Changes in the reducing power of synovial fluid from temporomandibular joints with "anchored disc phenomenon".
In this study, we examined the hypothesis that uncontrolled oxidative stress causes collapse of the lubrication system, which is considered a major initiator of temporomandibular joint (TMJ) dysfunction. The oxidative stress was evaluated by measuring the overall antioxidant capacity of the low-molecular-weight antioxidants in the TMJ, using cyclic voltammetry (CV), in synovial fluid from normal and anchored disc phenomenon (ADP) TMJs. Synovial fluids samples were taken from 13 normally functioning and 33 ADP TMJs. The samples were frozen initially on collection and analyzed in CV to measure their overall reducing power. CV measurements of the fluids collected from 90% of the healthy joints showed an anodic waves at peak potential [Ep(a)1/2] of 290 +/- 30 mV. Of the samples 56% showed another wave at 650 +/- 100 mV. These waves were generally absent in the fluid collected from ADP TMJs, but 2 new waves at 465 +/- 90 mV and greater than 750 mV were detected in 68% and 87% of the patients, respectively. The results show more anodic waves, most of which of higher potentials (greater than 750 mV) in ADP TMJs, indicating that the capacity to cope with oxidative stress is lower in these joints. It is not clear whether this is due to absence of low-molecular-weight antioxidants or their consumption by uncontrolled production of reactive oxygen species, which might be the initial step in the collapse of the lubrication system.


Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.
Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations. Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors. Prediction of germline mutation status was compared for combinations of tumor characteristics, age at diagnosis, and various clinical criteria (Amsterdam, Bethesda, Society of Gynecologic Oncology, ANECS). Tumor MMR-protein deficiency was detected in 170 (24%) of 702 cases. Germline testing of 158 MMR-deficient cases identified 22 truncating mutations (3% of all cases) and four unclassified variants. Tumor MLH1 methylation was detected in 99 (89%) of 111 cases demonstrating MLH1/PMS2 IHC loss; all were germline MLH1 mutation negative. A combination of MMR IHC plus MLH1 methylation testing in women younger than 60 years of age at diagnosis provided the highest positive predictive value for the identification of mutation carriers at 46% versus ≤ 41% for any other criteria considered. Population-level identification of patients with MMR mutation-positive endometrial cancer is optimized by stepwise testing for tumor MMR IHC loss in patients younger than 60 years, tumor MLH1 methylation in individuals with MLH1 IHC loss, and germline mutations in patients exhibiting loss of MSH6, MSH2, or PMS2 or loss of MLH1/PMS2 with absence of MLH1 methylation.


Combination effects of amphetamines under hyperthermia - the role played by oxidative stress.
Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 °C. The results were compared with normothermia data (37.0 °C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Δψm) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 °C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse.


Use of high-dose ibuprofen in a pediatric cystic fibrosis center.
Despite its apparent benefits, high-dose ibuprofen has been infrequently applied to children with cystic fibrosis. We have noted a decrease in the use of high-dose ibuprofen at our pediatric cystic fibrosis center during the past decade. In this retrospective study, we examined our clinical experience with high-dose ibuprofen and other anti-inflammatory drugs in cystic fibrosis patients. The medical records of all patients, ages 5 to 18 years, followed at the cystic fibrosis center from 1995 to 2002, were reviewed and children were classified into two cohorts: ibuprofen-treated and untreated groups. Patterns of ibuprofen use and pharmacokinetics in treated patients, and for patients who discontinued ibuprofen, the reasons for stopping the medication, including adverse effects, were assessed. Pulmonary function decline and hospitalization rates for each group were compared, examining both intent to treat and patients who continued therapy for at least 4 years. Nearly half of the patients in our pediatric cystic fibrosis center who were prescribed with high-dose ibuprofen discontinued therapy due to adverse events, not because of poor adherence or patient choice. Neither use of high-dose ibuprofen nor its cessation resulted in a significant change in the rate of decline in pulmonary function or influenced hospitalization rates.


Exocrine pancreatic and enterocyte function in patients with advanced pancreatic cancer.
Exocrine pancreatic function is affected in patients with locally advanced pancreatic cancer (LAPC), clinically leading to steatorrhea. It is unknown whether maldigestion and malabsorption can also be attributed to impaired intestinal enterocyte function. In this exploratory study enterocyte function was assessed in patients with locally advanced pancreatic cancer, treated with Irreversible Electroporation (IRE). Enterocyte function was studied by Citrulline Generation Test (CGT). Intestinal absorption capacity of energy and fat was calculated from the differences between nutritional intake (four-days diary) and quantified fecal losses energy and fat in three-days feces collection. Twelve patients were included before IRE, and 5 patients had follow-up measurements. Fasted citrulline [CIT] and glutamine [GLU] levels were below reference levels of healthy subjects ([CIT] 38 ± 8 μmol/L; [GLU] 561 ± 77 μmol/L) both before ([CIT] 25 ± 9 μmol/L; [GLU] 65 ± 35 μmol/L) and after IRE ([CIT] 19 ± 9 μmol/L; [GLU] 53 ± 26 μmol/L) whereas CGT curves were normal, indicating normal enterocyte function (slope 0.21 ± 0.12 and 0.17 ± 0.07 μmol/L/min; [CIT] increment 63 ± 39 and 80 ± 44% respectively). Severe energy/fat malabsorption was present in 6 out of 12 patients with LAPC (mean loss 349 kcal/d, 13 g fat/d) before and in 4 out of 5 patients (mean loss 509 kcal/d, 32 g fat/d) after IRE respectively. Enterocyte function was generally within reference limits in patients with advanced pancreatic cancer. Severe malabsorption may be explained by exocrine pancreatic insufficiency.


Influence of Mg2+ and pH on n.m.r. spectra and radioligand binding of inositol 1,4,5-trisphosphate.
We and others have shown that the binding of Ins(1,4,5)P3 to its receptor is pH-sensitive and can be inhibited by Mg2+. In the present study we have used 1H- and 31P-n.m.r. spectroscopy to study whether these effects results from increased ionization of Ins(1,4,5)P3 and a direct interaction with Mg2+ respectively. Under near-physiological conditions of ionic strength (100 mM-KCl), three ionizable groups were observed. The pH titration curve of the 1-phosphate was monophasic, with a pKa of 6.3. The titration curves of the 4- and 5-phosphates were biphasic, suggesting that these groups interact; the pKa values for the 4-phosphate determined by 31P-n.m.r. were 5.7 and 7.8, and for the 5-phosphate they were 5.3 and 7.9. 1H- and 31P-n.m.r. measurements suggest that Mg2+ binds weakly to Ins(1,4,5)P3 at physiological pH. Mg2+ non-competitively inhibited binding of Ins(1,4,5)P3 to its receptor in rat cerebellum and bovine adrenal cortex. Inhibition curves for rat cerebellum at pH 7.1 and 8.5, and also for bovine adrenal cortex at pH 8.5, appeared to be monophasic, with IC50 values (concn. of displacer giving 50% inhibition of specific binding) of 214 microM, 572 microM and 9.1 mM respectively. Scatchard analysis revealed that Mg2+ inhibited binding of Ins(1,4,5)P3 to bovine adrenal cortex at pH 8.5 in a non-competitive manner. Our results suggest that the previously reported pH-sensitivity of the binding of Ins(1,4,5)P3 may be caused by ionization of the phosphate groups in positions 4 and 5, and that the ability of Mg2+ to inhibit the binding of Ins(1,4,5)P3 is not mediated by direct chelation but through a site located on, or close to, the Ins(1,4,5)P3 receptor. Inhibition by Mg2+ is pH-sensitive and can vary at least 10-fold between tissues, suggesting possible receptor heterogeneity. Mg2+ may exert an important regulatory control on the release of Ca2+ by Ins(1,4,5)P3.


Geographic variation for wing shape in Drosophila serrata.
Geographic variation in wing shape in female Drosophila serrata was examined by characterizing isofemale strains from 19 localities collected along a transect on the eastern coast of Australia. Shape variation was analyzed by Procrustes superimposition of landmark data followed by canonical variate analysis. The first extracted canonical variate showed a nonlinear association with latitude and accounted for 43% of the variance. There was a sharp increase in this variate at low latitudes as well as a gradual increase at high latitudes. These shape changes were associated with two landmarks at the edge of the wing. There was also a linear change in wing aspect. The isofemale heritability for two measures of shape was around 30%. Allometric relationships were weak both between localities and among isofemale strains within localities. The possibility that wing shape parameters are under selection independent of wing size is discussed.


Animal Sound Identifier (ASI): software for automated identification of vocal animals.
Automated audio recording offers a powerful tool for acoustic monitoring schemes of bird, bat, frog and other vocal organisms, but the lack of automated species identification methods has made it difficult to fully utilise such data. We developed Animal Sound Identifier (ASI), a MATLAB software that performs probabilistic classification of species occurrences from field recordings. Unlike most previous approaches, ASI locates training data directly from the field recordings and thus avoids the need of pre-defined reference libraries. We apply ASI to a case study on Amazonian birds, in which we classify the vocalisations of 14 species in 194 504 one-minute audio segments using in total two weeks of expert time to construct, parameterise, and validate the classification models. We compare the classification performance of ASI (with training templates extracted automatically from field data) to that of monitoR (with training templates extracted manually from the Xeno-Canto database), the results showing ASI to have substantially higher recall and precision rates.


Performance-Enhancing Drugs Abuse Caused Cardiomyopathy and Acute Hepatic Injury in a Young Bodybuilder.
A number of performance-enhancing drugs (PEDs) are used illicitly to improve muscle strength by the bodybuilders. The misuse of these drugs is associated with serious adverse effects to different organs. A previously healthy 22-year-old male bodybuilder after taking stanozolol, clenbuterol, and triiodothyronine for 10 days presented to the hospital with symptoms of icteric sclera, progressive dyspnea, intermittent cough, and bloody sputum. He was diagnosed with dilated cardiomyopathy and acute hepatic injury. Rapidly progressive dilated cardiomyopathy and acute hepatic injury among bodybuilders in such a short period of time have not been reported. People using these drugs must monitor liver and cardiac functions regularly, and they should discontinue using PEDs after diagnosis of liver or cardiac abnormalities. Physicians should always consider the possibility of the PED abuse in the context of a young athlete suffering cardiomyopathy or hepatic injury.


