alone (n = 649), HBoV coinfection with RSV (n = 28), with human rhinovirus (HRV) (n = 39) and with other virus (n = 19). Length of hospitalization was longer in HBoV coinfection with RSV group than HBoV (9.0 days vs. 7.0 days, p = 0.001), RSV (9.0 days vs. 8.0 days, p = 0.016) infection alone group. Pneumonia was more common in the HBoV coinfection with RSV group compared with the HBoV, RSV infection alone group, respectively (75.0% vs. 44.2%, 31.3%, p < 0.001). HBoV DNA copy numbers (383 000 copies/ml) were positively correlated with the length of hospitalization (r = 0.334, p < 0.001). HBoV coinfection with RSV increases HBoV infection severity.


Induction of apoptosis in oral cancer cells: agents and mechanisms for potential therapy and prevention.
Oral cancer is one of the most disfiguring types of cancer, since the surgical removal of the tumor may result in facial distortion. Oral cancer is also known to exhibit "field cancerization", resulting in the development of a second primary tumor. Furthermore, the five-year survival rate of this disease has remained approximately 50% during the past 30 years. Prevention and early detection/treatment of oral cancer could significantly improve the quality of life for individuals at risk. Recently, the targeted elimination of oral squamous cell carcinoma cells by inducing apoptosis has emerged as a valued strategy to combat oral cancer. Studies utilizing a variety of chemical or biological interventions demonstrated promising results for induction of apoptosis in oral malignant cells. This review summarizes the results of a number of investigations focused specifically on induction of apoptosis in oral cancer cells by synthetic compounds and naturally occurring chemopreventive agents with apoptotic potential.


Molecular, biochemical and ecological characterisation of a bio-catalytic calcification reactor.
Bio-catalytic calcification (BCC) reactors utilise microbial urea hydrolysis by autochthonous bacteria for the precipitation-removal of calcium, as calcite, from industrial wastewater. Due to the limited knowledge available concerning natural ureolytic microbial calcium carbonate (CaCO(3)) precipitation, the microbial ecology of BCC reactors has remained a black box to date. This paper characterises BCC reactor evolution from initialisation to optimisation over a 6-week period. Three key parameters were studied: (1) microbial evolution, (2) the (bio)chemical CaCO(3) precipitation pathway, and (3) crystal nucleation site development. Six weeks were required to establish optimal reactor performance, which coincided with an increase in urease activity from an initial 7 mg urea l(-1) reactor h(-1) to about 100 mg urea l(-1) reactor h(-1). Urease activity in the optimal period was directly proportional to Ca(2+) removal, but urease gene diversity was seemingly limited to a single gene. Denaturing gradient gel electrophoresis of 16S rRNA genes revealed the dynamic evolution of the microbial community structure of the calcareous sludge, which was eventually dominated by a few species including Porphyromonas sp., Arcobacter sp. and Bacteroides sp. Epi-fluorescence and scanning electron microscopy showed that the calcareous sludge was colonised with living bacteria, as well as the calcified remains of organisms. It appears that the precipitation event is localised in a micro-environment, due to colonisation of crystal nucleation sites (calcareous sludge) by the precipitating organisms.


Costochondral grafting in condylar replacement and mandibular reconstruction.
Thirty costochondral grafts in 22 patients were retrospectively studied with a mean follow-up of five (range, 2 to 11) years. The functional results, esthetics, and incidence of complications in these patients were determined. A discussion of these findings as well as the surgical technique is included. The results confirm previous studies and indicate that free costochondral grafting is a successful and physiologically sound method for reconstruction of portions of the mandible and its temporal articulation.


