Trends in cerebrovascular disease mortality in Singapore: 1970-1994.
Cerebrovascular disease has been the third leading cause of death in Singapore for the last 25 years. This study was carried out to examine recent trends in cerebrovascular disease mortality in Singapore, and to study corresponding changes in stroke risk factors in our population. The Registry of Births and Deaths, Singapore, publishes annual reports on births and deaths. The cause of death is coded using the International Classification of Diseases Revisions 8 (1969-1978) and 9 (1979 onwards). Data for this study were obtained using rubrics 430-438. Death rates were age- and sex-standardized to the World Standard Population, and separately for males and females. Cerebrovascular disease risk factor patterns were derived from national epidemiological health surveys conducted from 1970 and 1994. The absolute number of deaths annually from cerebrovascular disease rose from 1041 in 1970 to 1692 in 1994. Crude death rates remained stable at 50-60 per 100000, accounting for 10-12% of all deaths. Standardized death rates showed a distinct fall from 99 per 100000 in 1976 to 59 per 100000 in 1994, 101 to 60 per 100000 in males and 95 to 57 per 100000 in females. National health surveys have shown a fall in the prevalence of undetected hypertension, smoking and hyperlipidaemia; the prevalence of obesity was unchanged, while that of diabetes mellitus rose over the same period. The mortality trends found in this study are unlikely to be due to changing fashions in coding or inadequate data collection. As in many countries in the world, cerebrovascular disease mortality in Singapore has fallen over the last 25 years; this may in part be related to the decline in stroke risk factors in our population.


Monoclonal antibodies for cancer therapy.
Monoclonal antibodies directed at tumor-associated antigens have been used clinically since 1981. In most of the completed clinical trials, the McAbs were of murine origin. Twenty-six of 184 patients (14%) receiving McAbs demonstrated a major clinical response, including 3 complete responders. Toxicities are primarily related to immune responses. The immune response triggering the toxic manifestations may be mediated by interactions between the administered McAb and the target tumor-associated antigens, or between the McAb and host antibodies made in response to its administration. Analysis of the mechanism of action, pharmacokinetics and toxicity of McAb administration should lead to improved design of clinical protocols, and provide a basis for the use of human McAbs and McAbs conjugated to radioisotopes, toxins or chemotherapeutic agents.


Posterior lumbar interbody fusion for degenerative disc disease using a minimally invasive B-twin expandable spinal spacer: a multicenter study.
Acquired degenerative disc disease causes gradual disc space collapse, concurrent discogenic or facet-induced pain, and possible compression radiculopathy. Surgical treatment aims to re-expand the intervertebral space and stabilize the involved segment in balanced alignment until fusion is complete. The prevailing methods make use of a twin cage device of predetermined size. Their implantation requires extensive exposure, entailing the sacrifice of posterior stabilizing structures. The procedure also results in significant traction on the dural sac and the cauda equina and is thereby a potential source of neurologic damage. The new expandable spinal spacer (ESS) was designed to mitigate all the shortcomings alluded to above. A prospective multicenter clinical study was conducted of 87 patients with chronic low back pain due to degenerative disc disease, treated by posterior lumbar interbody fusion (PLIF) using a newly designed ESS. The study protocol was approved by the ethics committees of all the participating institutions. The objective was to test the safety and efficacy of the device. Each participant was followed periodically for >1 postoperative year. The ongoing record included intraoperative difficulties and complications, if any, radiologic evidence of fusion and clinical outcome as scored by pre- and postoperative questionnaires pertaining to pain intensity and degree of disability. No dural lacerations or neurologic deficit occurred. There were no mechanical failures of the spacer. Radiologic study demonstrated fusion in all but one patient. Disc space height that averaged 7.53 +/- 2.42 mm before surgery increased to 10.03 +/- 2.00 mm at the time of surgery and stabilized at 9.47 +/- 2.10 mm upon final follow-up. Visual Analog Scale and Oswestry Index decreased by 60% and 58%, respectively. PLIF using the ESS achieves the same ultimate outcome as do other methods currently in use but does not share the handicaps and hazards and is more user-friendly to the surgeon.


Association between body positioning and gastroesophageal reflux in paediatric age.
Postural measures are frequently recommended for gastroesophageal reflux (GER) symptoms, despite limited evidence. This was the first study to assess the impact of upright and recumbent body positions on GER episodes in children and adolescents, not just infants. We retrospectively assessed the pH-impedance parameters of paediatric patients referred for possible GER-related symptoms to two hospitals in Naples and Rome, Italy, from September 2016 to September 2018. Data were separately obtained for the time that the patients spent in upright and recumbent positions. Data from 187 patients under the age of 18 were collected, at a mean age of just over seven years. We found that the acid exposure time was stable irrespective of changes in body position (P > .05). The mean number of reflux episodes per hour was 2.99 during the upright position and 1.21 during the recumbent position (P < .05), and the mean oesophageal acid clearance time was 44.4 and 93.4 seconds, respectively (P < .05). Most paediatric patients experienced reflux in the upright rather than recumbent position, probably as a result of frequent transient lower oesophageal sphincter relaxations while they were awake. In particular, our findings provide new insights into postural measures for reflux in children and adolescents.


Gastric cancer: factors affecting survival.
The present multicenter, retrospective study aimed at determining the factors affecting survival in patients who were operated on due to gastric cancer (GC). The data of 234 patients, who underwent elective surgery due to GC were retrospectively analyzed. The demographic characteristics, tumor localization and diameter, type of resection and lymph node dissection, experience of the operating surgeon (senior or junior), tumor grade, pT stage, number of lymph nodes harvested, number of lymph nodes with and without metastasis, tumor stage and survival data were recorded. Survival was better a tumor diameter <4 cm, lower localization, experience of the operating surgeon (senior), without metastatic lymph nodes, tumor grade and decreased invasion depth (p < .05). There was no statistically significant difference between D1 LND and D2 LND with respect to survival (p = .793). Mortality was higher and survival was lower in patients with metastatic lymph nodes (p = .001). A number of harvested lymph nodes of 16 or more increased mortality (p = .003). Also, as disease stage increased, there was a decrease in survival and increase in mortality rates (p = .001). Survival outcomes in resectable GCs are affected by the experience of the surgeon and patient-related factors at the time of surgery, including tumor size, T stage, and presence of metastatic lymph nodes.


Film wrap nanoparticle system with the graphene nano-spacer for SERS detection.
Film wrap nanoparticle system (FWPS) is proposed and fabricated to perform SERS effect, where the Ag nanoparticle was completely wrapped by Au film and the double-layered graphene was selected as the sub-nano spacer. In this system, the designed nanostructure can be fully rather than partly used to generate hotspots and absorb probe molecules, compared to the nanoparticle to nanoparticle system (PTPS) or nanoparticle to film system (PTFS). The optimal fabricating condition and performance of this system were studied by the COMSOL Multiphysics. The simulation results show that the strongly large-scale localized electromagnetic field appears in the whole space between the Ag nanoparticle and Au film. The experimental results show that the FWPS presents excellent sensitivity (crystal violet (CV): 10-11 M), uniformity, stability and high enhancement factor (EF: 2.23×108). Malachite green (MG; 10-10 M) on the surface of fish and DNA strands with different base sequence (A, T, C) were successfully detected. These advanced results indicate that FWPS is highly promising to be applied for the detection of environmental pollution and biomolecules.


Using GPS data to evaluate the accuracy of state-space methods for correction of Argos satellite telemetry error.
Recent studies have applied state-space models to satellite telemetry data in order to remove noise from raw location estimates and infer the true tracks of animals. However, while the resulting tracks may appear plausible, it is difficult to determine the accuracy of the estimated positions, especially for position estimates interpolated to times between satellite locations. In this study, we use data from two gray seals (Halichoerus grypus) carrying tags that transmitted Fastloc GPS positions via Argos satellites. This combination of Service Argos data and highly accurate GPS data allowed examination of the accuracy of state-space position estimates and their uncertainty derived from satellite telemetry data. After applying a speed filter to remove aberrant satellite telemetry locations, we fit a continuous-time Kalman filter to estimate the parameters of a random walk, used Kalman smoothing to infer positions at the times of the GPS measurements, and then compared the filtered telemetry estimates with the actual GPS measurements. We investigated the effect of varying maximum speed thresholds in the speed-filtering algorithm on the root mean-square error (RMSE) estimates and used minimum RMSE as a criterion to guide the final choice of speed threshold. The optimal speed thresholds differed between the two animals (1.1 m/s and 2.5 m/s) and retained 50% and 65% of the data for each seal. However, using a speed filter of 1.1 m/s resulted in very similar RMSE for both animals. For the two seals, the RMSE of the Kalman-filtered estimates of location were 5.9 and 12.76 km, respectively, and 75% of the modeled positions had errors less than 6.25 km and 11.7 km for each seal. Confidence interval coverage was close to correct at typical levels (80-95%), although it tended to be overly generous at smaller sizes. The reliability of uncertainty estimates was also affected by the chosen speed threshold. The combination of speed and Kalman filtering allows for effective calculation of location and also indicates the limits of accuracy when correcting service Argos locations and linking satellite telemetry data to spatial covariate and habitat data.


Designing and developing a nature-based virtual reality with heart rate variability biofeedback for surgical anxiety and pain management: evidence from total knee arthroplasty patients.
Total knee arthroplasty (TKA) is one of the most common joint surgeries, with over a million procedures performed annually in the US. Over 70% of patients report moderate to high pain and anxiety surrounding TKA surgery, and 96% are discharged with an opioid prescription. This population requires special attention as approximately 90% of TKA patients are older adults and one of the riskiest groups prone to misusing opioids. This study aimed to develop and compare the efficacy of nature-based virtual reality (VR) with heart rate variability biofeedback (HRVBF) to mitigate surgical pain and anxiety. This randomized control trial recruited 30 patients (mean age = 66.3 ± 8.2 years, 23 F, 7 M) undergoing TKA surgery and randomly assigned to a control, 2D video with HRVBF, or VR with HRVBF group. A visual analog scale (VAS) was used to measure pain levels before and after the intervention. In addition, a second VAS and the State-Trait Anxiety Inventory (STAI) were used to measure anxiety before and after the intervention. Electrocardiogram (ECG) was used to continuously measure HRV and respiration rate in preoperative and postoperative settings. VR and 2D-video with HRVBF decreased pain and anxiety post-intervention compared with the control group, p's <.01. On analyzing physiological signals, both treatment groups showed greater parasympathetic activity levels, and VR with HRVBF reduced pain more than the 2D video, p < .01. Nature-based VR and 2D video with HRVBF can mitigate surgical pain and anxiety. However, VR may be more efficacious than 2D video in reducing pain.


