Immobilization of biomolecules to plasma polymerized pentafluorophenyl methacrylate.
Thin films of plasma polymerized pentafluorophenyl methacrylate (pp-PFM) offer highly reactive ester groups throughout the structure of the film that allow for subsequent reactions with different aminated reagents and biological molecules. The present paper follows on from previous work on the plasma deposition of pentafluorophenyl methacrylate (PFM) for optimum functional group retention (Francesch, L.; Borros, S.; Knoll, W.; Foerch, R. Langmuir 2007, 23, 3927) and reactivity in aqueous solution (Duque, L.; Queralto, N.; Francesch, L.; Bumbu, G. G.; Borros, S.; Berger, R.; Förch, R. Plasma Process. Polym. 2010, accepted for publication) to investigate the binding of a biologically active peptide known to induce cellular adhesion (IKVAV) and of biochemically active proteins such as BSA and fibrinogen. Analyses of the films and of the immobilization of the biomolecules were carried out using infrared reflection absorption spectroscopy (IRRAS), X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM). The attachment of the biomolecules on pulsed plasma polymerized pentafluorophenyl methacrylate was monitored using surface plasmon resonance spectroscopy (SPR). SPR analysis confirmed the presence of immobilized biomolecules on the plasma polymer and was used to determine the mass coverage of the peptide and proteins adsorbed onto the films. The combined analysis of the surfaces suggests the covalent binding of the peptide and proteins to the surface of the pp-PFM.


Combination of acupuncture and fluoxetine for depression: a randomized, double-blind, sham-controlled trial.
The current pharmacological management of depression remains limited. The aim of this study was to assess the efficacy and safety of acupuncture in combination with fluoxetine as an intervention for major depressive disorder (MDD). A total of 80 patients with MDD (DSM-IV) were randomized to two groups: VA group received verum acupuncture, 10 mg/day fluoxetine and placebo; SA group received sham acupuncture and 20-30 mg/day fluoxetine. Acupuncture was applied 5 times a week over a period of 6 weeks. A randomized, double-blind, double-dummy, sham-controlled trial was conducted in Dehong Prefecture Traditional Chinese Medicine Hospital. All subjects were assessed in a double-blind fashion at four time points (i.e., baseline, the end of the second, fourth, and sixth week of treatment. The primary outcome measure was the therapeutic response rate based on the rate of total score change in the 17-item Hamilton Rating Scale for Depression (HRSD). Anxious symptoms, antidepressant side-effects, and acupuncture adverse effects were also measured additionally. At the end of the treatment period, the therapeutic response rates were not statistically significant between groups (80.0% for the VA group and 77.5% for the SA group, respectively). No statistical significance was found between the 2 groups in the rate of HRSD score change (z = 1.80, p = 0.07), but patients in the VA group showed better improvement than the SA group in symptoms of anxiety and side-effects of antidepressant (z = 2.60, p = 0.01 and z = 23.60, p < 0.001, respectively). The overall rate of adverse events due to acupuncture was 8.75%. Additionally applied standardized acupuncture to low-dose fluoxetine for depression is as effective as a recommended dose of fluoxetine treatment. Depressive patients with severe anxious symptoms and/or intolerable side-effects of antidepressants can benefit from it.


Effect of Continuous Systemic Administration of Esmolol on Intraocular Pressure During Surgery in a Sustained Steep Trendelenburg Position.
To investigate the effects of continuous systemic administration of esmolol on intraocular pressure (IOP) during laparoscopic and robotic surgeries for recto-sigmoid cancer in a steep Trendelenburg position. A total of 50 patients undergoing laparoscopic surgery in a steep Trendelenburg position were included. Patients in the esmolol (E) group received a 0.25 mg/kg IV loading dose of esmolol before anesthesia, followed by an infusion of 15 μg/kg/min throughout the operation. Patients in the saline (S) group were infused with the same volume of normal saline. IOP and ocular perfusion pressure were measured 16 times: before anesthetic induction (T1), before administration of the study drug (T2), after administration of anesthetic induction agents (T3), after tracheal intubation (T4), 1, 3, 5, and 10 minutes after tracheal intubation (T5-T8), immediately after intraperitoneal CO2 insufflation (T9), immediately after the steep Trendelenburg position (T10), 1, 2, and 4 hours after the steep Trendelenburg position (T11-T13), just before the supine position (T14), and 10 and 30 minutes after the supine position (T15, T16). The IOP increased markedly after adopting the steep Trendelenburg position, reaching 28.8±4.4 mm Hg in group S. The IOP at T13 in group S was ∼5.7 mm Hg higher than in group E. The IOP at T13 was ∼10.6 mm Hg higher than in T1 in group S, but only ∼4.4 mm Hg higher than in group E. Continuous systemic administration of esmolol can alleviate the increase in IOP during a sustained steep Trendelenburg position without adverse cardiovascular effects.


Induced sarcoid-like reactions in patients with metastatic melanoma treated with dabrafenib and trametinib: a monocentric retrospective study.
Combined BRAF and MEK inhibition is one of the first-line treatment strategies for patients with advanced BRAF-mutant melanoma. Sarcoid-like reactions (SLRs) have occasionally been described with melanoma systemic treatments such as immunotherapy or the BRAF inhibitor vemurafenib, but very few cases have been reported with dabrafenib and trametinib. Our aim was to better characterize SLR induced by this combination. We conducted a monocentric retrospective observational study among patients treated with dabrafenib and trametinib for BRAF-mutant advanced melanoma from January 2015 to March 2019. Patients presenting with histologically proven SLR were included. We also searched Medline database for all reported cases of SLR induced by targeted therapy. Of 63 patients on dabrafenib/trametinib combination, seven were diagnosed with a SLR. They all had specific cutaneous involvement, and one also displayed mediastinal and salivary glands involvement. None required systemic corticosteroids or dabrafenib/trametinib discontinuation. Three of them (43%) reached melanoma complete remission and are still on targeted therapy; and four patients progressed and died. A literature review yielded 22 additional cases of SLR induced by targeted therapy: the main affected organ was the skin, 11 patients (50%) had systemic involvement, five patients (23%) required systemic corticosteroids to reach partial or complete remission of SLR, 12 (55%) reached partial or complete response of melanoma while six (27%) progressed. BRAF and MEK inhibitors are potential triggers of SLR, although pathological mechanisms remain unclear. The mainstay of treatment is systemic or topical corticotherapy; targeted therapy discontinuation is usually not necessary.


Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia Are Associated With the Diabetic Retinopathy Stage and Cognitive Decline in Patients With Type 2 Diabetes.
Purpose: The aim of this study was to evaluate whether perivascular space (PVS) severity and retinal ganglion cell layer (GCL) thickness differed based on the stage of diabetic retinopathy (DR) and the cognitive status in patients with DR. Methods: A total of 81 patients with DR (51 in the non-proliferative group and 30 in the proliferative group) were included in this retrospective, cross-sectional study. PVS severity was assessed in the basal ganglia (BG) and centrum semiovale using MRI. The total cerebral small vessel disease (SVD) score was determined based on the numbers of lacunes and microbleeds and the severity of white matter hyperintensity. Optical coherence tomography was used to measure foveal and perifoveal GCL thicknesses. Cerebral SVD markers and cognitive function were compared between the groups, and correlations between the BG-PVS severity and the Mini-Mental Status Examination (MMSE) scores and GCL parameters were evaluated. Results: Patients with proliferative DR had higher BG-PVS severity (P = 0.012), higher total cerebral SVD scores (P = 0.035), reduced GCL thicknesses in the inferior (P = 0.027), superior (P = 0.046), and temporal (P = 0.038) subfields compared to patients with non-proliferative DR. In addition, the BG-PVS severity was negatively correlated with the MMSE score (P = 0.007), and the GCL thickness was negatively correlated with the BG-PVS severity (P-values < 0.05 for inferior, superior, and temporal subfields). Conclusion: BG-PVS severity and retinal GCL thickness may represent novel imaging biomarkers reflecting the stage of DR and cognitive decline in diabetic patients. Furthermore, these results suggest a possible link between cerebral and retinal neurodegeneration at the clinical level.


Metabolomic Analysis of Two Parmotrema Lichens: P. robustum (Degel.) Hale and P. andinum (Mull. Arg.) Hale Using UHPLC-ESI-OT-MS-MS.
Lichens are symbiotic associations of fungi with microalgae and/or cyanobacteria. Lichens belonging to the Parmeliaceae family comprise 2700 species of lichens, including the Parmotrema genus which is composed of 300 species. The metabolites of this genus include depsides, depsidones, phenolics, polysaccharides, lipids, diphenylethers and dibenzofurans, which are responsible for the biological activities reported including antidiabetic, antihelmintic, anticancer, antioxidant, antibacterial, anti-inflammatory, antimitotic, antitumoral, antifungal, and antioxidant enzyme inhibitory. Due to scarce knowledge of metabolomic profiles of Parmotrema species (P. andinum and P. robustum), a full metabolome study based on ultra-high performance liquid chromatography- diode array detector-electrospray ionization-quadrupole-orbitrap-mass-spectrometry (UHPLC-DAD-ESI-Q-orbitrap MS) was performed for a comprehensive characterization of their substances. From the methanolic extracts of these species, a total of 54 metabolites were identified for the first time using this hyphenated technique, including thirty compounds in P. andinum, and thirty-seven in P. robustum. Moreover, two compounds were not identified as known compounds, and could be new structures, according to our data. This report shows that this technique is effective and accurate for rapid chemical identification of lichen substances and the compounds identified could serve as chemotaxonomic markers to differentiate these ruffle lichens.


Experimental transmission of dermal sarcoma to the sauger Stizostedion canadense.
Walleye dermal sarcoma virus (WDSV) has been identified as the causative agent of a benign neoplasia of walleye Stizostedion vitreum, walleye dermal sarcoma (WDS). We conducted an experimental transmission regimen to determine if WDSV is capable of inducing dermal sarcoma in the closely related sauger S. canadense. Nearly all of young-of-the-year saugers (96%) inoculated with filtrates of spring-collected tumors developed dermal sarcomas, while all of the inoculated walleyes developed tumors. Most of the sauger tumors were limited to the skin, but invasive tumors, similar to those previously observed in experimental walleyes, were observed in some fish.