Impact of BRCA1/2 Mutations on the Efficacy of Secondary Cytoreductive Surgery.
Phase III trials evaluating the role of secondary cytoreductive surgery (SCS) in recurrent ovarian cancer have pointed to the importance of patient selection. Two studies showed conflicting results regarding the benefit of SCS in BRCA1/2 mutation carriers. Our aim was to evaluate the impact of SCS on recurrent ovarian cancer according to BRCA1/2 status. All patients with ovarian carcinoma with platinum-sensitive recurrent disease and tested for BRCA1/2 germline mutations were included. Cox regression and log rank test were used to evaluate the impact of SCS on progression-free survival (PFS) and the influence of BRCA1/2 mutations on the effect of SCS. 127 patients were included, 45.6% were treated with SCS and chemotherapy and 54.3% treated with chemotherapy only. Patients treated with SCS were younger, presented better performance status, had lower CA125, and had a longer platinum-free interval. In multivariate analysis SCS was associated with longer PFS (HR 0.42, 95% CI 0.25-0.72, p = 0.002). BRCA1/2 mutations were found in 35 patients (27.5%), and 11.8% of patients were treated with PARP inhibitors. Although not statistically significant, both BRCA1/2 wild type patients (PFS: 21.6 vs 18.4 months; p = 0.114) and BRCA1/2 mutation carriers (PFS: 23.1 vs 18.2 months, p = 0.193) appeared to derive benefit from SCS. The present study suggests a benefit of SCS irrespective of BRCA1/2 status among patients mostly not treated with PARP inhibitor. Further data on post hoc analysis from the phase III trials are warranted to confirm whether BRCA1/2 mutated patients should be selected for SCS.


Observations concerning the course of glaucoma.
Four cases with glaucomatous damage to the optic nerve head preceding a rise in intraocular pressure from normal or borderline to high values, are reported. The question of whether such cases are exceptional or typical and, therefore, best explained by a coincidence of diseases or by one disease going through successive stages is discussed on the basis of 10 further cases from a population study. Many clinicians claim that there are two groups of patients: a large one with 'ordinary' glaucomas supposedly caused by high intraocular pressures and a small one with low tension glaucomas presumed to have low perfusion pressures for other reasons. This classification circumvents the discussion on etiology and gives theoretical support to conventional treatment. Accumulated clinical observations indicate, however, that it should not be accepted without discussion. We describe here a few selected cases with glaucomatous damage to the optic nerve head preceding a rise in the intraocular pressure from normal or borderline to high values.


Essential role of Rnd1 in innate immunity during viral and bacterial infections.
Intracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.


A scoring system for predicting the survival prognosis of patients receiving stereotactic body radiation therapy (SBRT) for 1-3 lung metastases.
The main goal of the present study was the development of a survival scoring system for patients treated with stereotactic body radiation therapy (SBRT) for very few lung metastases. Such an instrument would be of value when selecting the optimal dose for individual patients with a limited number of pulmonary lesions. Forty-six patients receiving SBRT for 1-3 lung metastases were retrospectively analyzed. The biologically effective dose plus nine characteristics [gender, age, performance score, interval from tumor diagnosis to SBRT, primary tumor type, additional (extra-pulmonary) metastases, major location of lung metastases, number of pulmonary lesions, and volume treated with SBRT] were evaluated. Characteristics significantly associated with the survival on Cox regression analysis were incorporated in the scoring system. Scoring points were received from 1-year survival rates divided by 10. Sums of these scoring points represented the scores for the individual patients. Survival rates at 1 and 2 years were 66 and 56 %, respectively. On Cox regression analysis, performance score (p = 0.025), the type of primary tumor (p = 0.013) and the additional metastases (p = 0.032) had a significant impact on survival. Scores for patients ranged from 15 to 25 points. Three groups were designed: 15 points, 16-20 points, and 21-25 points. One-year survival rates were 0, 52, and 83 %, respectively (p = 0.005); 2-year survival rates were 0, 52, and 66 %, respectively. A survival scoring system for patients receiving SBRT for very few lung metastases was developed. This score allowed us to estimate the survival prognosis of these patients and can aid physicians when aiming to choose the optimal SBRT dose for individual patients.


