How to Select the Lower Instrumented Vertebra in Traditional Growing Rods Index Surgery.
There are still no consensus criteria on how to select the lower instrumented vertebra (LIV) for traditional growing rods (TGRs) at index surgery. The aim was to evaluate whether the criteria used for adolescent idiopathic scoliosis fusion adapts to early onset scoliosis (EOS). Retrospective analysis of prospectively longitudinal collected data in a consecutive cohort of patients with EOS treated with TGR, expanding from index surgery to 2 years after graduation. The LIV was analyzed regarding its relation to the stable vertebra (SV), substantially touched vertebra (STV), and not STV (NSTV). Failure of LIV selection was considered when revision surgery with distal extension was needed during follow up, due to adding on (ΔLIV tilt > 10°). A total of 25 patients met inclusion criteria. Mean age was 8.6 ± 3 (at index surgery), 15.1 ± 1.8 (at graduation), and 17.8 ± 1.6 (at final follow up). The most frequent LIV at index surgery was L3 (13/25); in 13 cases, STV was selected as LIV; in 7, it was NSTV; and in 5, SV on the standard postero-anterior radiographs. During follow up, a significant increase in the mean LIV tilt (P = .049) and distal junctional angle (P = .017) was found. Nine of the 25 patients (36%) developed adding on: 20% (1/5) of those with LIV at SV, 38.5% (5/13) at STV, and 42.8% (3/7) at NSTV. Of those 9 cases of adding on, only four needed distal extension (mean LIV tilt = 17.6°): 2 STV patients (15.4%), and 2 NSTV patients (28.6%). None of the patients with the LIV chosen at SV needed distal extension due to adding on. The more cranial the selection of the LIV above the SV, the higher the risk of adding on and of revision surgery with distal extension during follow up. Saving motion segments could be justified by choosing STV as LIV because the need for distal extension is not high, and it can be scheduled during lengthening procedures or at graduation surgery. 4. Choosing the correct LIV in TGR index surgery is crucial to have a secure distal foundation, control and correct the deformity during growth, and save distal segments to allow growth and mobility.


Prime-boost immunization with DNA vaccine: mucosal route of administration changes the rules.
In this study we assessed prime-boost immunization strategies with a DNA vaccine (gB DNA) and attenuated recombinant vaccinia virus vector (rvacgB), both encoding the gB protein of HSV, for their effectiveness at inducing mucosal as well as systemic immunity to HSV. Confirming the reports of others, systemic priming with gB DNA and systemic boosting with rvacgB were the most effective means of inducing serum Ab and splenic T cell responses. Nevertheless, the systemic prime-boost approach failed to induce detectable humoral or T cell responses at mucosal sites. However, such responses, at both proximal and distal locations, were induced if immunizations, especially the priming dose, were administered mucosally. Curiously, whereas optimal immunity with systemic priming and boosting occurred when gB DNA was used to prime and rvacgB was used as a boost, mucosal responses were optimal when animals were mucosally primed with rvacgB and boosted with gB DNA given mucosally. Furthermore, notable mucosal responses also occurred in animals mucosally primed with rvacgB and subsequently boosted systemically with gB DNA. Because the mucosal prime-boost immunization protocol also induced excellent systemic immune responses, the approach should be useful to vaccinate against agents for which both mucosal and systemic immunity are important for protection.


Factors Associated with the Combined Use of Antidepressants and Benzodiazepines in Major Depression: A Case-Control Study.
The aim of this study was to identify the factors associated with the combined use of antidepressants and benzodiazepines (BDZs) in patients with major depression. We conducted a case-control study in the public health service of the city of São Paulo, Brazil. The participants were all patients being treated with antidepressants, who were diagnosed with major depression. Patients who received a combination of antidepressants and BDZs were classified as cases, and those who used only antidepressants, as controls. Data were obtained from a pharmacy database, medical records and interviews with the healthcare team. The association of predisposing factors for combined therapy was analysed using logistic regression analysis, and the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Of the 1355 users of antidepressants, 265 had major depression, of whom 138 were cases and 127 were controls. The factors associated with combined use were age older than 35 years (OR 2.2, 95% CI 1.0-4.7), absence of comorbidities (OR 2.3, 95% CI 1.4-4.1) and no use of other drugs (OR 1.9, 95% CI 1.1-3.3). Patients with combined use were more likely to exhibit inadequate prescribing, including inappropriate antidepressants (OR 4.7, 95% CI 2.2-9.9), inadequate dosages (OR 3.62, 95% CI 1.4-9.6) and/or a non-recommended duration (OR 66.6, 95% CI 18.4-240.7). The factors identified showed the groups most susceptible to combined use in this population, who in turn are more likely to receive inappropriate prescriptions.


Mutant RB1 enhances therapeutic efficacy of PARPis in lung adenocarcinoma by triggering the cGAS/STING pathway.
Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved for cancer therapy according to their synthetic lethal interactions, and clinical trials have been applied in non-small cell lung cancer. However, the therapeutic efficacy of PARPis in lung adenocarcinoma (LUAD) is still unknown. We explored the effect of a mutated retinoblastoma gene (RB1) on PARPi sensitivity in LUAD. Bioinformatic screening was performed to identify PARPi-sensitive biomarkers. Here, we showed that viability of LUAD cell lines with mutated RB1 was significantly decreased by PARPis (niraparib, rucaparib, and olaparib). RB1 deficiency induced genomic instability, prompted cytosolic double-stranded DNA (dsDNA) formation, activated the cGAS/STING pathway, and upregulated downstream chemokines CCL5 and CXCL10, triggering immune cell infiltration. Xenograft experiments indicated that PARPi treatment reduced tumorigenesis in RB1-KO mice. Additionally, single-cell RNA sequencing analysis showed that malignant cells with downregulated expression of RB1 had more communications with other cell types, exhibiting activation of specific signaling such as GAS, IFN response, and antigen-presenting and cytokine activities. Our findings suggest that RB1 mutation mediates the sensitivity to PARPis through a synthetic lethal effect by triggering the cGAS/STING pathway and upregulation of immune infiltration in LUAD, which may be a potential therapeutic strategy.


Induction of antitumor immunity using dendritic cells electroporated with Polo-like kinase 1 (Plk1) mRNA in murine tumor models.
Polo-like kinase 1 (Plk1), a serine-threonine kinase, plays a key role in the regulation of the cell cycle. Elevated Plk1 expression in various cancers is correlated with poor prognosis and poor patient survival rates. Several Plk1 inhibitors are currently being developed as potential treatments for cancer. In the present study, we investigated whether dendritic cells (DC) electroporated with mouse Plk1RNA (mPlk1RNA/DC) can induce Plk1-specific immune responses and exert antitumor effects in various murine tumor models. Overexpression of Plk1 protein was confirmed in several mouse and human tumor cell lines and various cancer tissues. Furthermore, Plk1-specific CD4(+) and CD8(+) T cells were induced by vaccination with mPlk1RNA/DC and the cytotoxic activity of the T cells was demonstrated against several Plk1-expressing tumor cell lines. Vaccination with mPlk1RNA/DC inhibited the growth of MC-38 and B16F10 tumors in C57BL/6 mice and the growth of CT26 tumors in BALB/c mice. Depletion of CD8(+) T cells reversed the inhibition of tumor growth by mPlk1RNA/DC vaccination. Homologous human Plk1RNA-electroporated DC also inhibited tumor growth in MC-38 tumor-bearing mice. In addition, Plk1-specific cytotoxic T lymphocytes from PBMC of healthy donors could be induced using autologous monocyte-derived DC electroporated with RNA encoding the whole gene of human Plk1. Taken together, the results of the present study suggest that Plk1 could be a universal tumor antigen recognized by cytotoxic T lymphocytes for cancer immunotherapy.


Critical Packing Density of Water-Mediated Nonstick Self-Assembled Monolayer Coatings.
Nanoparticle-mineral surface interactions are relevant in many biological and geological applications. We have previously studied nanoparticle coatings based on closely packed bicomponent polyol-fluoroalkane self-assembled monolayers (SAMs) that can have tunable stickiness on calcite surfaces by changing the compositions of fluoroalkanes in SAMs, where the coatings show nonstick properties if fluoroalkanes can effectively perturb hydration layers on calcite surfaces. However, when applying coatings on nanoparticles, it can be challenging to predict the maximum achievable coating density. Here, we study how would water-mediated SAM-calcite interactions change with different SAM coating densities. Molecular dynamics simulations show that compositionally repulsive, closely packed polyol-fluoroalkane SAMs become adhesive to calcite surfaces with decreasing coating densities. Our modeling shows that this results from the collapsing of fluoroalkanes into the voids of SAMs, where fluoroalkanes can no longer perturb hydration layers on calcite surfaces. Interestingly, we find that the nonstick-stick transition occurs when the volume fractions of the voids on SAMs are greater than the volume fractions of hydrophilic coating molecules.


Treatment of recurrent earlobe keloids.
The use of complete surgical excision and postoperative pressure with steroid-impregnated tape has been evaluated in fifty-seven patients with recurrent earlobe keloids. All patients underwent conventional treatment previously, which was not curative. In a four-year follow-up of the method described here, four recurrences occurred. Patients' failure to use the recommended pressure earring and alteration in endocrine balance were noted in three of the four patients with recurrent keloids.


Wound metastases following laparoscopic and open surgery for abdominal cancer in a rat model.
The recent application of laparoscopic resection techniques to malignant disease has raised safety concerns due to metastasis to surgical access wounds. The significance and incidence of this problem are controversial. In the present study a rat model, in which an implanted tumour was lacerated, was used to investigate whether application of laparoscopic techniques for malignant abdominal disease leads to an increased risk of tumour dissemination and implantation within the peritoneal cavity, and abdominal wall wounds. Malignant cells were implanted into the abdominal wall of 42 rats, resulting 7 days later in the growth of a tumour measuring 20-25 mm in diameter. There were three control groups: no surgery (n = 6); blunt manipulation of the tumour laparoscopically (n = 6); and blunt manipulation of the tumour at laparotomy (n = 6). Twenty-four rats underwent surgical laceration of the tumour capsule at either laparoscopy (n = 12) or laparotomy (n = 12). All rats were killed 1 week later, and examined for macroscopic evidence of tumour metastasis. The abdominal surgical wounds were excised for independent microscopic examination by a histopathologist. Growth of the primary tumour was greater in rats that had an operation than in unoperated controls, and was greater after laparotomy. However, wound metastases were five times more likely after laparoscopic tumour laceration than after the same procedure through an open incision (ten of 12 rats versus two of 12, P = 0.0033). Wound metastases following laparoscopic tumour manipulation are an important and real problem, with significant implications for the application of laparoscopic techniques to excise malignant disease in humans.


