Acantharian fluxes and strontium to chlorinity ratios in the north pacific ocean.
Data on particulate strontium sulfate fluxes and strontium to chlorinity ratios were compared to provide insights into the strontium cycle of the North Pacific. Freedrifting sediment traps were used to derive large particle fluxes between depths of 100 and 3500 meters in the eastern and western North Pacific Ocean. Flux data revealed substantial quantities of acantharian skeletons and cysts (both made of strontium sulfate) settling through the upper kilometer of the water column. The greatest fluxes of celestite were detected at 400 meters. Minimal to nondetectable fluxes noted at and below 900 meters provide evidence that by this horizon, the majority of acantharian specimens had dissolved, thereby contributing to the pool of dissolved strontium. Growth and subsequent dissolution of acantharians in the upper kilometer are qualitatively consistent with the well-developed minimum and maximum strontium to chlorinity ratios that are consistently noted in these waters. These fluxes of particulate strontium and model calculations for fluxes of dissolved strontium indicate that acantharians play an important role in the ocean's strontium budget.


The cecal appendix: one more immune component with a function disturbed by post-industrial culture.
This review assesses the current state of knowledge regarding the cecal appendix, its apparent function, and its evolution. The association of the cecal appendix with substantial amounts of immune tissue has long been taken as an indicator that the appendix may have some immune function. Recently, an improved understanding of the interactions between the normal gut flora and the immune system has led to the identification of the appendix as an apparent safe-house for normal gut bacteria. Further, a variety of observations related to the evolution and morphology of the appendix, including the identification of the structure as a "recurrent trait" in some clades, the presence of appendix-like structures in monotremes and some non-mammalian species, and consistent features of the cecal appendix such as its narrow diameter, provide direct support for an important function of the appendix. This bacterial safe-house, which is likely important in the event of diarrheal illness, is presumably of minimal importance to humans living with abundant nutritional resources, modern medicine and modern hygiene practices that include clean drinking water. Consistent with this idea, epidemiologic studies demonstrate that diarrheal illness is indeed a major source of selection pressure in developing countries but not in developed countries, whereas appendicitis shows the opposite trend, being associated with modern hygiene and medicine. The cecal appendix may thus be viewed as a part of the immune system that, like those immune compartments that cause allergy, is vital to life in a "natural" environment, but which is poorly suited to post-industrialized societies.


Adhesive properties of bonded orthodontic retainers to enamel: stainless steel wire vs fiber-reinforced composites.
The objectives of this study were to compare the bond strength of a stainless steel orthodontic wire vs various fiber-reinforced composites (FRC) used as orthodontic retainers on enamel, analyze the failure types after debonding, and investigate the influence of different application procedures of stainless steel wires on bond strength. Caries-free, intact human mandibular incisors (N = 80, n = 10 per group) were selected and randomly distributed into 8 groups. After etching with 37% H3PO4 for 30 s, rinsing and drying, bonding agent (Stick Resin) was applied and light polymerized. Then one of the following FRC materials was applied on the flowable composite (Stick Flow) using standard molds: group 1: Angelus Fibrex Ribbon; group 2: DentaPreg Splint; group 3: ever-Stick Ortho; group 4: Ribbond. In group 5, Quad Cat Wire was applied in the same manner as in FRC groups. In group 6, after applying bonding agent (Stick Resin), Quad Cat Wire was placed directly on the tooth surface and covered with Stick Flow composite. In group 7, after bonding agent (Heliobond) was applied, Quad Cat Wire was placed directly on the tooth surface and covered with Tetric Flow composite. In group 8, after applying bonding agent (Heliobond) and polymerization, Tetric Flow composite was applied, not polymerized, and Quad Cat Wire was placed and covered with Tetric Flow again. Specimens were thermocycled for 6000 cycles between 5 degrees C and 55 degrees C and loaded in a universal testing machine under shear stress (crosshead speed: 1 mm/min) until debonding occurred. The failure sites were examined under an optical light microscope. Data were analyzed using one-way ANOVA and the Tukey-Kramer adjustment test (alpha = 0.05). Significant differences were found between the groups (p = 0.0011) (ANOVA). Bond strength results did not significantly differ either between the FRC groups (groups 1 to 4) (6.1 +/- 2.5 to 8.4 +/- 3.7 MPa) (p > 0.05) or the wire groups (groups 5 to 8) (10.6 +/- 3.8 to 14 +/- 6.7 MPa) (p > 0.05). Failure types varied within the FRC groups, but mainly composite was found left adhered on the enamel surface at varying degrees. In the stainless steel wire groups, when the retainer was applied onto the bonding agent and then covered with flowable resin, partially attached composite on the enamel was often found after debonding. When the wires were embedded in the flowable composite, the Heliobond group (group 8) showed more adhesive failures between the enamel and the composite compared to group 5, where the bonding agent was Stick Resin. Regardless of their application mode, stainless steel orthodontic bonded retainers delivered higher bond strengths than those of fiber retainers. The differences were statistically significant compared to those of Angelus Fibrex Ribbon and DentaPreg Splint.


A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity.
Mutant contractile protein genes that cause familial hypertrophic cardiomyopathy (FHC) are presumed to encode mutant proteins that interfere with contractile function. However, it has generally not been possible to show mutant protein expression and incorporation into the sarcomere in vivo. This study aimed to assess whether a mutant alpha-fast tropomyosin (TM) responsible for FHC is actually expressed and determines abnormal contractile function. Since alpha-fast TM is expressed in heart and skeletal muscle, samples from vastus lateralis muscles were studied from two FHC patients carrying an Asp175Asn alpha-fast TM mutation and two healthy control subjects. TM isoforms from whole biopsy samples and single fibers were identified by gel electrophoresis and Western blot analysis. An additional faster-migrating TM band was observed in both FHC patients. The aberrant TM was identified as the Asp175Asn alpha-fast TM by comigration with purified recombinant human Asp175Asn alpha-fast TM. Densitometric quantification of mutant and wild-type alpha-fast TMs suggested equal expression of the two proteins. Contractile parameters of single skinned muscle fibers from FHC patients and healthy control subjects were compared. Calcium sensitivity was significantly increased in muscle fibers containing Asp175Asn alpha-fast Tm compared with fibers lacking the mutant TM. No discernible difference was found regarding cooperativity, maximum force, and maximum shortening velocity. This is the first demonstration that the mutant TM that causes FHC is indeed expressed and almost certainly incorporated into muscle in vivo and does result in altered contractile function; this confirms a dominant-negative, rather than null allele, action. Since the mutant TM was associated with increased calcium sensitivity, this mutation might be associated with an enhancement and not a depression of cardiac contractile performance. If so, this contrasts with the hypothesis that FHC mutations induce contractile impairment followed by compensatory hypertrophy.