N,N-Diethyl-2,6,6-trimethyl-4-(3-nitrophenyl)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide.
The title compound, C(23)H(29)N(3)O(4), has potential calcium modulatory properties. The conformation of the 1,4-dihydropyridine ring is unusual in that it is planar, instead of the usual shallow boat. The 3-nitrophenyl substituent is in the synperiplanar orientation with respect to the dihydropyridine ring plane. The oxocyclohexene ring has a distorted envelope conformation, with the out-of-plane atom being disordered on opposite sides of the ring plane. The molecules are linked into chains by intermolecular hydrogen bonds.


Kinetics of oxygen consumption after a single flash of light in photoreceptors of the drone (Apis mellifera).
The time course of the rate of oxygen consumption (QO2) after a single flash of light has been measured in 300-micrometers slices of drone retina at 22 degrees C. To measure delta QO2(t), the change in QO2 from its level in darkness, the transients of the partial pressure of O2 (PO2) were recorded with O2 microelectrodes simultaneously in two sites in the slice and delta QO2 was calculated by a computer using Fourier transforms. After a 40-ms flash of intense light, delta QO2, reached a peak of 40 microliters O2/g.min and then declined exponentially to the baseline with a time constant tau 1 = 4.96 +/- 0.49 s (SD, n = 10). The rising phase was characterized by a time constant tau 2 = 1.90 +/- 0.35 s (SD, n = 10). The peak amplitude of delta QO2 increased linearly with the log of the light intensity. Replacement of Na+ by choline, known to decrease greatly the light-induced transmembrane current, caused a 63% decrease of delta QO2. With these changes, however, the kinetics of delta QO2 (t) were unchanged. This suggest that the recovery phase is rate-limited by a single reaction with apparent first-order kinetics. Evidence is provided that suggests that this reaction may be the working of the sodium pump. Exposure of the retina to high concentrations of ouabain or strophanthidin (inhibitors of the sodium pump) reduced the peak amplitude of delta QO2 by approximately 80% and increased tau 1. The increase of tau 1 was an exponential function of the time of exposure to the cardioactive steroids. Hence, it seems likely that the greatest part of delta QO2 is used for the working of the pump, whose activity is the mechanism underlying the rate constant of the descending limb of delta QO2 (t).


Starvation of Flavobacterium psychrophilum in broth, stream water and distilled water.
Physical changes in Flavobacterium psychrophilum, the causative agent of rainbow trout fry syndrome (RTFS), were examined over a 19 wk period of starvation. Bacteria were maintained in either Cytophaga broth, filtered stream water, or filtered distilled water, or were maintained in broth after disinfection as a negative control for dead bacteria. Culturability and viability of the bacterium were assessed using colony-forming units (CFUs) and a commercially available live/dead kit. Antigenic profiles and general morphology of the bacterium were also examined using Western blot analysis and electron microscopy, respectively. The bacterium appeared to stop multiplying and became smaller and rounded when maintained in stream water. Its culturability declined until it was no longer possible to obtain colonies on agar plates at the end of the trial at 19 wk, and results from the live/dead kit did not correspond with the viability obtained as CFUs in culture. However, it was still possible to obtain growth of the bacterium after 36 wk with a resuscitation step in Cytophaga broth. Bacteria maintained in distilled water or treated with a disinfectant appeared non-viable using the live/dead kit and were unable to grow on agar 1 h after setting up the experiment; no morphological changes were observed in the bacteria maintained under these conditions. Bacteria maintained in broth were present as long, slim rods, some of which developed into 'ring' formations. Small differences were observed in the antigen profiles of the bacteria maintained under the different treatments, possibly due to a reduction in the size and metabolism of the bacteria. There was also a marked decline in the sensitivity of the PCR with bacteria maintained under the different treatments 14 wk from the onset of the study.


Cracking the elusive alignment hypothesis: the microtubule-cellulose synthase nexus unraveled.
Directed plant cell growth is governed by deposition and alterations of cell wall components under turgor pressure. A key regulatory element of anisotropic growth, and hence cell shape, is the directional deposition of cellulose microfibrils. The microfibrils are synthesized by plasma membrane-located cellulose synthase complexes that co-align with and move along cortical microtubules. That the parallel relation between cortical microtubules and extracellular microfibrils is causal has been named the alignment hypothesis. Three recent studies revealed that the previously identified pom2 mutant codes for a large cellulose synthases interacting (CSI1) protein which also binds cortical microtubules. This review summarizes these findings, provides structure-function models and discusses the inferred mechanisms in the context of plant growth.


Compromised Fanconi anemia response due to BRCA1 deficiency in cisplatin-sensitive head and neck cancer cell lines.
Head and neck cancers are commonly treated with the DNA-damaging agent cisplatin. While many tumors respond well to cisplatin treatment, some do not. The mechanism for this differential sensitivity of head and neck tumors to cisplatin is not understood in detail. In this study, we explored whether the functional status of the Fanconi anemia and BRCA pathway (FA/BRCA) would predict cisplatin sensitivity in head and neck cancer cells. The FA/BRCA pathway is critical for the orchestration of the cellular response to cisplatin and other DNA cross-linking agents. It was found that three out of four cisplatin-sensitive head and neck cancer cell lines showed defective formation of FANCD2 nuclear foci while all four cisplatin-resistant cell lines tested were proficient in FANCD2 foci formation following cisplatin treatment. The defect in FANCD2 foci formation in the cisplatin-sensitive cell lines was not due to defective monoubiquitylation of FANCD2 but appeared to be due to reduced expression or defective function of BRCA1 since expression of exogenous BRCA1 restored the ability of these cells to induce FANCD2 foci following cisplatin treatment and enhanced cisplatin resistance. These results suggest a possible role for BRCA1 in modulating cisplatin sensitivity in head and neck cancer cells.


Antimicrobial therapy utilization in neonates with hypoxic-ischemic encephalopathy (HIE): a report from the Children's Hospital Neonatal Database (CHND).
Quantify antimicrobial therapy (AMT) use in newborns with hypoxic-ischemic encephalopathy treated with therapeutic hypothermia (HIE/TH). Newborns with HIE/TH were identified from the Children's Hospital Neonatal Database (CHND). Early infection (onset ≤7 days of life) was defined as "confirmed" (culture proven) or "suspected infection" (culture negative but treated) and compared with a "no infection" group. 1501/1534 (97.8%) neonates received AMT. 36 (2.3%) had confirmed, 255 (16.6%) suspected, and 1243 (81.0%) had no infection. The median (IQR) AMT duration was 13 (8-21), 8 (7-10), and 3 (3-7) days for the three groups, respectively (p < 0.001). AMT duration of use varied significantly across centers, adjusted for covariates (OR 1.88, 95% CI: 1.43-2.46). Incidence of early confirmed infection in neonates with HIE/TH (23/1000) is significantly higher than reported rates of early onset sepsis in term and near term infants (0.5-1.0/1000 live births). Antimicrobial-stewardship opportunities exist in infants with negative cultures.


Mechanisms of stem cell effects: insights from MRI.
Early results from stem cell trials to treat myocardial infarction have shown promise. Several types of stem cells have moved through phase I trials to demonstrate safety and some at the same time have shown significant potential for myocardial regeneration and functional recovery. The means by which stem cells contribute to improving myocardial function, however, remains unknown. Challenges in labeling stem cells for tracking and fate determination after cell transplantation have precluded establishing whether transplanted stem cell engraftment, expansion after engraftment, endogenous stem cell activation or a combination of these mechanisms contribute to improved function. Cardiac magnetic resonance imaging (cMRI), due to its inherent capabilities, has emerged as the imaging modality of choice to provide important insights into remodeling of myocardium after stem cell transplantation and its consequences on cardiac function. Of cMRI capabilities, excellent spatial resolution is instrumental in assessment of global and regional function and feasibility of scar quantification sets it apart from other imaging modalities and facilitates critical analysis. These capabilities permit the identification of dysfunctional myocardium and scar and changes in these regions over time. The effect of stem cell therapeutics on dysfunctional myocardium and scar can then be highlighted in longitudinal assessment in clinical trials. This has been demonstrated in the inaugural Phase I SCIPIO trial where patients received autologous C-kitPos cardiac stem cell (CSC) transplantation. Although the global function improved significantly with CSC transplantation, regional/segmental analysis provided crucial insights into the effects of CSCs on the most dysfunctional myocardial segments. Magnetic resonance imaging is also a contending and complementing modality in molecular imaging essential for mechanistic studies.


Placental malaria diminishes development of antibody responses to Plasmodium falciparum epitopes in infants residing in an area of western Kenya where P. falciparum is endemic.
To determine the effect of placental malaria (PM) infection on the development of antibody responses to malaria in infants, we measured immunoglobulin G levels to seven different Plasmodium falciparum epitopes by using plasma samples collected at monthly intervals from infants born to mothers with and without PM. Overall, PM was associated with diminished antibody levels to all of the epitopes tested, especially with infants aged >or=4 to 12 months, and the difference was statistically significant for four of the seven epitopes (P<0.0035). These findings suggest that PM can negatively influence the development of immune responses to malaria in infants.