Reflectance measurements of hematocrit and oxyhemoglobin saturation.
Fiberoptic oximeters measure oxyhemoglobin saturation from the optical reflectance of whole blood, but the calibration of such oximeters is hematocrit dependent. Therefore, using photon-diffusion theory and an empirical approach, we have developed a new reflectance method that determines hematocrit and correspondingly corrects the oxyhemoglobin-saturation measurement. Our method employs four fiber-optic light guides, a photodetector, and three inexpensive light-emitting diodes (one with emissions at 660 nm and two at 813 nm). Hematocrit is determined from the ratio of reflectances from the differently spaced emitting fibers at 813 nm and is used to correct the 813-660 nm measurement of oxyhemoglobin saturation. In red cell suspensions, the mean difference between reflectance measurements of hematocrit and conventional determinations was only 2.09% (r = 0.99), and when compared with conventional gasometric measurements of oxyhemoglobin saturation, the reflectance method yielded the same calibration curve for different hematocrits and gave a mean difference of only 2.67%. Although the technique is demonstrated with a cuvette appropriate for an extracorporeal circulation in animal experiments, it could possibly be further developed for fiber-optic catheter oximeters.


Uncoupling of the order of the S and M phases: effects of staurosporine on human cell cycle kinases.
The protein kinase inhibitor staurosporine (SSP) was employed to study the involvement of kinases in human cell cycle progression. Thirty to 100 ng/ml SSP blocks entry into S phase and M phase. Lack of entry into S phase is due to impaired activity of the retinoblastoma protein kinase. The requirement for any of the SSP-sensitive kinases for cell cycle progression can be abrogated in tumour cells. Therefore, these kinases act in a checkpoint network negatively controlling the initiation of S phase, M phase and cytokinesis, rather than being inherent parts of a substrate-product chain required for the initiation of the cell cycle phases. As a consequence of the lack of certain checkpoint effectors, tumour cells may endoreduplicate or binucleate in the presence of SSP. The latter processes, as well as meiosis, are naturally occurring in specialized cell types, leading to the idea that this checkpoint network controls the order of the cell cycle phases in normal cells. A model is presented where the cell cycle is envisioned as two independently running cycles, the S and the M cycle, which are controlled by intra and intercycledependent checkpoints in human somatic cells. The model accounts for the dependency of S and M phase initiation on the successful completion of the previous M and S phase, respectively, as well as entry into a resting state.


Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial.
Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections. In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447. Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30-0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34-0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3-43·7), of diarrhoea was 134·1 (129·2-139·2), and of pneumonia was 22·3 (20·4-24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79-1.14], diarrhoea [1·06, 0·96-1·16], pneumonia [1·11, 0·90-1·38]) or praziquantel treatment (malaria [1·00, 0·84-1·20], diarrhoea [1·07, 0·98-1·18], pneumonia [1·00, 0·80-1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35-1·42) or praziquantel (0·60, 0·29-1·23) treatment. These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed. Wellcome Trust.


Mode-splitting in a microring resonator for self-referenced biosensing.
Self-referenced biosensing based on mode-splitting on a microring resonator is experimentally demonstrated. A Bragg grating integrated on the surface of the ring provides coupling between the clockwise and counterclockwise travelling modes of the pristine ring resonator lifting their degeneracy. The amount of mode-splitting is directly related to the reflectivity of the grating and it is only affected by structurally modifying the grating. Environmental perturbations to the surroundings of the gratings, such as temperature and bulk refractive index variations, have a minor effect on the amount of mode-splitting. This principle allows the realization of a self-referenced sensing scheme based on the detection of variations of the mode-splitting induced by structural changes to the grating. In this work, a polymethyl methacrylate (PMMA) Bragg grating is integrated onto a ring resonator in Al2O3. It is shown both theoretically and experimentally that the amount of splitting of a resonance varies minimally under temperature or bulk refractive index perturbations. However, the structural change of attaching a layer of biomolecules inside the grating does affect its reflectivity and the amount of mode splitting present. This result represents the first proof-of-concept demonstration of an integrated mode-splitting biosensor insensitive to temperature and refractive index variations of the liquid matrix where the molecules to be detected are embedded. The reported results pave the road towards the realization of truly self-referenced biosensors.


Signatures of sluggish dynamics and local structural ordering during ice nucleation.
We investigate the microscopic pathway of spontaneous crystallization in the ST2 model of water under deeply supercooled conditions via unbiased classical molecular dynamics simulations. After quenching below the liquid-liquid critical point, the ST2 model spontaneously separates into low-density liquid (LDL) and high-density liquid phases, respectively. The LDL phase, which is characterized by lower molecular mobility and enhanced structural order, fosters the formation of a sub-critical ice nucleus that, after a stabilization time, develops into the critical nucleus and grows. Polymorphic selection coincides with the development of the sub-critical nucleus and favors the formation of cubic (Ic) over hexagonal (Ih) ice. We rationalize polymorphic selection in terms of geometric arguments based on differences in the symmetry of second neighbor shells of ice Ic and Ih, which are posited to favor formation of the former. The rapidly growing critical nucleus absorbs both Ic and Ih crystallites dispersed in the liquid phase, a crystal with stacking faults. Our results are consistent with, and expand upon, recent observations of non-classical nucleation pathways in several systems.


Development of a Simple, Serum Biomarker-based Model Predictive of the Need for Early Biologic Therapy in Crohn's Disease.
Early or first-line treatment with biologics, as opposed to conventional immunomodulators, is not always necessary to achieve remission in Crohn's disease [CD] and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy, in order to risk-stratify CD patients and guide initial treatment selection. A model-building study using supervised statistical learning methods was conducted using a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between January 1, 2004 and December 31, 2016, were included. A predictive score was derived using Cox regression modelling of immunomodulator failure, and was internally validated using bootstrap resampling. Of 410 patients [median age 37 years, 47% male, median disease duration 4.7 years], 229 [56%] experienced immunomodulator failure [39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation] with a median time to failure of 16 months. Independent predictors of treatment failure included raised C-reactive protein [CRP], low albumin, complex disease behaviour, younger age, and baseline steroids. Highest CRP and lowest albumin measured within the 3 months preceding immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin [CICA] index demonstrated robust optimism-corrected discriminative performance at 12, 24, and 36 months (area under the curve [AUC] 0.84, 0.83, 0.81, respectively). The derived CICA index based on simple, widely available markers is feasible, internally valid, and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.


Sodium Intake and Health: What Should We Recommend Based on the Current Evidence?
Several health organizations recommend low sodium intake (below 2.3 g/day, 5.8 g/day of salt) for entire populations, on the premise that lowering of sodium intake, irrespective of its level of intake, will lower blood pressure and, in turn, will result in a lower incidence of cardiovascular disease. These guidelines were developed without effective interventions to achieve long term sodium intakes at low levels in free-living individuals and without high-quality evidence that low sodium intake reduces cardiovascular events (compared with average levels of intake). In this review, we examine whether advice to consume low amounts of sodium is supported by robust evidence. We contend that current evidence indicates that most people around the world consume a moderate range of dietary sodium (3 to 5 g/day), that this level of intake is associated with the lowest risk of cardiovascular disease and mortality, and that the risk of adverse health outcomes increases when sodium intakes exceeds 5 g/day or is below 3 g/day. While the current evidence has limitations, it is reasonable, based upon prospective cohort studies, to suggest a mean target of below 5 g/day in populations, while awaiting the results of large randomized controlled trials of sodium reduction on cardiovascular disease and death.


Prospective study of surgical outcomes and bleb morphology using indocyanine green as a surgical dye in trabeculectomy with mitomycin C.
To investigate the effect of adding indocyanine green to mitomycin C in augmented trabeculectomy. A prospective, non-comparative interventional case series. A total of 37 eyes of 37 patients followed up for 1 year. A solution containing 12.5 mg/mL of indocyanine green was added to mitomycin C, resulting in an mitomycin C concentration of 0.2-0.4 mg/mL, which was applied to bare sclera and Tenon's capsule for 3 min during trabeculectomy. Visual acuity, intraocular pressure, bleb morphology, Moorfields Bleb Grading System scores and complications. Indocyanine green could be visualized on clinical examination for all eyes on the first postoperative day. Mean intraocular pressure decreased from 22.9 ± 6.2 mmHg to 12.1 ± 4.4 mmHg postoperatively (P < 0.001) at 1 year. Thirty-four eyes (91.9%) achieved an intraocular pressure of less than 21 mmHg at final visit without additional topical intraocular pressure-lowering medications. Three eyes (8.1%) developed bleb failure and required Baerveldt device implantation. There were no cases of blebitis or late bleb leak. No adverse effects attributable to indocyanine green could be identified postoperatively. The addition of indocyanine green during trabeculectomy improves the visibility of antimetabolites intraoperatively and allows for the estimation of antimetabolite treatment area intraoperatively and postoperatively. It appears to have no adverse effect on surgical outcomes and complication rates, while improving safety of antimetabolite use.