Plasma Cell-Free Human Papillomavirus Oncogene E6 and E7 DNA Predicts Outcome in Oropharyngeal Squamous Cell Carcinoma.
Persistent human papillomavirus (HPV) infection is associated with the development of oropharyngeal squamous cell carcinoma (OPSCC), and increasing incidences of OPSCC are reported. The generally favorable treatment outcome in patients with HPV-driven OPSCC has brought de-escalation of treatment into discussion. Nevertheless, 13% to 25% develop a relapse within two years after current standard treatment. New biomarkers are urgently required to monitor therapy response, tumor burden, and minimal residual disease during follow-up. This observational study examined 50 patients with OPSCC to investigate plasma cell-free (cf) HPV-DNA derived from tumor cells before therapy and during follow-up. Real-time quantitative PCR was applied to quantify the DNA concentration of HPV oncogenes E6 and E7. A total of 85.7% of pretreatment samples from patients with HPV-driven OPSCC (n = 28) were positive for at least one marker, and cfHPV-DNA concentration increased with tumor size. Virtually no signals were detected in HPV-negative OPSCC patients (n = 20; P ≤ 0.001). Patients without clinical evidence of recurrence had significantly reduced cfHPV-DNA concentrations after therapy (P ≤ 0.001). Conversely, cfHPV-DNA levels increased or remained above threshold in five patients who had residual disease or developed recurrence. In conclusion, plasma cfHPV-DNA detection correlates with the clinical course of disease in patients with HPV-driven OPSCC. Consequently, extensive clinical investigation should be considered if cfHPV-DNA is detected during follow-up of patients with HPV-driven OPSCC.


Misoprostol versus misoprostol and foley catheter combination in 2nd trimester pregnancy terminations.
The efficacy and safety were assessed of a misoprostol regimen used alone or in combination with foley catheter for second trimester pregnancy termination. A retrospective examination was made of the records of patients who underwent pregnancy termination at 14-24 weeks of gestation in our university hospital between January 2011 and June 2014. Records were available for patients 378 who underwent terminations. Group 1 comprised patients with no history of cesarean section. An initial dose of 200 μg misoprostol was administered intravaginally and then until the termination was completed an additional 200 μgr dose was administered sublingually every 4 hours (Group 1: 234 patients). Group 2 comprised patients with a history of cesarean section. An initial dose of 200 μg misoprostol was administered intravaginally and 2 hours later an intracervical foley catheter was inserted (Group 2: 144 patients). The total misoprostol dosage used was 1160 μg and 560 μg (p< 0.001), intervals from the administration of the first misoprostol tablet until termination were 854.8 and 704.2 minutes (p= 0.03) in Groups 1 and 2, respectively. The misoprostol + foley catheter combination reduces the total dosage of misoprostol required for termination and shortens the termination interval, thereby increasing patient's comfort. Based on these results, the usage of the misoprostol + foley catheter combination can be recommended especially for patients with a history of caesarian section.


[Prognosis in the social and occupational adaptation of patients with slowly progressive schizophrenia].
A series of 190 patients with slowly progressive schizophrenia have been examined with the aim of studying the prognosis of their social and occupational adaptation. The authors have analyzed the dynamics of the mental status and adaptation over years. Criteria of the prognosis of social and occupational adaptation have been identified. The adaptive behaviour and prognosis in patients with slowly progressive schizophrenia have been found to depend on the type of the personality abnormality in the premorbid period, age at the disease onset, its pattern, and clinical characteristics of the active period of the disease.


Exploring the psychological morbidity of waiting for sinus surgery using a mixed methods approach.
Patients with chronic rhinosinusitis (CRS) often have to endure significant wait times for endoscopic sinus surgery (ESS). The pyschiatric impact of placement on a waitlist for ESS has not been explored. Questionnaires measuring CRS symptom severity and health-related anxiety and stress (SNOT-22, HADS, WPAI-GH) were sent to patients diagnosed with CRS and currently on a waitlist for ESS. Fifteen representative waitlisted patients participated in one-on-one semi-structured interviews discussing their experience with their wait for ESS. A deductive thematic analysis was used to interpret the interview data using a quantitative driven mixed methods analysis. Participants waiting for ESS reported worsening clinical symptomatology during their waiting period. Participants reported waitlist and CRS impact on both work and social aspects of their lives. The HADS scale showed no overall significant level of depression or anxiety in the HADS screening questionnaire. The qualitative data describe the effects of the symptom burden of CRS. Patients waitlisted for ESS did not demonstrate any significant level of psychiatric distress, however variability exists. The qualitative arm of this study elucidates how patients cope with their wait.