Design of effective kernels for spectroscopy and molecular transport: time-dependent current-density-functional theory.
Time-dependent current-density-functional theory (TDCDFT) provides an, in principle, exact scheme to calculate efficiently response functions for a very broad range of applications. However, the lack of approximations valid for a range of parameters met in experimental conditions has so far delayed its extensive use in inhomogeneous systems. On the other side, in many-body perturbation theory accurate approximations are available, but at a price of a higher computational cost. In the present work, the possibility of combining the advantages of both approaches is exploited. In this way, an exact equation for the exchange-correlation kernel of TDCDFT is obtained, which opens the way for a systematic improvement of the approximations adopted in practical applications. Finally, an approximate kernel for an efficient calculation of spectra of solids and molecular conductances is suggested and its validity is discussed.


Measuring quality of life in women with osteoporosis. Osteoporosis Quality of Life Study Group.
The objective of the study was to test an instrument for measuring health-related quality of life (HRQL) for women with osteoporosis and back pain caused by vertebral fractures related to osteoporosis. A longitudinal cohort study design was used in which women were seen at baseline, after 2 weeks, and after 6 months. The setting was a secondary care rheumatology practice in Canada and four separate secondary care metabolic bone disease practices in the United States. The patients were 226 women suffering from osteoporosis and back pain with a mean bone mineral density of 0.84 +/- 0.14 g/cm2 and a mean of 2.78 (median 2, range 1-11) vertebral fractures. We administered the Osteoporosis Quality of Life Questionnaire (OQLQ) with 30 items distributed across five domains: Symptoms, Physical Function, Activities of Daily Living, Emotional Function, and Leisure. In addition, we administered the Sickness Impact Profile (SIP), the 36-item short form of the Medical Outcomes Survey instrument (MOS SF-36), and the Brief Pain Inventory (BPI). On the basis of what women told us about the areas of their lives adversely affected by their osteoporosis, we constructed the OQLQ. Reliability coefficients between baseline and 2-week follow-up varied from 0.80 to 0.89 for the five domains. Cross-sectional correlations between OQLQ domains and other measures were consistently higher than predicted (0.51-0.81). The OQLQ proved to be as powerful or more powerful than alternative instruments for detecting improvement or deterioration in patients whose status changed. Sample sizes of less than 150 per group should be required to detect minimally important differences in parallel-group clinical trials. Longitudinal correlations between OQLQ and other measures were generally lower than predicted. This may be due to limitations in either the OQLQ or the other instruments. It is concluded that the OQLQ may prove to be a useful instrument for discriminating between women with different levels of impaired HRQL, and for evaluating change in women undergoing treatment for back pain related to osteoporosis.


Differentially expressed proteins of pathogenic Penicillium marneffei in yeast and mycelial phases.
Penicillium marneffei is a dimorphic fungus endemic in southeast Asia. The incidence of P. marneffei infection has increased greatly in this region with the spread of human immunodeficiency virus, but the infection routes and pathogenic mechanisms of P. marneffei remain poorly understood. P. marneffei is an opportunistic human pathogen exhibiting a temperature-dependent dimorphic switch. At 25 degrees C it grows as filamentous hyphae, whilst at 37 degrees C it forms uninucleate yeast cells and divides by fission. Dimorphic fungal pathogenicity is frequently associated with the dimorphic switch, but the mechanism that regulates the switch has remained obscure. In this report, two-dimensional difference gel electrophoresis was used to investigate the proteins expressed differentially in the yeast and mycelial phases of a wild-type isolate of P. marneffei. Among thousands of protein molecules displayed, more than 500 showed differential expression between the two phases. In particular, 26 proteins were identified using matrix-assisted laser desorption/ionization time-of-flight MS. Expression of catalase-peroxidase, isocitrate lyase, Hsp90, binding protein and cytochrome P-450 increased significantly in the yeast phase, whereas levels of poly(A) polymerase and SNF22 were reduced.


Power monitoring in dielectric-loaded plasmonic waveguides with internal Wheatstone bridges.
We report on monitoring the mode power in dielectric-loaded surface plasmon polariton waveguides (DLSPPWs) by measuring the resistance of gold electrodes, supporting the DLSPPW mode propagation, with internal (on-chip) Wheatstone bridges. The investigated DLSPPW configuration consisted of 1-μm-thick and 10-μm-wide cycloaliphatic acrylate polymer ridges tapered laterally to a 1-μm-wide ridge placed on a 50-nm-thin and 4-um wide gold stripe, all supported by a ~1.7-µm-thick Cytop layer deposited on a Si wafer. The fabricated DLSPPW power monitors were characterized at telecom wavelengths, showing very high responsivities reaching up to ~6.4 μV/μW (for a bias voltage of 245 mV) and the operation bandwidth exceeding 40 kHz.


Outcomes of women treated with progestin and metformin for atypical endometrial hyperplasia and early endometrial cancer: a systematic review and meta-analysis.
Progestin therapy is the recommended fertility-sparing management of atypical endometrial hyperplasia or early-stage endometrial cancer in reproductive-aged women. Our objective was to evaluate disease relapse after progestin and metformin versus progestin therapy alone in patients with endometrial hyperplasia or cancer. Our secondary outcomes were disease remission, clinical pregnancy and live birth rate. A systematic review of the literature was conducted (MEDLINE, Web of Science, Cochrane Library, CINAHL, LILACS, clinicaltrials.gov) from inception to April 2021. Studies of reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer who received progestin and metformin or progestin alone for fertility-sparing management, were included in the review. Early endometrial cancer was defined as grade 1, stage 1 disease. Exclusion criteria included women with higher grade endometrial cancer and when conservative management was not for fertility-sparing purposes. Data are presented as odds ratios (ORs) and 95% confidence intervals (CIs) with fixed or random effects meta-analysis. Quality scoring was based on the Newcastle-Ottawa and Jadad scales. In total, 271 reports were identified and six studies met the inclusion criteria. These studies included 621 women; 241 (38.8%) patients received combined therapy and 380 (61.2%) received progestin therapy alone. Relapse rates were lower for progestin and metformin than for progestin therapy alone (pooled OR 0.46, 95% CI 0.24 to 0.91, p=0.03). The remission rates were not different (pooled OR 1.35, 95% CI 0.91 to 2.00, p=0.14). Women who received progestin and metformin achieved pregnancy and live birth rates similar to those who received progestin therapy only (pooled OR 1.01, 95% CI 0.44 to 2.35, p=0.98; pooled OR 0.46, 95% CI 0.21 to 1.03, p=0.06). For reproductive-aged women with atypical endometrial hyperplasia or early endometrial cancer, progestin and metformin therapy compared with progestin therapy alone is associated with lower relapse rates, and similar remission, clinical pregnancy and live birth rates. CRD42020179069.disease remission.


Apoptosis-inducing factor is a key factor in neuronal cell death propagated by BAX-dependent and BAX-independent mechanisms.
Mitochondria release proteins that propagate both caspase-dependent and caspase-independent cell death pathways. AIF (apoptosis-inducing factor) is an important caspase-independent death regulator in multiple neuronal injury pathways. Presently, there is considerable controversy as to whether AIF is neuroprotective or proapoptotic in neuronal injury, such as oxidative stress or excitotoxicity. To evaluate the role of AIF in BAX-dependent (DNA damage induced) and BAX-independent (excitotoxic) neuronal death, we used Harlequin (Hq) mice, which are hypomorphic for AIF. Neurons carrying double mutations for Hq/Apaf1-/- (apoptosis proteases-activating factor) are impaired in both caspase-dependent and AIF-mediated mitochondrial cell death pathways. These mutant cells exhibit extended neuroprotection against DNA damage, as well as glutamate-induced excitotoxicity. Specifically, AIF is involved in NMDA- and kainic acid- but not AMPA-induced excitotoxicity. In vivo excitotoxic studies using kainic acid-induced seizure showed that Hq mice had significantly less hippocampal damage than wild-type littermates. Our results demonstrate an important role for AIF in both BAX-dependent and BAX-independent mechanisms of neuronal injury.


Modulation of mast cell adhesion, proliferation, and cytokine secretion on electrospun bioresorbable vascular grafts.
Mast cells synthesize several potent angiogenic factors and can also stimulate fibroblasts, endothelial cells, and macrophages. An understanding of how they participate in wound healing and angiogenesis is important to further our knowledge about in situ vascular prosthetic regeneration. The adhesion, proliferation, and cytokine secretion of bone marrow-derived murine mast cells (BMMC) on electrospun polydioxanone, polycaprolactone, and silk scaffolds, as well as tissue culture plastic, has been investigated in the presence or absence of IL-3, stem cell factor, IgE and IgE with a crosslinking antigen, dinitrophenol-conjugated albumin (DNP). It was previously believed that only activated BMMCs exhibit adhesion and cytokine secretion. However, this study shows nonactivated BMMC adhesion to electrospun scaffolds. Silk scaffold was not found to be conducive for mast cell adhesion and cytokine secretion. Activation by IgE and DNP significantly enhanced mast cell adhesion, proliferation, migration, and secretion of tumor necrosis factor alpha, macrophage inflammatory protein-1α, and IL-13. This indicates that mast cells might play a role in the process of biomaterial integration into the host tissue, regeneration, and possibly angiogenesis.


Feasibility of lumbar puncture in the study of cerebrospinal fluid biomarkers for Alzheimer's disease: a multicenter study in Spain.
Lumbar puncture (LP) is increasingly performed in memory units due to the usefulness of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease. The feasibility of this procedure in this context, however, is controversial. Our aim was to analyze the incidence of complications and their associated factors so as to determine the impact of LP in the study of CSF biomarkers of Alzheimer's disease. In the context of a larger international initiative, we prospectively collected data from 689 participants who underwent LP in three memory units in Spain. Data included demographic factors, headache history, subjective attitude toward the procedure, patient positioning, needle characteristics, volume of CSF extracted, attempts needed, and resting time after CSF acquisition. Five to seven days after the procedure, we asked participants about complications through a semi-structured telephone interview. No adverse events were reported in 441 (64.0%) participants. The most frequent complication was headache, reported by 171 (24.8%) subjects. It was severe in only 17 (2.5%). Headache was more frequent in younger participants and when a cutting-edge needle was used. Back pain was present in 111 (16.1%) cases, and it was associated with female gender, cutting-edge needles, increased number of attempts, and longer resting time after LP. No major complications were reported. The use of pen-point needles showed a trend toward a higher frequency of hematic CSF. LP can be safely performed to study CSF biomarkers. The main complication is headache, associated with younger age and use of cutting-edge needles.