An early event in the interferon-induced transmembrane signaling process.
Human interferon stimulates a transient two- to threefold increase in the concentration of diacylglycerol and inositol tris-phosphate within 15 to 30 seconds of cell exposure to interferon. Antibodies to interferon inhibit this effect. The stimulation was measurable in isolated cell membranes exposed to interferon. Human alpha and beta, but not gamma, interferon stimulate this increase in cells containing the appropriate interferon receptor. The effect was proportional to the number of interferon receptors. Both the diacylglycerol increase and antiviral effects induced by interferon could be correlated in terms of dose dependence. Thus, a transient diacylglycerol increase is an early event in the interferon-induced transmembrane signaling process.


Altered proteoglycan synthesis by micromelial limbs induced by 6-aminonicotinamide. Appearance of abnormal forms of cartilage-characteristic proteoglycan (PG-H).
Since administration of 6-aminonicotinamide (10 micrograms) to day-4 chick embryos in ovo was shown to induce micromelial limbs, biosynthesis of cartilage-characteristic proteoglycan-H (PG-H) as an important index of limb chondrogenesis was examined in day-7 normal and micromelial hind limbs by biochemical and immunological methods. (1) Metabolic labelling of the micromelial limbs with [6-3H]glucosamine and either [35S]sulphate or [35S]methionine, followed by analyses of labelled PG-H by glycerol density-gradient centrifugation under dissociative conditions, showed a marked reduction in the PG-H synthesis. (2) PG-H synthesized by the micromelial limbs was much lower than that synthesized by the normal limbs in the biosynthetic ratio of chondroitin sulphate to keratan sulphate and glycoprotein-type oligosaccharide, although no significant difference was observed in the immunological properties of these proteoglycans. (3) The degree of sulphation of chondroitin sulphates of PG-H was lowered in the micromelial limbs as judged by the increase of unsulphated disaccharide (delta Di-OS) released by chrondroitinase ABC digestion, although there were no significant differences between the normal and the micromelial limbs in the average molecular size (Mr = 38,000) of labelled chondroitin sulphates of PG-H. (4) Addition of beta-D-xyloside, an artificial initiator for chondroitin sulphate synthesis, to the micromelial limbs in culture recovered the incorporation of labelled glucosamine into chondroitin sulphate to that comparable with the normal control with beta-D-xyloside, although the incorporation of [35S]sulphate was lower in the micromelia than in the control with beta-D-xyloside. These results suggest that the reduction in the biosynthesis of the PG-H as well as the production of altered forms of PG-H induced by 6-aminonicotinamide during a critical period of limb morphogenesis may be an important factor for the micromelia.


Calcium carbonate polymorph selection in fish otoliths: a key role of phosphorylation of Starmaker-like protein.
Fish otoliths are calcium carbonate biominerals found in the inner ear commonly used for tracking fish biochronologies and as a model system for biomineralization. The process of fish otolith formation is biologically controlled by numerous biomacromolecules which not only affect crystal size, shape, mechanical properties, but also selection of calcium carbonate polymorph (e.g., aragonite, vaterite). The proteinaceous control over calcium carbonate polymorph selection occurs in many other species (e.g., corals, mollusks, echinoderms) but the exact mechanism of protein interactions with calcium and carbonate ions - constituents of CaCO3 - are not fully elucidated. Herein, we focus on a native Starmaker-like protein isolated from vaterite asteriscus otoliths from Cyprinus carpio. The proteomic studies show the presence of the phosphorylated protein in vaterite otoliths. In a series of in vitro mineralization experiments with Starmaker-like, we show that native phosphorylation is a crucial determinant for the selection of a crystal's polymorphic form. This is the first report showing that the switch in calcium carbonate phase depends on the phosphorylation pattern of a single isolated protein. STATEMENT OF SIGNIFICANCE: Calcium carbonate has numerous applications in industry and medicine. However, we still do not understand the mechanism of biologically driven polymorph selection which results in specific biomineral properties. Previous work on calcium carbonate biominerals showed that either several macromolecular factors or high magnesium concentration (non-physiological) are required for proper polymorph selection (e.g., in mollusk shells, corals and otoliths). In this work, we showed for the first time that protein phosphorylation is a crucial factor for controlling the calcium carbonate crystal phase. This is important because a single protein from the otolith organic matrix could switch between polymorphs depending on the phosphorylation level. It seems that protein post-translational modifications (native, not artificial) are more important for biomolecular control of crystal growth than previously considered.


Laryngeal electromyography: an evidence-based review.
This article reports on an evidence-based review of laryngeal electromyography (EMG) as a technique for use in the diagnosis, prognosis, and treatment of laryngeal movement disorders including the laryngeal dystonias, vocal fold paralysis, and other neurolaryngological disorders. The authors performed a systematic review of the medical literature from 1944 through 2001 on the clinical application of EMG to laryngeal disorders. Thirty-three of the 584 articles met the predefined inclusion criteria. The evidence demonstrated that in a double-blind treatment trial of botulinum toxin versus saline, laryngeal EMG used to guide injections into the thyroarytenoid muscle in persons with adductor spasmodic dysphonia was beneficial. A cross-over comparison between laryngeal EMG-guided injection and endoscopic injection of botulinum toxin into the posterior cricoarytenoid muscle in abductor spasmodic dysphonia found no significant difference between the two techniques and no significant treatment benefit. Based on the evidence, laryngeal EMG is possibly useful for the injection of botulinum toxin into the thyroarytenoid muscle in the treatment of adductor spasmodic dysphonia. There were no evidence-based data sufficient to support or refute the value of laryngeal EMG for the other uses investigated, although there is extensive anecdotal literature suggesting that it is useful for each of them. There is an urgent need for evidence-based research addressing the use of laryngeal EMG for other applications.


[Changes in the protein composition of chromatin in the presence of supplementary total histone].
Relationships have been studied between call thymus chromatin isolated in a medium of low ionic strength (0.7 mM Na-phosphate buffer, pH 7) and total histone which was added in different amounts (up to a 40-fold excess) with respect to chromatin DNA. The maximum protein/DNA ratio in chromatin-histone complexes being formed was 3.27. It has been demonstrated for the first time that with an elevation in the amount of supplementary total histone there took place a release of natural histones of chromatin, first of HI and then of H2A and H2B. It is concluded that supplementary histone interacts with DNA, modifying its interplay and chromatin protein even though the dissociation is not fixed yet.


Necessary alternatives: patients' views of asthma treatment.
This article is based on semistructured interviews and focus groups conducted with 27 asthma patients in The Netherlands who chose complementary and alternative medicine (CAM) for treatment of their condition. All subjects were contacted through an online forum for asthma patients hosted by the Dutch Asthma Foundation. Nineteen subjects (12 women and seven men) between the ages of 29 and 65 years participated in the interviews, held between June 2009 and January 2010. All of the participating subjects had experience with conventional medications, including anti-inflammatory corticosteroids and bronchodilators. For the focus group meeting, held in February 2010, the sample included seven subjects (four women and three men) between the ages of 31 and 46 years, none of whom had ever used conventional medication and all of whom were using CAM. All subjects in the sample had been diagnosed with asthma by their physician or lung specialist. The study examined the causes of patient noncompliance with the prescribed medical regime. It is argued that evidence-based rationality on the part of subjects is an overlooked dimension of their experience of asthma. This study demonstrates the role that the patients' social network, including medical practitioners, friends, and family, and other asthmatics, plays in the process of decision-making and choices about treating asthma. It also demonstrates the role of patients' information-searching strategies. The author concludes that patient noncompliance with commonly prescribed medication and selection of alternative medical treatment is less a matter of denial of their diagnosis or the severity of their illness, but more a matter of choice informed by evidence-based rationality.


Cognitive functioning in patients with chronic obstructive pulmonary disease and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls.
To examine neuropsychologic functions in patients with chronic obstructive pulmonary disease (COPD) and mild hypoxemia compared with patients with mild Alzheimer disease and normal controls. Cognitive deficits have been documented in patients with COPD, but few studies have compared the neuropsychologic status of these patients with that of other neurologic groups. Cognitive test results from 32 patients with COPD and mild hypoxemia (mean age, 70.3 years; mean education, 13.2 years; mean partial arterial oxygen pressure, 68.8 mm Hg) who had no neurologic symptoms were compared with 31 subjects with mild Alzheimer disease (AD) and 31 normal controls similar in age, education, and sex. Seventy-three percent of the patients with COPD were receiving supplementary oxygen. Significant group differences across 11 cognitive scores were found using analysis of variance, and post hoc analyses indicated that patients with mild AD performed significantly worse than normal controls and patients with COPD on most tests. The group with COPD and the group with AD demonstrated lower letter fluency compared with controls. Although the patients with COPD performed significantly worse than controls on verbal fluency tasks, they were not in the clinically impaired range, and, overall, the group with COPD was similar to the controls on most cognitive tests. These findings suggest that many patients with COPD and mild hypoxemia who don't have neuropsychiatric histories may perform normally on cognitive measures. Oxygen therapy may partially account for preservation of cognitive function in these patients. Results also suggest that patients with COPD and normal controls can be readily distinguished from patients with mild AD based on levels and patterns of neuropsychologic test results. Any significant cognitive deficits in patients with mildly hypoxemic COPD may warrant continued neurologic evaluation.