Reoperation after the failure of Wang procedure on pectus excavatum: Wung procedure + Wenlin procedure.
Wang procedure for pectus excavatum is a simple and safe surgery. However, improper operation may lead to failure of the surgery. We received a 7-year-old male patient with pectus excavatum who failed Wang procedure. We used the combination of Wung procedure and Wenlin procedure to correct the deformity and achieved satisfactory results.


Are redox changes a critical switch for mitotic progression?
Cell-cycle dependent redox changes result in increased protein oxidation in mitotic cells. We show that oxidative modifications of a conserved cysteine residue within Aurora A kinase (AURKA) can promote its activation during mitosis. Targeting redox-sensitive cysteine residues within AURKA may lead to the development of novel anti-cancer agents with improved clinical efficacy.


Studies on Structural, Morphological and Optical Properties of Chemically Deposited CdS(1-x)Se(x) Thin Films.
The thin films of CdS(1-x)Se(x) were successfully deposited over glass substrates by chemical bath deposition technique. Cadmium acetate, thiourea and sodium selenosulfate were used as source materials for Cd(2+), S(2-) and Se(2-) ions, while 2-mercaptoethanol was used as capping agent. The various deposition conditions such as precursor concentration, deposition temperature, pH and deposition time were optimized for the deposition of CdS(1-x)Se(x) thin films of good quality and the films were annealed at 200° and 300 °C. The structural, morphological, chemical and optical properties were examined by various characterization techniques and discussed in detail. The optical band gap of CdS(1-x)Se(x) thin film samples were estimated and found in the range from 2.11 to 1.79 eV for as-deposited and annealed thin films.


Action of crystalline acid carboxypeptidase from Penicillium janthinellum.
Acid carboxypeptidase (EC 3.4.12.-) crystallized from culture filtrate of Penicillium janthinellum has been investigated for its use in carboxy-terminal sequence determination of Z-Gly-Pro-Leu-Gly, Z-Gly-Pro-Leu-Gly-Pro, angiotensin I, native lysozyme, native ribonuclease T1, and reduced S-carboxy-methyl-lysozyme. The examination indicated that proline and glycine were liberated from Z-Gly-Pro-Leu-Gly-Pro. At high enzyme concentration, the enzyme catalyzed complete sequential release of amino acids from the carboxy-terminal leucine to the amino-terminal aspartic acid of angiotensin I. The enzyme released the carboxy-terminal leucine from native lysozyme, however, no release of the threonine from native ribonuclease T1 was observed after a prolonged period of incubation with the enzyme. The sequence of the first nine carboxy-terminal residues of denatured lysozyme, leucine, arginine, S-carboxymethyl-cysteine, glycine, arginine, isoleucine, tryptophane, alanine, and glutamine, could be deduced unequivocally from a time release plot of an incubation mixture with the enzyme.


10-year-outcomes after rituximab for myasthenia gravis: Efficacy, safety, costs of inhospital care, and impact on childbearing potential.
Rituximab (RTX) has emerged as an attractive off-label treatment option for patients with myasthenia gravis (MG) refractory to other immune therapies. However, data on long-term outcome after RTX for MG are still scarce. Here we present the 10-year outcomes [median (range) 10.1 (6.7-11.2) years] with respect to efficacy, safety, costs of inhospital care, and impact on childbearing potential in all four MG patients treated by one of the authors with RTX. In all patients, RTX led to sustained clinical improvement and eventual tapering of other immune therapies. RTX was well tolerated, and complications were not observed. After the start of RTX, annual costs for hospital admissions were markedly reduced compared to costs in the year preceding RTX. Under close clinical observation, two patients had uncomplicated pregnancies giving birth to a healthy child. With regard to its efficacy, excellent tolerance, lack of complications, low frequency of repeat infusions and pending patent expiry in many countries, RTX appears to compare favourably with other immune therapies used for MG. Multicentre trials and registries are urgently needed to further address long-term safety issues and clarify the efficacy and role of RTX in managing MG.