Monitoring Matches and Small-sided Games in Elite Young Soccer Players.
The aim of this study was to compare the distances at various intensity in matches and small-sided games in elite-young soccer players using the metabolic power approach and running speed methods through fixed and individual speed zones. The second aim was to investigate the difference in high intensity external workload (% of total distances covered > 16 km/h or > 20 W/kg) between matches and small-sided games. Global positioning system data from 14 elite-youth players were analyzed during 13 matches and two types of small sided-games. Five intensity zones were used to compare the running distances between the metabolic power approach and the classic performance analysis. Metabolic power recorded more distances covered at high intensity than the running speed methods for every playing situations, except for the zone 5 of fixed speed (> 19 km/h) in matches (P<0.05). Smaller differences of external workload at high intensity were found when using the metabolic power approach compared to the traditional performance analysis. Our results highlight that the traditional analysis underestimates the athlete's high intensity efforts. The metabolic power approach seems more relevant to monitor matches and training situations but also to compare matches to small-sided games in elite-young soccer players.


Sodium bicarbonate abuse: a case report.
Sodium bicarbonate abuse is unusual, and rarely reported. A patient was extensively investigated at several hospitals for a recurrent hypokalaemic metabolic alkalosis; it transpired that she had been abusing sodium bicarbonate for 8 years and had gained hospital admission at will by taking large amounts. She also showed features of the Munchausen syndrome.


Endothelial cells and human cerebral small vessel disease.
Brain endothelial cells have unique properties in terms of barrier function, local molecular signaling, regulation of local cerebral blood flow (CBF) and interactions with other members of the neurovascular unit. In cerebral small vessel disease (arteriolosclerosis; SVD), the endothelial cells in small arteries survive, even when mural pathology is advanced and myocytes are severely depleted. Here, we review aspects of altered endothelial functions that have been implicated in SVD: local CBF dysregulation, endothelial activation and blood-brain barrier (BBB) dysfunction. Reduced CBF is reported in the diffuse white matter lesions that are a neuroradiological signature of SVD. This may reflect an underlying deficit in local CBF regulation (possibly via the nitric oxide/cGMP signaling pathway). While many laboratories have observed an association of symptomatic SVD with serum markers of endothelial activation, it is apparent that the origin of these circulating markers need not be brain endothelium. Our own neuropathology studies did not confirm local endothelial activation in small vessels exhibiting SVD. Local BBB failure has been proposed as a cause of SVD and associated parenchymal lesions. Some groups find that computational analyses of magnetic resonance imaging (MRI) scans, following systemic injection of a gadolinium-based contrast agent, suggest that extravasation into brain parenchyma is heightened in people with SVD. Our recent histochemical studies of donated brain tissue, using immunolabeling for large plasma proteins [fibrinogen, immunoglobulin G (IgG)], do not support an association of SVD with recent plasma protein extravasation. It is possible that a trigger leakage episode, or a size-selective loosening of the BBB, participates in SVD pathology.


Expanding RN Scope of Knowledge-Genetics/Genomics: The New Frontier.
Introducing a new competency into nursing practice requires the support of nursing leadership. A knowledge survey was used to assess nurses' knowledge following a yearlong genomics education initiative. Findings indicate that nurses benefit from repeated exposure to genetics-related content. Recommendations from this study include development and implementation of strategies that can be used to prepare nurses at all levels for the application of genetics and genomics. Clinical nurses with knowledge of genetics will be able to implement evidence-based interventions to manage acute and chronic illnesses. These nurses will then be able to engage patients more fully, thereby helping them to understand the relationship of genetics to healthy outcomes.


[Color-coded M-mode Doppler echocardiography in the diagnosis of fetal arrhythmia].
Colour-coded M-mode Doppler echocardiography is a simultaneous registration of the conventional M-mode echocardiogram and of the pulsed wave colour-coded Doppler echocardiogram with simultaneous analysis of several sample volumes along the ultrasound cursor with a high timely resolution, guided by the two-dimensional imaging. Within 9 months, 36 foetuses with arrhythmias were prospectively examined (24 foetuses with atrial premature beats, 9 foetuses with supraventricular tachycardia, and 3 foetuses with complete heart block). The classification of arrhythmia by the colour-coded M-mode Doppler echocardiography was always possible at first examination. The most important advantage of this method is the simultaneous registration of the information of conventional M-mode and Doppler echocardiography. Therefore, the intervals between atrial and ventricular contractions can also be analysed even when the angle of insonation to the foetal heart is unfavourable, since contractions cannot only be identified by wall movements but also by the flow velocities. Furthermore, the duration of regurgitation of atrioventricular valves can be exactly measured by colour-coded M-mode Doppler echocardiography. In foetal supraventricular tachycardia, it appears that severity of congestive heart failure is correlated with the duration of atrioventricular valve regurgitation up to a holosystolic insufficiency. Thus, it seems possible, that the duration of insufficiency of atrioventricular valves is a good parameter for evaluation of cardiac function and for modifying antiarrhythmic treatment in cases of supraventricular tachycardia.


Sialic acid and sialidase activity in human endometrial tissue, uterine fluid and plasma under different conditions of uterine dysfunction.
Sialic acid content in endometrial tissue and sialidase activity in the endometrium, uterine fluid and plasma has been measured in normal and in conditions of uterine dysfunctions. It has been observed that an antagonistic effect exists between endometrial sialidase and sialic acid content, but in all the cases of uterine dysfunctions, the sialidase activity in uterine fluid and plasma decreases, whereas it increases during pregnancy.


The ocular adverse effects of oral drugs.
Some commonly prescribed drugs have ocular adverse effects. Many parts of the eye can be affected by oral drugs. Some ocular adverse effects may be reversed with medical or surgical intervention whereas other drugs may cause irreversible loss of vision The risk of visual loss can be reduced by a number of approaches, including monitoring for ocular toxicity, reducing the drug dose, or stopping the drug and looking for an alternative. This can be supported by good communication between the prescribing clinician and ophthalmologist Infrequent or delayed ocular adverse effects may not be identified in clinical trials of new drugs. Reporting adverse events is therefore important.


The spectral resolution of DOM in urban rivers affected by different non-point source intensities using self-organizing maps.
UV-Vis, three-dimensional excitation-emission matrix fluorescence spectroscopy (EEMs) and a self-organizing map (SOM) were used to study changes in the composition and constituent concentrations of dissolved organic matter (DOM) in the water column of two urban rivers with different non-point source inputs during spring and summer. The level of humification and the relative molecular mass of DOM were remarkably higher in the summer than in the spring (P < 0.01) in both rivers. The SOM model showed that the fluorescence intensity of the spring component was lower than in summer in water bodies with higher levels of non-point source inputs, while the opposite was true for water bodies with lower levels of non-point source inputs. Principal component analysis (PCA) showed that nutrients like nitrogen and phosphorus promoted autogenous processes in these water bodies. Seasonal variations and differing intensities of non-point source inputs had remarkable effects on urban river waters (R2 = 0.775, P < 0.001). Non-point source inputs increased the concentrations of humus-like fractions and promoted autogenesis in the water bodies.


T-cell epitopes predicted from the Nucleocapsid protein of Sin Nombre virus restricted to 30 HLA alleles common to the North American population.
Hantavirus cardiopulmonary syndrome in North America is caused by Sin Nombre virus (SNV) and poses a public health problem. We identified T-cell epitopes restricted to HLA alleles commonly seen in the N. American population. Nucleocapsid (N) protein is 428 aminoacid in length and binds to RNA and functions also as a key molecule between virus and host cell processes. The predicted epitopes from N protein that bind to class I MHC were analyzed for human proteasomes cleavage, TAP efficiency, immunogenicity and antigenicity. We identified 8 epitopes through MHC binding prediction, proteasomal cleavage prediction and TAP efficiency. Epitope VMGVIGFSF had highest Vaxijen score and the epitope, TNRAYFITR had highest immunogenicity score. Epitope AAVSALETK and TIACGLFPA had 100% homology to many HCPS causing viruses. Our study focused on T-cell epitope prediction specific to restricted HLA haplotypes of racial groups in North America for the potential vaccine development. Among the candidate epitopes, FLAARCPFL was conserved in SNV, which is suitable for vaccine specific to the virus genotype. Peptide-based vaccines can be designed to include multiple determinants from several hantavirus genotypes, or multiple epitopes from the same genotype. Thereby, immune response will focus solely on relevant epitopes, avoiding non-protective responses or immune evasion. The other advantages include absence of infectious material unlike in live or attenuated vaccines. There is no risk of reversion or formation of adverse reassortants leading to virulence and no risk of genetic integration or recombination forming a rationale for vaccine design including for distinct geographical regions.


Oxygen consumption and evaporative water loss in infants with congenital heart disease.
The relation between environmental temperature, heat production, oxygen consumption, and evaporative water loss was studied in 67 infants with congenital heart disease. The majority of the cyanosed infants had a low minimum oxygen consumption, a low evaporative water loss, and a diminished metabolic response to cold stress. Minimum oxygen consumption and evaporative water loss rose in 6 of these infants after the construction of a surgical shunt. Many of the ill acyanotic infants had an abnormally high minimum oxygen consumption, and those in cardiac failure often continued to sweat in an environment below the thermoneutral temperature zone.


Inhibition of brush border dipeptidase with cilastatin reduces toxic accumulation of cyclosporin A in kidney proximal tubule epithelial cells.
Cilastatin reduces nephrotoxicity associated with cyclosporin A (CyA) in solid organ and bone marrow transplantation. This appears to be unrelated to changes in renal haemodynamics or CyA metabolism. How cilastatin induces this protection is unclear, but it could result from changes on accumulation of CyA proximal cells. We investigated the effects of cilastatin on primary cultures of pig kidney proximal tubule epithelial cells (PTECs) treated with CyA and FK506. Cell membrane fluidity and membrane-bound cholesterol-rich raft (MBCR) distribution were evaluated by fluorescence microscopy, and CyA transport by radioimmunoassay. Changes in CyA- and FK506-induced apoptosis were also evaluated by electron and light microscopy, flow cytometry, and detection of cytoplasmic nucleosones by enzyme-linked immuosorbent assay. CyA caused a dose-dependent reduction of cell membrane fluidity, which was prevented by pre-treating PTECs with cilastatin. Cilastatin also inhibited CyA transport across membranes and reduced recovery of CyA in mitochondria and membrane-bound fractions from cilastatin-treated PTECs. This effect was not related to an altered distribution of MBCRs, which are essential for CyA transport. Cilastatin protected against CyA- and FK506-induced apoptosis. Prevention of CyA-induced reduction of cell membrane fluidity and inhibition of CyA transport are features of cilastatin's direct effects on PTECs. Unaltered distribution of MBCRs in the presence of cilastatin suggests that cilastatin binding to raft-bound dipeptidases, rather than MBCR modifications, causes interference with CyA transport. These results provide additional insight into the mechanisms and scope of cilastatin nephroprotection.