Prepubertal Continuous Dietary Folate Fortification Enhances the Brain Function of Adult Mice by Modulating Antioxidant Status, Inflammation, and Brain Neurotransmitter Levels.
The benefits of folic acid supplementation have been documented in several studies. However, while evidence exists regarding its benefits for growth and haematologic parameters, its possible effects on the brain have been less examined. The study aimed to examine the benefits of dietary folic acid supplementation (beginning in the prepubertal period) on neurobehaviour, oxidative stress, inflammatory parameters, and neurotransmitter levels in adult mice. Forty-eight prepubertal male mice were assigned into four groups of 12 animals each. Mice were grouped into normal control (fed standard diet) and three groups fed folic acid supplemented diet at 2.5, 5, and 10 mg/kg of feed. Animals were fed a standard diet or folic acid-supplemented diet for eight weeks during which food intake and body weight were assessed. On postnatal day 78, animals were exposed to the open-field, Y-maze, radial arm maze, elevated plus maze, bar test, and models of behavioural despair. 24 hours after the last behavioural test, animals were made to fast overnight and then sacrificed by cervical dislocation. Blood was then taken for the assessment of blood glucose, leptin, and insulin levels. Homogenates of brain tissue were prepared and used for the assessment of biochemical parameters. Results showed a concentration-dependent increase in body weight, and improved antiox-idant status, memory scores, and acetylcholine levels. Also, a decrease in food intake, blood glucose, insulin, and leptin levels was observed. A reduction in open-field behaviour, anxiety-related behaviour, and proinflammatory markers, was also observed. The beneficial effect of prepubertal continuous dietary folate fortification on the brain (as the animal ages) has been shown in this study.


Noise refocusing in a five-blade neutron interferometer.
We provide a quantum information description of a proposed five-blade neutron interferometer geometry and show that it is robust against low-frequency mechanical vibrations and dephasing due to the dynamical phase. The extent to which the dynamical phase affects the contrast in a neutron interferometer is experimentally shown. In our model, we consider the coherent evolution of a neutron wavepacket in an interferometer crystal blade and simulate the effect of mechanical vibrations and momentum spread of the neutron through the interferometer. The standard three-blade neutron interferometer is shown to be immune to dynamical phase noise but prone to noise from mechanical vibrations, and the decoherence free subspace four-blade neutron interferometer is shown to be immune to mechanical vibration noise but prone to noise from the dynamical phase. Here, we propose a five-blade neutron interferometer and show that it is immune to both low-frequency mechanical vibration noise and dynamical phase noise.


The persistent problem of malaria: addressing the fundamental causes of a global killer.
Despite decades of global eradication and control efforts and explosive global economic development, malaria is the most important vector-borne disease of our day, killing more people today than 40 years ago and affecting millions worldwide, particularly poor residents of tropical regions. Global eradication efforts from the 1950s through the 1980s largely failed, leaving vector and parasite resistance in their wake. The persistence of malaria and the magnitude of its effects call for an action paradigm that links the traditional proximal arenas of intervention with malaria's fundamental causes by addressing the environmental, economic, and political dimensions of risk. We explore the more distal determinants of malaria burden that create underlying vulnerabilities, evaluating malaria risk as a function of socioeconomic context, environmental conditions, global inequality, systems of health care provision, and research. We recommend that future action to combat malaria be directed by a broad-spectrum approach that meaningfully addresses both the proximal and fundamental causes of this disease.


Intrauterine Device Placement Success for Adolescents and Young Adults at Community-based Reproductive Health Clinics.
Despite the endorsement of intrauterine device (IUD) use in adolescents and young adults (AYA) by leading professional organizations and demonstrated acceptance and desirability by AYA, clinicians may worry about procedural difficulty of IUD device placement in younger patients. The aim of this study was to evaluate the clinical outcomes of first-attempt IUD placement in an AYA population by vaginal delivery (VD) history. We performed a retrospective cohort study of patients <25 years at reproductive health clinics with an IUD placement attempt between January 1-August 31, 2017. We abstracted sociodemographic characteristics, pregnancy history, and procedural characteristics including complications. Bivariate analyses compared successful first attempt IUD placement by VD history. We also assessed frequency of secondary clinical outcomes including ancillary measures used, provider type, symptoms reported during the procedure, and complications. We included 1,325 participants (median age=21.3 years) including 42 (3.2%) with a prior VD. Nearly all IUD placements were successful at first attempt (n=1,301, 98.2%) and performed by advanced practice clinicians (n=1,314, 99.2%). First-attempt IUD placement success was similar in those participants with and without VD (p>0.999). Ancillary measures other than NSAIDS were used infrequently (n=16, 3.6%.) .(Among participants with an unsuccessful placement, 66.7% returned, and all had a successful IUD placement on the second attempt. Documented complications within six months of placement were rare (n=29) and mostly comprised of expulsions (n=27, 93.1%). IUD placement success among AYA at community-based reproductive health clinics is very high and is not associated with a history of prior vaginal delivery.


Adverse birth outcomes related to concentrations of per- and polyfluoroalkyl substances (PFAS) in maternal blood collected from pregnant women in 1960-1966.
Prior animal and epidemiological studies suggest that per- and polyfluoroalkyl substances (PFAS) exposure may be associated with reduced birth weight. However, results from prior studies evaluated a relatively small set of PFAS. Determine associations of gestational PFAS concentrations in maternal serum samples banked for 60 years with birth outcomes. We used data from 97 pregnant women from Boston and Providence that enrolled in the Collaborative Perinatal Project (CPP) study (1960-1966). We quantified concentrations of 27 PFAS in maternal serum in pregnancy and measured infant weight, height and ponderal index at birth. Covariate-adjusted associations between 11 PFAS concentrations (>75% detection limits) and birth outcomes were estimated using linear regression methods. Median concentrations of PFOA, PFNA, PFHxS, and PFOS were 6.189, 0.330, 14.432, and 38.170 ng/mL, respectively. We found that elevated PFAS concentrations during pregnancy were significantly associated with lower birth weight and ponderal index at birth, but no significant associations were found with birth length. Specifically, infants born to women with PFAS concentrations ≥ median levels had significantly lower birth weight (PFOS: β = -0.323, P = 0.006; PFHxS: β = -0.292, P = 0.015; PFOA: β = -0.233, P = 0.03; PFHpS: β = -0.239, P = 0.023; PFNA: β = -0.239, P = 0.017). Similarly, women with PFAS concentrations ≥ median levels had significantly lower ponderal index (PFHxS: β = -0.168, P = 0.020; PFHxA: β = -0.148, P = 0.018). Using data from this US-based cohort study, we found that 1) maternal PFAS levels from the 1960s exceeded values in contemporaneous populations and 2) that gestational concentrations of certain PFAS were associated with lower birth weight and infant ponderal index. Additional studies with larger sample size are needed to further examine the associations of gestational exposure to individual PFAS and their mixtures with adverse birth outcomes.


Development of a low-cost imaging system for remote mosquito surveillance.
Targeted vector control strategies aiming to prevent mosquito borne disease are severely limited by the logistical burden of vector surveillance, the monitoring of an area to understand mosquito species composition, abundance and spatial distribution. We describe development of an imaging system within a mosquito trap to remotely identify caught mosquitoes, including selection of the image resolution requirement, a design to meet that specification, and evaluation of the system. The necessary trap image resolution was determined to be 16 lp/mm, or 31.25um. An optics system meeting these specifications was implemented in a BG-GAT mosquito trap. Its ability to provide images suitable for accurate specimen identification was evaluated by providing entomologists with images of individual specimens, taken either with a microscope or within the trap and asking them to provide a species identification, then comparing these results. No difference in identification accuracy between the microscope and the trap images was found; however, due to limitations of human species classification from a single image, the system is only able to provide accurate genus-level mosquito classification. Further integration of this system with machine learning computer vision algorithms has the potential to provide near-real time mosquito surveillance data at the species level.


Spatially adaptive multiplicative noise image denoising technique.
A new image denoising technique in the wavelet transform domain for multiplicative noise is presented. Unlike most existing techniques, this approach does not require prior modeling of either the image or the noise statistics. It uses the variance of the detail wavelet coefficients to decide whether to smooth or to preserve these coefficients. The approach takes advantage of wavelet transform property in generating three detail subimages each providing specific information with certain feature directivity. This allows the ability to combine information provided by different detail subimages to direct the filtering operation. The algorithm uses the hypothesis test based on the F-distribution to decide whether detail wavelet coefficients are due to image related features or they are due to noise. The effectiveness of the proposed technique is tested for orthogonal as well as biorthogonal mother wavelets in order to study the effect of the smoothing process under different wavelet types.


The influence of the hydrophilic-lipophilic environment on the structure of silk fibroin protein.
The present study examines the influence of the hydrophilic-lipophilic environment, mediated by small molecules, on the structural changes in silk protein fibroin. Small molecules mediate the various hydrophilic-lipophilic balances (HLBs) that impact the organisation of silk protein chains. Changes in the silk fibroin structure due to additives are related to the HLB value. At HLB > 10, silk fibroin primarily forms Silk I crystalline structures. Small molecules with HLB < 8.9 primarily induce the formation of Silk II crystalline structures. When 8.9 < HLB < 10, the crystalline structure of silk is related to the content of small molecules. The Silk I structure is primarily formed when the content of small molecules is low, whereas the Silk II structure is formed when the small molecule content is high. The structure of silk fibroin is maintained by regulating the HLB in the fibroin environment. This type of control for the functional design of materials may play a role in fine-tuning the biomaterial properties of silk fibroin protein.


The reliability of two different cybex isokinetic systems.
The ability to accurately assess the strength of a variety of muscles is basic to professionals in a number of fields. The purposes of this study were to determine: 1) the intertest reliability of muscular strength utilizing two different Cybex II(R) isokinetic dynamometry systems and 2) reliability of peak torque values (PTV) obtained from two methods of data reduction [Cybex Data Reduction Computers (CDRC) and Cybex Strip Chart Recorders (SCR)]. Subjects (N = 50) were required to complete four knee extension/flexion cycles at two speeds (60 and 240 degrees /sec) on each of 2 test days which were separated by 1 day of rest. Correlation coefficients were used to determine the relationship between values obtained from two different Cybex systems and to determine the relationship of values obtained within each system from the CDRC and the SCR. ANOVA procedures were used to determine differences between values obtained using the two systems and between CDRC and SCR values obtained within a system. Correlation coefficients between CDRC and SCR PTVs indicated a strong relationship between values obtained within a system (r = 0.987 and r = 0.985 for Cybex A and B, respectively) and across systems (r = 0.983 and r = 0.982 for CDRC and SCR values, respectively). However, ANOVA results indicated that the Cybex II system (Cybex A) CDRC PTVs were higher (F = 5.64 and F = 23.90, p < 0.05 for extension and flexion, respectively) than those of the Cybex II+ system (Cybex B). No differences were noted between systems (F = 0.14 and F = 2.05, p > 0.05 for extension and flexion, respectively) for SCR PTVs. Clinicians should be aware that CDRC PTVs determined on different Cybex systems may not be comparable. However, SCR PTVs determined on different systems appear to be comparable. It should also be noted by clinicians that CDRCs and SCRs within the same system appear to be comparable. J Orthop Sports Phys Ther 1990;12(4):157-162.