The interrelationship between the olfactory bulbs and the basomedical hypothalamus in controlling food intake, obesity and endocrine functions in the chicken.
Surgical removal of the olfactory bulbs (OB) in the chicken indicated an increase in thyrotropic activity followed by a compensatory increase in food intake, as shown earlier. Basomedial hypothalamic (BMH) lesions in these birds caused changes in certain parameters which strongly infer hypoactivity of the thyrotropic axis. The lesions also caused development of typical hypothalamic obesity demonstrating both dynamic and static phases. Removal of the OB in BMH lesioned birds in their static phase of obesity, caused no demonstrable physiological changes. While removal of the OB caused an increase in somatotropic activity, the opposite was found in BMH lesioned birds. Those animals in which OB were removed and BMH was destroyed, demonstrated a decrease in somatotropic activity. It is suggested that the syndrome caused by BMH lesions dominates that caused by removal of the OB. The possibility of involvement of the OB in the control of thyrotropic and somatotropic activities mediated by the basomedial hypothalamus, is discussed.


Alpha-fetoprotein receptors in a human breast cancer cell line.
Evidence is presented for the existence of specific receptors for alpha-fetoprotein on the surface of MCF-7 human breast cancer cells. At 4 degrees C, the binding of alpha-fetoprotein to these cells displayed a biphasic saturation curve. Scatchard analysis revealed the presence of at least two binding sites with dissociation constants of 4.5 X 10(-9) M (2,000 sites/cell) and 1.3 X 10(-8) M (135,000 sites/cell), respectively. Binding was inhibited by 85% in the presence of a 5,000-fold excess of unlabeled alpha-fetoprotein and by 50% with the same excess of serum albumin. Competition by other serum proteins was not significant. At 37 degrees C, alpha-fetoprotein was endocytosed and the uptake curve reached a plateau after 3-4 hours of incubation.


Pledget- and patch-holding clamp: a new instrument.
A new clamp designed to facilitate the handling and placement of various shapes and sizes of cardiac patching materials is described.


Effect of intraduodenal peptone on the lower esophageal sphincter pressure in the dog.
The role of the duodenum in the regulation of the lower esophageal sphincter pressure (LESP) was investigated in 4 unrestrained dogs equipped with a chronic Komarov type esophagostomy, a cutaneous duodenal fistula, a gastrojejunostomy, and a Y anastomosis between the distal end of the duodenum and the midjejunum. Installation of NaCl solution into the duodenum or into the stomach did not effect LESP during the following 60-min observation period. Peptone instillation into the duodenum or into the stomach produced a sustained elevation LESP. The rise of LESP was significantly greater after duodenal than after gastric instillation. Duodenal peptone did not raise serum gastrin. It is concluded that the duodenum may be an important regulator of LESP in the dog and that this effect is not mediated by circulating gastrin.


Multiple pituitary hormone deficiencies in a patient with spinocerebellar ataxia: magnetic resonance imaging and hormonal studies.
Degenerative spinocerebellar ataxia has a rare association with hypogonadotropic hypogonadism. In this report we present the results of the detailed endocrine evaluation and magnetic resonance imaging in one such patient. A 20-year-old male with progressive cerebellar ataxia, hypogonadism, and short stature was investigated. Basal testing revealed hypogonadotropic hypogonadism (LH < 5 mU/L, FSH < 5 mU/L, testosterone 2.5 nM/L). There was no rise in LH after stimulation with LHRH, peak LH level being < 5 mU/L. Insulin hypoglycemia testing was consistent with GH deficiency, with peak GH being 3.2 mU/L. On TRH stimulation, there was no significant rise in prolactin, though the TSH response was normal. Magnetic resonance imaging revealed cerebellar atrophy. The anterior pituitary was atrophic, with a height of 1.4 mm. The posterior pituitary and the pituitary stalk were normal in size and position. This patient with degenerative spinocerebellar ataxia had multiple pituitary hormone deficiencies. The results of our endocrine evaluation and MR imaging lead us to believe that these deficits may result from a lesion at the level of the pituitary gland.


Oxidation of As(III) by potassium permanganate.
The oxidation of As(III) with potassium permanganate was studied under conditions including pH, initial As(III) concentration and dosage of Mn(VII). The results have shown that potassium permanganate was an effective agent for oxidation of As(III) in a wide pH range. The pH value of tested water was not a significant factor affecting the oxidation of As(III) by Mn(VII). Although theoretical redox analyses suggest that Mn(VII) should have better performance in oxidization of As(III) within lower pH ranges, the experimental results show that the oxidation efficiencies of As(III) under basic and acidic conditions were similar, which may be due to the adsorption of As(III) on the Mn(OH)2 and MnO2 resulting from the oxidation of As(III).