Raman amplification-based WDM-PON architecture with centralized Raman pump-driven, spectrum-sliced erbium ASE and polarization-insensitive EAMs.
We propose a novel wavelength division multiplexed (WDM) passive optical network (PON) architecture based on the distributed Raman amplification and pump recycling techniques, which features fully bidirectional transmission, relaxed signal power margin, and active light source-free, colorless subscriber units. The reuse of non-negligible residual Raman pump power as a pump for an erbium fiber-based upstream broadband ASE source allows for fully-centralized control of light sources at optical network units (ONUs), while distributed Raman amplification over a transmission link enables us to obtain lossless low power signal transmission. Furthermore, low-cost and colorless ONUs can be realized by use of the Raman pump-recycled erbium ASE and polarization-insensitive electroabsorption modulators. Error-free upstream transmission over a 50 km fiber link is successfully achieved at a data rate of 622 Mbit/s.


Serum salusin-α levels in systemic lupus erythematosus and systemic sclerosis.
Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), chronic inflammatory diseases, demonstrate an increased incidence of cardiovascular manifestations and subclinical atherosclerotic disease. Salusin-α is a novel bioactive peptide that suppresses the formation of macrophage foam cells, and its serum level is significantly lower in patients with angiographically proven coronary artery disease. The aims of the study were to assess serum salusin-α level and its potential association with the predictors of atherosclerosis in SLE and SSc. The study included 20 SLE and 22 SSc patients and 23 healthy controls (HC). All of the participants were female. Tumour necrosis factor-α (TNF-α), IL-6 and salusin-α levels, homeostasis model assessment for insulin resistance (HOMA-IR) index and common carotid intima-media thickness (IMT) were determined. Salusin-α levels were lower and the IMTs were higher in the SLE and SSc groups than in the HC group. The salusin-α level was correlated with neither the disease activity scores nor cytokine levels and IMT in the SLE and SSc groups, although it was correlated with triglyceride level in the SLE group (r=-0.564, p=0.012), and with HOMA-IR index in the HC group (r=0.485, p=0.019). The present preliminary study may support the idea that SSc leads to subclinical atherosclerosis, as in SLE. Moreover, it can be concluded that the decreased salusin-α levels in SLE and SSc may contribute to subclinical atherosclerosis. However, further studies with larger sample size are needed to demonstrate this contribution in SLE and SSc.


Suicide and social change in China.
Using recently available data from China's Disease Surveillance Points system, we estimate that there are over 300,000 suicides in China per year; this makes suicide one of the most important causes of death in the country and makes the suicide rate in China one of the highest in the world. Moreover, the pattern of suicides in China is quite different than in other parts of the world--there are more completed suicides among females than males and rural rates are three-fold urban rates. The lack of reliable suicide data prior to 1987 makes it difficult to determine whether the rates are currently rising, falling, or staying constant. However, reports of suicides in the Chinese press and case studies conducted by the authors suggest (but do not prove) that the high rates of suicide currently experienced are related to the social changes that have occurred with the economic reforms (which started in 1978). Another possible explanation for the high rates of suicide is the large numbers of persons with depressive illness in China who remain untreated. Single-cause models of suicide (i.e., social factors or mental illness) do not do justice to the complexity of the processes involved and, therefore, do not provide useful information about the etiology and prevention of suicide in China or elsewhere. We describe our own dynamic model of suicide that includes five interacting factors which, we believe, collectively determine the suicide rates in a community.


Obtaining consensus regarding international transplantation continues to be difficult for pediatric centers in the United States.
Organ transplant is life-saving and any given organ may be valuable to a multitude of potential recipients. An allocation system must be used to reconcile the difference between supply and demand, and this system must take into account the impact that accepting international patients may have on the local system. The principles for allocation must be clear, equitable, provide utility and must be monitored so as to maintain public trust. The impact of the system on metrics deemed to be critical must be measured. Finally, strategies must take into account the local culture, size of the region to be supported, the number and experience of transplant centers, and the resources of the healthcare delivery system. Our focus is on the United States, recognizing that strategies and challenges may vary across countries.


Efficacy and safety of ablation for people with non-paroxysmal atrial fibrillation.
The optimal rhythm management strategy for people with non-paroxysmal (persistent or long-standing persistent) atrial fibrilation is currently not well defined. Antiarrhythmic drugs have been the mainstay of therapy. But recently, in people who have not responded to antiarrhythmic drugs, the use of ablation (catheter and surgical) has emerged as an alternative to maintain sinus rhythm to avoid long-term atrial fibrillation complications. However, evidence from randomised trials about the efficacy and safety of ablation in non-paroxysmal atrial fibrillation is limited. To determine the efficacy and safety of ablation (catheter and surgical) in people with non-paroxysmal (persistent or long-standing persistent) atrial fibrillation compared to antiarrhythmic drugs. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, conference abstracts, clinical trial registries, and Health Technology Assessment Database. We searched these databases from their inception to 1 April 2016. We used no language restrictions. We included randomised trials evaluating the effect of radiofrequency catheter ablation (RFCA) or surgical ablation compared with antiarrhythmic drugs in adults with non-paroxysmal atrial fibrillation, regardless of any concomitant underlying heart disease, with at least 12 months of follow-up. Two review authors independently selected studies and extracted data. We evaluated risk of bias using the Cochrane 'Risk of bias' tool. We calculated risk ratios (RRs) for dichotomous data with 95% confidence intervals (CIs) a using fixed-effect model when heterogeneity was low (I² <= 40%) and a random-effects model when heterogeneity was moderate or substantial (I² > 40%). Using the GRADE approach, we evaluated the quality of the evidence and used the GRADE profiler (GRADEpro) to import data from Review Manager 5 to create 'Summary of findings' tables. We included three randomised trials with 261 participants (mean age: 60 years) comparing RFCA (159 participants) to antiarrhythmic drugs (102) for non-paroxysmal atrial fibrillation. We generally assessed the included studies as having low or unclear risk of bias across multiple domains, with reported outcomes generally lacking precision due to low event rates. Evidence showed that RFCA was superior to antiarrhythmic drugs in achieving freedom from atrial arrhythmias (RR 1.84, 95% CI 1.17 to 2.88; 3 studies, 261 participants; low-quality evidence), reducing the need for cardioversion (RR 0.62, 95% CI 0.47 to 0.82; 3 studies, 261 participants; moderate-quality evidence), and reducing cardiac-related hospitalisation (RR 0.27, 95% CI 0.10 to 0.72; 2 studies, 216 participants; low-quality evidence) at 12 months follow-up. There was substantial uncertainty surrounding the effect of RFCA regarding significant bradycardia (or need for a pacemaker) (RR 0.20, 95% CI 0.02 to 1.63; 3 studies, 261 participants; low-quality evidence), periprocedural complications, and other safety outcomes (RR 0.94, 95% CI 0.16 to 5.68; 3 studies, 261 participants; very low-quality evidence). In people with non-paroxysmal atrial fibrillation, evidence suggests a superiority of RFCA to antiarrhythmic drugs in achieving freedom from atrial arrhythmias, reducing the need for cardioversion, and reducing cardiac-related hospitalisations. There was uncertainty surrounding the effect of RFCA with significant bradycardia (or need for a pacemaker), periprocedural complications, and other safety outcomes. Evidence should be interpreted with caution, as event rates were low and quality of evidence ranged from moderate to very low.