Pharmacokinetics, metabolism, and excretion of the intestinal peptide transporter 1 (SLC15A1)-targeted prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-amino)propionyl]aminobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid (LY544344) in rats and dogs: assessment of first-pass bioactivation and dose linearity.
The peptidyl prodrug (1S,2S,5R,6S)-2-[(2'S)-(2-Amino)propionyl]a-minobicyclo[3.1.0.]hexen-2,6-dicarboxylic acid, also known as LY544344, was discovered to improve the oral bioavailability of the parent drug (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), a potent group II metabotropic glutamate receptor agonist. This prodrug has been shown to deliver high plasma concentrations of the active drug via intestinal peptide transporter 1 (SLC15A1) (PepT1)-mediated intestinal transport and presystemic hydrolysis in preclinical species. The current data describe the pharmacokinetic behavior of LY544344 and LY354740, with a specific focus on the first-pass activation processes and dose linearity in rats and dogs. The PepT1 transporter makes an attractive prodrug target because of its high capacity and relatively broad substrate specificity. This was demonstrated by the wide dose proportionality observed in both species (up to 1000 mg/kg in rats and 140 mg/kg in dogs). After oral administration of LY544344, absorption and bioactivation were extensive and rapid, with greater than 97% of prodrug hydrolysis occurring before its appearance in the hepatic portal vein. Systemic activation was likewise extensive, with 100% conversion of a 7-mg/kg intravenous dose in dogs. Radiolabeled studies confirmed that hydrolysis to LY354740 was the only metabolic pathway and that the excretion pattern of the active drug was not altered by administration of the prodrug. These results demonstrate the nearly ideal prodrug properties of LY544344 and further validate the utility of the peptide transporter-directed approach to prodrug design.


[Adolescent sexuality in rural Norway 1997-2001].
In order to understand and prevent unwanted health consequences related to sexual behaviour, we need to know the status and changes of sexual behaviour in adolescence. In 1997 and 2001, surveys were conducted including a total of 1665 adolescents and young adults aged 15 to 24 (response rate > 90%) in secondary schools in a small town in a rural district in Norway. We analysed frequencies for boys and girls and estimated the change in median age of first intercourse. Logistic regression analyses of median age and other health-related parameters were performed. A greater proportion of the respondents reported sexual experience in 2001 than in 1997. Girls have their first intercourse at a younger age than boys, often with older partners. 21% of the girls had experienced unwanted sexual situations. Use of contraception has increased, though insignificantly. Still, 11% of sexually active girls had had unwanted pregnancies. First intercourse during adolescence is clearly associated with other forms of behaviour that compromise health. However, a great and stable majority report a stable partner during adolescence. In accordance with other studies we find changes in sexual behaviour over a short period of time among adolescents in rural Norway. Stable sexual relations may still be a protective factor.


Emptying and filling a tunnel bronze.
The classical orthorhombic layered phase of V2O5 has long been regarded as the thermodynamic sink for binary vanadium oxides and has found great practical utility as a result of its open framework and easily accessible redox states. Herein, we exploit a cation-exchange mechanism to synthesize a new stable tunnel-structured polymorph of V2O5 (ζ-V2O5) and demonstrate the subsequent ability of this framework to accommodate Li and Mg ions. The facile extraction and insertion of cations and stabilization of the novel tunnel framework is facilitated by the nanometer-sized dimensions of the materials, which leads to accommodation of strain without amorphization. The topotactic approach demonstrated here indicates not just novel intercalation chemistry accessible at nanoscale dimensions but also suggests a facile synthetic route to ternary vanadium oxide bronzes (M x V2O5) exhibiting intriguing physical properties that range from electronic phase transitions to charge ordering and superconductivity.


Amino acid sequence of a neurotoxic phospholipase A2 enzyme from common death adder (Acanthophis antracticus) venom.
The amino acid sequence of the first neurotoxic phospholipase A2, acanthoxin A1, purified from the venom of the Common death adder (Acanthophis antarcticus) was determined. Acanthoxin A1 shows high homology with other Australian elapid PLA2 neurotoxins, in particular Acanthin-I and -II, also from Death adder, Pseudexin A from the Red-bellied black snake (Pseudechis porphyriacus), and Pa-12a and Pa-9c from the King brown snake (Pseudechis australis). Acanthoxin A1 is a single-chain 118 amino acid residue PLA2, including 14 half cystine residues and the essential residues forming the ubiquitous calcium binding pocket and catalytic site. Critical analysis of the residues hypothesized to be important for neurotoxicity is presented.


The impact of a bladder training video versus standard urotherapy on quality of life of children with bladder and bowel dysfunction: A randomized controlled trial.
Bladder and bowel dysfunction (BBD) can negatively impact the quality of life (QoL) of children. Urotherapy is an accepted treatment option for BBD; however, literature that examines the impact of management options on QoL in this population is scarce. To determine whether a bladder training video (BTV) is non-inferior to standard urotherapy (SU) in improving QoL in children with BBD. Children aged 5-10 years and who scored ≥11 on the Vancouver Non-Neurogenic Lower Urinary Tract Dysfunction/Dysfunctional Elimination Syndrome Questionnaire (NLUTD/DES) were recruited from a pediatric tertiary care center. Children were excluded with known vesicoureteral reflux; spinal dysraphism; learning disabilities; recent urotherapy; and primary nocturnal enuresis. Quality of life was evaluated using the Pediatric Incontinence Quality-of-Life questionnaire (PinQ). Questionnaires were administered at the baseline and 3-month follow-up clinic visits. Following centralized electronic blocked randomization schemes to guarantee allocation concealment, patients were assigned to receive SU or BTV during their regular clinic visits. An intention-to-treat protocol was followed. Between-group baseline and follow-up QoL scores were compared using paired and unpaired t-tests, and linear regression analysis. Of the 539 BBD patients who were screened, 173 (32%) were eligible, and 150 (87%) were randomized. Of these, 143 (96%) completed the study, five (3%) were lost to follow-up, and two (1%) withdrew. In total, 140/143 (97%) completed the QoL questionnaire at baseline and follow-up. Mean follow-up time was 3.5 ± 1.1 months for BTV patients and 3.7 ± 1.6 months for SU. At baseline, BTV and SU patients had a mean QoL score of 26.6 ± 13 and 23.8 ± 12, respectively (P = 0.17). Between-group mean change in PinQ scores from baseline was not statistically significant (BTV: 6.25 ± 12.5 vs SU: 3.75 ± 12.2; P = 0.23; Summary Fig.). Significant predictors of positive change in QoL were: higher symptomatology score, with a correlation coefficient of 0.5 (95% CI: 0.2-0.9; P = 0.003), and worse baseline QoL score, with a correlation coefficient of 0.5 (95% CI: 0.4-0.7; P < 0.001). Overall, most patients had improved symptomatology and QoL scores. Significant and similar QoL changes from baseline to follow-up were observed in both the BTV and SU groups, suggesting that BTV was non-inferior to SU in improving QoL in children with BBD. Quality of life assessment should be considered when evaluating interventions for BBD, as it appears to be an important clinical outcome with which to determine urotherapy success.


Do Children and Adolescents With Mild Traumatic Brain Injury and Persistent Symptoms Benefit From Treatment? A Systematic Review.
To review the literature on treatment interventions in children and adolescents with mild traumatic brain injury (mTBI) and persistent symptoms. Systematic review of the literature yielding 6 studies incorporating 421 children and adolescents with mTBI. A variety of medical and nonmedical interventions have been used to treat the persistent symptoms of mTBI in children and adolescents. Treatment included medications for headaches, transcranial stimulation for headaches, giving information booklets, nurse visits, cognitive and physical rest, and active rehabilitation (exercise). All 6 studies reported positive results; but none was a randomized controlled trial, only 1 included a no-treatment comparison group, and none compared different interventions. It is difficult to determine whether the positive findings resulted from intervention or reflected natural resolution of the symptoms with time. There is a need for more, higher-quality studies of interventions designed to reduce the duration and severity of persistent postconcussion symptoms.


Plant RNA binding proteins for control of RNA virus infection.
Plant RNA viruses have effective strategies to infect host plants through either direct or indirect interactions with various host proteins, thus suppressing the host immune system. When plant RNA viruses enter host cells exposed RNAs of viruses are recognized by the host immune system through processes such as siRNA-dependent silencing. Interestingly, some host RNA binding proteins have been involved in the inhibition of RNA virus replication, movement, and translation through RNA-specific binding. Host plants intensively use RNA binding proteins for defense against viral infections in nature. In this mini review, we will summarize the function of some host RNA binding proteins which act in a sequence-specific binding manner to the infecting virus RNA. It is important to understand how plants effectively suppress RNA virus infections via RNA binding proteins, and this defense system can be potentially developed as a synthetic virus defense strategy for use in crop engineering.


Hybrid energy storage: the merging of battery and supercapacitor chemistries.
The hybrid approach allows for a reinforcing combination of properties of dissimilar components in synergic combinations. From hybrid materials to hybrid devices the approach offers opportunities to tackle much needed improvements in the performance of energy storage devices. This paper reviews the different approaches and scales of hybrids, materials, electrodes and devices striving to advance along the diagonal of Ragone plots, providing enhanced energy and power densities by combining battery and supercapacitor materials and storage mechanisms. Furthermore, some theoretical aspects are considered regarding the possible hybrid combinations and tactics for the fabrication of optimized final devices. All of it aiming at enhancing the electrochemical performance of energy storage systems.