Effect on growth of exposure to maternal antiretroviral therapy in breastmilk versus extended infant nevirapine prophylaxis among HIV-exposed perinatally uninfected infants in the PROMISE randomized trial.
Malnutrition is highly prevalent in HIV-exposed perinatally uninfected infants (HEUs) increasing the risk of morbidity and mortality throughout the life course. We set out to compare the effect of postnatal exposure to maternal antiretroviral therapy (mART) in breastmilk versus infant Nevirapine prophylaxis (iNVP) on somatic growth of HEUs in the randomized PROMISE trial. We randomized 2431 mothers with HIV and their 2444 HEUs from six African countries and India 6-14 days after delivery to mART or iNVP for prevention of breastmilk HIV transmission. The mART regimen contained tenofovir/emtricitabine (99%) plus lopinavir/ritonavir. Infant growth parameters were compared at postnatal week 10, 26, 74 and 104 using World Health Organization (WHO) z-scores for length-for-age (LAZ), weight-for-age (WAZ), and head circumference-for-age (HCAZ). Week 26 LAZ was the primary endpoint measure. Student T-tests compared mean LAZ, WAZ, and HCAZ; estimated mean and 95% confidence interval (CI) are presented. Maternal and infant baseline characteristics were comparable between study arms. The estimated median breastfeeding duration was 70 weeks. After a mean follow-up of 88 weeks, mean LAZ and WAZ were below the WHO reference population mean at all timepoints, whereas mean HCAZ was not. The mART and iNVP arms did not differ for the primary outcome measure of LAZ at week 26 (p-value = 0.39; estimated mean difference (95%CI) of -0.05 (-0.18, 0.07)) or any of the other secondary growth outcome measures or timepoints (all p-values≥0.16). Secondary analyses of the primary outcome measure adjusting for week 0 LAZ and other covariates did not change these results (all p-values≥0.09). However, infants assigned to mART were more likely to have stunting compared to iNVP infants at week 26 (odds ratio (95% CI): 1.28 (1.05, 1.57)). In HEUs, growth effects from postnatal exposure to mART compared to iNVP were comparable for measures on length, weight and head circumference with no clinically relevant differences between the groups. Despite breastfeeding into the second year of life, length and weight were below reference population means at all ages in both arms. Further investment is needed to optimize postnatal growth of infants born to women with HIV. ClinicalTrials.gov number NCT01061151.


A phase I study of oxaliplatin and doxorubicin in pediatric patients with relapsed or refractory extracranial non-hematopoietic solid tumors.
The combination of a platinum agent and anthracycline has shown activity in pediatric solid tumors. This trial evaluated the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of oxaliplatin combined with doxorubicin in pediatric patients with recurrent solid tumors. Oxaliplatin was administered on day 1 and Doxorubicin on days 1-3 of each 21 day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels were evaluated: (1) oxaliplatin 105 mg/m(2) and doxorubicin 20 mg/m(2); (2) oxaliplatin 130 mg/m(2) and doxorubicin 20 mg/m(2); and (3) oxaliplatin 130 mg/m(2) and doxorubicin 25 mg/m(2). Dexrazoxane was administered at 10 times the doxorubicin dose prior to doxorubicin infusion. Seventeen patients were enrolled. Dose level 1 was the determined MTD. Grade 2 cardiac DLT was seen in one of six patients on dose level 1, grade 4 thrombocytopenia in two of five patients on dose level 2, and one each of grade 2 cardiac and grade 4 thrombocytopenia in five patients on dose level 3. Cardiac DLT was only noted in patients with prior exposure to both anthracycline and chest radiation. No grade 3 or 4 neurotoxicity or mucositis was seen. Objective responses were noted in two patients with neuroblastoma and one each of mixed germ cell tumor, thymic neuroendocrine carcinoma, and nasopharyngeal carcinoma. Oxaliplatin 105 mg/m(2) on day 1 combined with doxorubicin 20 mg/m(2) days 1-3 was the MTD. This combination shows sufficient activity to justify further studies in select pediatric tumors.


Direct sugar binding to LacY measured by resonance energy transfer.
Trp151 in the lactose permease of Escherichia coli (LacY) is an important component of the sugar-binding site and the only Trp residue out of six that is in close proximity to the galactopyranoside in the structure (1PV7). The short distance between Trp151 and the sugar is favorable for Förster resonance energy transfer (FRET) to nitrophenyl or dansyl derivatives with the fluorophore at the anomeric position of galactose. Modeling of 4-nitrophenyl-alpha-d-galactopyranoside (alpha-NPG) in the binding-site of LacY places the nitrophenyl moiety about 12 A away from Trp151, a distance commensurate with the Förster distance for a Trp-nitrobenzoyl pair. We demonstrate here that alpha-NPG binding to LacY containing all six native Trp residues causes galactopyranoside-specific FRET from Trp151. Moreover, binding of alpha-NPG is sufficiently slow to resolve time-dependent fluorescence changes by stopped-flow. The rate of change in Trp --> alpha-NPG FRET is linearly dependent upon sugar concentration, which allows estimation of kinetic parameters for binding. Furthermore, 2-(4'-maleimidylanilino)naphthalene-6-sulfonic acid (MIANS) covalently attached to the cytoplasmic end of helix X is sensitive to sugar binding, reflecting a ligand-induced conformational change. Stopped-flow kinetics of Trp --> alpha-NPG FRET and sugar-induced changes in MIANS fluorescence in the same protein reveal a two-step process: a relatively rapid binding step detected by Trp151 --> alpha-NPG FRET followed by a slower conformational change detected by a change in MIANS fluorescence.


Patient-perceived benefits and risks of off-label use of SGLT2 inhibitors and GLP-1 receptor agonists in type 1 diabetes: a structured qualitative assessment.
Patients with type 1 diabetes mellitus (T1DM) may have suboptimal glucose control and are interested in the use of adjuvant therapies. To determine, from the patients' perspective, the reasons for initiation of glucagon-like peptide 1 receptor agonist (GLP-1RA) and/or sodium glucose cotransporter 2 inhibitor (SGLT2i) in treating T1DM; perceived benefits/side effects, reasons for discontinuation, and willingness to reinitiate therapy. Retrospective chart review with structured telephone interviews. We identified patients with T1DM treated with a GLP-1RA and/or SGLT2i for >3 months at University of Texas Southwestern Medical Center (Dallas, TX, USA) and Poznan University (Poznan, Poland). We conducted structured telephone interviews regarding their experiences. We interviewed 68 participants treated with GLP-1RA and 82 with SGLT2i. Treatment was initiated for improving glycemic control (as reported by 61.8% versus 81.7% of GLP-1RA and SGLT2i users, respectively), weight loss/appetite suppression (51.4% versus 23.2%) and to reduce insulin requirement (13.2% versus 11%). Most participants (86.8% of GLP-1RA and 89.0% of SGLT2i users) reported ⩾1 benefit attributed to therapy. Reported benefits were improved glycemic control (reported by 58.8% versus 82.9% of GLP-1RA and SGLT2i users, respectively), weight loss/appetite suppression (63.2% versus 30.5%), and reduced insulin requirement (27.9% versus 34.1%). More GLP-1RA users reported side effects versus SGLT2i users (63.2% versus 36.6%); 22.6% discontinued GLP-1RA due to side effects versus 11.0% SGLT2i users. Diabetic ketoacidosis (DKA) was reported by 4.9% of SGLT2i users, but none in GLP-1RA users. Of those who discontinued medication, 60.7% of GLP-1RA versus 56.0% of SGLT2i prior users were willing to reinitiate treatment. Patients with T1DM report initiating adjuvant treatment with GLP-1RA and/or SGLT2i to improve glycemic control and lose weight; most patients reported perceived benefits from these therapies. Side effects (including DKA) are reported more commonly in real life than in clinical trials. Given patient interest in these medications, further studies should evaluate the long-term risk-benefits ratio in larger cohorts.


[A 60-year-old patient with sialadenitis, pulmonary round foci and vulvar ulcer].
The unusual case of a 60 year-old woman is discussed. She presented with sialadenitis, paresis of the facial nerve, keratoconjunctivitis and ulcus vulvae. Basic anamnestic information revealed primary enlargement of the submandibular gland, fever, otitis, sinusitis and a pulmonary tumour. The serum immunoglobulin E level was raised. In addition to the necrotic granulomas in the lungs, spleen and kidney, characteristic changes were found in the lymph nodes, liver, pancreas and colon.


[Gastrinoma: diagnosis and management of Zollinger-Ellison syndrome].
Diagnosis and management of Zollinger-Ellison syndrome (ZES) do not appear to be established even today. In the present study, 143 cases of ZES (including 12 of author's experience) were collected from Japanese literature and analyzed, and diagnosis and management were discussed. (1) Although 43% of patients showed high gastrin level (greater than or equal to 500pg/ml), it is worth to be stressed that gastrin level was below 300pg/ml in 29% of patients. (2) Secretin provocation test was essential for diagnosis and particularly useful for detecting ZES with low gastrin level. (3) Angiography and/or blood samplings of PTPC were widely used for localizing gastrinoma but the informations thus obtained were not always of help for complete removal of tumors since malignant or multiple gastrinomas were frequent. (4) An aim of management for ZES consists of complete removal of tumor but it is not always feasible. Therefore, removal of target organ (total gastrectomy) should be routinely added for long-term cure. (5) Value of chemical gastrectomy (H2-receptor antagonist) is still a matter of pros and cons but substantial value of this drug should be considered adjunct to surgery.