Plan and operation of the NHANES I Epidemiologic Followup Study, 1992.
The NHANES I Epidemiologic Followup Study (NHEFS) is a longitudinal study that uses as its baseline those adult persons 25-74 years of age who were examined in the first National Health and Nutrition Examination Survey (NHANES I). NHEFS was designed to investigate the association between factors measured at baseline and the development of specific health conditions. The three major objectives of NHEFS are to study morbidity and mortality associated with suspected risk factors, changes over time in participants' characteristics, and the natural history of chronic disease and functional impairments. Tracing and data collection in the 1992 Followup were undertaken for the 11,195 subjects who were not known to be deceased in the previous surveys. No additional information was collected in the 1992 NHEFS for the 3,212 subjects who were known to be deceased before the 1992 NHEFS data collection period. By the end of the 1992 NHEFS survey period, 90.0 percent of the 11,195 subjects in the 1992 Followup cohort had been successfully traced. Interviews were conducted for 9,281 subjects. An interview was conducted for 8,151 of the 8,687 surviving subjects; 551 interviews were administered to a proxy respondent because the subject was incapacitated. A proxy interview was conducted for 1,130 of the 1,392 decedents identified in the 1992 NHEFS. In addition, 10,535 facility stay records were collected for 4,162 subjects reporting overnight facility stays. Death certificates were obtained for 1,374 of the 1,392 subjects who were identified as deceased since last contact. Approximately 32 percent of the NHEFS cohort is known to be deceased with a death certificate available for 98 percent of the 4,604 NHEFS decedents.


Serum immune complexes as diagnostic and therapeutic markers in lymphatic filariasis.
In the present study we examined the utility of measuring antigen-specific soluble immune complexes (ICs) for the differential diagnosis and therapeutic monitoring of Bancroftian filariasis. Antigen-specific ICs were detected in significantly elevated levels in 90% of lymphatic filarial subjects suffering from disease manifestations, and very low levels in 8-10% of microfilaria (MF) carriers. The high incidence of antigen-specific ICs in the circulation of filarial subjects with clinical manifestations in contrast to the negligible presence in MF carriers facilitates serological differentiation of these two important stages of lymphatic filarial infection. A sudden spurt in circulating levels of antigen-specific ICs was recorded in all MF carriers on diethylcarbamazine (DEC) therapy, and the magnitude of the increase correlated positively with the pretreatment levels of circulating MF. Thus, it is evident from the present study that circulating ICs (CICs) are potential serological markers for both the differential diagnosis of filarial infection and therapeutic monitoring of MF carriers.


Effects of sediment-associated copper to the deposit-feeding snail, Potamopyrgus antipodarum: a comparison of Cu added in aqueous form or as nano- and micro-CuO particles.
Increasing use of engineered nanoparticles (NPs) is likely to result in release of these particles to the aquatic environment where the NPs may eventually accumulate in sediment. However, little is known about the potential ecotoxicity of sediment-associated engineered NPs. We here consider the case of metal oxide NPs using CuO to understand if the effects of NPs differ from micron-sized particles of CuO and aqueous Cu (CuCl₂). To address this issue, we compared effects of copper added to the sediment as aqueous Cu, nano- (6 nm) and micro- (<5 μm) CuO particles on the deposit-feeding snail, Potamopyrgus antipodarum. Effects were assessed as mortality, specific growth rate, feeding rate, reproduction, and bioaccumulation after 8 weeks of exposure to nominal concentrations of 0, 30, 60, 120 and 240 μg Cu/g dry weight sediment. The results demonstrate that copper added to sediment as nano-CuO had greater effects on growth, feeding rate, and reproduction of P. antipodarum than copper added as micro-CuO or aqueous Cu. P. antipodarum accumulated more copper in the nano-CuO treatment than in aqueous Cu or micro-CuO treatments, indicating that consideration of metal form may be important when assessing risks of metals to the aquatic environment.