Association between breast arterial calcifications found on mammography and coronary artery calcifications in asymptomatic Saudi women.
Currently, there are no data on the prevalence of breast arterial calcification (BAC) in Saudi women. Furthermore, there are no data on the relationship between BAC and coronary artery calcium score (CACS) as a coronary artery disease (CAD) risk factor in Saudi women who undergo mammography. Examine the role of BAC as a potential female-specific risk factor for CAD in Saudi women in order to investigate the relationship between BAC and CACS in women who undergo a screening mammography, and study the relationship between BAC and CAD risk factors, including age, diabetes mellitus, hypertension, chronic kidney disease (CKD), dyslipidemia, and family history of CAD. Retrospective, medical records review. Single tertiary care center. The study cohort included women who had mammograms and a CACS scan, and for whom data on CAD risk stratification and CAD risk factors had been collected within one year of each other from 2014 to 2017. Women with CAD were excluded from the study. Breast arterial calcification as a marker for coronary artery disease. 307 Saudi women. BAC was found in 142 (46%) patients in the study population. BAC+ women were significantly older than the BAC- women (P=.001), and a strong association was found between BAC and CACS (P=.0001), diabetes (P=.0001), hypertension (P=.021), and CKD (P=.0031). However, no association was found between BAC and tobacco smoking, dyslipidemia, and family history of CAD. In addition, a strong correlation was found between CACS and the components of the BAC score (P less than .001). Multivariate linear regression analysis revealed that age, CAC, and CKD are the only strong predictors of BAC. The proportion of BAC in Saudi women is 46%, and there may be a strong association between BAC and CAC, age, hypertension, and CKD. A large-scale prospective research study is necessary to validate the role of BAC on screening mammography as a CAD risk stratification tool and before routine reporting of BAC on a mammography report. Because this was a retrospective study, patient selection bias cannot be excluded. None.


Polio inactivated vaccine costs into routine childhood immunization in Brazil.
OBJECTIVE To analyze the costs of vaccination regimens for introducing inactivated polio vaccine in routine immunization in Brazil. METHODS A cost analysis was conducted for vaccines in five vaccination regimens, including inactivated polio vaccine, compared with the oral polio vaccine-only regimen. The costs of the vaccines were estimated for routine use and for the "National Immunization Days", during when the oral polio vaccine is administered to children aged less than five years, independent of their vaccine status, and the strategic stock of inactivated polio vaccine. The presented estimated costs are of 2011. RESULTS The annual costs of the oral vaccine-only program (routine and two National Immunization Days) were estimated at US$19,873,170. The incremental costs of inclusion of the inactivated vaccine depended on the number of vaccine doses, presentation of the vaccine (bottles with single dose or ten doses), and number of "National Immunization Days" carried out. The cost of the regimen adopted with two doses of inactivated vaccine followed by three doses of oral vaccine and one "National Immunization Day" was estimated at US$29,653,539. The concomitant replacement of the DTPw/Hib and HepB vaccines with the pentavalent vaccine enabled the introduction of the inactivated polio without increasing the number of injections or number of visits needed to complete the vaccination. CONCLUSIONS The introduction of the inactivated vaccine increased the annual costs of the polio vaccines by 49.2% compared with the oral vaccine-only regimen. This increase represented 1.13% of the expenditure of the National Immunization Program on the purchase of vaccines in 2011.


Emotion Regulation and Excess Weight: Impaired Affective Processing Characterized by Dysfunctional Insula Activation and Connectivity.
Emotion-regulation strategies are understood to influence food intake. This study examined the neurophysiological underpinnings of negative emotion processing and emotion regulation in individuals with excess weight compared to normal-weight controls. Fifteen participants with excess-weight (body mass index >25) and sixteen normal-weight controls (body mass index 18-25) performed an emotion-regulation task during functional magnetic resonance imaging. Participants were exposed to 24 negative affective or neutral pictures that they were instructed to Observe (neutral pictures), Maintain (sustain the emotion elicited by negative pictures) or Regulate (down-regulate the emotion provoked by negative pictures through previously trained reappraisal techniques). When instructed to regulate negative emotions by means of cognitive reappraisal, participants with excess weight displayed persistently heightened activation in the right anterior insula. Decreased responsivity was also found in right anterior insula, the orbitofrontal cortex and cerebellum during negative emotion experience in participants with excess weight. Psycho-physiological interaction analyses showed that excess-weight participants had decreased negative functional coupling between the right anterior insula and the right dlPFC, and the bilateral dmPFC during cognitive reappraisal. Our findings support contentions that excess weight is linked to an abnormal pattern of neural activation and connectivity during the experience and regulation of negative emotions, with the insula playing a key role in these alterations. We posit that ineffective regulation of emotional states contributes to the acquisition and preservation of excess weight.


The Host Response to Viral Infections Reveals Common and Virus-Specific Signatures in the Peripheral Blood.
Viruses cause a wide spectrum of clinical disease, the majority being acute respiratory infections (ARI). In most cases, ARI symptoms are similar for different viruses although severity can be variable. The objective of this study was to understand the shared and unique elements of the host transcriptional response to different viral pathogens. We identified 162 subjects in the US and Sri Lanka with infections due to influenza, enterovirus/rhinovirus, human metapneumovirus, dengue virus, cytomegalovirus, Epstein Barr Virus, or adenovirus. Our dataset allowed us to identify common pathways at the molecular level as well as virus-specific differences in the host immune response. Conserved elements of the host response to these viral infections highlighted the importance of interferon pathway activation. However, the magnitude of the responses varied between pathogens. We also identified virus-specific responses to influenza, enterovirus/rhinovirus, and dengue infections. Influenza-specific differentially expressed genes (DEG) revealed up-regulation of pathways related to viral defense and down-regulation of pathways related to T cell and neutrophil responses. Functional analysis of entero/rhinovirus-specific DEGs revealed up-regulation of pathways for neutrophil activation, negative regulation of immune response, and p38MAPK cascade and down-regulation of virus defenses and complement activation. Functional analysis of dengue-specific up-regulated DEGs showed enrichment of pathways for DNA replication and cell division whereas down-regulated DEGs were mainly associated with erythrocyte and myeloid cell homeostasis, reactive oxygen and peroxide metabolic processes. In conclusion, our study will contribute to a better understanding of molecular mechanisms to viral infections in humans and the identification of biomarkers to distinguish different types of viral infections.


[Effect of moderate acupuncture-stimulation of "Taichong" (LR 3) on blood pressure and plasma endothelin-1 levels in spontaneous hypertension rats].
To observe the effect of different strength of acupuncture stimulation on blood pressure and plasma endothelin (E)-1 in spontaneous hypertension rats (SHR) ,so as to seek a better acupuncture parameter for clinical treatment of hypertension. Twenty-eight 9-week-old SHRs were randomized into mild-stimulation group, moderate-stimulation group, strong-stimulation group and model group (n = 7 in each group). Seven normotensive SD rats served as a normal control group. Acupuncture stimulation with mild, moderate and strong stimulation was applied to bilateral "Taichong" (LR 3) for 5 min, once daily for 7 days. Blood pressure (BP) was determined by using a non-invasive BP-6 detection system. Plasma ET-1 was assayed by radioimmunoassay. Compared with the model group, the systolic pressure of the moderate-stimulation group on the 6th and 7th day was decreased significantly after acupuncture of "Taichong" (LR 3) (P<0. 01), being significantly lower than that of the mild- and strong-stimulation groups (P<0. 01). In comparison with the normal control group, plasma ET-1 level in the model group was increased significantly (P<0.01), while compared with the model group, only that in the moderate-stimulation group was down-regulated considerably (P<0. 01). No significant differences were found between the mild-stimulation and model groups, between the strong-stimulation and model groups, and between the mild-stimulation and strong-stimulation groups in plasma ET-1 level (P>0. 05). Moderate-stimulation of "Taichong" (LR 3) can lower blood pressure and plasma EA-1 level in spontaneous hypertension rats. The reduced level of plasma ET-1 may be one of its mechanisms underlying improving hypertension.


Bacterial growth state distinguished by single-cell protein profiling: does chlorination kill coliforms in municipal effluent?
Municipal effluent is the largest reservoir of human enteric bacteria. Its public health significance, however, depends upon the physiological status of the wastewater bacterial community. A novel immunofluorescence assay was developed and used to examine the bacterial growth state during wastewater disinfection. Quantitative levels of three highly conserved cytosolic proteins (DnaK, Dps, and Fis) were determined by using enterobacterium-specific antibody fluorochrome-coupled probes. Enterobacterial Fis homologs were abundant in growing cells and nearly undetectable in stationary-phase cells. In contrast, enterobacterial Dps homologs were abundant in stationary-phase cells but virtually undetectable in growing cells. The range of variation in the abundance of both proteins was at least 100-fold as determined by Western blotting and immunofluorescence analysis. Enterobacterial DnaK homologs were nearly invariant with growth state, enabling their use as permeabilization controls. The cellular growth states of individual enterobacteria in wastewater samples were determined by measurement of Fis, Dps, and DnaK abundance (protein profiling). Intermediate levels of Fis and Dps were evident and occurred in response to physiological transitions. The results indicate that chlorination failed to kill coliforms but rather elicited nutrient starvation and a reversible nonculturable state. These studies suggest that the current standard procedures for wastewater analysis which rely on detection of culturable cells likely underestimate fecal coliform content.


Biological activity of A-289099: an orally active tubulin-binding indolyloxazoline derivative.
In this report, we describe the antitumor activity of A-289099, an indolyloxazoline derivative with antimitotic activity. A-289099 decreased the proliferation of a variety of cells with EC(50) values ranging from 5.1 to 12.8 nM in a P-glycoprotein-independent manner. In cultured cells, microtubules depolymerized in a time- and dose-dependent manner when treated with A-289099. In competition-binding assays, A-298099 competed with [(3)H]colchicine for binding to tubulin (K(i) = 0.65 micro M); however, it did not compete with [(3)H]paclitaxel or [(3)H]vincristine. There was an accumulation of cells in G(2)-M after treatment with A-289099 for 8 h and a subsequent increase in a subdiploid population and an increase in caspase-3 activity, indicative of apoptosis after treatment for 24 and 48 h. The antitumor activities of A-289099 were evaluated using the syngeneic M5076 murine reticulum sarcoma flank tumor model. Animals size-matched for established tumors ( approximately 350 mm(3)) were dosed p.o. (50 mg/kg every day) for 11 days starting on day 10 postinoculation. Tumors from A-289099-treated animals regressed throughout the 11-day dosing period with a percentage of the average treated-tumor-volume divided by the average vehicle-control-tumor-volume (% T/C) value of 11% after treatment for 7 days. Examination of tumor sections revealed an increase in internucleosomal DNA fragmentation or cell death within the central core after drug-treatment. A decrease in the perfusion of tumors was observed after drug-treatment that was localized primarily to the central core and closely associated with the regions of cell death. In summary, our findings indicate A-289099 is a promising, orally active tubulin-binding compound with antitumor activity in vivo.