Development of disease-resistant rice using regulatory components of induced disease resistance.
Infectious diseases cause huge crop losses annually. In response to pathogen attacks, plants activate defense systems that are mediated through various signaling pathways. The salicylic acid (SA) signaling pathway is the most powerful of these pathways. Several regulatory components of the SA signaling pathway have been identified, and are potential targets for genetic manipulation of plants' disease resistance. However, the resistance associated with these regulatory components is often accompanied by fitness costs; that is, negative effects on plant growth and crop yield. Chemical defense inducers, such as benzothiadiazole and probenazole, act on the SA pathway and induce strong resistance to various pathogens without major fitness costs, owing to their 'priming effect.' Studies on how benzothiadiazole induces disease resistance in rice have identified WRKY45, a key transcription factor in the branched SA pathway, and OsNPR1/NH1. Rice plants overexpressing WRKY45 were extremely resistant to rice blast disease caused by the fungus Magnaporthe oryzae and bacterial leaf blight disease caused by Xanthomonas oryzae pv. oryzae (Xoo), the two major rice diseases. Disease resistance is often accompanied by fitness costs; however, WRKY45 overexpression imposed relatively small fitness costs on rice because of its priming effect. This priming effect was similar to that of chemical defense inducers, although the fitness costs were amplified by some environmental factors. WRKY45 is degraded by the ubiquitin-proteasome system, and the dual role of this degradation partly explains the priming effect. The synergistic interaction between SA and cytokinin signaling that activates WRKY45 also likely contributes to the priming effect. With a main focus on these studies, I review the current knowledge of SA-pathway-dependent defense in rice by comparing it with that in Arabidopsis, and discuss potential strategies to develop disease-resistant rice using signaling components.


A new benzenediamine derivative modulates Toll-like receptors-induced myeloid dendritic cells activation and ameliorates lupus-like syndrome in MRLlpr/lpr mice.
Modulators of the over-activation of myeloid dendritic cells (mDCs) by Toll-like receptors (TLRs) have an advantage in the treatment of systemic lupus erythematosus (SLE). This study was designed to evaluate the effects of FC-99, a novel benzenediamine derivative, on TLR-induced activation of mDCs, and to assess the efficacy of FC-99 in a murine model of SLE. In vitro, FC-99 inhibited the phenotypic (CD40 and MHC-II) and functional activation (IL-12 and CXCL10) of mDCs induced by TLR ligands. In vivo, MRLlpr/lpr mice displayed renal diseases associated with increased levels of proteinuria and immunoglobulin, which were ameliorated by FC-99. Enhanced accumulation and activation of mDCs in lymphoid organs was also impaired by FC-99. Additionally, FC-99 inhibited the activation of IκB-α and upregulated the expression of TNFα-induced protein 3 (TNFAIP3) in vitro and in vivo. These results indicate that FC-99 modulates TLR-induced activation of mDCs and ameliorates lupus-like syndrome in MRLlpr/lpr mice. This effect is closely associated with the inhibition of IκB-α and upregulation of TNFAIP3.


Brucine inhibits TNF-α-induced HFLS-RA cell proliferation by activating the JNK signaling pathway.
Rheumatoid arthritis (RA) is a diffuse connective tissue disease. Brucine selectively inhibits cell immunity, immune hypersensitivity and induces apoptosis. The current study aimed to investigate effects of brucine on human fibroblast-like synoviocytes (HFLS) of RA and to clarify associated molecular mechanisms. HFLS-RA were treated with tumor necrosis factor (TNF)-α prior to treatment with brucine at carrying concentrations. Cell Counting Kit-8 assays were performed to evaluate HFLS-RA proliferation. Western blot assays were employed to examine c-Jun N-terminal kinase (JNK) expression and phosphorylation in TNF-α-induced HFLS-RA. An association between brucine treatment and JNK phosphorylation was assessed by employing a linear regression analysis. The results suggested that low doses of brucine (0.125 and 0.25 mg/ml) significantly reversed proliferation effects induced by TNF-α, however, final cell viabilities were increased compared with the untreated control (P>0.05 and P<0.05, respectively). High brucine doses (≥0.5 mg/ml) significantly reversed TNF-α-induced proliferation and further inhibited viability compared with the untreated control (P<0.05). Regarding JNK expression, there were no significant differences among the brucine treatment, and between the Control and the TNF-α groups (P>0.05). Brucine treatment significantly decreased JNK phosphorylation compared with the TNF-α group (P<0.05). JNK specific inhibitor, SP600125, significantly inhibited brucine-induced cell viability enhancement compared with the brucine-treated groups without inhibitor (P<0.05). A linear regression analysis suggested that brucine was associated with JNK phosphorylation in TNF-α-treated HFLS-RA. In conclusion, brucine significantly inhibited TNF-α-induced HFLS-RA proliferation by activating the JNK signaling pathway. Therefore, brucine may have potential clinical applications in the treatment of RA.


HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures.
To examine the clinical effects of electroconvulsive therapy (ECT) on depressed patients with medication treatment failures, we investigated the alterations in hypothalamic-pituitary-adrenocortical (HPA) function and regional cerebral metabolism rate of glucose (rCMRGlu) after ECT in these patients. Before and after ECT, the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test was administered to seven patients who were referred for ECT. In the same patients, (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was also assessed. Cortisol response in the DEX/CRH test significantly decreased after a successful ECT. A significant hypometabolism in various frontal regions and hypermetabolism in the parietal regions of these patients when compared with controls remained after ECT. Depressed patients who failed trials of antidepressant medication showed a remission with ECT that was accompanied by resolution of HPA dysregulation. However, measures of cerebral brain metabolism did not resolve.


A large-scale study of the ultrawideband microwave dielectric properties of normal, benign and malignant breast tissues obtained from cancer surgeries.
The development of microwave breast cancer detection and treatment techniques has been driven by reports of substantial contrast in the dielectric properties of malignant and normal breast tissues. However, definitive knowledge of the dielectric properties of normal and diseased breast tissues at microwave frequencies has been limited by gaps and discrepancies across previously published studies. To address these issues, we conducted a large-scale study to experimentally determine the ultrawideband microwave dielectric properties of a variety of normal, malignant and benign breast tissues, measured from 0.5 to 20 GHz using a precision open-ended coaxial probe. Previously, we reported the dielectric properties of normal breast tissue samples obtained from reduction surgeries. Here, we report the dielectric properties of normal (adipose, glandular and fibroconnective), malignant (invasive and non-invasive ductal and lobular carcinomas) and benign (fibroadenomas and cysts) breast tissue samples obtained from cancer surgeries. We fit a one-pole Cole-Cole model to the complex permittivity data set of each characterized sample. Our analyses show that the contrast in the microwave-frequency dielectric properties between malignant and normal adipose-dominated tissues in the breast is considerable, as large as 10:1, while the contrast in the microwave-frequency dielectric properties between malignant and normal glandular/fibroconnective tissues in the breast is no more than about 10%.


Self-medication among nursing students in the state of Amazonas - Brazil.
To determine the prevalence of self-medication and associated factors among nursing students. This is a cross-sectional study with 116 nursing students from the public university in the state of Amazonas, Brazil, from March to April 2014. Data were collected using a questionnaire with socioeconomic and medicine use variables. The data were subjected to bivariate analysis and logistic regression at a significance level of 5%. The prevalence of self-medication was 76.0%, chiefly motivated by the belief that the health condition did not require a medical appointment (46.6%). Half of the students reported pain-related complaints. The most commonly used pharmacological groups were non-steroidal anti-inflammatory drugs (63.2%) and antibiotics (11.1%). Lack of awareness of the negative implications of self-medication was associated with self-medication (OR = 6.0). The high prevalence of self-medication that may lead to adverse reactions reveals the students' irrational use of medicines, especially considering the role of these future professionals in patient safety.


[Revised guideline 'Diabetic retinopathy: screening, diagnosis and treatment'].
The revised evidence-based guideline 'Diabetic retinopathy: screening, diagnosis and treatment' contains important recommendations concerning screening, diagnosis and treatment of diabetic retinopathy. Regular screening and the treatment of risk factors, such as hyperglycemia, hypertension, adipositas and dyslipidemia, can prevent retinopathy and slow down its development. Fundus photography is recommended as a screening method. If necessary, diagnosis by biomicroscopy and a treatment consisting of photocoagulation and/or vitrectomy should be performed by the ophthalmologist. The reassessment of responsibilities is a vital component of the implementation of the guideline bearing in mind that the screening in particular, can be performed by personnel other than ophthalmologists.


[Concentration of beta endorphin in blood as a criterion of adequacy of general anesthesia].
Considering beta-endorphin as a sign of tension and adaptation, the changes in its level have been studied during operations and surgery in patients with congenital heart valve defects subjected to cardiopulmonary bypass surgery. The goal of the study was determination of beta-endorphin concentration for the assessment of general anesthesia adequacy. A step-by-step study of beta-endorphin blood concentration, central and peripheral hemodynamics, diuresis, changes in temperature taken in 3 spots, adrenalin, dopamine and noradrenaline blood levels has been performed in 12 patients aged 4 to 17 years. A stable beta-endorphin blood content at all stages of anesthesia and surgery has been established. A correlation has been established between changes in adrenalin and dopamine blood levels, temperature gradient, diuresis intensity and mean BP, on the one hand, and changes in beta-endorphin blood level, on the other hand. Multifactor systemic analysis of the data obtained makes it possible to conclude that beta-endorphin blood level is informative when assessing the adequacy of general anesthesia.


IDENTIFICATION OF VDR ANTAGONISTS AMONG NUCLEAR RECEPTOR LIGANDS USING VIRTUAL SCREENING.
Herein, we described the development of two virtual screens to identify new vitamin D receptor (VDR) antagonists among nuclear receptor (NR) ligands. Therefore, a database of 14330 nuclear receptor ligands and their NR affinities was assembled using the online available "Binding Database". Two different virtual screens were carried out in conjunction with a reported VDR crystal structure applying a stringent and less stringent pharmacophore model to filter docked NR ligand conformations. The pharmacophore models were based on the spatial orientation of the hydroxyl functionalities of VDR's natural ligands 1,25(OH2)D3 and 25(OH2)D3. The first virtual screen identified 32 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. All but nordihydroguaiaretic acid (NDGA) are VDR ligands, which inhibited the interaction between VDR and coactivator peptide SRC2-3 with an IC50 value of 15.8 µM. The second screen identified 162 NR ligands with a calculate free energy of VDR binding of more than -6.0 kJ/mol. More than half of these ligands were developed to bind VDR followed by ERα/β ligands (26%), TRα/β ligands (7%) and LxRα/β ligands (7%). The binding between VDR and ERα ligand H6036 as well as TRα/β ligand triiodothyronine and a homoserine analog thereof was confirmed by fluorescence polarization.