Danish Prostate Cancer Registry - methodology and early results from a novel national database.
Systematized Nomenclature of Medicine (SNOMED) codes are computer-processable medical terms used to describe histopathological evaluations. SNOMED codes are not readily usable for analysis. We invented an algorithm that converts prostate SNOMED codes into an analyzable format. We present the methodology and early results from a new national Danish prostate database containing clinical data from all males who had evaluation of prostate tissue from 1995 to 2011. SNOMED codes were retrieved from the Danish Pathology Register. A total of 26,295 combinations of SNOMED codes were identified. A computer algorithm was developed to transcode SNOMED codes into an analyzable format including procedure (eg, biopsy, transurethral resection, etc), diagnosis, and date of diagnosis. For validation, ~55,000 pathological reports were manually reviewed. Prostate-specific antigen, vital status, causes of death, and tumor-node-metastasis classification were integrated from national registries. Of the 161,525 specimens from 113,801 males identified, 83,379 (51.6%) were sets of prostate biopsies, 56,118 (34.7%) were transurethral/transvesical resections of the prostate (TUR-Ps), and the remaining 22,028 (13.6%) specimens were derived from radical prostatectomies, bladder interventions, etc. A total of 48,078 (42.2%) males had histopathologically verified prostate cancer, and of these, 78.8% and 16.8% were diagnosed on prostate biopsies and TUR-Ps, respectively. A validated algorithm was successfully developed to convert complex prostate SNOMED codes into clinical useful data. A unique database, including males with both normal and cancerous histopathological data, was created to form the most comprehensive national prostate database to date. Potentially, our algorithm can be used for conversion of other SNOMED data and is available upon request.


Oral vitamin C administration reduces early recurrence rates after electrical cardioversion of persistent atrial fibrillation and attenuates associated inflammation.
Inflammation and oxidative stress have been recently implicated in the pathophysiology of atrial fibrillation (AF). The aim of this study was to examine the potential benefit of vitamin C on the early recurrence rates and on inflammatory indices after successful cardioversion of persistent AF, as well as to investigate the time course of changes in these indices post-cardioversion. We prospectively studied 44 consecutive patients after successful electrical cardioversion of persistent AF. All patients received standard treatment and were randomised in one to one fashion to either oral vitamin C administration or no additional therapy. We followed-up the patients for 7 days performing successive measurements of white blood cell (WBC) count, C-reactive protein (CRP), fibrinogen, and ferritin levels. One week after successful cardioversion, AF recurred in 4.5% of patients in the vitamin C group and in 36.3% of patients in the control group (p=0.024). Compared to baseline values, inflammatory indices decreased after cardioversion in patients receiving vitamin C but did not change significantly in the control group. A significant variance was found in the serial measurements of WBC counts (F=5.86, p=0.001) and of fibrinogen levels (F=4.10, p=0.0084) in the two groups. In the vitamin C group CRP levels were lower on the seventh day (p<0.05). CRP and fibrinogen levels were higher in patients who relapsed into AF compared to patients who maintained sinus rhythm (F=2.77, p=0.044 and F=3.51, p=0.017, respectively). These findings suggest that vitamin C reduces the early recurrence rates after cardioversion of persistent AF and attenuates the associated low-level inflammation. These effects indicate that therapeutic approaches targeting at inflammation and oxidative stress may exert favourable effects on atrial electrical remodeling.


Vaccination against GnRH may suppress aggressive behaviour and musth in African elephant (Loxodonta africana) bulls--a pilot study.
Aggressive behaviour and musth are constant problems in captive and sometimes in free-ranging African elephant bulls. Aggressive bulls are difficult and musth bulls almost impossible to manage without severely restricting their movement either by leg-chaining or using tranquillisers. This study investigated the relationship between faecal androgen metabolites (FAM) and faecal cortisol metabolites (FCM) concentrations and aggressive behaviour and tested a GnRH vaccine as a means of down-regulating aggressive behaviour and musth in 1 free-ranging and 5 captive elephant bulls. The bulls were non-aggressive (n=3), aggressive (n=2) or in musth (n=1) at the onset of the study. The bulls were injected with a GnRH vaccine-adjuvant combination 3 or 4 times at 3- to 7-week intervals. Behaviour, FAM and FCM concentrations were measured during every week prior to vaccination until 4 months after the last vaccination. FAM concentrations were positively correlated with aggressive behaviour before the 1st vaccination. Androgen production, as reflected by FAM concentrations, was down-regulated in 3 of the 6 immunised bulls. At least 2 bulls and possibly a 3rd showed behavioural improvement following GnRH vaccination and in all 3 temporal gland secretion ceased. No further aggressive behaviour was observed until the end of the study in any of the bulls. The results of this 1st GnRH immunisation study suggest that it could be a useful method to control aggressive behaviour and musth in African elephant bulls.


Reagent approaches for improved detection of chlorate and perchlorate salts via thermal desorption and ionization.
Techniques for improving the detectability of chlorate and perchlorate salts with thermal desorption based ionizers (i.e. radioactive, corona discharge and photoionization-based) are desired. This work employs acidic reagents to chemically transform chlorate and perchlorate anions into traces of chloric and perchloric acid. These high vapor pressure acids are easier to detect than the originating salts. The efficacy of the reagent chemistry was quantified with a triple-quadrupole mass spectrometer interfaced with a custom-built thermal-desorption atmospheric-pressure chemical ionization (TD-APCI) source. Additional experiments were conducted using tandem IMS/MS instrumentation. Reagent pKa and pH values were varied in order to gain a better understanding of how those parameters affect the degree of observed signal enhancement. Samples of chlorates and perchlorates treated with liquid acidic reagents exhibit signal enhancement of up to six orders of magnitude compared with signals from untreated analytes. Three orders of magnitude of signal enhancement are demonstrated using solid-state reagents, such as weakly acidic salts and polymeric acids. Data is presented that demonstrates the compatibility of the solid-state approach with both MS and IMS/MS platforms. Several methods of acidification were demonstrated for enhanced vaporization and detection of chlorates and perchlorates. For applications where rapid surface collection and analysis for chlorates and perchlorates are desired, the solid-state approaches offer the simplest means to integrate the reagent chemistry into MS or IMS detection.