Acute aortic syndromes: diagnosis and management, an update.
Acute aortic syndromes (AAS) encompass a constellation of life-threatening medical conditions including classic acute aortic dissection (AAD), intramural haematoma, and penetrating atherosclerotic aortic ulcer. Given the non-specific symptoms and physical signs, a high clinical index of suspicion is necessary to detect the disease before irreversible lethal complications occur. In order to reduce the diagnostic time delay, a comprehensive flowchart for decision-making based on pre-test sensitivity of AAS has been designed by the European Society of Cardiology guidelines on aortic diseases and should be thus applied in the emergency scenario. When the definitive diagnosis is made, prompt and appropriate therapeutic interventions should be undertaken if indicated by a highly specialized aortic team. Urgent surgery for AAD involving the ascending aorta (Type A) and medical therapy alone for AAD not involving the ascending aorta (Type B) are typically recommended. In complicated Type B AAD, thoracic endovascular aortic repair (TEVAR) is generally indicated. On the other hand, in uncomplicated Type B AAD, pre-emptive TEVAR rather than medical therapy alone to prevent late complications, while intuitive, requires further study in randomized cohorts. Finally, it should be highlighted that there is an urgent need to increase awareness of AAS worldwide, including dedicated education/prevention programmes, and to improve diagnostic and therapeutic strategies, outcomes, and lifelong surveillance.


Effect of functional group and carbon chain length on the odor detection threshold of aliphatic compounds.
Odor detection thresholds (ODTs) are used for assessing outdoor and indoor air quality. They are obtained experimentally by olfactometry and psychophysical methods, and large compilations are available in the literature. A non-linear regression equation was fitted to describe the ODT variability of 114 aliphatic compounds based on the alkyl chain length for different homologous series (carboxylic acids, aldehydes, 2-ketones, esters, 1-alcohols, amines, thiols, thioethers and hydrocarbons). The resulting equation reveals an effect of the functional group, molecular size and also an interaction between both factors. Although the mechanistic interpretation of results is uncertain, the relatively high goodness-of-fit (R(2) = 0.90) suggests that ODT values of aliphatic compounds can be predicted rather accurately, which is not the case for rigid molecules. This equation may serve as a basis for the development of more complex ODT models taking into account diverse structural features of odorants. The variability of power-law exponents was also investigated for the homologous series.


Effects of budesonide inhalation suspension compared with cromolyn sodium nebulizer solution on health status and caregiver quality of life in childhood asthma.
To compare the effects of 2 nebulizable controller asthma medications on caregiver and pediatric quality of life. In this 52-week, randomized trial, children aged 2 to 6 years with mild to moderate persistent asthma received budesonide inhalation suspension 0.5 mg (total daily dose) once or twice daily (n = 168) or cromolyn sodium nebulizer solution 20 mg 4 times daily (n = 167) for 8 weeks, with dosage adjustment thereafter at the investigators' discretion. The Pediatric Asthma Caregiver's Quality of Life Questionnaire (PACQLQ), Compliance/Caregiver Satisfaction Questionnaire (CCSQ), Modified Child Health Questionnaire-Parent Form 50 (CHQ-PF50), and Functional Status-II(R) (FS-II[R]) Questionnaire were administered at baseline and weeks 8, 28, and 52. Global assessments of ease of asthma management and child health status were obtained from caregivers and physicians at the end of the study. Improvements from baseline in domain-specific (activities and emotional function) and total PACQLQ scores were greater at each time point (weeks 8, 28, and 52) for caregivers of patients treated with budesonide compared with caregivers of patients receiving cromolyn sodium. Only the budesonide group met the criterion for a clinically important improvement (>or=0.5 unit change) in all PACQLQ domains by week 8, which was maintained at weeks 28 and 52. Moreover, improvements surpassed the criterion for moderate clinical importance (1.0 unit change) in all PACQLQ domains for the budesonide group, but this level of improvement was only achieved in the activities domain (at week 28) for the cromolyn sodium group. Based on the CCSQ, budesonide resulted in greater caregiver satisfaction, treatment convenience, ease of use, and compliance compared with cromolyn sodium. Thus, 90.7% of caregivers in the budesonide group were "completely or very satisfied" compared with 53.4% in the cromolyn sodium group. Over half (54.6%) of caregivers in the budesonide group rated budesonide "highly or very convenient" compared with 23% for cromolyn sodium; 77% rated budesonide "extremely or very easy" to use compared with 47% for cromolyn. Adherence with daily medication regimens was reported for 76% of children in the budesonide group compared with 57% in the cromolyn sodium group. Child health status, as indicated by mean FS-II(R) scores, showed improvements from baseline in both groups at weeks 8, 28, and 52. There was a trend for these improvements to be superior in the budesonide group. Additionally, budesonide was superior to cromolyn sodium in caregiver and physician global assessments. At the end of the study, 76% of caregivers of children receiving budesonide reported asthma management to be "a great deal easier" compared with the start of the study, and 74% rated the overall health status of their child as "much better now than 1 year ago." In contrast, only 29% and 37% of caregivers whose children received cromolyn sodium provided these respective ratings. Budesonide inhalation suspension improved the quality of life for caregivers of children with asthma. Caregivers of children treated with budesonide had significantly fewer limitations in daily activities and emotional functioning compared with caregivers of children treated with cromolyn sodium nebulizer solution. The improvements in caregiver quality of life occurred earlier with budesonide compared with cromolyn sodium. Only caregivers in the budesonide group had a clinically important mean change from baseline in all PACQLQ domains by week 8. These benefits were maintained at week 52. Children treated with budesonide inhalation suspension and cromolyn sodium experienced improvements in health status, assessed using the FS-II(R). The greatest differences between treatments were seen in the disease-specific portion of the FS-II(R), which relates impairments in functional status to the child's illness. Caregiver and physician global assessment indicated significantly better overall child health after 1 year of treatment with budesonide, supporting an improvement in health status. Clinical trials in children 4 to 16 years of age with asthma have demonstrated greater effectiveness of inhaled corticosteroids versus cromolyn sodium on several clinical measures of efficacy. Measures of asthma control in this study, reported in detail elsewhere [Leflein et al. Pediatrics 2002;109:866-872], also have shown greater improvements with budesonide therapy. Treatment with budesonide inhalation suspension resulted in a significantly lower mean rate of asthma exacerbations, significantly longer times to first asthma exacerbation, significantly longer times to first additional use of chronic asthma therapy, and significant improvements in asthma symptom scores and breakthrough medication use compared with cromolyn sodium therapy. Additionally, children receiving budesonide inhalation suspension experienced more symptom-free days and episode-free days compared with children receiving cromolyn sodium. Safety profiles were similar between the 2 treatment groups. Budesonide inhalation suspension was associated with significantly greater caregiver satisfaction, convenience, ease of use, and compliance compared with cromolyn sodium nebulizer solution. This greater caregiver satisfaction and quality of life may be related to the greater asthma control achieved in children treated with budesonide therapy compared with cromolyn sodium. In addition, the convenience of once- or twice-daily dosing with budesonide inhalation suspension, compared with 3- or 4-times-daily dosing of cromolyn sodium, may decrease caregiver burden and enhance the willingness of caregivers to adhere to treatment regimens prescribed for their young children with asthma. This effect on caregiver adherence could further improve treatment effectiveness. This is the first clinical trial comparing the effects of a nebulized corticosteroid with that of an alternative nebulized therapy on quality of life in young children with asthma and their families. Compared with nebulized cromolyn sodium, budesonide inhalation suspension not only provides better overall child health status and asthma management, but greater caregiver quality of life and greater caregiver satisfaction, convenience, ease of use, and compliance.


Lung cancer cell lines as tools for biomedical discovery and research.
Lung cancer cell lines have made a substantial contribution to lung cancer translational research and biomedical discovery. A systematic approach to initiating and characterizing cell lines from small cell and non-small cell lung carcinomas has led to the current collection of more than 200 lung cancer cell lines, a number that exceeds those for other common epithelial cancers combined. The ready availability and widespread dissemination of the lines to investigators worldwide have resulted in more than 9000 citations, including multiple examples of important biomedical discoveries. The high (but not perfect) genomic similarities between lung cancer cell lines and the lung tumor type from which they were derived provide evidence of the relevance of their use. However, major problems including misidentification or cell line contamination remain. Ongoing studies and new approaches are expected to reveal the full potential of the lung cancer cell line panel.


Notchless defines a stage-specific requirement for ribosome biogenesis during lineage progression in adult skeletal myogenesis.
Cell fate decisions occur through the action of multiple factors, including signalling molecules and transcription factors. Recently, the regulation of translation has emerged as an important step for modulating cellular function and fate, as exemplified by ribosomes that play distinct roles in regulating cell behaviour. Notchless (Nle) is a conserved nuclear protein that is involved in a crucial step in ribosome biogenesis, and is required for the maintenance of adult haematopoietic and intestinal stem/progenitor cells. Here, we show that activated skeletal muscle satellite cells in conditional Nle mutant mice are arrested in proliferation; however, deletion of Nle in myofibres does not impair myogenesis. Furthermore, conditional deletion of Nle in satellite cells during homeostasis did not impact on their fate for up to 3 months. In contrast, loss of Nle function in primary myogenic cells blocked proliferation because of major defects in ribosome formation. Taken together, we show that muscle stem cells undergo a stage-specific regulation of ribosome biogenesis, thereby underscoring the importance of differential modulation of mRNA translation for controlling cell fate decisions.