Tyrosine 140 of the gamma-aminobutyric acid transporter GAT-1 plays a critical role in neurotransmitter recognition.
The gamma-aminobutyric acid (GABA) transporter GAT-1 is located in nerve terminals and catalyzes the electrogenic reuptake of the neurotransmitter with two sodium ions and one chloride. We now identify a single tyrosine residue that is critical for GABA recognition and transport. It is completely conserved throughout the superfamily, and even substitution to the other aromatic amino acids, phenylalanine (Y140F) and tryptophan (Y140W), results in completely inactive transporters. Electrophysiological characterization reveals that both mutant transporters exhibit the sodium-dependent transient currents associated with sodium binding as well as the chloride-dependent lithium leak currents characteristic of GAT-1. On the other hand, in both mutants GABA is neither able to induce a steady-state transport current nor to block their transient currents. The nontransportable analog SKF 100330A potently inhibits the sodium-dependent transient in the wild type GAT-1 but not in the Y140W transporter. It partly blocks the transient of Y140F. Thus, although sodium and chloride binding are unimpaired in the tyrosine mutants, they have a specific defect in the binding of GABA. The total conservation of the residue throughout the family suggests that tyrosine 140 may be involved in the liganding of the amino group, the moiety common to all of the neurotransmitters.


Neuronal subtype-specific expression directed by the GABA(A) receptor delta subunit gene promoter/upstream region in transgenic mice and in cultured cells.
The promoter of the GABA(A) receptor delta subunit gene was analyzed in transgenic mice and in cultured cells to study sequences involved in neuronal subtype-specific gene expression. A 6.4-kb genomic fragment faithfully directed neuron-specific transcription of a lacZ reporter gene in the central nervous system. The transgene expression pattern in the cerebral cortex, hippocampal formation, thalamus, and brainstem was consistent with the regional and neuronal subtype-specific expression of the endogenous delta subunit protein in both developing and mature brain. In the cerebellum, however, the transgene was ectopically expressed in Purkinje cells and silent in granule cells, where the endogenous delta subunit is abundantly expressed. These mice provide a useful tool for investigating activity-dependent regulation of GABA(A) receptor expression under physiological and pathological conditions. Transfection studies using primary cortical neurons and astroglial cells revealed that the delta subunit gene promoter was selectively active in neurons even when truncated to a 267-bp core fragment. In conclusion, the delta subunit gene promoter/upstream region contains the information for neuronal subtype-specific expression in the entire brain except in the cerebellum and is selectively active in primary cortical neurons in vitro.


[A Shigella sonnei outbreak in Nagasaki].
We have experienced an outbreak of dysentery in Nagasaki. Shigella sonnei were positively cultured from 467 patients out of suspected 821 cases, and 346 patients were admitted. 121 patients were treated with oral antimicrobials in the outpatient clinic. Five patients were diagnosed as secondary infection. We treated a total of 96 patients in Nagasaki Municipal Medical Center, and studied the clinical and bacterial features in these 96 patients. Chief complaints included fever, abdominal pain and diarrhea. Most diarrheal patients showed waterly diarrhea and only a few were bloody (3 of 47). Treatment of levofloxacine 300 mg a day for 5 days successfully eliminated S. sonnei from all culture positive patients. An environmental surveillance revealed that water in a well at the university to which many patients were using was the origin of the infection with positive cultures of S. sonnei. No difference between the clinical and environmental isolates was observed in results on biochemical, serological and enzymatic tests. All isolates were susceptible to levofloxacin and to ofloxacin, but three isolates showed resistance of fosfomycin with MIC above 64 micrograms/ml. In analysis of pulsed-field gel electrophoresis, both clinical and environmental isolates were considered to be closely related.


Inner Macular Changes in Fellow Eye of Patients With Unilateral Idiopathic Epiretinal Membrane.
We evaluated a series of fellow eyes (FEs) in patients affected by unilateral idiopathic epiretinal membrane (IERM) with spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCT-A) to determine if a previous defect in the inner retina is present before the mechanical damage to the inner limiting membrane (ILM) caused by posterior vitreous detachment. In patients with IERM (N = 39), ganglion cell layer (GCL) thickness in FEs was assessed with SD-OCT; in a subgroup (N = 25) the vessel density (VD) at the superficial (SCP) and deep capillary plexus (DCP) was assessed with swept-source OCT-A (SS-OCT-A). These values were then compared with 30 age-matched healthy control eyes (CEs). The statistical analyses used SPSS software version 15.0 (SPSS, Inc., Chicago, IL, USA). Data collected underwent 1-way ANOVA. A level of P < 0.05 was accepted as statistically significant. The GCL thickness in the FEs was significantly lower than in CEs, with a significant thinning in all sectors except temporal ones (mean P < 0.001, superior P = 0.0002, superonasal P < 0.001, inferonasal P < 0.001, and inferior P = 0.002). The VD was significantly lower in the FEs in all sectors of SCP (mean P = 0.009, inner ring P = 0.028, and outer ring P = 0.007). GCL and SCP are significantly reduced in the FEs. These data suggest that a vascular defect in the SCP could cause a cellular loss in the inner retina that may determine the cascade events leading to the IERM proliferation; the diagnosis in a preclinical phase could provide a treatment strategy to prevent the progression of the disease.


Vasopressin receptor 2 mutations in the nephrogenic syndrome of inappropriate antidiuresis show different mechanisms of constitutive activation for G protein coupled receptors.
Vasopressin receptor 2 (V2R) mutations causing the nephrogenic syndrome of inappropriate antidiuresis (NSIAD) can generate two constitutively active receptor phenotypes. One type results from residue substitutions in several V2R domains and is sensitive to vaptan inverse agonists. The other is only caused by Arg 137 replacements and is vaptan resistant. We compared constitutive and agonist-driven interactions of the vaptan-sensitive F229V and vaptan-resistant R137C/L V2R mutations with β-arrestin 1, β-arrestin 2, and Gαs, using null fibroblasts reconstituted with individual versions of the ablated transduction protein genes. F229V displayed very high level of constitutive activation for Gs but not for β-arrestins, and enhanced or normal responsiveness to agonists and inverse agonists. In contrast, R137C/L mutants exhibited maximal levels of constitutive activation for βarrestin 2 and Gs, minimal levels for β-arrestin 1, but a sharp decline of ligands sensitivity at all transducer interactions. The enhanced constitutive activity and reduced ligand sensitivity of R137 mutants on cAMP signaling persisted in cells lacking β-arrestins, indicating that these are intrinsic molecular properties of the mutations, not the consequence of altered receptor trafficking. The results suggest that the two groups of NSIAD mutations represent two distinct molecular mechanisms of constitutive activation in GPCRs.


Effects of very short rest periods on hormonal responses to resistance exercise in men.
The effect of 3 different rest periods on the acute hormonal responses to resistance exercise (RE) was examined in 10 experienced resistance trained men (age: 20.37 +/- 2.24 years, weight: 65.5 +/- 26.70 kg). On 3 separate sessions of an RE protocol, subjects were assigned in a random order a rest interval of 60 seconds (P60), 90 seconds (P90), or 120 seconds (P120) between sets. The RE session consisted of 4 sets of squat and bench press to failure using 85% of 1 repetition maximum. Blood draws occurred at pre-exercise (T0), immediately post (T1), and 30 minutes post (T30) exercise for measurement of serum growth hormone (GH), testosterone (TS), and blood-lactate concentrations. Serum GH concentrations were significantly higher at T1 in P60 (64%) compared with P120. Also, serum TS concentrations were significantly higher at T1 in P120 (65%) and P90 (76%) compared to P60 (p < or = 0.05). Blood-lactate concentrations significantly increased at T1 for 3 protocols, but no significant protocols differences were observed. Although, training volume by using P90 and P120 was greater than that of P60, statistically a significant difference in training volume was not observed. The results of the present study support rest period in RE sets as an important variable to increase the anabolic hormone concentrations, and it should be mentioned that short rest intervals elevated greater increase in GH concentration compared with 120-second rest. However, TS response was greater in the RE protocol with a 120-second rest interval between sets.


"I felt like a new person." the effects of mindfulness meditation on older adults with chronic pain: qualitative narrative analysis of diary entries.
To identify the effects of mindfulness meditation on older adults with chronic low back pain (CLBP), we conducted a qualitative study based on grounded theory and used content analysis of diary entries from older adults who had participated in a clinical trial of an 8-week mindfulness meditation program. Participants were 27 adults > or = 65 years of age with CLBP of at least moderate severity and of at least 3 months duration. We found several themes reflecting the beneficial effects of mindfulness meditation on pain, attention, sleep, and achieving well-being. Various methods of pain reduction were used, including distraction, increased body awareness leading to behavior change, better pain coping, and direct pain reduction through meditation. Participants described improved attention skills. A number of participants reported improved sleep latency as well as quality of sleep. Participants described achieving well-being during and after a meditation session that had immediate effects on mood elevation but also long-term global effects on improved quality of life. Several themes were identified related to pain reduction, improved attention, improved sleep, and achieving well-being resulting from mindfulness meditation that suggest it has promising potential as a nonpharmacologic treatment of chronic pain for older adults. Community-dwelling older adults with chronic low back pain experience numerous benefits from mindfulness meditation including less pain, improved attention, better sleep, enhanced well-being, and improved quality of life. Additional research is needed to determine how mindfulness meditation works and how it might help with other chronic illnesses.


Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors.
Marine-derived fungi have proven to be important sources of bioactive natural organohalides. The genus Penicillium is recognized as a rich source of chemically diverse bioactive secondary metabolites. This study reports the fermentation, isolation and identification of a marine-derived Penicillium species. Bioassay-guided fractionation afforded the indole diterpene alkaloids penitrems A, B, D, E and F as well as paspaline and emnidole SB (1-7). Supplementing the fermentation broth of the growing fungus with KBr afforded the new 6-bromopenitrem B (8) and the known 6-bromopenitrem E (9). These compounds showed good antiproliferative, antimigratory and anti-invasive properties against human breast cancer cells. Penitrem B also showed a good activity profile in the NCI-60 DTP human tumor cell line screen. The nematode Caenorhabditis elegans was used to assess the BK channel inhibitory activity and toxicity of select compounds. A pharmacophore model was generated to explain the structural relationships of 1-9 with respect to their antiproliferative activity against the breast cancer MCF-7 cells. The structurally less complex biosynthetic precursors, paspaline (6) and emindole SB (7), were identified as potential hits suitable for future studies.