A conserved cysteine motif is critical for rice ceramide kinase activity and function.
Ceramide kinase (CERK) is a key regulator of cell survival in dicotyledonous plants and animals. Much less is known about the roles of CERK and ceramides in mediating cellular processes in monocot plants. Here, we report the characterization of a ceramide kinase, OsCERK, from rice (Oryza sativa spp. Japonica cv. Nipponbare) and investigate the effects of ceramides on rice cell viability. OsCERK can complement the Arabidopsis CERK mutant acd5. Recombinant OsCERK has ceramide kinase activity with Michaelis-Menten kinetics and optimal activity at 7.0 pH and 40°C. Mg2+ activates OsCERK in a concentration-dependent manner. Importantly, a CXXXCXXC motif, conserved in all ceramide kinases and important for the activity of the human enzyme, is critical for OsCERK enzyme activity and in planta function. In a rice protoplast system, inhibition of CERK leads to cell death and the ratio of added ceramide and ceramide-1-phosphate, CERK's substrate and product, respectively, influences cell survival. Ceramide-induced rice cell death has apoptotic features and is an active process that requires both de novo protein synthesis and phosphorylation, respectively. Finally, mitochondria membrane potential loss previously associated with ceramide-induced cell death in Arabidopsis was also found in rice, but it occurred with different timing. OsCERK is a bona fide ceramide kinase with a functionally and evolutionarily conserved Cys-rich motif that plays an important role in modulating cell fate in plants. The vital function of the conserved motif in both human and rice CERKs suggests that the biochemical mechanism of CERKs is similar in animals and plants. Furthermore, ceramides induce cell death with similar features in monocot and dicot plants.


Null mutations in the lin-31 gene indicate two functions during Caenorhabditis elegans vulval development.
The lin-31 gene is required for the proper specification of vulval cell fates in the nematode Caenorhabditis elegans and encodes a member of the winged-helix family of transcription factors. Members of this important family have been identified in many organisms and are known to bind specific DNA targets involved in a variety of developmental processes. DNA sequencing of 13 lin-31 alleles revealed six nonsense mutations and two missense mutations within the DNA-binding domain, plus three deletions, one transposon insertion, and one frameshift mutation that all cause large-scale disruptions in the gene. The missense mutations are amino acid substitutions in the DNA-binding domain and probably disrupt interactions of the LIN-31 transcription factor with its DNA target. In addition, detailed phenotypic analysis of all 19 alleles showed similar penetrance for several characteristics examined. From our analysis we conclude: (1) the null phenotype of lin-31 is the phenotype displayed by almost all of the existing alleles, (2) the DNA-binding domain plays a critical role in LIN-31 function, and (3) direct screens for multivulva and vulvaless mutants will probably yield only null (or strong) alleles of lin-31.


A Randomized, Double-Blind, Placebo Controlled Trial to Determine the Effectiveness a Polyphenolic Extract (Hibiscus sabdariffa and Lippia citriodora) in the Reduction of Body Fat Mass in Healthy Subjects.
: The location and quantity of body fat determine the health risks, limiting people with obesity. Recently, polyphenols have attracted the attention of the scientific community because of their potential use for the reduction of obesity. A proprietary formula comprised of a blend of Lippia citriodora and Hibiscus sabdariffa has been recognized for its high content of polyphenols, powerful antioxidant molecules that may prevent weight gain and could be helpful for the treatment of obesity, as proven previously by in vivo models. The aim of the present study is to determine if the supplementation with Lippia citriodora and Hibiscus sabdariffa is useful for the treatment of obesity and/or weight control in subjects without a controlled diet. The intake of the extract for 84 days reduced body weight, the body mass index, and the fat mass measured with both bioimpedance and densitometry. This decrease in fat mass was observed to a greater extent, being significant, in the fat mass of the trunk (chest and torso).


Innovation adoption in substance abuse treatment: exposure, trialability, and the Clinical Trials Network.
Researchers and policymakers are increasingly focusing on factors that facilitate or impede the diffusion of evidence-based treatment techniques into routine clinical practice. One potentially fruitful avenue of research is the influence of involvement in research networks as a predictor of organizational innovation. The Clinical Trials Network (CTN) is examining a number of behavioral and pharmacological treatment techniques in controlled multisite studies. Using data from participating CTN treatment programs and large samples of programs outside the CTN, these analyses examine the influence of exposure to clinical trials on the subsequent adoption of buprenorphine and voucher-based motivational incentives. The analyses show that, controlling for a variety of organizational characteristics, direct exposure to buprenorphine clinical trials in the CTN significantly increased the odds of subsequent adoption. By contrast, the adoption of motivational incentives was entirely explained by organizational characteristics. The findings suggest that adoption of treatment innovations is a function of exposure, organizational resources, nature of innovations, and stage of the diffusion process.


Knowing the fishery to know the bycatch: bias-corrected estimates of harbour porpoise bycatch in gillnet fisheries.
Incidental captures (bycatch) remain a key global conservation threat for cetaceans. Bycatch of harbour porpoise Phocoena phocoena in set gillnets is routinely monitored in European Union fisheries, but generally relies on data collected at low spatio-temporal resolution or over short periods. In Denmark, a long-term monitoring programme started in 2010 using electronic monitoring to collect data on porpoise bycatch and gillnet fishing effort at a fine spatial and temporal scale, including time and position of each fishing operation, together with every associated bycatch event. We used these observations to model bycatch rates, given the operational and ecological characteristics of each haul observed in Danish waters. Data on fishing effort from the Danish and Swedish gillnet fleets were collected to predict fleet-wide porpoise bycatch in gillnets at regional level. Between 2010 and 2020, yearly total bycatch averaged 2088 animals (95% Cl: 667-6798). For the Western Baltic assessment unit, bycatch levels were above sustainability thresholds. These results demonstrate that fishing characteristics are key determinants of porpoise bycatch and that classical approaches ignoring these features would produce biased estimates. It emphasizes the need for efficient and informative monitoring methods to understand possible conservation impacts of marine mammal bycatch and to implement tailored mitigation techniques.