Hispanic Ethnicity and Cervical Cancer Precursors Among Low-Income Women in Arizona.
In the United States, Hispanics are more likely to be diagnosed with cervical cancer compared to Non-Hispanic Whites. Annually, 250,000 to 1 million women are diagnosed with a precursor to CC. The aim of this study was to assess whether Hispanics have a higher prevalence of cervical dysplasia compared to Non-Hispanics Whites among a population of low-income women. We analyzed the results of 10,911 cervical cytology tests administered between 2003 and 2016 that were funded through the Center for Disease Control and Prevention's (CDC) program for low-income, uninsured women entitled the National Breast and Cervical Cancer Early Detection Program (NBCCEDP). In the state of Arizona, the program is called the Well Women HealthCheck Program (WWHP). Logistic regression was used to identify increased risk of dysplasia, including low-grade squamous intraepithelial lesions (LSIL) and high-grade squamous intraepithelial lesions (HSIL/ICC), and multinomial logistic regression was used to assess increased likelihood for LSIL and HSIL/ICC as separate categories. In the crude analysis, Hispanic ethnicity was modestly associated with higher prevalence of LSIL (odds ratio (OR)=1.39, 95% CI=1.01-1.91), but this association was not statistically significant after adjusting for confounders. However, in the final models, lower income was independently associated with LSIL (adjusted odds ratio [aOR]=1.55, 95% CI=1.30-1.44), while smoking (aOR=2.88, 95% CI=1.21-6.84) and no history of Pap test within five years (aOR=3.54, 95% CI=1.61-6.99) were independently associated with HSIL. After adjusting for confounding in a sample of low-income women with comparable Pap screening rates, ethnicity was not associated with greater prevalence of abnormal pap smears. However, other variables were independently associated with LSIL and HSIL. The higher proportion of LSIL cases among lower income individuals compared to those with higher incomes, and the higher proportion of HSIL cases observed among those screened least regularly stresses the importance of programs like WWHP: programs that target low-income, uninsured women. These programs help save lives.


[Trends of malnutrition in Mexican children under five years from 1988 to 2016: Analysis of five national surveys].
To study the magnitude, distribution and trends of undernutrition and overweight in Mexican children un¬der five years between 1988 and 2016. Underweight, wasting, stunting and overweight prevalences were calculated, at national, regional and rural/ urban locality levels in children under five years from the 1988, 1999, 2006, 2012 and 2016 national probabilistic surveys. Currently 3.9% suffer underweight, 1.9% wasting and 10% stunting. There was an decrease in stunting from 1988 to 2016 (26.9 vs 10.0%), in rural (43.1 vs 12.6%) and urban (22.5 vs 9.1%) localities and in South (38.6 vs 13.4%), Center (29.2 vs 8.4%) and Mexico City (13.6 vs 4.7%). In the North region the decrease was smaller (13.3 vs 11.4%). Overweight diminished from 9.7% to 5.8, mainly between 2012-2016. Stunting has continued its decline in Mexico, but high prevalences persist in some vulnerable groups. Overweight had an unexpected decline between 2012-2016.


Cerebral blood flow in acute mountain sickness.
Changes in cerebral blood flow (CBF) were measured using the radioactive xenon technique and were related to the development of acute mountain sickness (AMS). In 12 subjects, ascending from 150 to 3,475 m, CBF was 24% increased at 24 h [45.1 to 55.9 initial slope index (ISI) units] and 4% increased at 6 days (47.1 ISI units). Four subjects had similar increases of CBF when ascending to 3,200 m 3 mo later, indicating the reproducibility of the measurements. In nine subjects, ascending from 3,200 to 4,785-5,430 m, CBF increased to 76.4 ISI units, 53% above estimated sea-level values. CBF and increases in CBF were similar in subjects with or without AMS. In six subjects, CBF was measured before and after therapeutic intervention. At 2 h CBF increased 22% (71.3 to 87.3 ISI units) above pretreatment values in three subjects given 1.5 g acetazolamide, while three subjects given placebo showed no change. Symptoms remained unaltered in all subjects during the 2 h of the study. Overall, the results indicated that increases in CBF were similar in subjects with or without AMS while acetazolamide-provoked increases of CBF in AMS subjects caused no acute change in symptoms. Alterations in CBF cannot be directly implicated in the pathogenesis of AMS.


Producing Fluorine- and Lubricant-Free Flexible Pathogen- and Blood-Repellent Surfaces Using Polysiloxane-Based Hierarchical Structures.
High-touch surfaces are known to be a major route for the spread of pathogens in healthcare and public settings. Antimicrobial coatings have, therefore, garnered significant attention to help mitigate the transmission of infectious diseases via the surface route. Among antimicrobial coatings, pathogen-repellent surfaces provide unique advantages in terms of safety in public settings such as instant repellency, affordability, biocompatibility, and long-term stability. While there have been many advances in the fabrication of biorepellent surfaces in the past two decades, this area of research continues to suffer challenges in scalability, cost, compatibility with high-touch applications, and performance for pathogen repellency. These features are critical for high-touch surfaces to be used in public settings. Additionally, the environmental impact of manufacturing repellent surfaces remains a challenge, mainly due to the use of fluorinated coatings. Here, we present a flexible hierarchical coating with straightforward and cost-effective manufacturing without the use of fluorine or a lubricant. Hierarchical surfaces were prepared through the growth of polysiloxane nanostructures using n-propyltrichlorosilane (n-PTCS) on activated polyolefin (PO), followed by heat shrinking to induce microscale wrinkles. The developed coatings demonstrated repellency, with contact angles over 153° and sliding angles <1°. In assays mimicking touch, these hierarchical surfaces demonstrated a 97.5% reduction in transmission of Escherichia coli (E.coli), demonstrating their potential as antimicrobial coatings to mitigate the spread of infectious diseases. Additionally, the developed surfaces displayed a 93% reduction in blood staining after incubation with human whole blood, confirming repellent properties that reduce bacterial deposition.


[New antibiotics in infection treatment].
The introduction of new molecules with antimicrobial activity is an opportunity for modern antibiotic therapy in the era of rapidly growing resistance to antibiotics. Beta-lactamase-inhibiting antibiotics, cephalosporinases and carbapenemases represent a breakthrough in previous treatments for infections caused by resistant pathogens. Ceftazidime with avibactam and ceftolozane with tazobactam show exceptional efficacy in severe infections. Karbavans is a combination of meropenem and a new boron beta-lactamase inhibitor, as well as the combination of avibactam and aztreonam, are a hope for the treatment of infections caused by Klebsiella pneumoniae resistant to the majority of available antibiotics. S649266 is itself an inhibitor of beta-lactamases. Plazomycin, in turn, is a new aminoglycoside that allows the control of severe bacterial infections caused by multiresistant Enterobacteriaceae, including those resistant to carbapenems. In contrast, omadacyclin, a semi-synthetic derivative of tetracycline, has activity against Gram-positive, Gram-negative, aerobic and anaerobic as well as atypical bacteria. Solithromycin, a new ketolide, has immunomodulatory effects and a broad antiinflammatory spectrum, with no side effects caused by older generations of macrolides. New fluoroquinolones (delafloxacin, zabofloxacin, finefloxacin, nemonoxacin, zoliflodacin) show a wide spectrum of action with less and less side effects. The new MRX-1 preapplate, alongside tedizolid and cadazolid, are further oxazolidinones that show significant activity against multi-resistant Gram-positive pathogens. The presented palette of new molecules with antimicrobial activity will certainly significantly improve the effectiveness of antibiotic therapy.


Identification of histidine 118 in the D1 polypeptide of photosystem II as the axial ligand to chlorophyll Z.
Chlorophyll Z (ChlZ) is a redox-active chlorophyll (Chl) which is photooxidized by low-temperature (<100 K) illumination of photosystem II (PSII) to form a cation radical, ChlZ+. This cofactor has been proposed to be an "accessory" Chl in the PSII reaction center and is expected to be buried in the transmembrane region of the PSII complex, but the location of ChlZ is unknown. A series of single-replacement site-directed mutants of PSII were made in which each of two potentially Chl-ligating histidines, D1-H118 or D2-H117, was substituted with amino acids which varied in their ability to coordinate Chl. Assays of the wild-type and mutant strains showed parallel phenotypes for the D1-118 and D2-117 mutants: noncoordinating or poorly coordinating residues at either position decreased photosynthetic competence and impaired assembly of PSII complexes. Only the mutants substituted with glutamine (D1-H118Q and D2-H117Q) had phenotypes comparable to the wild-type strain. The ChlZ+ cation was characterized by low-temperature electron paramagnetic resonance (EPR), near-infrared (IR) absorbance, and resonance Raman (RR) spectroscopies in wild-type, H118Q, and H117Q PSII core complexes. The quantum yield of ChlZ+ formation is the same (approximately 2.5% per saturating flash at 77 K) for wild-type, H118Q, and H117Q, indicating that its efficiency of photooxidation is unchanged by the mutations. Similarly, the EPR and near-IR absorbance spectra of ChlZ+ are insensitive to the mutations made at D1-118 and D2-117. In contrast, the RR signature of ChlZ+ in H118Q PSII, obtained by selective near-IR excitation into the ChlZ+ cation absorbance band, is significantly altered relative to wild-type PSII while the RR spectrum of ChlZ+ in the H117Q mutant remains identical to wild-type. Shifts in the RR spectrum of ChlZ+ in H118Q reflect a change in the structure of the Chl ring, most likely due to a perturbation of the core size and/or extent of doming caused by a change in the axial ligand to Mg(II). Thus, we conclude that the axial ligand to ChlZ is H118 of the D1 polypeptide. Furthermore, we propose that H117 of the D2 polypeptide is the ligand to a homologous redox-inactive accessory Chl which we term ChlD. The Chl Z and D terminology reflects the 2-fold structural symmetry of PSII which is apparent in the redox-active tyrosines, YZ and YD, and the active/inactive branch homology of the D1/D2 polypeptides with the L/M polypeptides of the bacterial reaction center.


Body image: a survey of children in Caribbean Bonaire.
In Bonaire, the prevalence of overweight and obesity is twice as high compared with Northern Europe but similar to other Caribbean Islands and the USA. Having a realistic body image may be an important tool in the battle against childhood obesity. Previous studies have demonstrated associations between having a realistic body image and efforts to control weight. The aim of the study was to explore the body image of children in Bonaire. In a cross-sectional study from March to May 2015 in Bonaire, weight and height were measured in all children aged 10-14 years attending school. Body mass index (kg/m2) was classified according to the International Obesity Task Force. The children were asked about their body image using a validated questionnaire. Body mass index was measured in 939 of 1029 (91.3%) children aged 10-14 years (51.5% boys) in Bonaire. Of all children, 9.7% was underweight, 57.6% was normal weight, 32.7% was overweight (including obesity) and 11.6% was obese. The question pertaining to body image was completed by 750 of 939 (79.9%) children. Having a realistic perception of body image varied per weight category from 65% in underweight girls to 13% in obese boys. The percentage of obese children who underestimate their weight is high (boys 87%, girls 77%). In many children in Caribbean Bonaire, perceived body image is not in agreement with actual weight status. This applies especially to obese children. Disagreement between perceived body image and actual weight status may prevent weight management in overweight children. Future research is needed to elucidate determinants of disagreement between body image and actual weight status.