Sensor Fusion and Advanced Controller for Connected and Automated Vehicles.
Nowadays, intelligent vehicles are equipped with a number of advanced sensors, such as radar and cameras [...].


Potential Toxic Elements and Their Carcinogenic and Non-Carcinogenic Risk Assessment in Some Commercially Important Fish Species from a Ramsar Site.
Potentially toxic elements (PTEs) such as Hg, As, and Pb have become concentrated in the aquatic ecosystem as a result of increased human activities. However, these substances frequently have synergistic or antagonistic effects on the human body or other animals. As a result, there are concerns world-wide that commercially available food products, especially fish, may be contaminated with hazardous elements. In this study, samples of four selected fishes, Gutum (Lepidocephalichthys guntea), Baim (Macrognathus pancalus), Baila (Glossogobius giuris), Meni (Nandus nandus) were analyzed from one of the largest freshwater wetlands (designed as a Ramsar Site) in South Asia to evaluate PTEs contamination status and human health risk assessment. The result demonstrated that the degree of contamination for six PTEs decreased in the following sequences for fish: Fe > Zn > Cu > Pb > As > Hg. The edible part of G. giuris had the maximum value for Hg (0.42 μg/g dw), while N. nandus predominantly accumulated As (<0.41 μg/g dw). The estimated daily intake (EDI) values ranged from 0.003 to 1.75, which was much lower than the recommended values. The hazard index (HI), THQ, total target hazard quotient (TTHQ) scores through consuming fish followed the decreasing order of Fe > Hg > Cu > Zn > Pb. The values for each index were less than 1, indicating that there were no substantial health risks for the consumers. The carcinogenic risks (CR) derived from the intake of Pb ranged from 4.92 × 10-8 to 4.14 × 10-8 for males and 5.45 × 10-8 to 4.59 × 10-8 for females, which also did not exceed the standard limit (1.00 × 10-6). This study demonstrated that, under the existing consumption rate, there was no potential health harm to consumers from consuming the studied fishes. This study offers a chance to regularly check PTEs in this environment, reducing the contamination of heavy metals.


[Anastomosis between the left internal spermatic and splanchnic veins. Retrospective analysis of 305 patients].
To investigate the presence and the rate of anastomoses between the internal spermatic vein (ISP) and visceral veins in patients with idiopathic varicocele. We retrospectively reviewed the venographic findings of 305 patients (age range 14-40 years; mean age 28 years) with a US diagnosis of varicocele who were submitted to sclerotherapy from 1991 to 1997. All the venographic examinations had been carried out with selective injection of the ISP for complete mapping of gonadal vessels. The most frequent venographic patterns (type I) was identified in 139/305 patients (45.5%), type III was found in 86/305 (28.2%), type V in 37/305 (12.1%). Type IVb was found in 32 cases (10.4%) and type IVa in 9 (2.9%). Type II was seen in 2/305 patients only (0.6%). Single or double anastomoses between the ISP and portal or systemic veins were found in 34 patients (11.1%); a single or double communication with the left colic vein was observed in 24 cases (7.8%) and a communication with the paravertebral venous system in 10 patients (3.2%). Other anastomoses with the inferior mesenteric veins and splenic veins were seen in 7 and 4 patients (2.2% and 1.3%, respectively). The presence of vascular variants and of communications of the ISP with the visceral veins needs accurate venographic studies preliminary to sclerotherapy and a skilled interventional radiologist in order to reduce the number of recurrences.