[Preventive vaccinations in dentistry].
The purpose of this current paper is to give a simple update and overview about vaccinations for dental health care workers considering the new guidelines published in February 2014 by the Swiss Federal Office of Public Health. It is recommended to have at least a valid protection against hepatitis B, measles, mumps, rubella, influenza, varicella, diphtheria, tetanus, poliomyelitis and pertussis. Dental health care workers are highly exposed and high risk carriers for inoculable diseases, therefore regular refreshment of vaccinations is necessary for public health and their own health.


Comparing abrocitinib and dupilumab in the treatment of atopic dermatitis: a plain language summary.
Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the signs and symptoms of AD. However, these treatments are not always enough to provide relief. A new medicine called abrocitinib, which is taken every day as a tablet, reduces part of the body's immune response that happens in AD. The clinical study described in this plain language summary, called JADE COMPARE, investigated how well and how safely 16 weeks of treatment with abrocitinib worked in adults with AD compared to placebo ('dummy treatment') and a medicine that is already approved for AD, called dupilumab. The study showed that abrocitinib was better than placebo in improving the signs and symptoms of AD after 16 weeks. In addition, patients who were taking abrocitinib 200 mg for 2 weeks experienced greater relief from itch than patients who were taking abrocitinib 100 mg, placebo, or dupilumab. More people who took abrocitinib 200 mg reported side effects than those taking abrocitinib 100 mg, placebo, or dupilumab, but most of these side effects were mild or moderate. ClinicalTrials.gov NCT number: NCT03720470.


Pain experienced during vaginal and anal intercourse with other-sex partners: findings from a nationally representative probability study in the United States.
Recent U.S. nationally representative data indicate that about 30% of women and 5% of men reported pain occurring during their most recent sexual event; however, little is known about the severity, duration, or context of such pain, or its prevalence during vaginal vs. anal intercourse. To document the prevalence and characteristics of pain during vaginal and anal intercourse among U.S. women and men (ages 18+) at their most recent other-sex sexual event, including the self-reported severity, duration, and location of their pain; how participants addressed their pain; and partner communication related to the pain. Data from a subsample of 1,738 women and men in the 2012 National Survey of Sexual Health Behavior, a nationally representative probability survey of Americans ages 18+ collected via the Internet, were analyzed. Participants responded to items about their background characteristics; whether they had vaginal or anal intercourse during their most recent sexual experience; the severity, duration, and location of any pain experienced during said sexual event; and whether they responded to or communicated about the pain. About 30% of women and 7% of men reported pain during vaginal intercourse events, and most of the reports of pain were mild and of short duration. About 72% of women and 15% of men reported pain during anal intercourse events, with more of these events including moderate or severe pain (for the women) and of mixed duration. Large proportions of Americans do not tell their partner when sex hurts. Pain is a relatively common, and often not discussed, aspect of both vaginal and anal intercourse events occurring between women and men. Individual and clinical implications are discussed.


Improving the biomedical research literature: insights from authors' editors can help journal editors define and refine their core competencies.
A team of stakeholders in biomedical publishing recently proposed a set of core competencies for journal editors, as a resource that can inform training programs for editors and ultimately improve the quality of the biomedical research literature. This initiative, still in its early stages, would benefit from additional sources of expert information. Based on our experiences as authors' editors, we offer two suggestions on how to strengthen these competencies so that they better respond to the needs of readers and authors - the main users of and contributors to research journals. First, journal editors should be able to ensure that authors are given useful feedback on the language and writing in submitted manuscripts, beyond a (possibly incorrect) blanket judgement of whether the English is "acceptable" or not. Second, journal editors should be able to deal effectively with inappropriate text re-use and plagiarism. These additional competencies would, we believe, be valued by other stakeholders in biomedical research publication as markers of editorial quality.


Taenia solium taeniosis and cysticercosis literature in Tanzania provides research evidence justification for control: A systematic scoping review.
Despite Taenia solium taeniosis/cysticercosis (TSTC) having been put high on the global agenda of neglected tropical diseases (NTDs), which over the last years has received a lot of attention, there has been no control programmes in place in sub-Saharan Africa, a highly endemic region. This could be attributed to lack of awareness of many stakeholders on the burden and impact of T. solium. This information is essential in guiding TSTC policies, practices and research agendas as well as encouraging cross-sectoral collaboration in the control of this important zoonotic parasite using a One Health approach. National elimination of the parasite is the foundation for global eradication. This will require that substantial country-level information is provided to all key stakeholders. We have mapped out TSTC research evidence in Tanzania to inform on disease burden and potential for integrated control measures. A scoping review of all TSTC studies undertaken in Tanzania and published up to December 2018 was conducted. The articles were searched from PUBMED, AJOL, Google Scholar and Google in general. Fifty-one (51) articles met the inclusion criteria and were reviewed. Prevalence of taeniosis of 2.3% - 5.2% was estimated based on copro-antigen ELISA while human cysticercosis of >16% was estimated based on serum antigen ELISA (Ag-ELISA) or IgG Western Blot. Neurocysticercosis (NCC) contributed significantly to epilepsy in adults. Farm prevalence of porcine cysticercosis were 6.0% - 17.4% (lingual examination) and 1.5% - 33.3% (Ag-ELISA). Slaughter-slab prevalence were 0% - 18.2% (routine meat inspection). Lacking latrines, watering pigs with river or pond water, and feeding pigs with potato peels were associated with porcine cysticercosis prevalence. Washing hands by dipping method increased the risk of human cysticercosis. In 2012, the number of DALYs/1000 person-years for NCC-associated epilepsy was 0.7 (95% UI, 0.2-1.6), around 5 million USD (95% UI, 797,535-16,933,477) were spent due to NCC-associated epilepsy and nearly 3 million USD (95% UI, 1,095,960-5,366,038) were potentially lost due to porcine cysticercosis. Three rounds of annual treatment of school-age children with praziquantel significantly reduced prevalence of taeniosis and porcine cysticercosis. Health education was efficacious in improving knowledge and attitudes favourable for control of TSTC while a single dose of oxfendazole 30 mg/kg body weight was efficacious in eliminating T. solium cysticerci from pig musculature. The observed high burden of TSTC and the significant contribution of NCC to epilepsy in Tanzania warrant urgent interventions. Evaluation of best control options should make use of disease transmission dynamics models such as cystiSim, taking into account findings from the field based intervention studies. In addition, locally adapted management guidelines for people suffering from NCC are urgently needed.


Sub-picosecond laser damage growth on high reflective coatings for high power applications.
Growth of laser damage on High Reflection (HR) thin film coatings is investigated at the wavelength of 1.030µm in the sub-picosecond regime. An experimental laser damage setup in a pump / probe configuration is used to study the growth behavior of engineered damage sites as well as laser damage sites. Results demonstrate that engineered sites and laser damage sites grow identically which indicates that the growth phenomenon is intrinsic to materials and stack design. In order to analyze the experimental results, we have developed a numerical model to simulate growth. Using FEM simulations, we demonstrate that growth is governed by the evolution of the electric field distribution in the mirror stack under the successive laser shots, which is supported by time-resolved observations of damage growth events. Eventually the results are compared to laser damage observations made on of full scale PETAL mirrors, which fully support the approach.


Mycobiome in the Lower Respiratory Tract - A Clinical Perspective.
Recently the paradigm that the healthy lung is sterile was challenged and it is now believed that the lungs harbor a diverse microbiota also contributing to the pathogenesis of various diseases. Most of the research studies targeting the respiratory microbiome have focused on bacteria and their impact on lung health and lung diseases. Recently, also the mycobiome has gained attention. Lower respiratory tract (LRT) diseases (e.g., cystic fibrosis) and other diseases or conditions (e.g., HIV infection, lung transplantation, and treatment at intensive care units) have been investigated with regard to possible involvement of mycobiome in development or progression of diseases. It has been shown that diversities of mycobiome in the LRT vary in different populations and conditions. It has been proposed that the mycobiome diversity associated with LRT can vary with different stages of diseases. Overall, Candida was the dominant fungal genus in LRT samples. In this review, we summarize the recent findings regarding the human LRT mycobiome from a clinical perspective focussing on characterization of investigated patient groups and healthy controls as well as sampling techniques. From these data, clinical implications for further studies or routine practice are drawn. To obtain clinically relevant answers efforts should be enhanced to collect well characterized and described patient groups as well as healthy individuals for comparative data analysis and to apply thorough sampling techniques. We need to proceed with elucidation of the role of mycobiota in healthy LRT and LRT diseases to hopefully improve patient care.


Surgical resection for lung metastases from colorectal cancer.
The lung is the second most common site of metastasis from colorectal cancer. Of all patients who undergo a curative resection for colorectal cancer, 10% to 15% will develop lung metastasis. As a hepatic resection of colorectal liver metastases results in improved survival, many reports have suggested that a pulmonary resection of a colorectal lung metastasis would also improve survival. The aim of this study was to analyze the postoperative outcomes of and the prognostic factors for a surgical resection of a lung metastasis. Between August 1997 and March 2006, 27 patients underwent surgical resections for colorectal lung metastases at Seoul St. Mary's hospital. A retrospective review of patients' characteristics and various tumor factors was performed. The mean interval between colorectal resection and lung metastasis was 24.0 ± 15.1 months. The overall 3- and 5-year survival rates were 76.5% and 22.2%, respectively. The mean follow-up after pulmonary resection was 39.5 ± 21.6 months (range, 3.3 to 115 months). Except for the existence of hilar-lymph-node metastasis (P < 0.001), no risk factors that we studied were statistically significant. Two patients had hilar-lymph-node metastasis. They survived for only for 3.3- and 11.6-months, respectively. In our study, we found that a pulmonary resection for metastases from colorectal cancer may improve survival in selected patients.


Quantum-enhanced greedy combinatorial optimization solver.
Combinatorial optimization is a broadly attractive area for potential quantum advantage, but no quantum algorithm has yet made the leap. Noise in quantum hardware remains a challenge, and more sophisticated quantum-classical algorithms are required to bolster their performance. Here, we introduce an iterative quantum heuristic optimization algorithm to solve combinatorial optimization problems. The quantum algorithm reduces to a classical greedy algorithm in the presence of strong noise. We implement the quantum algorithm on a programmable superconducting quantum system using up to 72 qubits for solving paradigmatic Sherrington-Kirkpatrick Ising spin glass problems. We find the quantum algorithm systematically outperforms its classical greedy counterpart, signaling a quantum enhancement. Moreover, we observe an absolute performance comparable with a state-of-the-art semidefinite programming method. Classical simulations of the algorithm illustrate that a key challenge to reaching quantum advantage remains improving the quantum device characteristics.