Evaluation of antioxidant and wound healing potentials of Sphaeranthus amaranthoides Burm.f.
Sphaeranthus amaranthoides commonly known as sivakaranthai is used in folklore medicine for the treatment of skin diseases. The antioxidant activity of the extract and its fraction was evaluated by using 2, 2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity, total antioxidant capacity, and total phenolic content. The tested plant extracts showed variable degrees of antioxidant activity. In the present study, methanolic extract of the whole plant of S. amaranthoides and a flavonoid fraction obtained from column chromatography were studied for wound healing activity by incorporating the sample in simple ointment base. Wound healing activity was studied in excision wound model in rats, following which, wound contraction, period of epithelization, hydroxyproline content, and collagen levels in the scab were studied. Methanolic extract showed the highest antioxidant effect (72.05%) and diethyl ether extract has the least (29.34%) compared to the standard (74.53%). Treatment of wound with ointment containing 5% (w/w) methanolic extract and 5% (w/w) flavonoid fraction exhibited better wound healing activity than positive control (silver sulfadiazine). Finally, histopathology studies conformed wound healing activity in Sphaeranthus amaranthoides. The methanolic extract and flavonoid fraction exhibited good wound healing activity probably due to the presence of phenolic and flavonoid constituents. The methanolic extract and flavonoid fraction significantly enhanced the rate of wound contraction and the period of epithelialization comparable to silver sulfadiazine.


A specific role for TRH in release of diacetyl alpha-MSH in tilapia stressed by acid water.
After exposure of tilapia for 7 days to low-pH water, plasma thyrotropin-releasing hormone (TRH) levels were elevated, and the melanocyte-stimulating hormone (MSH) cells in the pituitary pars intermedia had increased in size and showed enhanced synthetic and secretory activity. The MSH cells became more sensitive to TRH but not to corticotropin-releasing hormone (CRH). Stimulation by TRH (but not by CRH) of the MSH cells of tilapia exposed to low pH specifically enhanced the release of diacetyl alpha-MSH, the most potent corticotropic form of alpha-MSH. Acute stress imposed by handling and confinement for 1 h elevated the plasma cortisol level but did not affect blood plasma alpha-MSH levels. We conclude that stimulation by TRH is pivotal for an enhanced release of diacetyl alpha-MSH during low-pH adaptation. These results are further evidence of a role for TRH and alpha-MSH in the activation of the hypothalamopituitary-interrenal axis during adaptation to low pH.


Dynamic random-dot stereograms reveal up-down anisotropy and left-right isotropy between cortical hemifields.
With the use of dynamic random-dot sterograms (which are devoid of all monocular depth cues), the temporal duration for detecting a small, briefly presented test square of different depth than the surround varied as a function of its location in the central portion of the visual field. Test squares presented in the upper hemifield were detectable at consistently shorter durations than those in the lower hemifield when the fixation marker was in front of the surround, and vice versa when the marker was behind. No such anisotropy was found for left and right hemifield. Esploratory studies suggested a similar up-down anisotropy and left-right isotropy in spatial resolution. Thus, the upper hemifield representation at the cortex shows a general superiority over the lower one for vinocular detectors tuned to uncrossed disparitites, and the lower hemifield shows superiority for those tuned to crossed disparities.


Determination of metabolic resistance mechanisms in pyrethroid-resistant and fipronil-tolerant brown dog ticks.
Rhipicephalus sanguineus (Latreille) (Ixodida: Ixodidae) is a three-host dog tick found worldwide that is able to complete its' entire lifecycle indoors. Options for the management of R. sanguineus are limited and its' control relies largely on only a few acaricidal active ingredients. Previous studies have confirmed permethrin resistance and fipronil tolerance in R. sanguineus populations, commonly conferred by metabolic detoxification or target site mutations. Herein, five strains of permethrin-resistant and three strains of fipronil-tolerant ticks were evaluated for metabolic resistance using synergists to block metabolic enzymes. Synergist studies were completed with triphenyl phosphate (TPP) for esterase inhibition, piperonyl butoxide (PBO) for cytochrome P450 inhibition, and diethyl maleate (DEM) for glutathione-S-transferase inhibition. Additionally, increased esterase activity was confirmed using gel electrophoresis. The most important metabolic detoxification mechanism in permethrin-resistant ticks was increased esterase activity, followed by increased cytochrome P450 activity. The inhibition of metabolic enzymes did not have a marked impact on fipronil-tolerant tick strains.


Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus.
Zika virus (ZIKV) is a re-emerging virus that has recently spread into dengue virus (DENV) endemic regions and cross-reactive antibodies (Abs) could potentially affect ZIKV pathogenesis. Using DENV-immune serum, it has been shown in vitro that antibody-dependent enhancement (ADE) of ZIKV infection can occur. Here we study the effects of pre-existing DENV immunity on ZIKV infection in vivo. We infect two cohorts of rhesus macaques with ZIKV; one cohort has been exposed to DENV 2.8 years earlier and a second control cohort is naïve to flaviviral infection. Our results, while confirming ADE in vitro, suggest that pre-existing DENV immunity does not result in more severe ZIKV disease. Rather our results show a reduction in the number of days of ZIKV viremia compared to naïve macaques and that the previous exposure to DENV may result in modulation of the immune response without resulting in enhancement of ZIKV pathogenesis.


Obstetrical associated renal, cortical necrosis: uncommon but not rare!
Renal cortical necrosis (RCN) carries high morbidity and mortality in South East Asia. The purpose of this study was to look specifically at the incidence of obstetrical related RCN in renal biopsies and to evaluate its precipitating factors. In addition, prognosis, impact of aetiology and outcomes on discharge were also considered. The study was conducted in the Department of Nephrology, Lady Reading Hospital Peshawar, Pakistan. Renal biopsies of 1,670 patients were analysed during the study period of 1998 to 2008. All the patients with obstetrical related RCN were included. Patient records, demographic data, urine output on admission and preceding history of ante-partum haemorrhage (APH), post-partum haemorrhage (PPH), septicaemia, operative interventions and retained product of conception (ROPC) was noted and need for dialysis was considered. Out of 1670 kidney biopsies analysed, 48 turned out to be RCN. Among them 39 patients (81.3%) had diffuse cortical necrosis, 6 patients (12.5%) had patchy cortical necrosis with ATN while 3 patients (6.3%) had predominant ATN with partial patchy cortical necrosis. Out of 48 patients, 25 (52.1%) were oliguric, 18 (37.5%) were anuric while 5 (10.4%) had urine output > 800 ml 24 hr. Operative interventions were found in 29 patients while 19 patients had normal vaginal delivery (NVD). 16 (55.2%) patients with operative intervention had PPH. Thus the association proved to be significant (p = 0.037). Overall incidence of RCN was 2.9%. Oliguria/anuria on admission and dialysis dependency are associated with RCN. PPH and history of operative intervention have significant association and are contributing factors to development of RCN.


Synthesis of ppTppp via phosphotriester intermediates.
The bifunctional and crystalline phosphorylating agent morpholino-0,0-bis[1-benzotriazolyl]phosphate has been used for the preparation of a 3',5'-bis-phosphotriester intermediate of thymidine. The latter has been converted into ppTppp by the following consecutive steps; removal of the benzotriazolyl group followed by the addition of phosphoric acid and removal of the 2-(4-nitrophenyl)-ethyl group followed by the addition of pyrophosphoric acid.


The clinical and cost-effectiveness of left ventricular assist devices for end-stage heart failure: a systematic review and economic evaluation.
To assess the clinical and cost-effectiveness of left ventricular assist devices (LVADs) as a bridge to heart transplantation (BTT), as a bridge to myocardial recovery (BTR) or as a long-term chronic support (LTCS) for people with end-stage heart failure (ESHF). For the systematic review, electronic databases and bibliographies of related publications plus experts and manufacturers. For the economic evaluations, data originated from the systematic review of clinical and cost-effectiveness, UK hospitals, device manufacturers and expert opinion. For the systematic review, studies were selected and assessed against a set of rigorous criteria; data were then synthesised using a narrative approach through subgroup analysis based on the indication for treatment, type of LVAD and quality of studies. The economic evaluation developed two models to evaluate the use of LVADs, first as a BTT and second as LTCS for patients suffering from ESHF. Sixteen studies assessed the clinical effectiveness of LVADs as a BTT. Despite the poor methodological quality of the evidence, LVADs appeared beneficial compared to other treatment options (i.e. inotropic agents or usual care) or to no care (i.e. the natural history of ESHF) improving the survival of people with ESHF during the period of support and following heart transplantation. Patients supported by an LVAD appeared to have an improved functional status compared with those on usual care and experienced an improvement in their quality of life from before device implantation to the period during support. Serious adverse events are a risk for patients with an LVAD. With a scarcity of evidence directly comparing different devices, it is difficult to identify specific devices as the most clinically effective. The HeartMate LVAD is the only device that has evidence comparing it with the different alternatives, appearing to be more clinically effective than inotropic agents and usual care and as clinically effective as the Novacor device. Second generation devices, such as Jarvik 2000 and MicroMed Debakey LVADs, are early in their development but show considerable promise that should be assessed through long-term studies. Evidence of the clinical effectiveness of LVADs as a BTR was limited to seven non-comparative observational studies that appeared to show that the LVADs were beneficial in providing support until myocardial recovery. It was not possible to assess whether the LVADs are more effective than other alternatives or specific devices. No evidence was found on the quality of life or functional status of patients and limited information on adverse events was reported. Six studies assessed the clinical effectiveness of LVADs as an LTCS and from these it was evident that LVADs provided benefits in terms of improved survival, functional status and quality of life. Nineteen studies assessed the costs and cost-effectiveness of LVADS for people with ESHF, with the majority being simple costing studies and very few studies of the cost-effectiveness of LVADs. With no relevant cost-effectiveness studies available, an economic evaluation for BTT and LTCS was developed. The economic evaluation has shown that neither LVAD indication considered, that is, BTT and LTCS, is a cost-effective use. For the HeartMate LVAD used as a BTT the cost per QALY was pound 65,242. In the less restrictive indication, LTCS, where LVADs are not just given to patients awaiting transplantation, the analysis has shown that LTCS is not cost-effective. The baseline cost per QALY of the first-generation HeartMate LVAD was pound 170,616. One- and multi-way sensitivity analysis had limited effect on the cost per QALY. A hypothetical scenario based on the cost of a second-generation MicroMed DeBakey device illustrated that a 60% improvement in survival over first-generation devices was necessary before the incremental cost-effectiveness approached pound 40,000 per QALY. Although the review showed that LVADs are clinically effective as a BTT with ESHF, the economic evaluation indicated that they are not cost-effective. With the limited and declining availability of donor hearts for transplantation, it appears that the future of the technology is in its use as an LTCS. Further research is needed to examine the clinical effectiveness of LVADs for people with ESHF, assessing patient survival, functional ability, quality of life and adverse events. Evaluations of the clinical effectiveness of LVADs should include economic evaluations, as well as data on quality of life, utilities, resources and costs. A systematic review of the epidemiology of ESHF should be undertaken to assess its potential impact.