Regularity analysis in a compartmental model of chopper units in the anteroventral cochlear nucleus.
1. We investigate the discharge patterns of chopper units in the anteroventral cochlear nucleus (AVCN) by developing an equivalent cylinder compartmental model of AVCN stellate cells, which are the sources of the chopper response pattern. The model consists of a passive dendritic tree connected to somatic and axonal compartments with voltage-sensitive channels. Synaptic inputs to the model are simulated auditory nerve fiber responses to best-frequency tones. 2. We adjust the anatomic and electrical parameters of the model to agree with available intracellular data from stellate cells in the AVCN of the mouse and the cat and compare the response of the model to injected current with responses recorded in vitro. The model shows approximately linear current-voltage characteristics for small hyperpolarizing currents. The model's input resistance and the time course of its response to hyperpolarizing current applied at the soma are comparable with those measured from stellate cells in vitro. In response to sustained depolarizing current, the model fires repetitively with nearly perfect regularity, a property also observed in vitro. 3. Auditory nerve inputs to the cell are modeled as deadtime-modified Poisson processes with a multiexponential adaptation in the Poisson rate. We are able to adjust the number, rate, and location of excitatory and inhibitory inputs to the model and succeed in simulating chopper response patterns seen in vivo. 4. Chopper units exhibit a variety of regularity and adaptation patterns in response to tone stimuli. Physiological data from brain slice experiments and experiments in vivo imply that this heterogeneity is primarily due to differences in input configurations. By systematically varying the number and position of excitatory and inhibitory inputs, we can simulate a range of chopper response patterns. 5. We quantify the regularity of the model's response using the coefficient of variation (CV) of the interspike interval. We find that the CV decreases, i.e., the regularity increases, as the number of converging inputs or their distance from the soma increases. The regularity of the output is more sensitive to the number of converging inputs than to their location on the dendritic tree. The statistics of the first spike latency (FSL) are also sensitive to the configuration of excitatory inputs. The mean and minimum FSL are more sensitive to the electrotonic distance of the inputs from the soma than to the number of inputs, whereas the standard deviation of the FSL is highly dependent on the number of converging inputs and is nearly independent of their location.(ABSTRACT TRUNCATED AT 400 WORDS)


Fully Bayesian inference for structural MRI: application to segmentation and statistical analysis of T2-hypointensities.
Aiming at iron-related T2-hypointensity, which is related to normal aging and neurodegenerative processes, we here present two practicable approaches, based on Bayesian inference, for preprocessing and statistical analysis of a complex set of structural MRI data. In particular, Markov Chain Monte Carlo methods were used to simulate posterior distributions. First, we rendered a segmentation algorithm that uses outlier detection based on model checking techniques within a Bayesian mixture model. Second, we rendered an analytical tool comprising a Bayesian regression model with smoothness priors (in the form of Gaussian Markov random fields) mitigating the necessity to smooth data prior to statistical analysis. For validation, we used simulated data and MRI data of 27 healthy controls (age: [Formula: see text]; range, [Formula: see text]). We first observed robust segmentation of both simulated T2-hypointensities and gray-matter regions known to be T2-hypointense. Second, simulated data and images of segmented T2-hypointensity were analyzed. We found not only robust identification of simulated effects but also a biologically plausible age-related increase of T2-hypointensity primarily within the dentate nucleus but also within the globus pallidus, substantia nigra, and red nucleus. Our results indicate that fully Bayesian inference can successfully be applied for preprocessing and statistical analysis of structural MRI data.


Inflammatory mechanisms linking maternal and childhood asthma.
Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness, inflammation, and remodeling. Asthma often develops during childhood and causes lifelong decrements in lung function and quality of life. Risk factors for childhood asthma are numerous and include genetic, epigenetic, developmental, and environmental factors. Uncontrolled maternal asthma during pregnancy exposes the developing fetus to inflammatory insults, which further increase the risk of childhood asthma independent of genetic predisposition. This review focuses on the role of maternal asthma in the development of asthma in offspring. We will present maternal asthma as a targetable and modifiable risk factor for childhood asthma and discuss the mechanisms by which maternal inflammation increases childhood asthma risk. Topics include how exposure to maternal asthma in utero shapes structural lung development with a special emphasis on airway nerves, how maternal type-2 cytokines such as IL-5 activate the fetal immune system, and how changes in lung and immune cell development inform responses to aero-allergens later in life. Finally, we highlight emerging evidence that maternal asthma establishes a unique "asthma signature" in the airways of children, leading to novel mechanisms of airway hyperreactivity and inflammatory cell responses.


Modified open-door laminoplasty for treatment of neurological deficits in younger patients with congenital spinal stenosis: analysis of clinical and radiographic data.
Multilevel anterior cervical decompressive surgery and fusion effectively treats cervical myeloradiculopathy that is caused by severe cervical spinal stenosis, but degenerative changes at adjacent vertebral levels frequently result in long-term morbidity. The authors performed a modified open-door laminoplasty procedure in which allograft bone and titanium miniplates were used to treat cervical myeloradiculopathy in younger patients with congenital canal stenosis while maintaining functional cervical motion segments. Pre- and postoperative magnetic resonance imaging and/or computerized tomography myelography were performed to assess changes in cervical spinal canal dimensions. Pre- and postoperative flexion-extension radiographs were compared to determine the residual motion of the targeted operative segments. Twenty younger patients (average age 37.7 years) underwent modified open-door laminoplasty for treatment of myelopathy or myeloradiculopathy related to significant cervical spinal stenosis with or without associated central or lateral disc herniation or foraminal stenosis. These surgeries were performed during a 2-year period and follow-up review remains ongoing (average follow-up period 21.6 months). Reconstructive procedures were performed on an average of 4.1 levels (range three-six). Operative time averaged 186 minutes (range 93-229 minutes). Average blood loss was 305 ml (range 100-650 ml). No cases were complicated by neurological deterioration, infection, wound breakdown, graft displacement, or hardware failure. The patients' Nurick Scale grade improved from a preoperative average of 1.8 to a postoperative average of 0.5. Pre- and postoperative sagittal spinal diameter averaged 11.2 mm (8-14 mm) and 16.6 mm (13-19 mm), respectively. The sagittal compression ratio (sagittal/lateral x 100%) increased from 48% pre- to 72% postoperatively. The spinal canal area increased an average of 55% (range 19-127%). In patients in whom pre- and postoperative flexion-extension radiographs were obtained, 72.7% residual neck motion was maintained. No patient developed increased neck or shoulder pain. Neurological symptoms improved in all patients, with total relief of myelopathy in 50% and partial improvement in 50%. Modified open-door laminoplasty with allograft bone and titanium miniplates effectively treats neurological deficits in younger patients with congenital and spinal stenosis. Although long-term results are unknown, short-term results are good and there is a low incidence of complications.