Health Status and Health Care Needs of Drought-Related Migrants in the Horn of Africa-A Qualitative Investigation.
Somalia, Kenya and Ethiopia, situated in the Horn of Africa, are highly vulnerable to climate change, which manifests itself through increasing temperatures, erratic rains and prolonged droughts. Millions of people have to flee from droughts or floods either as cross-border refugees or as internally displaced persons (IDPs). The aim of this study was to identify knowledge status and gaps regarding public health consequences of large-scale displacement in these countries. After a scoping review, we conducted qualitative in-depth interviews during 2018 with 39 stakeholders from different disciplines and agencies in these three countries. A validation workshop was held with a selection of 13 interviewees and four project partners. Malnutrition and a lack of vaccination of displaced people are well-known challenges, while mental health problems and gender-based violence (GBV) are less visible to stakeholders. In particular, the needs of IDPs are not well understood. The treatment of mental health and GBV is insufficient, and IDPs have inadequate access to essential health services in refugee camps. Needs assessment and program evaluations with a patients' perspective are either lacking or inadequate in most situations. The Horn of Africa is facing chronic food insecurity, poor population health and mass displacement. IDPs are an underserved group, and mental health services are lacking. A development approach is necessary that moves beyond emergency responses to the building of long-term resilience, the provision of livelihood support and protection to reduce displacement by droughts.


1H NMR dipolar echo decay spectroscopy: a sensitive probe of membrane structure.
The structural and motional properties of membrane lipids in various physical states and macroscopic organizations are elucidated by 1H NMR dipolar echo decay spectroscopy (DECODE). Multilamellar lipid dispersions in the gel (L beta') and liquid-crystalline (L alpha) states and a nonbilayer, hexagonal (HII) phase are readily distinguished, a dynamic profile within these phases is identified, and dipolar order parameters are obtained in the fluid phases. The method is suitable for any pulsed NMR spectrometer. DECODE provides the first depth-dependent assay of lipid order that does not rely on isotopic labeling or exogenous probe.


A Global Strategy for Building Clinical Capacity and Advancing Research in the Context of Malnutrition and Cancer in Children within Low- and Middle-Income Countries.
Cancer is one of the prominent noncommunicable diseases and is responsible for more than 8 million deaths each year worldwide. It is expected to impact up to 22 million people annually by 2030, and more than 60% of new patient cases will be in Asia, Africa, and Central and South America. Despite improvements in the delivery of care to children in low- and middle-income countries, survival of those with cancer is as low as 10%; a figure that is in stark contrast to overall childhood cancer survival rates in North America and Western Europe. Although many factors are contributing to this disparity, access to well-educated health-care workers, knowledgeable in both antineoplastic and supportive care, particularly nutritional assessment and therapy, is necessary for effective treatment and reduced morbidities of children with cancer. To this end, we identify approaches for advancing nutritional care such as building nutritional capacity and education as well as advancing rigorous nutritional science through the establishment of multicountry research groups among pediatric oncology units located in low- and middle-income countries.


Synaptotagmin 1-triggered lipid signaling facilitates coupling of exo- and endocytosis.
Exocytosis and endocytosis are essential physiological processes and are of prime importance for brain function. Neurotransmission depends on the Ca2+-triggered exocytosis of synaptic vesicles (SVs). In neurons, exocytosis is spatiotemporally coupled to the retrieval of an equal amount of membrane and SV proteins by compensatory endocytosis. How exocytosis and endocytosis are balanced to maintain presynaptic membrane homeostasis and, thereby, sustain brain function is essentially unknown. We combine mouse genetics with optical imaging to show that the SV calcium sensor Synaptotagmin 1 couples exocytic SV fusion to the endocytic retrieval of SV membranes by promoting the local activity-dependent formation of the signaling lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) at presynaptic sites. Interference with these mechanisms impairs PI(4,5)P2-triggered SV membrane retrieval but not exocytic SV fusion. Our findings demonstrate that the coupling of SV exocytosis and endocytosis involves local Synaptotagmin 1-induced lipid signaling to maintain presynaptic membrane homeostasis in central nervous system neurons.


Prolonged food deprivation increases mRNA expression of deiodinase 1 and 2, and thyroid hormone receptor β-1 in a fasting-adapted mammal.
Food deprivation in mammals is typically associated with reduced thyroid hormone (TH) concentrations and deiodinase content and activity to suppress metabolism. However, in prolonged-fasted, metabolically active elephant seal pups, TH levels are maintained, if not elevated. The functional relevance of this apparent paradox is unknown and demonstrates variability in the regulation of TH levels, metabolism and function in food-deprived mammals. To address our hypothesis that cellular TH-mediated activity is upregulated with fasting duration, we quantified the mRNA expression and protein content of adipose and muscle deiodinase type I (DI1) and type II (DI2), and TH receptor beta-1 (THrβ-1) after 1, 3 and 7 weeks of fasting in northern elephant seal pups (N=5-7 per week). Fasting did not decrease the concentrations of plasma thyroid stimulating hormone, total triiodothyronine (tT3), free T3, total thyroxine (tT4) or free T4, suggesting that the hypothalamic-pituitary-thyroid axis is not suppressed, but rather maintained during fasting. Mean mRNA expression of adipose DI1 and DI2 increased threefold and fourfold, respectively, and 20- and 30-fold, respectively, in muscle. With the exception of adipose DI1, protein expression of adipose DI2 and muscle DI1 and DI2 increased twofold to fourfold. Fasting also increased adipose (fivefold) and muscle (fourfold) THrβ-1 mRNA expression, suggesting that the mechanisms mediating cellular TH activity are upregulated with prolonged fasting. The data demonstrate a unique, atypical mechanism of TH activity and regulation in mammals adapted to prolonged food deprivation in which the potential responsiveness of peripheral tissues and cellular TH activity are increased, which may contribute to their lipid-based metabolism.


Markers of bone formation and resorption identify subgroups of patients with clinical knee osteoarthritis who have reduced rates of cartilage loss.
To determine whether serum markers of bone formation and resorption, used individually or in combination, can be used to identify subgroups who lose cartilage volume at different rates over 2 years within a knee osteoarthritis (OA) population. Changes in cartilage volume over 2 years were measured in 117 subjects with knee OA using magnetic resonance imaging. We examined relationships between change in cartilage volume and baseline serum markers of bone formation [intact N-terminal propeptide of type I procollagen (PINP) and osteocalcin] and resorption [N-telopeptide of type I collagen (NTX-I), C-telopeptide of type I collagen (CTX-I), and C-telopeptide of type I collagen (ICTP). The baseline markers of bone formation, PINP and osteocalcin (p = 0.02, p = 0.01, respectively), and the baseline markers of bone resorption, CTX-I and NTX-I (p = 0.02 for both), were significantly associated with reduced cartilage loss. There were no significant associations between baseline ratios of bone formation to resorption markers and cartilage loss. However, when subjects were divided into subgroups with high or low bone formation markers (based on levels of marker >or= mean or < mean for the population, respectively), in the subgroup with high PINP there was a significant association between increasing bone resorption markers CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.001, respectively). Similarly, in the subgroup with high osteocalcin, there was a significant association between increasing CTX-I and NTX-I and reduced cartilage loss (p = 0.02, p = 0.003, respectively). In contrast, in subgroups with low bone formation markers, no significant associations were obtained between markers of bone resorption and cartilage loss. Overall, the results suggest that higher bone remodeling (i.e., higher serum levels of bone formation and resorption) is associated with reduced cartilage loss. Considering markers of bone formation and resorption together, it is possible to identify subgroups within the OA population who have reduced rates of cartilage loss.


One-incision endoscopic technique for posterior cruciate ligament reconstruction with quadriceps tendon-patellar bone autograft.
Quadriceps tendon-patellar bone autograft is an alternative graft choice for posterior cruciate ligament (PCL) reconstruction. A 2-incision technique with outside-in fixation at the femoral condyle is generally used. In this article, we describe a 1-incision endoscopic technique for PCL reconstruction with quadriceps tendon-patellar bone autograft. The graft consists of a proximal patellar bone plug and central quadriceps tendon. The bone plug is trapezoidal, 20 mm long, 10 mm wide, and 8 mm thick. The tendon portion is 80 mm long, 10 mm wide, and 6 mm thick, including the full-thickness of the rectus femoris and partial thickness of the vastus intermedius. Three arthroscopic portals, including anteromedial, anterolateral, and posteromedial, are used. All procedures are performed in an endoscopic manner with only 1 incision at the proximal tibia. At the femoral side, the bone plug is fixed by an interference screw. At the tibial side, the tendon portion is fixed by a suture to a screw on the anterior cortex and an interference bioscrew in the posterior tibial tunnel opening. Quadriceps tendon autograft has the advantages of being self-available, allowing for easier arthroscopic technique, and providing comparable graft size. The 1-incision technique provides a simple reconstruction method for PCL insufficiency without a second incision at the medial femoral condyle.


Intersections between patient-provider communication and antenatal anxiety in a public healthcare setting in Pakistan.
This study explores pregnant women's and healthcare providers' perspectives on the role of patient-provider communication in experiences of antenatal anxiety within a low-resource setting. In 2017-18, we consecutively sampled pregnant women (n = 19) with at least mild anxiety and purposively sampled antenatal care providers (n = 10) from a public hospital in Punjab Province, Pakistan. We then conducted in-depth interviews and thematically coded them with a combination of inductive and deductive coding methodologies. We found that patients expressed a desire for warm, empathetic communication from providers who demonstrate respect, attentiveness, and a shared lived experience. Providers revealed an awareness that their heavy caseloads, high stress levels, and discourteous tones adversely influenced communication with pregnant women and may exacerbate their anxieties, but also reported that compassionately addressing women's concerns, providing financial problem-solving and/or assistance, and moderating conflicting healthcare desires between patients and their families could alleviate anxiety in pregnant women. Patients reported feelings of anxiety stemming from a belief that they received lower quality communication from antenatal providers at public hospitals than patients received from antenatal providers at private hospitals, an experience that they partially attributed to their low socioeconomic status. Meanwhile, some providers disclosed potentially stigmatizing views of women from particular sociocultural backgrounds or low socioeconomic status, including perceptions that appeared to shape communication with these patients in antenatal care encounters. Our findings provide preliminary evidence that communication between pregnant women and antenatal providers that is warm, normalizes patient fears, and integrates patients' interpersonal and financial considerations can mitigate pregnant women's experiences of anxiety and reduce barriers to accessing antenatal care in Pakistan's public healthcare facilities.