Differential protein expression in aortic smooth muscle cells cultured from newborn and aged rats.
Atherosclerosis is a complex disease in which smooth muscle cells (SMC) play a fundamental role. Work from several laboratories has suggested that in experimental models of atheromatosis SMC heterogeneity is important in the establishment of intimal thickening. Moreover it has been shown that SMC cultured from different situations in vivo maintain distinct phenotypic features in vitro. In order to find proteins differentially expressed in SMC cultured from newborn and aged rats, total protein extracts were separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), high-resolution maps were built, and differentially expressed spots were identified by automatic computer analysis. Of the 14 differentially expressed protein spots, 4 were present in SMC of newborn and 10 in SMC of old animals; we describe their molecular weights and isoelectric points. One of these proteins (expressed only in cultured SMC of old rats) was successfully microsequenced for 16 amino acids and it was found identical to cellular retinol-binding protein. This results provides, to our knowledge, the first suggestion that retinoids are implicated in the differentiation and aging of vascular SMC.


Selenocysteine tRNA[Ser]Sec levels and selenium-dependent glutathione peroxidase activity in mouse embryonic stem cells heterozygous for a targeted mutation in the tRNA[Ser]Sec gene.
To investigate the effect of a reduced level of selenocysteine (Sec) tRNA[Ser]Sec in selenoprotein biosynthesis, two mouse embryonic stem (ES) cell lines heterozygous for the corresponding gene were generated by homologous recombination of the host genome with targeting vectors encoding a deleted or a disrupted tRNA[Ser]Sec gene. The presence of a single functional gene in ES cells afforded us an opportunity to determine directly in the cell line the effect of reduced gene dosage on (1) the levels of the Sec tRNA[Ser]Sec population, (2) the distributions of the isoacceptors within the Sec tRNA population, and (3) selenoprotein biosynthesis. We therefore determined the amounts and distributions of the two major tRNA[Ser]Sec isoacceptors, designated mcm5U and mcm5Um, within the Sec tRNA population and determined the activity of the anti-oxidant, selenium-containing glutathione peroxidase (GPx) in the heterozygotes and in wild type cells grown in media with and without added selenium. The level of the Sec tRNA[Ser]Sec population in the heterozygotes was approximately 60% of that of wild type cells grown in media under normal conditions, while the ratio of the mcmU isoacceptor in wild type vs mutant cells was approximately 2:1 and of the mcmUm isoacceptor approximately 1:1. In the presence of media supplemented with selenium, the Sec tRNA[Ser]Sec population increased about 20% in wild type cells and virtually not all in heterozygous cells, and the level of the Sec tRNA[Ser]Sec population was, therefore, approximately 50% of that of wild type cells. GPx activity was indistinguishable among these cell lines in either selenium-supplemented or unsupplemented media, indicating that the resultant changes in tRNA[Ser]Sec levels did not have a measurable effect on GPx biosynthesis.


Precision Medicine for Lysosomal Disorders.
Precision medicine (PM) is an emerging approach for disease treatment and prevention that accounts for the individual variability in the genes, environment, and lifestyle of each person. Lysosomal diseases (LDs) are a group of genetic metabolic disorders that include approximately 70 monogenic conditions caused by a defect in lysosomal function. LDs may result from primary lysosomal enzyme deficiencies or impairments in membrane-associated proteins, lysosomal enzyme activators, or modifiers that affect lysosomal function. LDs are heterogeneous disorders, and the phenotype of the affected individual depends on the type of substrate and where it accumulates, which may be impacted by the type of genetic change and residual enzymatic activity. LDs are individually rare, with a combined incidence of approximately 1:4000 individuals. Specific therapies are already available for several LDs, and many more are in development. Early identification may enable disease course prediction and a specific intervention, which is very important for clinical outcome. Driven by advances in omics technology, PM aims to provide the most appropriate management for each patient based on the disease susceptibility or treatment response predictions for specific subgroups. In this review, we focused on the emerging diagnostic technologies that may help to optimize the management of each LD patient and the therapeutic options available, as well as in clinical developments that enable customized approaches to be selected for each subject, according to the principles of PM.


[Assessment of the efficacy of bisoprolol administration by cardiopulmonary exercise testing in patients with heart failure].
It is well known that long-term therapy with beta-blockers reduces morbidity and mortality, improves left ventricular function in patients with heart failure. However the effect of beta-blockade on exercise tolerance in patients with heart failure remains unclear. In the present study we evaluated effects of the addition of bisoprolol to standart therapy with a diuretic and an angiotensin converting enzyme (ACE) inhibitor on exercise capacity in patients with chronic heart failure. We enrolled 52 patients (mean age 59+/-11 years) with stable, mild to moderate chronic heart failure and left ventricular ejection fraction of 40% or less receiving standart therapy with diuretic and ACE inhibitor. We randomly assigned patients to bisoprolol 1.25 mg (n=28) or control (n=24) groups. The drug progressively increased to a maximum dose of 5 mg per day. Cardiopulmonary exercise testing (CPET) was performed in all patients of the bisoprolol and control groups before and after 3 months from the beginning of the study. We found a significant increase in exercise duration, maximal O2 uptake (pik VO2), the O2 uptake at the anaerobic threshold (VO2-AT) and O2-pulse (pik VO2/HR), and improved functional capacity (p<0.001). Bisoprolol produced significant reduction in heart rate at rest (p=0.01) and during maximal exercise (p=0.041). In the control group no significant changes were observed. The addition of bisoprolol to the standart therapy in patients with mild to moderate heart failure is well tolerated and improves functional capacity.


Extracorporeal membrane oxygenation (ECMO) during pregnancy and postpartum.
Extracorporeal membrane oxygenation (ECMO) can provide respiratory support (VV-ECMO) or both respiratory and circulatory support (VA-ECMO). The use of ECMO has increased dramatically as a result of simpler technology. No level I evidence is yet available reflecting improved outcomes with ECMO. The use of this technology during pregnancy may be indicated in very select cases and should be delivered in centers with dedicated ECMO specialized units.


Regulation of transferrin receptor recycling by protein phosphorylation.
The effect of the protein phosphatase inhibitor okadaic acid on transferrin receptor internalization and recycling was examined in HeLa and K562 cells. Okadaic acid inhibited receptor uptake by more than 85% in both cell lines, whereas it affected transferrin recycling to differing degrees: recycling in HeLa cells was inhibited by greater than 90%, compared with only 65% in K562 cells. Okadaic acid also caused a marked redistribution of receptors in each cell line, which was accounted for by the difference in the extent to which transferrin uptake and recycling were inhibited. These effects were most likely mediated by a protein kinase, as they were delayed by 10-15 min and could be suppressed by prior incubation with certain protein kinase inhibitors. In addition, it was found that specific kinase inhibitors affected basal rates of transferrin uptake and recycling, although the extent of these effects differed between cell lines. Together, these results suggest that a complex pattern of protein phosphorylation influences the flux of the endocytic pathway in interphase cells.


Estimating survival of dental fillings on the basis of interval-censored data and multi-state models.
We aim to compare the life expectancy of a filling in a primary tooth between two types of treatments. We define the probabilities that a dental filling survives without complication until the permanent tooth erupts from beneath (exfoliation). We relate the time to exfoliation of the tooth to the age of the child and the time to failure of the filling to the duration since the treatment. We followed up fillings at repeated examinations where information is collected regarding the filling and the tooth. Several fillings can be placed in the same mouth, possibly by the same dentist. To deal with all these particularities, we propose to use a parametric four-state model with three random effects to take into account the hierarchical cluster structure. For inference, right and interval censoring as well as left truncation have to be dealt with. With the proposed approach, we can conclude that the estimated probability that a filling survives without complication until exfoliation is larger for one treatment than for the other, for all ages of the child at the time of treatment.