L-selectin binds to P-selectin glycoprotein ligand-1 on leukocytes: interactions between the lectin, epidermal growth factor, and consensus repeat domains of the selectins determine ligand binding specificity.
The selectins mediate cellular interactions by binding carbohydrate determinants present on a limited number of glycoprotein ligands. L-selectin binds multiple ligands expressed on endothelial cells, while P-selectin interacts exclusively with P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes. In this study, L-selectin was shown to bind leukocytes through the P-selectin ligand, PSGL-1, although at lower levels than P-selectin. L-selectin binding to PSGL-1 is specific since it was blocked by Abs to L-selectin or PSGL-1, required appropriate glycosylation of PSGL-1, and was Ca2+ dependent. The contributions of the extracellular domains of the selectins to ligand binding was assessed using a panel of chimeric selectins created by exchange of domains between L-selectin and P- or E-selectin. The lectin and epidermal growth factor domains of L- and P-selectin contributed significantly to binding through similar, if not identical, regions of PSGL-1. The different chimeric selectins revealed that the lectin domain was the dominant determinant for ligand binding, while cooperative interactions between the lectin, epidermal growth factor, and short consensus repeat domains of the selectins also modified ligand binding specificity. L-selectin binding to PSGL-1 expressed by leukocytes may mediate neutrophil rolling on stationary leukocytes bound to cytokine-induced endothelial cells, which was previously reported to be a L-selectin-dependent process.


Frequent expression of a novel cancer testis antigen, protein kinase human monopolar spindle 1 (hMps1/TTK) in human urinary bladder transitional cell carcinoma.
Urothelial bladder cancer (UBC) is a frequently occurring malignancy of the urinary tract. The present study was undertaken to evaluate the mRNA and immunohistochemical (IHC) expression of protein kinase human monopolar spindle 1 (hMps1/TTK) gene in transitional cell carcinoma (TCC) of the bladder and correlate its expression with the clinicopathological characteristics of patients. In the present study, quantitative real-time reverse-transcriptase polymerase chain reaction (qRT-PCR) was used to evaluate TTK mRNA expression in TCC. IHC analysis of TTK was also evaluated. Independent Student's t, ANOVA and chi-square (χ2) tests were used to analyze the data statistically. The frequency of TTK mRNA over expression was detected in 50% of UBC (38/76) by qRT-PCR. Relative mean fold expression of TTK mRNA was found significantly (p < 0.05) higher in muscle-invasive bladder cancer (MIBC) as compared to non-muscle-invasive bladder cancer (NMIBC) patients (8.96 ± 4.51 vs. 5.64 ± 3.53, p = 0.03). Moreover, IHC reveals heterogenous immunostaining pattern of TTK in TCC tissues. The frequency of TTK protein over expression was detected in 56.9% (37 of 65) UBC patients. No significant IHC expression of TTK was detected among adjacent noncancerous tissues (ANCTs) and benign prostatic hyperplasia (BPH) used as control. Collectively our study observations conclude that TTK is a novel cancer/testis antigen (CTA) as a diagnostic marker for early diagnosis of UBC.


Multiple functions for CD28 and cytotoxic T lymphocyte antigen-4 during different phases of T cell responses: implications for arthritis and autoimmune diseases.
Chronic T cell responses, as they occur in rheumatoid arthritis, are complex and are likely to involve many mechanisms. There is a growing body of evidence that, in concert with the T cell antigen receptor signal, CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) are the primary regulators of T cell responses. Whereas CD28 primarily activates T cell processes, CTLA-4 inhibits them. The mechanism for this dichotomy is not fully understood, especially as CD28 and CTLA-4 recruit similar signalling molecules. In addition, recent studies demonstrate that CD28 and CTLA-4 have multiple functions during T cell responses. In particular, CTLA-4 exerts independent distinct effects during different phases of T cell responses that could be exploited for the treatment of rheumatoid arthritis.


A novel, single nucleotide polymorphism-based assay to detect 22q11 deletions.
Velocardiofacial syndrome, DiGeorge syndrome, and conotruncal anomaly face syndrome, now collectively referred to as 22q11deletion syndrome (22q11DS) are caused by microdeletions on chromosome 22q11. The great majority ( approximately 90%) of these deletions are 3 Mb in size. The remaining deleted patients have nested break-points resulting in overlapping regions of hemizygosity. Diagnostic testing for the disorder is traditionally done by fluorescent in situ hybridization (FISH) using probes located in the proximal half of the region common to all deletions. We developed a novel, high-resolution single-nucleotide polymorphism (SNP) genotyping assay to detect 22q11 deletions. We validated this assay using DNA from 110 nondeleted controls and 77 patients with 22q11DS that had previously been tested by FISH. The assay was 100% sensitive (all deletions were correctly identified). Our assay was also able to detect a case of segmental uniparental disomy at 22q11 that was not detected by the FISH assay. We used Bayesian networks to identify a set of 17 SNPs that are sufficient to ascertain unambiguously the deletion status of 22q11DS patients. Our SNP based assay is a highly accurate, sensitive, and specific method for the diagnosis of 22q11 deletion syndrome.


Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.
The adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis. Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and other brain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains, respectively, to explore the roles of LepR in pancreatic β and α cells. Here, we use two newly-developed Cre lines to explore the role of leptin signalling in insulin and proglucagon-expressing cells. Leptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR. Mice lacking leptin signalling in pancreatic β, or in α and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediated recombination respectively of flox'd leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology and hormone secretion from isolated islets were assessed using standard techniques. Leptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptin signalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2 ± 3.2% decrease in area under curve; p < 0.05), and improved (39.0 ± 13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio. Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro. The use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study.


Effects of thermal water inhalation in chronic upper respiratory tract infections in elderly and young patients.
Chronic upper respiratory tract infections (cURTI) are very frequent illnesses which occur at any age of life. In elderly, cURTI are complicated by immunosenescence, with involvement of lung immune responsiveness. In the present study, 51 elderly (age range: 66-86) and 51 young (age range 24-58) cURTI patients underwent a single cycle (two weeks) of inhalatory therapy with salt-bromide-iodine thermal water in the thermal station "Margherita di Savoia" (Margherita di Savoia, BAT, Italy). Peripheral blood serum cytokines and clinical assessment were performed before therapy (T0) and after six months (T1) and 12 months (T2) from inhalatory treatment. In both elderly and young patients, at baseline an increased release of T helper (h)1-related cytokines [interleukin (IL)-2 and interferon-γ] and of Th2-related cytokine (IL-4) was documented. Inhalatory treatment reduced the excessive secretion of all the above-cited cytokines. IL-10 values were above normality at all times considered in both groups of patients. In addition, an increase in IL-17 and IL-21 serum levels following therapy was observed in both groups of patients. Pro-inflammatory cytokine (IL-1β, IL-6, IL-8 and tumor necrosis factor-α) baseline values were lower than normal values at T0 in both elderly and young cURTI patients. Their levels increased following inhalatory treatment. Clinically, at T2 a dramatic reduction of frequency of upper respiratory tract infections was recorded in both groups of patients. Thermal water inhalation is able to modulate systemic immune response in elderly and young cURTI patients, thus reducing excessive production of Th1 and Th2-related cytokines, on the one hand. On the other hand, increased levels of IL-21 (an inducer of Th17 cells) and of IL-17 may be interpreted as a protective mechanism, which likely leads to neutrophil recruitment in cURTI patients. Also restoration of pro-inflammatory cytokine release following inhalatory therapy may result in microbe eradication. Quite importantly, the maintenance of high levels of IL-10 during the follow-up would suggest a consistent regulatory role of this cytokine in attenuating the pro-inflammatory arm of the immune response.