An Approach to Discovering Novel Muscarinic M1 Receptor Positive Allosteric Modulators with Potent Cognitive Improvement and Minimized Gastrointestinal Dysfunction.
Activation of muscarinic M1 receptor (M1R) is a promising approach for improving cognitive impairment in Alzheimer's disease. However, an M1R-selective positive allosteric modulator (PAM), benzyl quinolone carboxylic acid (BQCA), at 30 mg/kg, induced diarrhea in wild-type mice, but not in M1R knockout mice. Moreover, BQCA (0.1-1000 nM) augmented electric field stimulation (EFS)-induced ileum contraction in an in vitro Magnus assay. Thus, we decided to establish a drug-screening strategy to discover novel M1 PAMs producing potent cognitive improvement with minimized gastrointestinal (GI) dysfunction. We assessed PAM parameters of various M1 PAMs with ≥100-fold selectivity over other muscarinic receptor subtypes by using in vitro binding and functional analysis. Evaluation of these M1 PAMs in the Magnus assay revealed a significant correlation between percentage of ileum contractions at 1 μM and their α-value, a PAM parameter associated with the binding cooperativity between acetylcholine and M1 PAM. M1 PAMs with lower α-value showed lower impact on EFS-induced ileum contraction. Next, we characterized in vivo profiles of two M1 PAMs: compound A (log α = 1.18) and compound B (log α = 3.30). Compound A, at 30 mg/kg, significantly improved scopolamine-induced cognitive deficits without prominent signs of diarrhea at up to 1000 mg/kg in mice. In contrast, compound B, at 10 mg/kg, showed both significant improvement of scopolamine-induced cognitive deficits and severe diarrhea. Thus, fine adjustment of the α-values could be a key to discovering M1 PAMs yielding potent cognitive improvement with a lower risk of GI effects.


Antibody development to viral and allogeneic tumor cell-associated antigens in patients with malignant melanoma and ovarian carcinoma treated with lysates of virus-infected tumor cells.
Pre- and postimmunization sera from six malignant melanoma and six ovarian carcinoma patients were used to investigate the humoral immune response to antigens expressed in extracts of allogeneic tumor cells and lysates of these same cells infected with virus. Nitrocellulose paper replicas of cell extracts, fractionated by polyacrylamide gel electrophoresis, were used as antigenic targets. Antibodies that bound to tumor cell antigens of defined molecular weight were identified with enzyme-linked probes specific for human immunoglobulins G, A, and M. Prior to therapy, all sera reacted with one or more antigens expressed by the unmodified tumor cells. Postimmunization sera from two malignant melanoma patients and one ovarian carcinoma patient reacted with antigens in extracts of uninfected tumor cells. These same antigens were not detected by preimmunization sera. Most postimmunization antibody responses were directed against antigens associated with the infecting virus itself and antigens found in extracts of virus-infected but not in extracts of uninfected tumor cells. These results suggest that treatment with lysates of virus-infected allogeneic human tumor cells elicits humoral immune responses against: (a) tumor cell-associated antigens; (b) antigens that are specifically virus associated; and (c) antigens that may be virus induced or virus modified cytoplasmic or nuclear antigens.


[Mathematical methods in clinical cardiology].
The use of mathematical methods along four interconnected directions in clinical cardiology is analysed: prognosis and diagnosis, elaboration of most accurate clinical concepts and classifications, rules of management of the patient, information-research systems.


Phospholipase C activator m-3M3FBS protects against morbidity and mortality associated with sepsis.
Although phospholipase C (PLC) is a crucial enzyme required for effective signal transduction and leukocyte activation, the role of PLC in polymicrobial sepsis remains unclear. In this study, we show that the direct PLC activator m-3M3FBS treatment significantly attenuates vital organ inflammation, widespread immune cell apoptosis, and mortality in a mouse sepsis model induced by lethal cecal ligation and puncture challenge. Mechanistically, m-3M3FBS-dependent protection was largely abolished by pretreatment of mice with the PLC-selective inhibitor U-73122, thus confirming PLC agonism by m-3M3FBS in vivo. PLC activation enhanced the bactericidal activity and hydrogen peroxide production of mouse neutrophils, and it also enhanced the production of IFN-γ and IL-12 while inhibiting proseptic TNF-α and IL-1β production in cecal ligation and puncture mice. In a second model of sepsis, PLC activation also inhibited the production of TNF-α and IL-1β following systemic LPS challenge. In conclusion, we show that agonizing the central signal transducing enzyme PLC by m-3M3FBS can reverse the progression of toxic shock by triggering multiple protective downstream signaling pathways to maintain organ function, leukocyte survival, and to enhance microbial killing.


Performance of the 12-item WHODAS 2.0 in prodromal Huntington disease.
The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM-5), recommends the World Health Organization Disability Assessment Schedule (WHODAS) 2.0 for routine clinical use. We tested the utility of the 12-item WHODAS 2.0 in prodromal Huntington disease. Using data from 726 participants and 630 companions over a 3-year follow-up, linear mixed models were fitted to test (1) baseline and longitudinal differences by progression group; (2) participant and companion differences within each group; and (3) sensitivity of the 12-item WHODAS in comparison to the 36-item WHODAS and the Total Functional Capacity (TFC) score from the Unified Huntington's Disease Rating Scale. Participants showed baseline group differences whereas companions showed baseline and longitudinal group differences. Companions reported worse functional decline over time than participants as the disease progresses. The 12-item WHODAS detected longitudinal change better than the 36-item WHODAS and the TFC in the medium progression group. Results suggest the 12-item WHODAS 2.0 can detect baseline and longitudinal differences in prodromal HD and may be useful in HD clinical trials.


Levofloxacin for the treatment of pneumonia caused by Streptococcus pneumoniae including multidrug-resistant strains: pooled analysis.
To determine the clinical and microbiologic efficacy of levofloxacin for the treatment of subjects with pneumonia caused by multidrug-resistant (MDR) Streptococcus pneumoniae (MDRSP) and non-MDRSP strains. A pooled analysis was conducted using data from ten clinical studies in pneumonia: five comparative studies and five noncomparative studies conducted from 1992 to 2002. This analysis included data from levofloxacin-treated subjects with S. pneumoniae isolated at study entry. Susceptibility of S. pneumoniae isolated from subjects at study entry was determined against representative agents from five antimicrobial classes: tetracyclines, sulfonamides, second-generation cephalosporins, penicillins, and macrolides. Isolates were classified as MDRSP (based on resistance to two or more antimicrobial classes) or non-MDRSP (intermediate resistance or susceptible to all classes or resistant to 1 antimicrobial class). Clinical and microbiologic efficacy of levofloxacin (i.v., p.o., or i.v./p.o. for 5 to 14 days) in the microbiologically evaluable population was determined at post-therapy; a test for homogeneity of the odds ratio of the difference in clinical success for comparative versus noncomparative studies was performed. The main outcome measures were clinical success rates and microbiologic eradication rates of 419 microbiologically evaluable levofloxacin-treated subjects with MDRSP or non-MDRSP. Clinical success rates were 96.3% (52/54) and 95.1% (347/365), respectively (difference -1.2; 95% confidence interval [CI]: -6.7, 4.3). Similarly, per pathogen microbiologic eradication rates for MDRSP and non-MDRSP were 96.3% (52/54) and 95.6% (350/366), respectively (difference -0.7; 95% CI: -6.1, 4.8). Study limitations include the use of data from comparative and noncomparative studies. A test for homogeneity of the odds ratios for clinical success in comparative versus noncomparative studies showed no significant difference (p = 0.27). These data support the use of levofloxacin for patients with community-acquired pneumonia caused by S. pneumoniae, including MDR strains.


Developmental expression of extracellular glutathione peroxidase suggests antioxidant roles in deciduum, visceral yolk sac, and skin.
Extracellular glutathione peroxidase (EGPx) is a secreted selenium-dependent enzyme that reduces hydroperoxides and organic hydroperoxides. Selenium deficiency in females is associated with infertility and spontaneous abortion, suggesting a role for selenium-requiring proteins during embryonic development. To gain insight into functions of EGPx in vivo, we determined sites of murine EGPx synthesis by in situ hybridization during embryogenesis and in adult tissues. At E7.5 of development, high EGPx expression was found in the maternally derived deciduum, with lower levels of accumulation in the embryonic visceral endoderm. At E9.5, the major sites of expression were the yolk sac endoderm and heart musculature. By E16.5, EGPx mRNA expression persisted in yolk sac endoderm but also accumulated significantly in atrially derived myocytes, ossification centers, adipose tissue, intestinal epithelium, and in a ventral-to-dorsal gradient in developing skin. Glutathione peroxidase activity due to EGPx protein was identified in the fluids surrounding the developing mouse embryo at midgestation. The expression of EGPx in tissues at the maternal-fetal interface--deciduum, visceral yolk sac, and skin--suggests that EGPx may serve to protect the embryo from oxidant damage. In adult mice, we identified the S1 segment of the kidney proximal tubules as the primary site of EGPx mRNA accumulation, with lower EGPx levels in atrial cardiac muscle, intestine, skin, and adipose tissue. These findings suggest that EGPx may serve a wider antioxidant role than previously recognized in the interstitium of multiple localized tissues, particularly those associated with the active transport of lipids.


Nonparaxial description of reflection and transmission at the interface between an isotropic medium and a uniaxial crystal.
Angular spectra of reflected and transmitted fields, induced by an arbitrary electromagnetic beam passing through the planar interface between a homogeneous medium and a uniaxially anisotropic medium, are derived and related to the incident medium. By using these formulas, we obtain the expressions for paraxial and slightly nonparaxial fields. The reflected paraxial field is related to the incident one by means of Fresnel relations; the transmitted paraxial field is the superposition of an ordinary and an extraordinary beam, multiplied by the Fresnel coefficient. We find that the nonparaxial corrections, owing to the medium discontinuity, are larger than their free-propagation counterparts and that they are very simply related to the paraxial solutions of the incident beam. The case of two homogeneous media with different refractive indices is also discussed. The general expressions obtained are applied to the case of a nonparaxial Gaussian beam.