Glymphatic dysfunction in patients with early-stage amyotrophic lateral sclerosis.
Recently, an astrocytic aquaporin 4-dependent drainage system, that is, the glymphatic system, has been identified in the live murine and human brain. Growing evidence suggests that glymphatic function is impaired in patients with several neurodegenerative diseases, including Alzheimer's and Parkinson's disease. As the third most common neurodegenerative disease, although animal studies have indicated that early glymphatic dysfunction is likely an important pathological mechanism underpinning amyotrophic lateral sclerosis (ALS), no available study has been conducted to thoroughly assess glymphatic function in vivo in ALS patients to date, particularly in early-stage ALS patients. Thus, using DTI analysis along the perivascular space (ALPS) index, an approximate measure of glymphatic function in vivo, we aimed to explore whether glymphatic function is impaired in early-stage ALS patients and the diagnostic performance of the ALPS index in distinguishing between early-stage ALS patients and healthy subjects. We also aimed to identify the relationships between glymphatic dysfunction and clinical disabilities and sleep problems in early-stage ALS patients. In this retrospective study, King's stage 1 ALS patients were defined as early-stage ALS patients. We enrolled 56 early-stage ALS patients and 32 age- and sex-matched healthy controls (HCs). All participants completed clinical screening, sleep assessment, and ALPS index analysis. For the sleep assessment, the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and polysomnography were used. Compared with HCs, early-stage ALS patients had a significantly lower ALPS index after family-wise error correction (p < 0.05). Moreover, receiver operating characteristic analysis showed that the area under the curve for the ALPS index was 0.792 (95% confidence interval 0.700-0.884). Partial correlation analyses showed that the ALPS index was significantly correlated with clinical disability and sleep disturbances in early-stage ALS patients. Multivariate analysis showed that sleep efficiency (r = 0.419; p = 0.002) and periodic limb movements in sleep index (r = -0.294; p = 0.017) were significant predictive factors of the ALPS index in early-stage ALS patients. In conclusion, our study continues to support an important role for glymphatic dysfunction in ALS pathology, and we provide additional insights into the early diagnostic value of glymphatic dysfunction and its correlation with sleep disturbances in vivo in early-stage ALS patients. Moreover, we suggest that early improvement of glymphatic function may be a promising strategy for slowing the neurodegenerative process in ALS. Future studies are needed to explore the diagnostic and therapeutic value of glymphatic dysfunction in individuals with presymptomatic-stage neurodegenerative diseases.


Clinical Data Interchange Standards in Clinical Trials on Alzheimer's Disease.
The Clinical Data Interchange Standards Consortium (CDISC) proposed outcome measures for clinical trials on Alzheimer's disease (AD) in the Therapeutic Area User Guide for AD (TAUG-AD). To investigate how well the clinical trials on AD registered in the ClinicalTrials.gov complied with the recommendations on outcome measures by the CDISC. We compared the outcome measures proposed in the TAUG-AD version 2.0.1 with those employed in the protocols of clinical trials on AD registered in ClinicalTrials.gov. We analyzed 101 outcome measures from 305 protocols. The TAUG-AD listed ten scales for outcome measures of clinical trials on AD. The scales for cognition, activities of daily living, behavioral and psychological symptoms of dementia, and global severity listed in TAUG-AD were most frequently employed in the clinical trials on AD. However, TAUG-AD did not include any scale on quality of life. Also, several scales such as Montreal Cognitive Assessment, Alzheimer's Disease Cooperative Study-Activities of Daily Living, and Cohen- Mansfield Agitation Inventory not listed in the TAUG-AD were commonly employed in the clinical trials on AD and changed over time. To properly standardize the data from clinical trials on AD, the gap between the TAUG-AD and the measures employed in real-world clinical trials should be filled.


Effects of static magnetic fields on the development and aging of Caenorhabditis elegans.
The current study investigated the possible effects of static magnetic fields (SMFs) on the developmental and aging processes of Caenorhabditis elegans. Nematodes were grown in the presence of SMFs of strengths varying from 0 to 200 mT. The rate of development and the lifespan were recorded. Treatment with a 200 mT SMF reduced the development time from the L2 to the L3 stage by 20%, from L3 to L4 by 23%, and from L4 to young adult by 31%. After SMF treatment, the average lifespan was reduced from 31 days to 24 days for wild-type nematodes. The up-regulation of clk-1, lim-7, daf-2, unc-3 and age-1 after SMF treatment was verified by quantitative real-time RT-PCR. Apparently, induction of gene expression is selective and dose dependent. The total developmental time was significantly reduced for the lin-4, lin-14, lin-41 and lim-7 mutants, but not for the let-7, clk-1, unc-3 and age-1 mutants. Lifespan analyses revealed that the let-7, unc-3 and age-1 mutants were not affected by SMF treatment. Here we show that SMFs accelerate nematode development and shorten nematode lifespan through pathways associated with let-7, clk-1, unc-3 and age-1.


Homoharringtonine: history, current research, and future direction.
Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S. The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors. HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy. HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.


RNA triphosphatase is essential in Schizosaccharomyces pombe and Candida albicans.
The first two steps in the capping of cellular mRNAs are catalyzed by the enzymes RNA triphosphatase and RNA guanylyltransferase. Although structural and mechanistic differences between fungal and mammalian RNA triphosphatases recommend this enzyme as a potential antifungal target, it has not been determined if RNA triphosphatase is essential for the growth of fungal species that cause human disease. We show by classical genetic methods that the triphosphatase (Pct1) and guanylyltransferase (Pce1) components of the capping apparatus in the fission yeast Schizosaccharomyces pombe are essential for growth. We were unable to disrupt both alleles of the Candida albicans RNA triphosphatase gene CaCET1, implying that the RNA triphosphatase enzyme is also essential for growth of C. albicans, a human fungal pathogen. Our results provide the first genetic evidence that cap synthesis is essential for growth of an organism other than Saccharomyces cerevisiae and they validate RNA triphosphatase as a target for antifungal drug discovery.


Distribution of cytosolic and mitochondrial aspartate aminotransferase in normal, ischemic, and necrotic myocardium. An immunohistochemical study.
We utilized immunoperoxidase methods to study the distribution of both cytosolic or soluble(s) and mitochondrial (m) aspartate aminotransferase (AspAT) in normal, ischemic, and necrotic myocardium. Human myocardium was obtained from autopsy (n = 9) and surgery (n = 6). Cardiac tissue from 26 dogs with experimental myocardial infarction induced by closed-chest balloon occlusion and four dogs with myocardial ischemia without necrosis induced by a 50% reduction in left main coronary artery flow for 3 hours were studied. Duration of occlusion was 45 minutes (n = 1), 3 hours (n = 11), 5 to 6 hours (n = 10), or 15 to 24 hours (n = 4). Highly purified m- and s-AspAT and specific antibodies were prepared in our laboratory. In all cases, control experiments were performed. Microscopically normal human and dog myocardium uniformly stained for m- and s-AspAT. Necrotic myocardium from patients with infarcts showed markedly reduced immunostaining. In those dogs with myocardial necrosis, all dogs with coronary occlusion of 5 to 24 hours, and eight of 11 dogs with 3-hour occlusions, immunostaining was significantly reduced for both s- and m-AspAT in regions confirmed to be necrotic by triphenyl tetrazolium chloride and hematoxylin and eosin staining. Myocardial necrosis was confirmed in the 3-hour infarcts by electron microscopy. In the four dogs with a 50% reduction in left main flow for 3 hours, and one dog with a 45-minute coronary occlusion, ischemia was demonstrated by glycogen loss in period acid-Schiff-stained sections but there was no evidence of necrosis by electron microscopy or triphenyl tetrazolium chloride staining and there was no loss of immunostaining evident for s- or m-AspAT. Thus, s- and m-AspAT were visualized in normal and ischemic myocardium with decreased staining in necrotic tissue using immunoperoxidase techniques. Loss of both s- and m-AspAT can be demonstrated in human myocardium and in experimental canine myocardium as early as 3 hours after coronary occlusion and appears to be specific for irreversible myocardial injury. No depletion of isoenzyme can be detected by immunohistochemical techniques in tissue that is ischemic but not necrotic. Furthermore, by these immunoperoxidase techniques, loss of s- and m-AspAT from necrotic myocardium appears to be simultaneous.


Coaching in self-efficacy improves care responses, health and well-being in dementia carers: a pre/post-test/follow-up study.
Maintaining the health and well-being of family carers of people with dementia is vital, given their potential for experiencing burden associated with the role. The study aimed to help dementia carers develop self-efficacy, be less hassled by the caring role and improve their health and well-being with goal-directed behaviour, by participating in an eight module carer coaching program. The study used mixed methods in a pre/post-test/follow-up design over 24 months, with assignment of consented dementia carers to either individualised (n = 16) or group coaching (n = 32), or usual carer support services (n = 43), depending on preference. Care-giving self-efficacy and hassles, carer health, well-being and goal-directed behaviours were assessed over time. Analysis of Variance (ANOVA) was used to compare changes over time and the effects of coaching on carer self-efficacy, hassles and health, using the Univariate General Linear Model (GLM). All carers were hassled by many aspects of caring at baseline. Participants receiving coaching reported non-significant improvements in most areas of self-efficacy for caring, hassles associated with caring and self-reported health at post-test and follow-up, than did carers receiving usual carer support. Group coaching had greater success in helping carers to achieve their goals and to seek help from informal and formal support networks and services. The study outcomes were generally positive, but need to be interpreted cautiously, given some methodological limitations. It has been shown, however, that health staff can assist dementia carers to develop self-efficacy in better managing their family member's limitations and behaviour, seek help from others and attend to their health. Teaching carers to use goal-directed behaviour may help them achieve these outcomes.


Longitudinal Cognitive Assessment in Low-Risk Very Preterm Infants.
Background and Objectives: Preterm infants are at higher risk of neurodevelopmental impairment both at preschool and school ages, even in the absence of major neurological deficits. The early identification of children at risk is essential for early intervention with rehabilitation to optimize potential outcomes during school years. The aim of our study is to assess cognitive outcomes at preschool age in a cohort of low-risk very preterm infants, previously studied at 12 and 24 months using the Griffiths scales. Materials and Methods: Sixty-six low-risk very preterm infants born at a gestational age of <32 weeks were assessed at 12 and 24 months corrected age using the Griffiths Mental Development Scales (second edition) and at preschool age with the Wechsler Preschool and Primary Scales of Intelligence (third edition) (WPPSI-III). Results: At 12 and 24 months and at preschool age, low-risk very preterm infants showed scores within normal ranges with similar scores in males and females. A statistically significant correlation was observed in the general developmental quotient between 12 and 24 months; a further significant correlation was observed between the early cognitive assessments and those performed at preschool age, with a better correlation using the assessments at 24 months. Conclusion: The present study showed a favourable trajectory of cognitive development in low-risk very preterm infants, from 12 months to preschool age.