Acetylated Microtubules Are Preferentially Bundled Leading to Enhanced Kinesin-1 Motility.
The motor proteins kinesin and dynein transport organelles, mRNA, proteins, and signaling molecules along the microtubule cytoskeleton. In addition to serving as tracks for transport, the microtubule cytoskeleton directs intracellular trafficking by regulating the activity of motor proteins through the organization of the filament network, microtubule-associated proteins, and tubulin posttranslational modifications. However, it is not well understood how these factors influence motor motility, and in vitro assays and live cell observations often produce disparate results. To systematically examine the factors that contribute to cytoskeleton-based regulation of motor protein motility, we extracted intact microtubule networks from cells and tracked the motility of single fluorescently labeled motor proteins on these cytoskeletons. We find that tubulin acetylation alone does not directly affect kinesin-1 motility. However, acetylated microtubules are predominantly bundled, and bundling enhances kinesin run lengths and provides a greater number of available kinesin binding sites. The neuronal MAP tau is also not sensitive to tubulin acetylation, but enriches preferentially on highly curved regions of microtubules where it strongly inhibits kinesin motility. Taken together, these results suggest that the organization of the microtubule network is a key contributor to the regulation of motor-based transport.


Bonding to resurfaced posterior composites.
Despite significant improvements in the wear resistance of posterior composite restorations, they still undergo occlusal wear, color change, and surface staining with time. One method of repairing these restorations is re-surfacing the old composite. This study investigated the bonding of new composite to the corresponding old composite material by several different mechanical conditioning steps, chemical conditioning steps, primer conditioning steps, and four posterior composites. Aged composite surfaces were conditioned, re-bonded to new composite, stored in artificial saliva for seven days at 37 degrees C, and tested in shear. The mean shear strength for unrepaired composites was 27 MPa. Optimal re-bond strengths were 88% (Estilux), 77% (Ful-Fil), 92% (Occlusin), and 102% (P-10) of original bulk shear strengths. General linear modeling revealed that the best combination tested was roughening with a D830 diamond bur, conditioning the surface with water, and priming with Scotchbond-1 dentin bonding agent.


[Feasibility of laparoscopic treatment of duodenal ulcers: results of 160 cases].
The objective of this study is to evaluate the feasibility, efficacy and safety of laparoscopic repair for perforated duodenal ulcer. One hundred and sixty patients were treated by coelioscopic procedure for a perforated duodenal ulcer. The procedure consists on a suture of perforated ulcer associated with a peritoneal lavage. A medical treatment of Helicobacter pylori associated with an inhibitor of the protons pomp was conducted. The coelioscopic procedure permitted to confirm the diagnostic of perforated duodenal ulcer in all cases. A simple suture of the ulcer was done in 155 cases. The conversion was compulsory in 5 cases, because of difficulties of the peritoneal lavage in 2 cases, a bleeding associated with perforation of the ulcer in one case and associated stenosis in 2 cases. Mean duration was 90 min (extremes 50 - 120 min). Complications occur in 3,1%. They were post - operative peritonitis in 3 cases and duodenal fistulae in 2 cases. All patients were reviewed at 16 months. A recurrence, either clinical or endoscopic occurs in 4 cases because of no adhesion to medical treatment. Coelioscopic treatment of perforated duodenal ulcer is a safe and efficacy method. It permits to avoid potential septic and parietal complications of laparotomy. The actual efficacy of medical treatment mustn't allow place to the radical treatment of ulcerous illness.


A binary pulsar in a 53-minute orbit.
Spider pulsars are neutron stars that have a companion star in a close orbit. The companion star sheds material to the neutron star, spinning it up to millisecond rotation periods, while the orbit shortens to hours. The companion is eventually ablated and destroyed by the pulsar wind and radiation1,2. Spider pulsars are key for studying the evolutionary link between accreting X-ray pulsars and isolated millisecond pulsars, pulsar irradiation effects and the birth of massive neutron stars3-6. Black widow pulsars in extremely compact orbits (as short as 62 minutes7) have companions with masses much smaller than 0.1 M⊙. They may have evolved from redback pulsars with companion masses of about 0.1-0.4 M⊙ and orbital periods of less than 1 day8. If this is true, then there should be a population of millisecond pulsars with moderate-mass companions and very short orbital periods9, but, hitherto, no such system was known. Here we report radio observations of the binary millisecond pulsar PSR J1953+1844 (M71E) that show it to have an orbital period of 53.3 minutes and a companion with a mass of around 0.07 M⊙. It is a faint X-ray source and located 2.5 arcminutes from the centre of the globular cluster M71.