A user authentication scheme using physiological and behavioral biometrics for multitouch devices.
With the rapid growth of mobile network, tablets and smart phones have become sorts of keys to access personal secured services in our daily life. People use these devices to manage personal finances, shop on the Internet, and even pay at vending machines. Besides, it also helps us get connected with friends and business partners through social network applications, which were widely used as personal identifications in both real and virtual societies. However, these devices use inherently weak authentication mechanism, based upon passwords and PINs that is not changed all the time. Although forcing users to change password periodically can enhance the security level, it may also be considered annoyances for users. Biometric technologies are straightforward because of the simple authentication process. However, most of the traditional biometrics methodologies require diverse equipment to acquire biometric information, which may be expensive and not portable. This paper proposes a multibiometric user authentication scheme with both physiological and behavioral biometrics. Only simple rotations with fingers on multitouch devices are required to enhance the security level without annoyances for users. In addition, the user credential is replaceable to prevent from the privacy leakage.


Photonic band-gap engineering in UV fiber gratings by the arc discharge technique.
Localized heat treatments combined with local non-adiabatic tapering is proposed as suitable tool for the engineering of photonic band-gaps in UV-written fiber Bragg gratings (FBGs). In particular, here, we propose the use of the electric arc discharge to achieve localized defects along the FBG structure, however differently from previously reported works, we demonstrate how this post processing tool properly modified can be exploited to achieve the full control of the spectral characteristics of the final device. Also, we show how the suitable choice of the grating features and the correct selection of the defect geometry can be efficiently used to achieve interesting features for both communication and sensing applications.


Refractive indices of TiO(2) films produced by reactive evaporation of various titanium-oxygen phases.
In this paper experiments with reactive evaporation of the starting materials Ti, TiO, Ti(2)O(3), Ti(3)O(5), and TiO(2) to obtain nonabsorbing TiO(2) films are under discussion. For the starting materials TiO and Ti(3)O(5) the dependence of the TiO(2) film refractive index on the substrate temperature, oxygen pressure, and deposition rate was measured. For TiO dispersion curves of the resulting TiO(2) films as a function of the substrate temperature during film formation were determined. The successive evaporation of the different starting materials resulted in the formation of lambda/4 TiO(2) films with different refractive indices. This phenomenon was most obvious during the first evaporation. It disappeared after several evaporations in two groups of TiO2 films with different refractive indices. From the beginning only the starting materials Ti and Ti(3)O(5) resulted in TiO(2) films with constant refractive indices. The first material produced a high, the latter a lower film index. Depending on the number of evaporations performed, both types of TiO(2) films can be obtained with TiO. The films and residues in the crucibles were also subjected to chemical analyses. An attempt was made to explain the optical properties of the resulting TiO(2) films with regard to crystal structure, chemical composition, packing density influenced by the molecular composition of the vapor beam, chemical reaction with the crucible, substrate temperature, O(2) pressure, and deposition rate.


An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study.
Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202,206 women in the European Prospective Investigation into Cancer and Nutrition study. Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81-1.01), in general there was no evidence for miscalibration. Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model.


Early-pregnancy multiple serum markers and second-trimester uterine artery Doppler in predicting preeclampsia.
To estimate the ability of maternal serum markers and uterine artery Doppler in predicting preeclampsia. In this nested case-control study, maternal serum concentrations of cystatin C, beta2-microglobulin, serum amyloid A, C-reactive protein (CRP), and neopterin were measured, and resistance index of uterine artery blood flow was assessed in 45 women in whom preeclampsia subsequently developed and in 125 women with normal pregnancy outcome. Univariable regression analysis was performed to estimate correlations between serum markers and resistance index for the development of preeclampsia. Significant variables were identified using multiple logistic regressions. Maternal serum markers were measured at a median gestational age of 14.7 weeks (interquartile range 3.1) in control group members and 16.3 weeks (interquartile range 4.8) in the case group members, and uterine resistance index was measured at the second-trimester scan. Univariable logistic regression showed that women with subsequent preeclampsia had increased levels of cystatin C, beta2-microglobulin, neopterin, CRP, and resistance index. Cystatin C, CRP, and resistance index remained independently associated with preeclampsia when multiple logistic regression was applied. Receiver-operating characteristic curve analysis showed that a combination of markers had a better area under the curve (AUC; 0.825) than when used in isolation (cystatin C, AUC 0.725; CRP, AUC 0.634; resistance index, AUC 0.728). Sensitivity of uterine artery resistance index, cystatin C, and CRP combined for predicting preeclampsia was 69.2% for a screen-positive rate of 15%. Maternal serum cystatin C, CRP, and uterine artery mean resistance index are independent predictors of preeclampsia. There is improved prediction of preeclampsia when serum markers are combined with Doppler indices.


CT-Defined Prosthesis-Patient Mismatch Downgrades Frequency and Severity, and Demonstrates No Association With Adverse Outcomes After Transcatheter Aortic Valve Replacement.
This study sought to determine if indexed effective orifice area (EOAi), using left ventricular outflow tract measured from computed tomography (EOAiCT), reclassified prosthesis-patient mismatch (PPM) compared with conventional echocardiogram-defined measurements (EOAiTTE). PPM does not predict mortality following transcatheter aortic valve replacement (TAVR). However, it is unknown if the EOAiCT of the left ventricular outflow tract improves risk stratification. A total of 765 TAVR patients from the PARTNER II (Placement of Aortic Transcatheter Valves II) trial S3i cohort were evaluated. EOAi was calculated using the continuity equation, and the left ventricular outflow tract area was derived from baseline computed tomography. Traditional echocardiographic categories defined PPM: absent (>0.85 cm2/m2), moderate (≥0.65 and ≤0.85 cm2/m2), or severe (≤0.65 cm2/m2). Correlation of EOAiCT and EOAiTTE to 1-year outcomes was performed. The incidence of PPM was 24% with EOACT compared with 45% with EOAiTTE. Only 6% of PPM was graded severe by EOAiCT compared with 9% by EOAiTTE. EOAiTTE, but not EOAiCT, defined PPM showed association with reduced left ventricular mass regression (p = 0.03 vs. p = 0.52). There was no association between PPM and death or rehospitalization at 1 year with either modality. EOACT was associated with minor stroke at 1 year (log-rank p = 0.04), and EOAiTTE with stroke/transient ischemic attack (log-rank p = 0.030). Furthermore, when subjects with mild or greater paravalvular regurgitation were excluded, the presence of PPM did not show association with any outcome. EOAiCT downgrades frequency and severity of PPM in patients after TAVR, and was not associated with mortality 1 year after TAVR. EOAiTTE, but not EOAiCT, was associated with less left ventricular mass regression.


α2δ-1 Is Essential for Sympathetic Output and NMDA Receptor Activity Potentiated by Angiotensin II in the Hypothalamus.
Both the sympathetic nervous system and the renin-angiotensin system are critically involved in hypertension development. Although angiotensin II (Ang II) stimulates hypothalamic paraventricular nucleus (PVN) neurons to increase sympathetic vasomotor tone, the molecular mechanism mediating this action remains unclear. The glutamate NMDAR in the PVN controls sympathetic outflow in hypertension. In this study, we determined the interaction between α2δ-1 (encoded by Cacna2d1), commonly known as a Ca2+ channel subunit, and NMDARs in the hypothalamus and its role in Ang II-induced synaptic NMDAR activity in PVN presympathetic neurons. Coimmunoprecipitation assays showed that α2δ-1 interacted with the NMDAR in the hypothalamus of male rats and humans (both sexes). Ang II increased the prevalence of synaptic α2δ-1-NMDAR complexes in the hypothalamus. Also, Ang II increased presynaptic and postsynaptic NMDAR activity via AT1 receptors, and such effects were abolished either by treatment with pregabalin, an inhibitory α2δ-1 ligand, or by interrupting the α2δ-1-NMDAR interaction with an α2δ-1 C terminus-interfering peptide. In Cacna2d1 knock-out mice (both sexes), Ang II failed to affect the presynaptic and postsynaptic NMDAR activity of PVN neurons. In addition, the α2δ-1 C terminus-interfering peptide blocked the sympathoexcitatory response to microinjection of Ang II into the PVN. Our findings indicate that Ang II augments sympathetic vasomotor tone and excitatory glutamatergic input to PVN presympathetic neurons by stimulating α2δ-1-bound NMDARs at synapses. This information extends our understanding of the molecular basis for the interaction between the sympathetic nervous and renin-angiotensin systems and suggests new strategies for treating neurogenic hypertension.SIGNIFICANCE STATEMENT Although both the sympathetic nervous system and renin-angiotensin system are closely involved in hypertension development, the molecular mechanisms mediating this involvement remain unclear. We showed that α2δ-1, previously known as a calcium channel subunit, interacts with NMDARs in the hypothalamus of rodents and humans. Angiotensin II (Ang II) increases the synaptic expression level of α2δ-1-NMDAR complexes. Furthermore, inhibiting α2δ-1, interrupting the α2δ-1-NMDAR interaction, or deleting α2δ-1 abolishes the potentiating effects of Ang II on presynaptic and postsynaptic NMDAR activity in the hypothalamus. In addition, the sympathoexcitatory response to Ang II depends on α2δ-1-bound NMDARs. Thus, α2δ-1-NMDAR complexes in the hypothalamus serve as an important molecular substrate for the interaction between the sympathetic nervous system and the renin-angiotensin system. This evidence suggests that α2δ-1 may be a useful target for the treatment neurogenic hypertension.