The Gomez' equations and renal hemodynamic function in kidney disease research.
Diabetic kidney disease (DKD) remains the leading cause of end-stage renal disease. A major challenge in preventing DKD is the difficulty in identifying high-risk patients at an early, pre-clinical stage. Albuminuria and eGFR as measures of renal function in DKD research and clinical practice are limited by regression of one-third of patients with microalbuminuria to normoalbuminuria and eGFR is biased and imprecise in the normal-elevated range. Moreover, existing methods that are used to assess renal function do not give detailed insight into the location of the renal hemodynamic effects of pharmacological agents at the segmental level. To gain additional information about the intrarenal circulation in-vivo in humans, mathematical equations were developed by Gomez et al in the 1950s. These equations used measurements of GFR, renal blood flow (RBF), effective renal plasma flow (ERPF), renal vascular resistance (RVR), hematocrit and serum protein to calculate afferent and efferent arteriolar resistances, glomerular hydrostatic pressure and filtration pressure. Although indirect and based on physiological assumptions, these techniques have the potential to improve researchers' ability to identify early pre-clinical changes in renal hemodynamic function in patients with a variety of conditions including DKD, thereby offering tremendous potential in mechanistic human research studies. In this review, we focus on the application of Gomez' equations and summarize the potential and limitations of this technique in DKD research. We also summarize illustrative data derived from Gomez' equations in patients with type 1 (T1D) and type 2 diabetes (T2D) and hypertension.


Centering the Organizing Center in the Arabidopsis thaliana Shoot Apical Meristem by a Combination of Cytokinin Signaling and Self-Organization.
Plants have the ability to continously generate new organs by maintaining populations of stem cells throught their lives. The shoot apical meristem (SAM) provides a stable environment for the maintenance of stem cells. All cells inside the SAM divide, yet boundaries and patterns are maintained. Experimental evidence indicates that patterning is independent of cell lineage, thus a dynamic self-regulatory mechanism is required. A pivotal role in the organization of the SAM is played by the WUSCHEL gene (WUS). An important question in this regard is that how WUS expression is positioned in the SAM via a cell-lineage independent signaling mechanism. In this study we demonstrate via mathematical modeling that a combination of an inhibitor of the Cytokinin (CK) receptor, Arabidopsis histidine kinase 4 (AHK4) and two morphogens originating from the top cell layer, can plausibly account for the cell lineage-independent centering of WUS expression within SAM. Furthermore, our laser ablation and microsurgical experiments support the hypothesis that patterning in SAM occurs at the level of CK reception and signaling. The model suggests that the interplay between CK signaling, WUS/CLV feedback loop and boundary signals can account for positioning of the WUS expression, and provides directions for further experimental investigation.


Antigenic relationships between canine parvovirus type 2, feline panleukopenia virus and mink enteritis virus using conventional antisera and monoclonal antibodies.
The antigenic relationships between three similar parvoviruses, canine parvovirus type 2 (CPV), feline panleukopenia virus (FPV) and mink enteritis virus (MEV) were investigated. Antisera against all 3 viruses and monoclonal antibodies (mAb) to CPV were prepared and the viruses compared using several serological methods. When conventional sera were used in the hemagglutination-inhibition and agar gel precipitin (AGP) tests there were no differences between the CPV viral isolates studied, but antigenic differences were revealed between the CPV isolates and the FPV or MEV. Of 16 mAb produced against CPV, six reacted only with the CPV. The other 10 mAb reacted with all three parvoviruses. Additionally, an antigenic difference was detected by AGP tests between one FPV isolate and the other FPV and MEV isolates. Including both conventional sera and mAb to CPV in a single AGP test with the CPV, MEV and FPV antigens permitted the comparison of results obtained with the different antibodies. The results reported revealed antigenic differences between CPV and FPV or MEV that were most clearly defined using mAb.


From the motor cortex to the movement and back again.
The motor cortex controls motor behaviors by generating movement-specific signals and transmitting them through spinal cord circuits and motoneurons to the muscles. Precise and well-coordinated muscle activation patterns are necessary for accurate movement execution. Therefore, the activity of cortical neurons should correlate with movement parameters. To investigate the specifics of such correlations among activities of the motor cortex, spinal cord network and muscles, we developed a model for neural control of goal-directed reaching movements that simulates the entire pathway from the motor cortex through spinal cord circuits to the muscles controlling arm movements. In this model, the arm consists of two joints (shoulder and elbow), whose movements are actuated by six muscles (4 single-joint and 2 double-joint flexors and extensors). The muscles provide afferent feedback to the spinal cord circuits. Cortical neurons are defined as cortical "controllers" that solve an inverse problem based on a proposed straight-line trajectory to a target position and a predefined bell-shaped velocity profile. Thus, the controller generates a motor program that produces a task-specific activation of low-level spinal circuits that in turn induce the muscle activation realizing the intended reaching movement. Using the model, we describe the mechanisms of correlation between cortical and motoneuronal activities and movement direction and other movement parameters. We show that the directional modulation of neuronal activity in the motor cortex and the spinal cord may result from direction-specific dynamics of muscle lengths. Our model suggests that directional modulation first emerges at the level of muscle forces, augments at the motoneuron level, and further increases at the level of the motor cortex due to the dependence of frictional forces in the joints, contractility of the muscles and afferent feedback on muscle lengths and/or velocities.


Protein kinase A determines timing of early differentiation through epigenetic regulation with G9a.
Timing of cell differentiation is strictly controlled and is crucial for normal development and stem cell differentiation. However, underlying mechanisms regulating differentiation timing are fully unknown. Here, we show a molecular mechanism determining differentiation timing from mouse embryonic stem cells (ESCs). Activation of protein kinase A (PKA) modulates differentiation timing to accelerate the appearance of mesoderm and other germ layer cells, reciprocally correlated with the earlier disappearance of pluripotent markers after ESC differentiation. PKA activation increases protein expression of G9a, an H3K9 methyltransferase, along with earlier H3K9 dimethylation and DNA methylation in Oct3/4 and Nanog gene promoters. Deletion of G9a completely abolishes PKA-elicited acceleration of differentiation and epigenetic modification. Furthermore, G9a knockout mice show prolonged expressions of Oct3/4 and Nanog at embryonic day 7.5 and delayed development. In this study, we demonstrate molecular machinery that regulates timing of multilineage differentiation by linking signaling with epigenetics.


Bending gender, ending gender: theoretical foundations for social work practice with the transgender community.
Gender is a ubiquitous social construct that wields power over every individual in our society. The traditional dichotomous gender paradigm is oppressive, especially for transgendered people whose sense of themselves as gendered people is incongruent with the gender they were assigned at birth. Transgendered individuals are targeted for mistreatment when others attempt to enforce conventional gender boundaries. This article discusses gender-based oppression and the resulting psychosocial difficulties experienced by many transgendered individuals. The discussion advances a critical analysis of the dominant gender paradigm using two alternative theoretical perspectives on gender--queer theory and social constructionism. The article argues that the transgender community is an at-risk population and that empowering practice with this population calls on social workers to target society's traditional gender dichotomy for change. An overview of practice implications and research needs is provided.


Translational impact of nanoparticle-drug conjugate CRLX101 with or without bevacizumab in advanced ovarian cancer.
Increased tumor hypoxia and hence elevated hypoxia-inducible factor-1α (HIF1α) is thought to limit the efficacy of vascular endothelial growth factor (VEGF) pathway-targeting drugs by upregulating adaptive resistance genes. One strategy to counteract this is to combine antiangiogenic drugs with agents able to suppress HIF1α. One such possibility is the investigational drug CRLX101, a nanoparticle-drug conjugate (NDC) containing the payload camptothecin, a known topoisomerase-I poison. CRLX101 was evaluated both as a monotherapy and combination with bevacizumab in a preclinical mouse model of advanced metastatic ovarian cancer. These preclinical studies contributed to the rationale for undertaking a phase II clinical study to evaluate CRLX101 monotherapy in patients with advanced platinum-resistant ovarian cancer. Preclinically, CRLX101 is highly efficacious as a monotherapy when administered at maximum-tolerated doses. Furthermore, chronic low-dose CRLX101 with bevacizumab reduced bevacizumab-induced HIF1α upregulation and resulted in synergistic efficacy, with minimal toxicity in mice. In parallel, initial data reported here from an ongoing phase II clinical study of CRLX101 monotherapy shows measurable tumor reductions in 74% of patients and a 16% RECIST response rate to date. Given these preclinical and initial clinical results, further clinical studies are currently evaluating CRLX101 in combination with bevacizumab in ovarian cancer and warrant the evaluation of this therapy combination in other cancer types where HIF1α is implicated in pathogenesis, as it may potentially be able to improve the efficacy of antiangiogenic drugs.