Diagnostic classifications in depression and somatization should include biomarkers, such as disorders in the tryptophan catabolite (TRYCAT) pathway.
The tryptophan catabolite (TRYCAT) pathway is induced by indoleamine 2,3-dioxygenase (IDO), which upon activation depletes plasma tryptophan (TRP) and increases the synthesis of TRYCATs. Both phenomena are associated with somatization and depression. The aims of this study are to examine whether disorders in the TRYCAT pathway are specific to depression or somatization and whether the diagnoses somatization, depression, and comorbid depression+somatization reflect qualitatively distinct clinical and biological categories. Plasma TRP, the kynurenine (KY)/TRP and KY/kynurenic acid (KA) ratios were measured in 36 patients with somatization, 35 depressed and 38 depressed+somatization patients and 22 controls. Using pattern recognition methods, the diagnosis comorbid depression+somatization could not be validated, while there was an important overlap between depression and somatization, which form one continuum. Cluster analysis detected a) a control cluster; b) a cluster with lower tryptophan, and higher KY/TRP and KY/KA ratios and somatization scores; and c) a cluster with increased depression but lower KY/TRP values. The differences between both patient clusters were quantitative and not qualitative. Within the patient group, cluster analysis has generated a "pathway phenotype", i.e. aberrations in the TRYCAT pathway, which are associated with somatization rather than with depression.


Pediatric neck abscesses: changing organisms and empiric therapies.
To examine the causative organisms in pediatric neck infections, delineate risk factors in methicillin-resistant Staphylococcus aureus (MRSA) pediatric neck infections, and define patient populations that should be empirically treated with MRSA sensitive antibiotics. Retrospective chart review. Two hundred twenty-eight consecutive patients were reviewed, ages 0 to 17, presenting at a tertiary care center between 1999 and 2007 with computed tomography proven neck abscesses. Characteristics of patients with differing causative organisms were compared. Forty-eight percent of all pediatric patients' with head and neck abscesses had S. aureus as the causative organism, 29% of which were community-acquired MRSA -- recent years showed that up to 66% of pediatric neck abscesses were MRSA culture positive. When comparing MRSA infections vs. other causative organisms multiple clinical characteristics were found which did not help to differentiate those patients at a higher risk for MRSA. Characteristics which did trend to predict an MRSA infection were few. For example, the average age of patients with MRSA was 32.5 months compared with only 16 months for the methicillin-sensitive S. aureus patients. MRSA sensitivities and resistances were also examined. This study presents a large cohort of pediatric neck abscess patients, in which the emergence and characteristics of MRSA are shown. As community-acquired MRSA infections become more prevalent, empiric antibiotic therapy must be considered. The results of this study show that the incidence of MRSA has greatly increased and clinical risk factors are not helpful in choosing those patients which may be at higher risk for an MRSA infection.


Hg2+ selective fluorescent and colorimetric sensor: its crystal structure and application to bioimaging.
A Hg(2+)-selective rhodamine 6G derivative bearing thiolactone moiety was synthesized, and its crystal structure with Hg(2+) is presented to explain the binding mode. In addition, highly selective "off-on"-type fluorescent change upon the addition of Hg(2+) was also applied to bioimaging.


Comprehensive Understanding for Application in Korean Patients with Type 2 Diabetes Mellitus of the Consensus Statement on Carbohydrate-Restricted Diets by Korean Diabetes Association, Korean Society for the Study of Obesity, and Korean Society of Hypertension.
The Joint Committee of the Korean Diabetes Association, the Korean Society for the Study of Obesity, and the Korean Society of Hypertension announced a consensus statement on carbohydrate-restricted diets and intermittent fasting, representing an emerging and popular dietary pattern. In this statement, we recommend moderately-low-carbohydrate or low-carbohydrate diets, not a very-low-carbohydrate diet, for patients with type 2 diabetes mellitus. These diets can be considered a dietary regimen to improve glycemic control and reduce body weight in adults with type 2 diabetes mellitus. This review provides the detailed results of a meta-analysis and systematic literature review on the potential harms and benefits of carbohydrate-restricted diets in patients with diabetes. We expect that this review will help experts and patients by fostering an in-depth understanding and appropriate application of carbohydrate-restricted diets in the comprehensive management of diabetes.