Recent Common Origin, Reduced Population Size, and Marked Admixture Have Shaped European Roma Genomes.
The Roma Diaspora-traditionally known as Gypsies-remains among the least explored population migratory events in historical times. It involved the migration of Roma ancestors out-of-India through the plateaus of Western Asia ultimately reaching Europe. The demographic effects of the Diaspora-bottlenecks, endogamy, and gene flow-might have left marked molecular traces in the Roma genomes. Here, we analyze the whole-genome sequence of 46 Roma individuals pertaining to four migrant groups in six European countries. Our analyses revealed a strong, early founder effect followed by a drastic reduction of ∼44% in effective population size. The Roma common ancestors split from the Punjabi population, from Northwest India, some generations before the Diaspora started, <2,000 years ago. The initial bottleneck and subsequent endogamy are revealed by the occurrence of extensive runs of homozygosity and identity-by-descent segments in all Roma populations. Furthermore, we provide evidence of gene flow from Armenian and Anatolian groups in present-day Roma, although the primary contribution to Roma gene pool comes from non-Roma Europeans, which accounts for >50% of their genomes. The linguistic and historical differentiation of Roma in migrant groups is confirmed by the differential proportion, but not a differential source, of European admixture in the Roma groups, which shows a westward cline. In the present study, we found that despite the strong admixture Roma had in their diaspora, the signature of the initial bottleneck and the subsequent endogamy is still present in Roma genomes.


Emergency reconstructive endovascular management of intraoperative complications involving the internal carotid artery from trans-sphenoidal surgery.
To report our experience with intraoperative complications involving the internal carotid artery (ICA) during trans-sphenoidal surgery and their outcome with reconstructive endovascular management. A retrospective review was conducted of patients with an ICA injury related to trans-sphenoidal surgery from 2000 to 2012. Demographic data, clinical charts, indications for treatment, radiographic images, lesion characteristics, operative notes, endovascular procedure notes and post-procedure hospital course were reviewed. Three men and one woman of mean age of 52 years (range 33-74) were identified. The lesions included two macroadenomas, one meningioma and one chondrosarcoma. Risk factors for ICA rupture included two patients with carotid dehiscence, one with sphenoid septal attachment to the ICA, two with revision surgery, one with prior radiation to the tumor, one with bromocriptine treatment and two with acromegaly. In three patients, covered stent placement achieved hemostasis at the site of injury within the ICA. One patient developed delayed bleeding 6 h after covered stent placement and underwent successful endovascular occlusion of the ICA but died 6 days after the injury. The fourth patient had an intraoperative ICA stroke requiring suction thrombectomy, thrombolysis, stent placement and evacuation of an epidural hematoma. At 1-year follow-up, two patients had a modified Rankin score (mRS) and National Institute of Health Stroke Scale (NIHSS) score of 0; in the patient who had a stroke the mRS score was 1 and the NIHSS score 2. Endovascular management with arterial reconstruction is helpful in the treatment of ICA injuries during trans-sphenoidal surgery.


QTL mapping for photoperiod insensitivity of a Japanese soybean landrace Sakamotowase.
The insensitivity of flowering to long daylength is an important characteristic which soybeans have used to adapt to environments at higher latitude. The objective of this study was to map the novel gene(s) for photoperiod insensitivity in the Japanese soybean landrace Sakamotowase. A previous study suggested that Sakamotowase possessed the genotype e1e1e3e3E4E4. The progeny of testcrosses with the Harosoy isoline for e3 (L62-667) produced the roughly expected segregation pattern for the monogenic inheritance, suggesting the major involvement of a single gene in photoperiod insensitivity of Sakamotowase. By mapping analysis for 6 linkage groups (LGs) harboring the known major genes and quantitative trait loci (QTLs) for flowering, we detected a major QTL for the insensitivity near an simple sequence repeat marker (Satt577) in LG C2 and a minor QTL in LG L. Our results therefore suggest that a novel gene for photoperiod insensitivity of Sakamotowase was located in LG C2. It was estimated from the position of the tagging marker that the novel gene may be an allele at the E1 or E7 loci or a novel gene tightly linked to the E1 locus.


Gastrointestinal parasite assemblages from the wild rodent capybara (Hydrochoerus hydrochaeris) inhabiting a natural protected area from Argentina.
Knowledge about parasitic diseases of wildlife will help us to understand the dynamics of parasites and their effects on host populations. The capybara (Hydrochoerus hydrochaeris) is the largest living rodent in the world, and its distribution is associated with the presence of tropical and subtropical wetlands in South America. The Los Padres Lake Integral Reserve (LPLIR) is an important conservation zone in the pampean region of Argentina. One of the emblematic species found within the reserve is the capybara. The objective of this study was to determine the gastrointestinal parasites present in wild capybaras of the LPLIR and to compare different coprological methodologies. Free-ranging capybara fresh feces from 57 individuals were randomly collected from the area of LPLIR in the summer of 2022. Three different techniques were applied: spontaneous sedimentation technique (SS), INTA modified McMaster technique (MM), and Mini-FLOTAC (MF) technique. Fifty-six samples from all samples analysed (56/57, 98%) were found to be positive for gastrointestinal parasites. Two species of Strongylida, Protozoophaga obesa, Echinocoleus hydrochaeris, one unidentified nematode, one unidentified spirurid, and at least two morphotypes of Eimeria spp. oocysts were recorded. There were found significant differences in the proportion of positive samples and in richness by technique, but no significant differences were found in parasite counting. In conclusion, the choice of methodology depends on the specific objectives of the study. This is the first parasitological study of capybaras from the LPLIR and represents an exploration of parasite communities present in these wild rodents at their southernmost distribution.


Extract and Characterize Hairpin Vortices in Turbulent Flows.
Hairpin vortices are one of the most important vortical structures in turbulent flows. Extracting and characterizing hairpin vortices provides useful insight into many behaviors in turbulent flows. However, hairpin vortices have complex configurations and might be entangled with other vortices, making their extraction difficult. In this work, we introduce a framework to extract and separate hairpin vortices in shear driven turbulent flows for their study. Our method first extracts general vortical regions with a region-growing strategy based on certain vortex criteria (e.g., λ2) and then separates those vortices with the help of progressive extraction of (λ2) iso-surfaces in a top-down fashion. This leads to a hierarchical tree representing the spatial proximity and merging relation of vortices. After separating individual vortices, their shape and orientation information is extracted. Candidate hairpin vortices are identified based on their shape and orientation information as well as their physical characteristics. An interactive visualization system is developed to aid the exploration, classification, and analysis of hairpin vortices based on their geometric and physical attributes. We also present additional use cases of the proposed system for the analysis and study of general vortices in other types of flows.


Multimodality imaging spectrum of complications of horseshoe kidney.
Horseshoe kidney is the most common congenital renal fusion anomaly with an incidence of 1 in 400-600 individuals. The most common type is fusion at the lower poles seen in greater than 90% of the cases, with the rest depicting fusion at the upper poles, resulting in an inverted horseshoe kidney. Embryologically, there are two theories hypothesizing the genesis of horseshoe kidney - mechanical fusion theory and teratogenic event theory. As an entity, horseshoe kidney is an association of two anatomic anomalies, namely, ectopia and malrotation. It is also associated with other anomalies including vascular, calyceal, and ureteral anomalies. Horseshoe kidney is prone to a number of complications due to its abnormal position as well as due to associated vascular and ureteral anomalies. Complications associated with horseshoe kidney include pelviureteric junction obstruction, renal stones, infection, tumors, and trauma. It can also be associated with abnormalities of cardiovascular, central nervous, musculoskeletal and genitourinary systems, as well as chromosomal abnormalities. Conventional imaging modalities (plain films, intravenous urogram) as well as advanced cross-sectional imaging modalities (ultrasound, computed tomography, and magnetic resonance imaging) play an important role in the evaluation of horseshoe kidney. This article briefly describes the embryology and anatomy of the horseshoe kidney, enumerates appropriate imaging modalities used for its evaluation, and reviews cross-sectional imaging features of associated complications.


National, Regional, State, and Selected Local Area Vaccination Coverage Among Adolescents Aged 13-17 Years - United States, 2018.
The Advisory Committee on Immunization Practices (ACIP) recommends routine vaccination of persons aged 11-12 years to protect against certain diseases, including human papillomavirus (HPV)-associated cancers, meningococcal disease, and pertussis (1). A booster dose of quadrivalent meningococcal conjugate vaccine (MenACWY) is recommended at age 16 years, and serogroup B meningococcal vaccine (MenB) may be administered to persons aged 16-23 years (1). To estimate vaccination coverage among adolescents in the United States, CDC analyzed data from the 2018 National Immunization Survey-Teen (NIS-Teen) which included 18,700 adolescents aged 13-17 years.* During 2017-2018, coverage with ≥1 dose of HPV vaccine increased from 65.5% to 68.1%, and the percentage of adolescents up-to-date† with the HPV vaccine series increased from 48.6% to 51.1%, although the increases were only observed among males. Vaccination coverage increases were also observed for ≥1 MenACWY dose (from 85.1% to 86.6%) and ≥2 MenACWY doses (from 44.3% to 50.8%). Coverage with tetanus and reduced diphtheria toxoids and acellular pertussis vaccine (Tdap) remained stable at 89%. Disparities in coverage by metropolitan statistical area (MSA)§ and health insurance status identified in previous years persisted (2). Coverage with ≥1 dose of HPV vaccine was higher among adolescents whose parents reported receiving a provider recommendation; however, prevalence of parents reporting receiving a recommendation for adolescent HPV vaccination varied by state (range = 60%-91%). Supporting providers to give strong recommendations and effectively address parental concerns remains a priority, especially in states and rural areas where provider recommendations were less commonly reported.