SPINE20 recommendations 2022: spine care-working together to recover stronger.
Globally, spine disorders are the leading cause of disability, affecting more than half a billion individuals. However, less than 50% of G20 countries specifically identify spine health within their public policy priorities. Therefore, it is crucial to raise awareness among policy makers of the disabling effect of spine disorders and their impact on the economic welfare of G20 nations. In 2019, SPINE20 was established as the leading advocacy group to bring global attention to spine disorders. Recommendations were developed through two Delphi methods with international and multi-professional panels. In 2022, seven recommendations were delivered to the leaders of G20 countries, urging them to: Develop action plans to provide universal access to evidence-based spine care that incorporates the needs of minorities and vulnerable populations. Invest in the development of sustainable human resource capacity, through multisectoral and inter-professional competency-based education and training to promote evidence-based approaches to spine care, and to build an appropriate healthcare working environment that optimizes the delivery of safe health services. Develop policies using the best available evidence to properly manage spine disorders and to prolong functional healthy life expectancy in the era of an aging population. Create a competent workforce and improve the healthcare infrastructure/facilities including equipment to provide evidence-based inter-professional rehabilitation services to patients with spinal cord injury throughout their continuum of care. Build collaborative and innovative translational research capacity within national, regional, and global healthcare systems for state-of-the-art and cost-effective spine care across the healthcare continuum ensuring equality, diversity, and inclusion of all stakeholders. Develop international consensus statements on patient outcomes and how they can be used to define and develop pathways for value-based care. Recognize that intervening on determinants of health including physical activity, nutrition, physical and psychosocial workplace environment, and smoking-free lifestyle can reduce the burden of spine disabilities and improve the health status and wellness of the population. At the third SPINE20 summit 2022 which took place in Bali, Indonesia, in August 2022, 17 associations endorsed its recommendations. SPINE20 advocacy efforts focus on developing public policy recommendations to improve the health, welfare, and wellness of all who suffer from spinal pain and disability. We propose that focusing on facilitating access to systems that prioritize value-based care delivered by a competent healthcare workforce will reduce disability and improve the productivity of the G20 nations.


Occupational nonsolar risk factors of squamous cell carcinoma of the skin: a population-based case-controlled study.
The purpose of this study was to investigate associations between occupation, nonsolar environmental exposures, and risk of squamous cell carcinoma (SCC) of the skin. Data from the Southeastern Arizona Health Study-2 were used. This was a population-based case-controlled study [n = 795) conducted during 1992-1996 in southeastern Arizona to primarily assess the risk of skin SCC in relation to sun exposure. Multivariate logistic regression was used to calculate odd ratios as the estimate of effect. High-risk occupations were identified through literature review. There was evidence of a slightly elevated risk of skin SCC for subjects reporting a history of construction work (OR = 1.38, 95 % CI = 0.61-3.14), and automobile and machine work (OR = 1.21, 95 % CI = 0.48-3.06) Furthermore, there were no statistically significant associations between risk of skin SCC and history of exposure to specific chemical and other nonsolar environmental agents. A slight indication of increased risk for skin SCC was noted for exposure to nonsolar light (OR = 1.33, 95 % CI = 0.92-2.26), construction/machinery materials (OR = 1.12, 95 % CI = 0.76-1.84), fluorescent light (OR = 1.56, 95 % CI = 0.92-2.61), gypsum (OR = 1.84, 95 % CI = 0.68-5.0), coal tar and dandruff shampoos (OR = 1.28, 95 % CI = 0.85-1.9), and cement dust (OR = 1.81, 95 % CI = 0.90-3.62). A large although statistically insignificant risk was seen for exposure to arsenic (OR = 4.21, 95 % CI = 0.40-43.9) and ethylene glycol (OR = 8.46, 95 % CI = 0.77-92.9). Several of the results of this analysis are consistent with literature and conclusions from previous epidemiological studies. However, lack of power and small sample size deem these results as inconclusive until more research and larger studies are conducted.


Does the face mask increase the impact of rapid maxillary expansion on sagittal airway dimensions?
Airway dimensions associated with the transversal and sagittal position of the maxilla are affected by orthodontic treatment. The objective of this study was to compare the effects of rapid maxillary expansion (RME) and RME followed by face mask (FM) therapies on the airway space and investigate whether application of the FM increases the short-term and long- term impact of RME on sagittal airway dimensions. A total of 26 patients were divided into two groups. Group I included 14 adolescents treated with RME (3 males, 11 females; mean age: 12.2 11 ± 2.1 years), and Group II included 12 adolescents treated with RME followed by FM therapy (7 males, 5 females; mean age: 11.6 ± 1.3 years). Sagittal and vertical skeletal measurements, as well as ten linear cross-sectional airway measurements, were calculated from pretreatment, posttreatment, and postretention cephalometric radiographs. RME followed by FM resulted in a significant increase in the SNA angle, ANB angle, and Wits parameter by the forward movement of the maxillary bone. A significant increase in the vertical dimensions was also observed. Regarding the airway measurements in both groups, significant oropharyngeal increases were revealed, and these were maintained in the follow-up period. However, there were no other significant differences in the short-term and long-term results obtained for Groups I and II. The dimensions of the airway were significantly affected by both therapies. However, no additional effect of FM was observed.


Delivering interventions to reduce the global burden of stillbirths: improving service supply and community demand.
Although a number of antenatal and intrapartum interventions have shown some evidence of impact on stillbirth incidence, much confusion surrounds ideal strategies for delivering these interventions within health systems, particularly in low-/middle-income countries where 98% of the world's stillbirths occur. Improving the uptake of quality antenatal and intrapartum care is critical for evidence-based interventions to generate an impact at the population level. This concluding paper of a series of papers reviewing the evidence for stillbirth interventions examines the evidence for community and health systems approaches to improve uptake and quality of antenatal and intrapartum care, and synthesises programme and policy recommendations for how best to deliver evidence-based interventions at community and facility levels, across the continuum of care, to reduce stillbirths. We systematically searched PubMed and the Cochrane Library for abstracts pertaining to community-based and health-systems strategies to increase uptake and quality of antenatal and intrapartum care services. We also sought abstracts which reported impact on stillbirths or perinatal mortality. Searches used multiple combinations of broad and specific search terms and prioritised rigorous randomised controlled trials and meta-analyses where available. Wherever eligible randomised controlled trials were identified after a Cochrane review had been published, we conducted new meta-analyses based on the original Cochrane criteria. In low-resource settings, cost, distance and the time needed to access care are major barriers for effective uptake of antenatal and particularly intrapartum services. A number of innovative strategies to surmount cost, distance, and time barriers to accessing care were identified and evaluated; of these, community financial incentives, loan/insurance schemes, and maternity waiting homes seem promising, but few studies have reported or evaluated the impact of the wide-scale implementation of these strategies on stillbirth rates. Strategies to improve quality of care by upgrading the skills of community cadres have shown demonstrable impact on perinatal mortality, particularly in conjunction with health systems strengthening and facilitation of referrals. Neonatal resuscitation training for physicians and other health workers shows potential to prevent many neonatal deaths currently misclassified as stillbirths. Perinatal audit systems, which aim to improve quality of care by identifying deficiencies in care, are a quality improvement measure that shows some evidence of benefit for changes in clinical practice that prevent stillbirths, and are strongly recommended wherever practical, whether as hospital case review or as confidential enquiry at district or national level. Delivering interventions to reduce the global burden of stillbirths requires action at all levels of the health system. Packages of interventions should be tailored to local conditions, including local levels and causes of stillbirth, accessibility of care and health system resources and provider skill. Antenatal care can potentially serve as a platform to deliver interventions to improve maternal nutrition, promote behaviour change to reduce harmful exposures and risk of infections, screen for and treat risk factors, and encourage skilled attendance at birth. Following the example of high-income countries, improving intrapartum monitoring for fetal distress and access to Caesarean section in low-/middle-income countries appears to be key to reducing intrapartum stillbirth. In remote or low-resource settings, families and communities can be galvanised to demand and seek quality care through financial incentives and health promotion efforts of local cadres of health workers, though these interventions often require simultaneous health systems strengthening. Perinatal audit can aid in the development of better standards of care, improving quality in health systems. Effective strategies to prevent stillbirth are known; gaps remain in the data, the evidence and perhaps most significantly, the political will to implement these strategies at scale.


Determining Particle Size and Position in a Coplanar Electrode Setup Using Measured Opacity for Microfluidic Cytometry.
Microfluidic impedance flow cytometers enable high-throughput, non-invasive, and label-free detection of single-cells. Cytometers with coplanar electrodes are easy and cheap to fabricate, but are sensitive to positional differences of passing particles, owing to the inhomogeneous electric field. We present a novel particle height compensation method, which employs the dependence of measured electrical opacity on particle height. The measured electrical opacity correlates with the particle height as a result of the constant electrical double layer series capacitance of the electrodes. As an alternative to existing compensation methods, we use only two coplanar electrodes and multi-frequency analysis to determine the particle size of a mixture of 5, 6, and 7 µm polystyrene beads with an accuracy (CV) of 5.8%, 4.0%, and 2.9%, respectively. Additionally, we can predict the bead height with an accuracy of 1.5 µm (8% of channel height) using the measured opacity and we demonstrate its application in flow cytometry with yeast. The use of only two electrodes is of special interest for simplified, easy-to-use chips with a minimum amount of instrumentation and of limited size.


Transient isomers in the photodissociation of bromoiodomethane.
The photochemistry of halomethanes is fascinating for the complex cascade reactions toward either the parent or newly synthesized molecules. Here, we address the structural rearrangement of photodissociated CH2IBr in methanol and cyclohexane, probed by time-resolved X-ray scattering in liquid solution. Upon selective laser cleavage of the C-I bond, we follow the reaction cascade of the two geminate geometrical isomers, CH2I-Br and CH2Br-I. Both meta-stable isomers decay on different time scales, mediated by solvent interaction, toward the original parent molecule. We observe the internal rearrangement of CH2Br-I to CH2I-Br in cyclohexane by extending the time window up to 3 μs. We track the photoproduct kinetics of CH2Br-I in methanol solution where only one isomer is observed. The effect of the polarity of solvent on the geminate recombination pathways is discussed.


Results of a surveillance program for persons living around the Nevada Test Site--1971 to 1980.
A continuing program has been conducted since 1970 to determine levels of radioactive nuclides in adults and children from families residing in communities and ranches surrounding the Nevada Test Site. Twice each year these persons receive a whole-body count and physical examination; a urine sample from each is also submitted for radionuclide analyses. The only fission-product radionuclide routinely found in whole-body counting has been 137Cs at concentrations similar to those in persons living in other areas of the United States. The physical examinations reveal a generally healthy population, and urine samples have shown no remarkable radionuclide content.