Novel penicillin-resistant clones of Streptococcus pneumoniae in the Czech Republic and in Slovakia.
Seventy-two penicillin-resistant Streptococcus pneumoniae isolates collected from clinical specimens in the Czech and Slovakian Republics between 1990 and 1992 were analyzed by a variety of molecular techniques. Most of the highly resistant isolates (40/72) (penicillin MIC between 1 up to 16 micrograms/ml) were represented by two distinct pneumococcal clones, and most of these isolates (35/40) were also resistant to at least two other antibiotics (tetracycline plus chloramphenicol or erythromycin). All 17 isolates belonging to the first clone were of serotype 14, had very high penicillin MICs (8-12 micrograms/ml), shared a common, abnormal penicillin-binding protein (PBP) pattern and one of two related pulsed-field gel electrophoretic (PFGE) patterns. The 15 isolates belonging to the second clone were all of serotype 19A, had penicillin MICs between 1 and 4 micrograms/ml, shared a unique, abnormal PBP pattern, and could be divided into two subgroups on the basis of PFGE patterns, one of which was indistinguishable from the PFGE pattern of a multiresistant capsular type 19A clone of S. pneumoniae already identified earlier in Hungary. Thirty-two of the 72 pneumococcal isolates had lower penicillin MICs (0.1-0.5 microgram/ml), and these isolates differed from the more highly resistant ones in several respects: They belonged to seven different serotypes, showed large variation in PFGE patterns (20 patterns in 32 isolates) and most of them (21/32) were resistant to penicillin only. Tentative explanations for these findings, in terms of epidemiological and molecular mechanisms, are considered.


Massive subcutaneous emphysema mimicking necrotizing fasciitis after dacryocystorhinostomy.
We present a case of massive subcutaneous emphysema mimicking necrotizing fasciitis after uncomplicated dacryocystorhinostomy surgery. Subcutaneous emphysema progressing down fascial planes of the head and neck after dacryocystorhinostomy has not been reported in the literature. Using the clinical presentation and radiographic imaging, we briefly review the underlying cause of subcutaneous emphysema after dacryocystorhinostomy.


Compressing inverse lyotropic systems: Structural behavior and energetics of dioleoyl phosphatidyl ethanolamine.
The pressure effects on the stability and energetics of lipid phases in the L-alpha-dioleoyl phosphatidyl ethanolamine (DOPE)-water system are presented. Using synchrotron diffraction experiments, performed at a wide range of concentrations, pressure-induced transitions from the inverse hexagonal (H(II)) to the lamellar L(alpha) phase and from the L(alpha) to the lamellar L(beta) phase are demonstrated. Moreover, in the most dehydrated samples an intermediate phase is found between the H(II) and the L(alpha) phases, confirming that the lamellar-to-nonlamellar phase transition occurs through key intermediate structures. Simple molecular packing arguments lead to an interpretation of the phase behavior: in fact, pressure induces a progressive stiffening of the DOPE hydrocarbon chains and a reduction of the cross-sectional area. Because pressure is more effective in reducing the cross-sectional area near the terminal methyl groups than at the water-lipid interface, the curvature of that interface in the H(II) phase is reduced during compression. The work of isothermal compression was then obtained and analyzed in terms of the elastic energetic contributions that should stabilize the DOPE phases during compression. As a result, we observe that the isothermal lateral compression modulus is almost independent of concentration, but it increases as a function of pressure, suggesting that the DOPE repulsion becomes very strong while the whole lipid shape becomes more cylindrical. On the other hand, the bending rigidity is observed to decrease with increasing pressure, while the spontaneous curvature becomes less negative. This suggests that the chain repulsion becomes relatively weaker, and thus less efficient in balancing the torque of head-group repulsion, as the order parameter increases.


Multimodal Metabolic Imaging Reveals Pigment Reduction and Lipid Accumulation in Metastatic Melanoma.
Objective and Impact Statement. Molecular signatures are needed for early diagnosis and improved treatment of metastatic melanoma. By high-resolution multimodal chemical imaging of human melanoma samples, we identify a metabolic reprogramming from pigmentation to lipid droplet (LD) accumulation in metastatic melanoma. Introduction. Metabolic plasticity promotes cancer survival and metastasis, which promises to serve as a prognostic marker and/or therapeutic target. However, identifying metabolic alterations has been challenged by difficulties in mapping localized metabolites with high spatial resolution. Methods. We developed a multimodal stimulated Raman scattering and pump-probe imaging platform. By time-domain measurement and phasor analysis, our platform allows simultaneous mapping of lipids and pigments at a subcellular level. Furthermore, we identify the sources of these metabolic signatures by tracking deuterium metabolites at a subcellular level. By validation with mass spectrometry, a specific fatty acid desaturase pathway was identified. Results. We identified metabolic reprogramming from a pigment-containing phenotype in low-grade melanoma to an LD-rich phenotype in metastatic melanoma. The LDs contain high levels of cholesteryl ester and unsaturated fatty acids. Elevated fatty acid uptake, but not de novo lipogenesis, contributes to the LD-rich phenotype. Monounsaturated sapienate, mediated by FADS2, is identified as an essential fatty acid that promotes cancer migration. Blocking such metabolic signatures effectively suppresses the migration capacity both in vitro and in vivo. Conclusion. By multimodal spectroscopic imaging and lipidomic analysis, the current study reveals lipid accumulation, mediated by fatty acid uptake, as a metabolic signature that can be harnessed for early diagnosis and improved treatment of metastatic melanoma.


Modelling the Effect of Matrix Metalloproteinases in Dermal Wound Healing.
With over 2 million people in the UK suffering from chronic wounds, understanding the biochemistry and pharmacology that underpins these wounds and wound healing is of high importance. Chronic wounds are characterised by high levels of matrix metalloproteinases (MMPs), which are necessary for the modification of healthy tissue in the healing process. Overexposure of MMPs, however, adversely affects healing of the wound by causing further destruction of the surrounding extracellular matrix. In this work, we propose a mathematical model that focuses on the interaction of MMPs with dermal cells using a system of partial differential equations. Using biologically realistic parameter values, this model gives rise to travelling waves corresponding to a front of healthy cells invading a wound. From the arising travelling wave analysis, we observe that deregulated apoptosis results in the emergence of chronic wounds, characterised by elevated MMP concentrations. We also observe hysteresis effects when both the apoptotic rate and MMP production rate are varied, providing further insight into the management (and potential reversal) of chronic wounds.


Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases.
Sirolimus (SRL) has been used for most islet recipients over the past 5 years. It provides balanced immunosuppression in combination with low-dose calcineurin inhibitors, while avoiding corticosteroids. This regimen decreases the risk of nephrotoxicity, neurotoxicity and diabetogenicity. SRL has also been used selectively in clinical liver and kidney transplantation. A number of common side effects including anemia, leucopenia, thrombocytopenia, hypercholesterolemia, mouth ulceration, joint pain, extremity edema and impaired wound healing have been associated with the use of SRL. As SRL is used more frequently, evidence has been gathered on its rare but severe side effects. We report 2 patients who underwent islet transplantation and developed symptomatic small bowel ulceration that resolved after complete withdrawal of SRL. Although small bowel ulceration is rare, it can potentially progress to more serious complications if not treated adequately. Our experience highlights an uncommon but potentially serious adverse effect of high-dose SRL in islet recipients.


Evoked activity and EEG phase resetting in the genesis of auditory Go/NoGo ERPs.
Current views of the genesis of the event-related potential (ERP) contrast the phase-reset and evoked activity models. In the former, a portion of the ongoing electroencephalographic (EEG) activity becomes phase-locked at stimulus onset; in the latter, processing in the brain contributes additional time-locked activity at each trial. This study aimed to explore these perspectives in an auditory Go/NoGo task. The interactions between these processes were examined using the amplitudes and topographies of pre- and post-stimulus EEGs in traditional bands, and the averaged ERPs, together with time-frequency analysis. Results indicate that both evoked activity and phase locking of ongoing EEG activity contribute substantially to the different Go and NoGo ERP components. Phase locking contributes most strongly to the early exogenous ERP components, with evoked brain activity related to cognitive processing contributing strongly to the endogenous ERP components. Evidence also suggests that extensive phase realignments may generate the power increases associated with early exogenous components. It is concluded that exogenous ERP components arise substantially from phase-resetting mechanisms involving ongoing EEG activity. In contrast, the endogenous components are substantially produced by evoked activity in various frequency bands, and their differences reflect differential cortical processing required for appropriate responding to the Go vs. NoGo stimuli.


Comparing adaptive and non-adaptive algorithms for cancer early detection with novel biomarkers.
It may be possible to reduce cancer mortality by monitoring the concentrations of serum biomarkers over time in men and women to detect their cancer early, when it is most curable. The simplest approach to using a biomarker for screening is to sequentially use fixed thresholds as a means to determine an abnormal test (e.g., PSA exceeding 4 mg/ml, CA 125 exceeding 30 U/ml). Alternatives to the simplest single threshold (ST) rules include more sophisticated algorithms that make use of screening history that accumulates over time and determines abnormal tests using individualized reference ranges. Although in principle longitudinal algorithms should out perform fixed threshold rules, the actual benefit gained will depend on behavior of the biomarker, the screening algorithm, and the screening frequency. Little information has been available to help predict when conditions should compel the adoption of the more sophisticated algorithms and when conditions suggest the simpler algorithms should suffice, or indeed be preferred. In this manuscript we evaluate the conditions under which one should expect great benefit, and when one should not expect benefit, by comparing the ability of simple and complex algorithms to detect cancer early under a variety of biomarker behaviors and screening frequencies.


Harvesting energy from water flow over graphene.
Water flow over carbon nanotubes has been shown to generate an induced voltage in the flow direction due to coupling of ions present in water with free charge carriers in the nanotubes. However, the induced voltages are typically of the order of a few millivolts, too small for significant power generation. Here we perform tests involving water flow with various molarities of hydrochloric acid (HCl) over few-layered graphene and report order of magnitude higher induced voltages for graphene as compared to nanotubes. The power generated by the flow of ∼0.6 M HCl solution at ∼0.01 m/sec was measured to be ∼85 nW for a ∼30 × 16 μm size graphene film, which equates to a power per unit area of ∼175 W/m(2). Molecular dynamics simulations indicate that the power generation is primarily caused by a net drift velocity of adsorbed Cl(-) ions on the continuous graphene film surface.