The role of correlated factors based on Pender health promotion model in brushing behavior in the 13-16 years old students of Guilan, Iran.
Tooth decay is one of the diseases that is closely related to people's behaviors and it can have adverse effects on their performance and their success in the future. Brushing twice a day is the simplest and most effective way to reduce tooth decay. The study aim was to determining the roles of correlational factors based on the Pender's health promotion model in brushing behavior of ninth grade students at urban public schools of Guilan province during the academic year 2019. The present study was cross-sectional and had a descriptive-analytical type. We performed the multi-stage random sampling on 761 ninth-grade students (374 girls and 387 boys) at urban public schools of six counties (ten cities) of Guilan province in 2019. The primary tool was a questionnaire on oral health behaviors focusing on brushing behavior. In the present study, which was conducted only on brushing behavior, we revised and changed the initial questionnaire during the sessions of the research team, and then confirmed its validity and reliability. The questionnaire consisted of three parts, demographic characteristics, constructs of health promotion model, and brushing behavior. We analyzed data in SPSS 21 using regression models. 20.1% of students brushed their teeth at least twice a day. Optimal behavior had a statistically significant relationship with parents' education level, and gender. Based on the regression model, the health promotion model constructs described 58% of the variance of the commitment to plan of action. Perceived self-efficacy, situational influences, and perceived barriers of action had significantly stronger relationships with commitment to plan of action respectively. Multiple logistic regression analysis indicated that one-unit increase in scores of commitment to plan of action and self-efficacy increased the chance of desired behavior by 12 and 14% respectively. Due to the low rate of brushing behavior in the students and the predictive power of the health promotion model in brushing behavior, we suggest planning and implementation of educational interventions for this group with an emphasis on influencing the commitment to plan of action, self-efficacy, and also the level of knowledge.


Side of onset in Parkinson's disease and alterations in religiosity: novel behavioral phenotypes.
Behavioral neurologists have long been interested in changes in religiosity following circumscribed brain lesions. Advances in neuroimaging and cognitive experimental techniques have been added to these classical lesion-correlational approaches in attempt to understand changes in religiosity due to brain damage. In this paper we assess processing dynamics of religious cognition in patients with Parkinson's disease (PD). We administered a four-condition story-based priming procedure, and then covertly probed for changes in religious belief. Story-based priming emphasized mortality salience, religious ritual, and beauty in nature (Aesthetic). In neurologically intact controls, religious belief-scores significantly increased following the Aesthetic prime condition. When comparing effects of right (RO) versus left onset (LO) in PD patients, a double-dissociation in religious belief-scores emerged based on prime condition. RO patients exhibited a significant increase in belief following the Aesthetic prime condition and LO patients significantly increased belief in the religious ritual prime condition. Results covaried with executive function measures. This suggests lateral cerebral specialization for ritual-based (left frontal) versus aesthetic-based (right frontal) religious cognition. Patient-centered individualized treatment plans should take religiosity into consideration as a complex disease-associated phenomenon connected to other clinical variables and health outcomes.


Air pollution and cardiovascular disease: the Paul Wood Lecture, British Cardiovascular Society 2021.
Air pollution is associated with up to 8.8 million excess deaths worldwide each year and is a major contributor to the global burden of disease. Cardiovascular conditions are the predominant cause for air pollution-related deaths and there is an urgent need to address the silent pandemic of air pollution on cardiovascular health. Air pollution exposure is associated with acute events like acute coronary syndrome and stroke, and with chronic conditions, such as atherosclerosis and heart failure. Several potential mechanisms have been proposed that link particle inhalation to cardiovascular disease including oxidative stress and inflammation, changes in autonomic balance and neuroendocrine regulation and the particle translocation into the circulation itself. This, in turn, can cause endothelial, vasomotor and fibrinolytic dysfunction and increased thrombogenicity and blood pressure which are implicated in the mediation of adverse cardiovascular events. Certain interventions can help mitigate these adverse effects. At an individual level, this includes the use of a facemask and indoor air purification systems. At an environmental level, interventions reducing the generation or release of combustion-derived pollutants are key and include public health policies to facilitate active transport, cleaner sources of energy and reductions in vehicular and fossil fuel emissions. In this review, we summarise the key pathways and mechanisms that draw together how air pollution can lead to adverse cardiovascular effects, as well as explore potential interventions to reduce the burden of air pollution-induced cardiovascular morbidity and mortality.


Modulatory Influence of Segmented Filamentous Bacteria on Transcriptomic Response of Gnotobiotic Mice Exposed to TCDD.
Environmental toxicants such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR), are known to induce host toxicity and structural shifts in the gut microbiota. Key bacterial populations with similar or opposing functional responses to AhR ligand exposure may potentially help regulate expression of genes associated with immune dysfunction. To examine this question and the mechanisms for AhR ligand-induced bacterial shifts, C57BL/6 gnotobiotic mice were colonized with and without segmented filamentous bacteria (SFB) - an immune activator. Mice were also colonized with polysaccharide A producing Bacteroides fragilis - an immune suppressor to serve as a commensal background. Following colonization, mice were administered TCDD (30 μg/kg) every 4 days for 28 days by oral gavage. Quantified with the nCounter® mouse immunology panel, opposing responses in ileal gene expression (e.g., genes associated with T-cell differentiation via the class II major histocompatibility complex) as a result of TCDD dosing and SFB colonization were observed. Genes that responded to TCDD in the presence of SFB did not show a significant response in the absence of SFB, and vice versa. Regulatory T-cells examined in the mesenteric lymph-nodes, spleen, and blood were also less impacted by TCDD in mice colonized with SFB. TCDD-induced shifts in abundance of SFB and B. fragilis compared with previous studies in mice with a traditional gut microbiome. With regard to the mouse model colonized with individual populations, results indicate that TCDD-induced host response was significantly modulated by the presence of SFB in the gut microbiome, providing insight into therapeutic potential between AhR ligands and key commensals.


Combined chemotherapy and radiation therapy for non-small-cell lung cancer.
In a previous study of patients with recurrent or disseminated non-small-cell lung cancer (NSCLC), the combination of bleomycin, etoposide, and cisplatin (BEP) produced objective responses in ten of 17 (59%) patients with large-cell anaplastic carcinoma and in 14 of 35 (40%) with squamous-cell carcinoma. These results prompted a pilot study of combined modality therapy in which two cycles of BEP were administered prior to split-course radiation therapy. Thirty patients with surgically unresectable stage II or III squamous- or large-cell cancer, were entered into the study, of whom 25 were evaluable for response to chemotherapy. One patient (4%) had a complete response (CR), ten (40%) with measureable disease had a partial response (PR), and four (16%) with evaluable disease had significant disease regression prior to radiotherapy (overall response rate, 60%). After radiotherapy, six of 22 (27%) evaluable patients achieved a CR, and six (27%) a PR, for an overall response rate of 55%. Symptom control was achieved with chemotherapy in the majority of patients. The median survival time after the initiation of BEP had not been reached at 52 weeks. The results of this pilot study suggest that a phase III study comparing BEP plus radiation therapy with radiation therapy alone should be undertaken in this subgroup of patients with NSCLC.


Study of written communication between general practitioners and departments of child psychiatry.
Previous studies have pointed to the general dissatisfaction with written communication between general practitioners and medical specialists, in terms of quality and usefulness to both groups. This study examined the letters of referral from general practitioners to two child psychiatry departments and the replies of the psychiatric staff, and looked at the information exchanged in the light of the needs of both groups. It was concluded that the requirements of both psychiatric staff and general practitioners were being met to a limited extent, but that there was room for improvementon both sides.


[The development of public health education: the Mauritius experience].
A public course has been initiated in 1990 in Mauritius for covering the national growing needs of public health specialists. This training course was organized jointly by the Ministry of Health, the University of Bordeaux II and the French Cooperation. After 3 sessions dedicated specifically to the Mauritian physicians, the course has been re-designed for the needs of the other countries of the region. A feasibility study performed in 1994 in the countries of the Indian ocean region showed that during the past decade, the district level had become the focus point to integrate the health programs. This process has progressively transferred a wider and stronger part of the responsibilities from the central level to the district level and the survey showed that most of the health district managers were physicians that did not have the proper background for carrying such responsibilities. According to these results, a course curriculum was created by the Mauritian Ministry of Health and the University of Bordeaux II and submitted to various organisms supporting health program development in the region. This proposal was strongly supported by several agencies (the french Cooperation, Unicef, WHO, World Bank...) who agreed to sponsor candidates for that training course. The first session was organized in 1995, a second one in 1996. This training course is targeted to the medical doctors who are in charge of the management of health services at the district level. It is divided in two parts: A six-weeks intensive training course performed in Mauritius that include formal teaching and practical exercises in small groups for a total of 210 hours. The curriculum is mainly targeted on the various aspects of management as the management of health information (biostatistics epidemiology and computing), the management of human resources, financial resources and material resources. In addition to these main topics, there is an introduction to pedagogy, communication skills and applied research methodology. Following this six-weeks, training the students come back to work in their country and have 8 months to perform a thesis supervised by a local public health specialist. The subject of the thesis has to be closely related with one of the topic taught and should provide an obvious improvement for the public health situation in the district where this physician is acting. In 1995, 22 candidates attend to the course (13 from Madagascar, 4 from Mauritius, 3 from Comoros, 1 from Angola, 1 from Equatorial Guinea and 1 from Tchad), 19 had successively completed all the modules and got the diploma of public health delivered by the University of Bordeaux II. This diploma has been recognized as an equivalent to a master in public health in Mauritius. The evaluation of the courses-performed by the students, the teachers and the financial agencies gave a very positive results although the workload was considered as too important for a six-weeks training course. The recommendations of the 1995 session were included in the 1996 programs which is still on going for 23 candidates. The 97 session will probably extend the number of students up to 40, divided in 4 subgroups for practical exercises. In parallel to the course, a quarterly bulletin will be created and sent to the present and past candidates of this course in order to support a continuous medical education training program targeted to the district physicians.