Valence States Modulation Strategy for Picomole Level Assay of Hg2+ in Drinking and Environmental Water by Directional Self-Assembly of Gold Nanorods.
In this study, we present a valence states modulation strategy for picomole level assay of Hg2+ using directional self-assembly of gold nanorods (AuNRs) as signal readout. Hg2+ ions are first controllably reduced to Hg+ ions by appropriate ascorbic acid, and the reduced Hg+ ions react with the tips of the preadded AuNRs and form gold amalgam. Such Hg+ decorated AuNRs then end-to-end self-assemble into one-dimensional architectures by the bridging effects of lysine based on the high affinity of NH2-Hg+ interactions. Correspondingly, the AuNRs' longitudinal surface plasmon resonance is gradually reduced and a new broad band appears at 900-1100 nm region simultaneously. The resulting distinctly ratiometric signal output is not only favorable for Hg2+ ions detection but competent for their quantification. Under optimal conditions, the linear range is 22.8 pM to 11.4 nM, and the detection limit is as low as 8.7 pM. Various transition/heavy metal ions, such as Pb2+, Ti2+, Co2+, Fe3+, Mn2+, Ba2+, Fe2+, Ni2+, Al3+, Cu2+, Ag+, and Au3+, do not interfere with the assay. Because of ultrahigh sensitivity and excellent selectivity, the proposed system can be employed for assaying ultratrace of Hg2+ containing in drinking and commonly environmental water samples, which is difficult to be achieved by conventional colorimetric systems. These results indicate that the present platform possesses specific advantages and potential applications in the assay of ultratrace amounts of Hg2+ ions.


Characterization of Lower Extremity Blast Injury.
Throughout history, traumatic amputation of the lower extremity has been a notable feature of all conflicts involving explosive incidents. Even at the close of the recent conflicts in Afghanistan, there were deaths that were deemed "potentially survivable." The purpose of this study is to characterize lower extremity blast injury and to determine if their amputation levels and associated injury characteristics correlate with a higher risk of mortality. the UK Joint Theatre Trauma Registry (JTTR) was interrogated to identify all lower extremity traumatic amputations sustained in both Iraq and Afghanistan between January 2003 and the end of UK operations in August 2014. The mortality rates for each amputation level and associated injuries were determined. Of the 977 casualties, there were 679 (69.5%) survivors and 298 fatalities (30.5%). There was an increase in survivability from traumatic amputation throughout the conflict, however, traumatic amputations at the close of military activity in 2014 still had a substantial fatality rate of 23%. A more proximal level of amputation, an associated pelvic fracture, and an associated abdominal injury all correlated with an increased mortality rate. Several specific injury characteristics associated with traumatic amputation have been identified that are associated with an increased mortality rate to include a more proximal amputation level, pelvic fracture, and abdominal injury. Injury prevention and mitigation measures should be explored to minimize the risk of the associated injuries following blast that portend a higher risk of mortality.


A concept analysis of self-efficacy and adolescent sexual risk-taking behavior.
Concept Analysis: Self-efficacy and Sexual Risk-Taking Behaviors of Adolescents This paper provides an in-depth analysis of the concept of self-efficacy and adolescent sexual risk-taking behaviors Using the Walker and Avant framework of concept analysis, the concept of self-efficacy has shown to be an important part in changing unhealthy behaviors. It has also shown that the concept of self-efficacy can be pivotal in health promotion activities of adolescents in a variety of settings, especially as it relates to adolescent sexual risk-taking behaviors. The concept of self-efficacy as it relates to adolescent sexual risk-taking behaviors has clear nursing implications and usage among the adolescent population. Self-efficacy is a key concept to be used in health promotion. Health promotion activities are pivotal in the prevention of sexually transmitted infections in the adolescent population. Knowledge of the self-efficacy level of the adolescent patient can give the nurse greater insight in the meaning of the patient's response in a given situation. This also helps the nurse identify which adolescents would benefit from early intervention with regard to sexual health.


Latin America: population, food supply and agricultural dependency.
The relationships among population growth, food supply, and agricultural dependency in Latin America since World War II are examined. The author notes that in the recent past, population growth and agricultural growth have kept pace with each other. However, "most countries appear to be caught in a dilemma common to the underdeveloped world: either increasing emphasis on basic foodstuffs to satisfy a growing population and increased per capita demand for food or increasing output of export agricultural commodities in order to earn the necessary foreign exchange for imports and development."


Drosophila ATR in double-strand break repair.
The ability of a cell to sense and respond to DNA damage is essential for genome stability. An important aspect of the response is arrest of the cell cycle, presumably to allow time for repair. Ataxia telangiectasia mutated (ATM) and ATR are essential for such cell-cycle control, but some observations suggest that they also play a direct role in DNA repair. The Drosophila ortholog of ATR, MEI-41, mediates the DNA damage-dependent G2-M checkpoint. We examined the role of MEI-41 in repair of double-strand breaks (DSBs) induced by P-element excision. We found that mei-41 mutants are defective in completing the later steps of homologous recombination repair, but have no defects in end-joining repair. We hypothesized that these repair defects are the result of loss of checkpoint control. To test this, we genetically reduced mitotic cyclin levels and also examined repair in grp (DmChk1) and lok (DmChk2) mutants. Our results suggest that a significant component of the repair defects is due to loss of MEI-41-dependent cell cycle regulation. However, this does not account for all of the defects we observed. We propose a novel role for MEI-41 in DSB repair, independent of the Chk1/Chk2-mediated checkpoint response.


Prenatal care: associations with prenatal depressive symptoms and social support in low-income urban women.
We examined associations of depressive symptoms and social support with late and inadequate prenatal care in a low-income urban population. The sample was prenatal care patients at five community health centers. Measures of depressive symptoms, social support, and covariates were collected at prenatal care entry. Prenatal care entry and adequacy came from birth certificates. We examined outcomes of late prenatal care and less than adequate care in multivariable models. Among 2341 study participants, 16% had elevated depressive symptoms, 70% had moderate/poor social support, 21% had no/low partner support, 37% had late prenatal care, and 29% had less than adequate prenatal care. Women with both no/low partner support and elevated depressive symptoms were at highest risk of late care (AOR 1.85, CI 1.31, 2.60, p < 0.001) compared to women with both good partner support and low depressive symptoms. Those with good partner support and elevated depressive symptoms were less likely to have late care (AOR 0.74, CI 0.54, 1.10, p = 0.051). Women with moderate/high depressive symptoms were less likely to experience less than adequate care compared to women with low symptoms (AOR 0.73, CI 0.56, 0.96, p = 0.022). Social support and partner support were negatively associated with indices of prenatal care use. Partner support was identified as protective for women with depressive symptoms with regard to late care. Study findings support public health initiatives focused on promoting models of care that address preconception and reproductive life planning. Practice-based implications include possible screening for social support and depression in preconception contexts.


Immunologic identification of elastin-derived peptides in the serums of dogs with experimental emphysema.
Pulmonary emphysema is a disease in which peptides formed by the enzymatic degradation of the amorphous component of interstitial elastin may be release from the lung. In order to provide a test that can monitor the destruction of lung elastin invivo, we developed a hemagglutination inhibiton assay that specifically and quantitatively measure elastin-derived peptides in serum. Using this method, was measured the concentration of elastin-derived peptides in the serums of dogs developing emphysema through the administration of porcine pancreatic elastase. Elastin-derived peptides could be detected in the serums for a period of 12 days after the administration of a single 25- or 50-mg dose of elastase, and for at least 40 days after a 100-mg dose. There was a good correlation between the maximal concentration of elastin derived peptides found in the serums and the amount of elastase administered to the animal. This immunologic method may be useful in following the progression of experiment emphysema.


Progress towards cell-mediated gene transfer in zebrafish.
Although the zebrafish possesses several favourable characteristics that make it an ideal model for genetic studies of vertebrate development, one disadvantage of this model system is the absence of methods for the production of gene knockouts. The authors' laboratory, and others, are working to develop zebrafish pluripotent embryonic stem (ES) and primordial germ cell (PGC) cultures that can be used for cell-mediated gene transfer and the production of knockout mutant lines of fish. Progress has been made in developing short-term cell cultures that possess the ability to contribute to multiple tissues, including the germ line of a host embryo, and transgenic lines of zebrafish have been established using the embryo cell cultures. Work is in progress to extend the length of time that the embryo cells can be maintained in culture without losing their ability to generate germ-line chimeras.


Characteristics of SARS-CoV2 that may be useful for nanoparticle pulmonary drug delivery.
As a non-invasive method of local and systemic drug delivery, the administration of active pharmaceutical ingredients (APIs) via the pulmonary route represents an ideal approach for the therapeutic treatment of pulmonary diseases. The pulmonary route provides a number of advantages, including the rapid absorption which results from a high level of vascularisation over a large surface area and the successful avoidance of first-pass metabolism. Aerosolization of nanoparticles (NPs) is presently under extensive investigation and exhibits a high potential for targeted delivery of therapeutic agents for the treatment of a wide range of diseases. NPs need to possess specific characteristics to facilitate their transport along the pulmonary tract and appropriately overcome the barriers presented by the pulmonary system. The most challenging aspect of delivering NP-based drugs via the pulmonary route is developing colloidal systems with the optimal physicochemical parameters for inhalation. The physiochemical properties of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been investigated as a template for the synthesis of NPs to assist in the formulation of virus-like particles (VLPs) for pharmaceutical delivery, vaccine production and diagnosis assays.


cAMP inhibits cytokine-induced biosynthesis of tetrahydrobiopterin in human umbilical vein endothelial cells.
We studied the effects of cAMP on cytokine (interferon-gamma plus tumor necrosis factor-alpha)-induced stimulation of tetrahydrobiopterin (BH4) synthesis in human umbilical vein endothelial cells (HUVEC). The cytokine mixture caused a marked increase in the biosynthesis and release of BH4 by HUVEC. Dibutyryl-cAMP produced a dose-dependent inhibition of this cytokine-induced stimulation of synthesis and release of BH4 by these cells. 8-Bromo-cAMP also caused a significant inhibition, although the effects were less marked than those of dibutyryl-cAMP. Both forskolin and the stable analog of prostacyclin, iloprost, caused cAMP accumulation and a concomitant diminution of the cytokine-induced BH4 synthesis in HUVEC. Dibutyryl-cAMP and iloprost also significantly inhibited the cytokine-induced stimulation of GTP cyclohydrolase I (GCHI) activity and mRNA production. We concluded that the suppression by the cAMP messenger system of cytokine-induced stimulation of synthesis and release of BH4 by HUVEC can be attributed to the inhibition of the activity of GCHI, the rate-limiting enzyme in BH4 biosynthetic pathway, in HUVEC. The data also suggest that the cAMP-mediated reduction in the GCHI mRNA level may at least partially explain the decline in GCHI activity. It is reasoned that under inflammatory conditions, cAMP-elevating agents such as prostacyclin exert regulatory effects on circulation by inhibiting cytokine-induced synthesis and release of BH4 by HUVEC.


Papillary thyroid carcinoma arising from a median ectopic thyroid with no thyroglossal duct remnant.
Thyroid carcinomas arising from ectopic thyroid tissue are uncommon;most of them arise from thyroid tissue in thyroglossal cysts. A rare case of a 66-year-old woman with papillary thyroid carcinoma arising from median ectopic thyroid tissue lacking a thyroglossal duct remnant is reported. The tumor was resected by Sistrunk's procedure, and the patient's postoperative course was good.


Curcumin as an In Vivo Selective Intestinal Breast Cancer Resistance Protein Inhibitor in Cynomolgus Monkeys.
To estimate the clinical impact of pharmacokinetic modulation via breast cancer resistance protein (BCRP), in vivo approaches in nonclinical settings are desired in drug development. Clinical observation has identified curcumin as a promising candidate for in vivo selective BCRP inhibition, in addition to several well known inhibitors, such as lapatinib and pantoprazole. This study aimed to confirm the inhibitory efficacy of curcumin on gastrointestinal BCRP function in cynomolgus monkeys and to perform comparisons with lapatinib and pantoprazole. Oral area under the plasma concentration-time curve (AUC) and bioavailability of well known BCRP (sulfasalazine and rosuvastatin), P-glycoprotein (fexofenadine, aliskiren, and talinolol), and CYP3A (midazolam) substrates were investigated in the presence and absence of inhibitors. Oral exposures of sulfasalazine and rosuvastatin were markedly elevated by curcumin with minimal changes in systemic clearance, whereas pharmacokinetic alterations after fexofenadine, aliskiren, and talinolol oral exposure were limited. Curcumin increased oral midazolam exposure without affecting systemic clearance, presumably owing to partial inhibition of intestinal CYP3A. Lapatinib increased the oral AUC for sulfasalazine to a greater extent than curcumin did, whereas pantoprazole had a smaller effect. However, lapatinib also exerted significant effects on fexofenadine, failed to selectively discriminate between BCRP and P-glycoprotein inhibition, and had an effect on oral midazolam exposure comparable with that of curcumin. Thus, pharmacokinetic evaluation in monkeys demonstrated that pretreatment with curcumin as an in vivo selective BCRP inhibitor was more appropriate than pretreatment with lapatinib and pantoprazole for the assessment of the impact of BCRP on gastrointestinal absorption in nonrodent models.


Unconventional gallium oxide nanowires.
Zigzag and helical beta-Ga(2)O(3) one-dimensional nanostructures were produced by thermal evaporation of gallium oxide in the presence of gallium nitride. High-resolution TEM analysis indicates that each individual zigzag nanostructure has a periodic arrangement of three distinct blocks: two structurally perfect blocks mirrored with respect to each other on the (002) plane, and one stacking-fault-rich block sandwiched between them. In a zigzag nanostructure, the growth orientation of a beta-Ga(2)O(3) crystal changes alternately in three blocks. The zigzag nanostructure as a whole has the [001] axial direction. In addition to zigzag nanostructures, single-crystalline helical nanowires were also obtained.


Respiratory complications of Ehlers-Danlos syndrome type IV.
Pulmonary complications are described in a case of Ehlers-Danlos syndrome type IV, established by studies of collagen biosynthesis. At age 20.5 years the patient, who had previously suffered a spontaneous colonic perforation, developed intermittent recurrent hemoptysis and had a spontaneous hemopneumothorax. At presentation, imaging studies revealed multiple scattered cavitary lesions in both lungs. On separate occasions large parenchymal cysts ensued and subsequently regressed. Reviews of other reported patients indicate that pulmonary complications do occur in patients with Ehlers-Danlos syndrome type IV but have not resulted directly in patient mortality.


Survival of differentiated thyroid carcinoma studied in 500 patients.
To analyze the factors that influence survival of patients with differentiated thyroid carcinoma treated by surgical thyroidectomy, radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in the case of locoregional recurrence. The survival of 500 patients with differentiated thyroid carcinoma was analyzed retrospectively with regard to mortality and survival rate (Kaplan-Meier). A total of 301 patients had papillary and 199 follicular thyroid carcinoma. The mean age of the 380 women and 120 men was 46.8 +/- 16.4 years at presentation. All patients were treated by surgical thyroidectomy, high-dose radioactive iodine, and early surgical reintervention with compartment-oriented lymphadenectomy in cases of locoregional recurrence, without routine adjuvant external radiotherapy of the neck. Patients were monitored up to 23 years, with a median follow-up time of 5.6 years. Twenty-nine of 500 patients died, 19 of thyroid cancer. The corrected overall 5-year survival rate (Kaplan-Meier) was 0.92. Among patients with tumor stage pT1-3NO-1MO (low risk), none died of thyroid carcinoma (5-year survival rate, 0.97); in patients with tumor stage pT4 and/or M1 (high risk), the 5-year survival rate was 0.83. The cause of death was locoregional recurrence in eight and metastatic disease in 11. Using multivariate analysis, risk factors that significantly influence survival were local invasion (pT4), metastatic disease (M1), and age. In differentiated thyroid carcinoma, the use of total surgical thyroidectomy followed by high-dose radioiodine therapy and early surgical reintervention in case of locoregional recurrence yields high survival rates, even without adjuvant external radiotherapy of the neck.


Role of COX-2 in microcirculatory disturbance in experimental pancreatitis.
To elucidate the role of COX-2 in the development of capillary leakage in rats with acute interstitial pancreatitis. Rats with acute interstitial pancreatitis were induced by caerulein subcutaneous injection. Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of COX-2 in pancreatic tissues, spectrophotometry was used to assay the parameters of acute pancreatitis such as the serum amylase and plasma myeloperoxidase, and determination of capillary permeability in the pancreas by quantifying the permeability index (PI) assisted response of pancreatic microvascular via intravital fluorescence microscope video image analysis system. A significant increase of COX-2 expression, elevation of serum amylase, and plasma myeloperoxidase were detected in rats with acute edematous pancreatitis compared with control rats. The changes of pancreatic microvascular after caerulein injection were as following: (a) the decrease of pancreatic capillary blood flow (4th h, 0.56+/-0.09 nL/min, P<0.05; 8 th h, 0.34+/-0.10 nL/min, P<0.001); (b) reduction of functional capillary density (4 th h, 381+/-9 cm(-1), P>0.05; 8th h, 277+/-13 cm(-1), P<0.001); (c) irregular and intermittent capillary perfusion was observed at the 8th h and these vessels were also prone to permeation. COX-2 plays an important role in mediating capillary permeability in pancreatitis, thereby contributing to capillary leakage.


Outcomes of shoulder arthroplasty in diabetic patients as assessed by peri-operative A1C.
Although diabetes mellitus (DM) has an adverse effect on complication rates in orthopaedic surgery, neither the effect of DM nor the association between haemoglobin A1C (HbA1C) and outcomes after shoulder arthroplasty (SA) has been studied. A retrospective review of 406 SAs (70 HAs, 188 total shoulder arthroplasties [TSAs], 148 reverse total shoulder arthroplasties [RSAs]) with HbA1Cs within 90 days of surgery was conducted. The average age was 70 years (range 27-97) and 55% were female. The average peri-operative HbA1C was 6.4% (range 4.7-9.8%), with 104 (26%) having a HbA1C of 7.0% or greater. Kaplan-Meier curves were constructed to determine complication, re-operation, and revision rates at two, five and ten years post-operatively. At mean follow-up of four years, 58 (16.5%) SAs were associated with post-operative complications including six (1.5%) infections. Kaplan-Meier two and five year survivorship free of any complication was 87.3 and 82.6% and of infection was 95.8 and 90.9%, respectively. Thirty-two (7.9%) SAs required reoperation with 26 (6.4%) of these being revisions. Survivorship at two and five years post-operatively was 97.1 and 92.7% for re-operation and 98.6 and 98.2% for revision, respectively. No increased risk of complications, re-operation, revision, or infection was seen with increased HbA1C analyzed as a continuous variable (hazard ratio = 0.97-1.11, 95% CI = 0.28-3.94, p = 0.5882-0.9445) or as a dichotomous variable with a cutoff of 7.0% (hazard ratio = 1.02-1.47, 95% CI = 0.20-7.48, p = 0.3253-0.9544). A collaborative and comprehensive approach to the pre-operative medical evaluation of patients with DM is critical, as is future investigation into alternative methods associated with outcomes after shoulder arthroplasty in patients with DM. Level IV.


Theoretical study on the charge transport properties of three series of dicyanomethylene quinoidal thiophene derivatives.
It is very important to analyse the most advantageous connection style for quinoidal thiophene derivatives, which are used in n-type organic semiconductor transport materials. In the present work, the charge transport properties of three series of quinoidal thiophene derivatives, oligothiophene (series A), thienothiophene (series B) and benzothiophene (series C), are systematically investigated by employing full quantum charge transfer theory combined with kinetic Monte-Carlo simulation. The single crystal structures of the molecules we had constructed were predicted using the USPEX program combined with density functional theory (DFT) and considering the dispersion corrected. Our theoretical results expounded how the different connection styles, including oligo-, thieno-, and benzo-thiophene in the quinoidal thiophenes derivatives, effectively tune their electronic structures, and revealed how their intermolecular interactions affect the molecular packing patterns and hence their charge transport properties by symmetry-adapted perturbation theory (SAPT). In the meantime we also elucidated the role of end-cyano groups in noncovalent interactions. Furthermore, it is clarified that quinoidal thiophene derivatives show excellent carrier transport properties due to their optimal molecular stacking motifs and larger electronic couplings besides their low energy gap. In addition, our theoretical results demonstrate that quinoidal oligothiophene derivatives (n = 3-5) with more thiophene rings will have ambipolar transport properties, so quinoidal thienothiophene and benzothiophene derivatives should be promising alternatives as n-type OSCs. When we focused only on the electronic transport properties in the three series of molecules, quinoidal benzothiophene derivatives were slightly better than quinoidal oligothiophene or thienothiophene derivatives.


The Role of Natural Antioxidants Against Reactive Oxygen Species Produced by Cadmium Toxicity: A Review.
Cadmium (Cd) is a significant ecotoxic heavy metal that adversely affects all biological processes of humans, animals and plants. Exposure to acute and chronic Cd damages many organs in humans and animals (e.g. lung, liver, brain, kidney, and testes). In humans, the Cd concentration at birth is zero, but because the biological half-life is long (about 30 years in humans), the concentration increases with age. The industrial developments of the last century have significantly increased the use of this metal. Especially in developing countries, this consumption is higher. Oxidative stress is the imbalance between antioxidants and oxidants. Cd increases reactive oxygen species (ROS) production and causes oxidative stress. Excess cellular levels of ROS cause damage to proteins, nucleic acids, lipids, membranes and organelles. This damage has been associated with various diseases. These include cancer, hypertension, ischemia/perfusion, cardiovascular diseases, chronic obstructive pulmonary disease, diabetes, insulin resistance, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, asthma, skin diseases, chronic kidney disease, eye diseases, neurodegenerative diseases (amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, and Huntington disease). Natural antioxidants are popular drugs that are used by the majority of people and have few side effects. Natural antioxidants play an important role in reducing free radicals caused by Cd toxicity. Our goal in this review is to establish the relationship between Cd and oxidative stress and to discuss the role of natural antioxidants in reducing Cd toxicity.


NATs at a glance.
Most proteins receive an acetyl group at the N terminus while in their nascency as the result of modification by co-translationally acting N-terminal acetyltransferases (NATs). The N-terminal acetyl group can influence several aspects of protein functionality. From studies of NAT-lacking cells, it is evident that several cellular processes are affected by this modification. More recently, an increasing number of genetic cases have demonstrated that N-terminal acetylation has crucial roles in human physiology and pathology. In this Cell Science at a Glance and the accompanying poster, we provide an overview of the human NAT enzymes and their properties, substrate coverage, cellular roles and connections to human disease.


Glucose Transporter-1 Cooperating with AKT Signaling Promote Gastric Cancer Progression.
High expression of GLUT1 has been observed in numerous solid cancers, facilitating glucose consumption for supporting tumor cell survival. The altered metabolic activity is regulated by series of signaling pathways, including AKT signaling that acts as a key role in glucose metabolism and shows close correlation with the malignant transformation. In this study, we aimed to elucidate the effect of GLUT1 on gastric cancer (GC) and to explore the relation between GLUT1 and AKT signaling. GLUT1, p-AKT, and p-S6k1 expression were investigated by immunohistochemistry and semi-quantitative analysis in 57 paired-GC samples. The relationship of GLUT1 with clinical indexes in GC tissues was investigated. The effects of GLUT1 on the prognosis of GC patients and the underlying mechanism involved were studied by subgroup analysis. In GC tissues, an obvious increase in GLUT1 expression was observed when compared with that of normal tissues (P<0.001). Advanced clinicopathological factors (tumor size P=0.019, invasion depth P=0.002, lymph node metastasis P<0.001, differentiation P=0.024, neural invasion P=0.003, and TNM staging P=0.001) correlated with high GLUT1 levels. GLUT1 was an independent risk factor resulting in poor prognosis (P=0.002, HR=5.132). GLUT1 increased the activation ratio of p-AKT (P<0.01) and p-S6K1 (P<0.001) in GC. The expression of p-S6K1 and GLUT1 was positively correlated. (P=0.001, R=0.173). The survival probability of GC patients with GLUT1(+)/p-S6K1(+) was worse when compared to that of GLUT1(+)/p-S6K1(-) or GLUT1(-)/p-S6K1(+) (P<0.001). High expression of GLUT1 facilitated GC progression, leading to poor prognosis. Overexpression of GLUT1 activated AKT-S6K1 axis, resulting in adverse outcomes of GC. GLUT1 is novel indicator of GC prognosis and GLUT1 targeted metabolic treatment that has potential therapeutic value.


Construction methods and materials for external prostheses--present and future.
In the first part of this paper the methods of constructing lower limb prostheses and their major components are discussed. Attention is paid to the foot, shank, knee joint, swing control, thigh, and hip joint. The second part is devoted to the use of thermoplastics in prosthesis and orthotics. Thermoplastics are polymers of varying chain length which can be moulded when heated. The properties of the various materials are discussed and their potential use described.


Assessment of cardiac risk in surgical patients.
Fifty patients admitted to the hospital for elective noncardiac surgery were carefully assessed for cardiac risk by exercise stress testing. Twenty-five of 38 (66%) patients with adequate testing had abnormal stress test results. Patients with symptoms of angina had a high incidence of abnormal stress test results (15 of 20). In the majority of these patients, the exercise stress test was true-positive, so that on angiography, severe coronary artery disease was present. In patients with no cardiac symptoms, 33% (ten of 30) had abnormal stress test results and seven patients had significant coronary artery disease. Our preliminary data indicate that exercise stress testing is a good noninvasive screening test to detect asymptomatic coronary artery disease. Those patients who have an abnormal stress test or an abnormal ECG or angina should undergo coronary angiography to determine extent of coronary disease.


A fast dual wavelength laser beam fluid-less optical CT scanner for radiotherapy 3D gel dosimetry II: dosimetric performance.
New clinical radiotherapy dosimetry systems need comprehensive demonstration of measurement quality. Practicality and reliability are other important aspects for clinical dosimeters. In this work the performance of an optical CT scanner for true 3D dosimetry is assessed using a radiochromic gel dosimeter. The fluid-less scanner utilised dual lasers to avoid the necessity for pre-irradiation scans and give greater robustness of image quality, enhancing practicality. Calibration methods using both cuvettes and reconstructed volumes were developed. Dosimetric accuracy was similar for dual and single wavelength measurements, except that cuvette calibration reliability was reduced for dual wavelength without pre-irradiation scanning. Detailed performance parameters were specified for the dosimetry system indicating the suitability for clinical use. The most significant limitations of the system were due to the gel dosimeter rather than the optical CT scanner. Quality assurance guidelines were developed to maintain dosimetry system performance in routine use.


Influence of culture medium pH and proteinase inhibitors on extracellular proteinase activity and cell growth of Sporothrix schenckii.
Sporothrix schenckii produces two extracellular proteinases in albumin- or collagen-supplemented unbuffered liquid medium. Proteinase I had an optimal pH of 6.0, and its activity was strongly inhibited by chymostatin. Proteinase II had an optimal pH of 3.5, and its activity was strongly inhibited by pepstatin. Speculating that these two proteinases are key enzymes for fungal growth, we investigated the influences of culture medium pH and either or both of the proteinase inhibitors pepstatin and chymostatin on the cell growth of S. schenckii. In buffered medium at a pH of 3.5, an optimal pH for proteinase II, only proteinase II activities were observed, while at pH 6.0, an optimal pH for proteinase I, only proteinase I activities were observed. However, there was no cell growth inhibition. These results suggested that the regulation of the production of the two proteinases is dependent on environmental pH. The addition of pepstatin or chymostatin to the culture medium did not inhibit the cell growth of S. schenckii, but the addition of both inhibitors at a concentration of 10 micrograms/ml strongly inhibited growth. These results suggested that at least one of the two proteinases was expressed to allow fungal growth in albumin-supplemented media. The indirect fungistatic action of the proteinase inhibitors, which inhibit proteolysis, may be applied to a topical therapeutic agent in vivo.


Workplace violence: Examination of the tensions between duty of care, worker safety, and zero tolerance.
Workplace violence (WPV) remains an international problem. This raises challenges for staff in meeting their duty of care to consumers while enforcing zero tolerance for violence directed toward them. The aim of the study was to expose the values and beliefs underpinning practice and reveal any flawed assumptions or evidence, upon which decisions related to WPV are made. By increasing staff awareness, the secondary aim is to decrease staff stress when confronted with conflicting policies and duty of care responsibilities. Explanatory research as part of a larger descriptive study was used. Semistructured interviews with a sample of managers and staff (n = 99) in Victorian Health Services (Australia) were performed. Initial descriptive analysis identified a tension between duty of care, worker safety, and zero tolerance. This article reports the secondary analysis to examine these relationships in depth. Feeling obligated and providing care for aggressive patients was difficult while maintaining own safety: "You cannot do both." Although there were contrasting views about the merits of zero tolerance, policies were rarely enacted: "We cannot refuse to treat." Incongruency between legislative requirements creates confusion for decision-making: "Which Act trumps what?" Despite policies supporting zero tolerance, staff do not enact these because they prioritize duty of care to consumers before duty of care to self. Zero tolerance, with incongruent legislation, compounds this tension and impairs decision-making. This article exposes the underlying values, beliefs, and flawed assumptions underpinning practice related to WPV. Managers need to amend policies to reduce staff confusion, adopt a trauma-sensitive and resilience approach, and develop a clearly written framework to guide decision-making related to duty of care to consumers and staff safety. Incident reports and staff well-being/satisfaction surveys need to evaluate the effects of zero tolerance on staff and consumers. Regulators need to ensue legislative requirements are congruent with staff safety and well-being.


The Efficacy of Antegrade Homodigital Neurovascular Island Flaps in Distal Fingertip Reconstruction: A Systematic Literature Review.
Antegrade homodigital neurovascular island flaps (AHIFs) are a heterogeneous group of pedicled flaps used for reconstruction of traumatic digital detipping injuries. While numerous single-center studies have documented their use, there are no large or multicentre studies validating their efficacy, applicability, and functional outcomes. We performed a systematic review of the contemporary literature to establish the safety and functional outcomes of this technique. Electronic searches were performed using PubMED, Embase, and MEDLINE from inception date to October 2020, with further studies identified from study reference lists and independent searches. Relevant studies reported on complications and functional outcomes of the AHIFs, as used for digital detipping injuries. Data were then extracted and analyzed. Twenty-seven studies published between 1974 and 2019 yielded 744 patients. Four studies provided incomplete epidemiologic data, resulting in a total of 559 patients with 584 digital injuries. Index and middle fingers were most frequently involved. Mean final 2-point discrimination (2-PD) was 4.9 mm static and 5.1 mm dynamic, with dynamic 2-PD reported in 2 studies. Mean total active motion of the digit was 200.3°. Mean time to return to work was 6.7 weeks in 10 studies. Flap survivorship was found to be 99.6% in 23 studies. Cold intolerance was the most common complication at 18%, followed by pain and hypersensitivity. Antegrade homodigital neurovascular island flaps provide a safe and effective method of treating distal finger amputations, yielding satisfactory functional outcomes across all ages. Further studies comparing outcomes between the AHIFs and other reconstructive modalities would be useful.