High leukocyte count is associated with peripheral vascular dysfunction in individuals with low cardiovascular risk.
Vascular dysfunction is a surrogate marker of early-stage atherosclerosis. Serum leukocyte count is a non-traditional risk factor of cardiovascular (CV) disease and has predictive value for CV outcome. The aim of this study was to investigate the relationship between leukocyte count and peripheral vascular dysfunction. In this cross-sectional study, 357 individuals without known CV disease and with low Framingham risk (10-year hard coronary heart disease risk <10%) were identified. Vascular function was measured by assessing reactive hyperemia-induced vasodilation (reactive hyperemia index, RHI). In 105 individuals with vascular dysfunction (29.4%), the median leukocyte count was significantly higher than in those with normal RHI (6.4 × 10(9)/L vs. 6.0 × 10(9)/L; P=0.04). The neutrophil count was the strongest predictor of impaired vascular function among leukocyte subtypes (odds ratio [OR], 2.70; 95% confidence interval [CI]: 1.58-4.60, P<0.001). In a multivariate logistic regression model, the highest quintile of neutrophil count (OR, 2.36; 95% CI: 1.35-4.12; P=0.003), body mass index (OR, 1.05; 95% CI: 1.01-1.09; P=0.009) and systolic blood pressure (OR, 0.97; 95% CI: 0.97-0.99; P<0.001) were independently predictive for vascular dysfunction. The highest quintile of leukocyte count is independently associated with vascular dysfunction in individuals with low CV risk. This suggests that subclinical inflammation affects vascular function. Leukocyte count may be useful for personalized risk stratification.


Mediation of plant-mycorrhizal interaction by a lectin receptor-like kinase.
The molecular mechanisms underlying mycorrhizal symbioses, the most ubiquitous and impactful mutualistic plant-microbial interaction in nature, are largely unknown. Through genetic mapping, resequencing and molecular validation, we demonstrate that a G-type lectin receptor-like kinase (lecRLK) mediates the symbiotic interaction between Populus and the ectomycorrhizal fungus Laccaria bicolor. This finding uncovers an important molecular step in the establishment of symbiotic plant-fungal associations and provides a molecular target for engineering beneficial mycorrhizal relationships.


Patient Satisfaction with Hospital Inpatient Care: Effects of Trust, Medical Insurance and Perceived Quality of Care.
Deteriorations in the patient-provider relationship in China have attracted increasing attention in the international community. This study aims to explore the role of trust in patient satisfaction with hospital inpatient care, and how patient-provider trust is shaped from the perspectives of both patients and providers. We adopted a mixed methods approach comprising a multivariate logistic regression model using secondary data (1200 people with inpatient experiences over the past year) from the fifth National Health Service Survey (NHSS, 2013) in Heilongjiang Province to determine the associations between patient satisfaction and trust, financial burden and perceived quality of care, followed by in-depth interviews with 62 conveniently selected key informants (27 from health and 35 from non-health sectors). A thematic analysis established a conceptual framework to explain deteriorating patient-provider relationships. About 24% of respondents reported being dissatisfied with hospital inpatient care. The logistic regression model indicated that patient satisfaction was positively associated with higher level of trust (OR = 14.995), lower levels of hospital medical expenditure (OR = 5.736-1.829 as compared with the highest quintile of hospital expenditure), good staff attitude (OR = 3.155) as well as good ward environment (OR = 2.361). But patient satisfaction was negatively associated with medical insurance for urban residents and other insurance status (OR = 0.215-0.357 as compared with medical insurance for urban employees). The qualitative analysis showed that patient trust-the most significant predictor of patient satisfaction-is shaped by perceived high quality of service delivery, empathic and caring interpersonal interactions, and a better designed medical insurance that provides stronger financial protection and enables more equitable access to health care. At the core of high levels of patient dissatisfaction with hospital care is the lack of trust. The current health care system reform in China has yet to address the fundamental problems embedded in the system that caused distrust. A singular focus on doctor-patient inter-personal interactions will not offer a successful solution to the deteriorated patient-provider relationships unless a systems approach to accountability is put into place involving all stakeholders.


Evaluation of serological diagnostic tests for typhoid fever in Papua New Guinea using a composite reference standard.
Typhoid fever remains a major global health problem. A major impediment to improving outcomes is the lack of appropriate diagnostic tools, which have not significantly improved in low-income settings for 100 years. We evaluated two commercially available rapid diagnostic tests (Tubex and TyphiDot), a prototype (TyphiRapid TR-02), and the commonly used single-serum Widal test in a previously reported high-burden area of Papua New Guinea. Samples were collected from 530 outpatients with axillary temperatures of ≥37.5°C, and analysis was conducted on all malaria-negative samples (n = 500). A composite reference standard of blood culture and PCR was used, by which 47 participants (9.4%) were considered typhoid fever positive. The sensitivity and specificity of the Tubex (51.1% and 88.3%, respectively) and TyphiDot (70.0% and 80.1%, respectively) tests were not high enough to warrant their ongoing use in this setting; however, the sensitivity and specificity for the TR-02 prototype were promising (89.4% and 85.0%, respectively). An axillary temperature of ≥38.5°C correlated with typhoid fever (P = 0.014). With an appropriate diagnostic test, conducting typhoid fever diagnosis only on patients with high-grade fever could dramatically decrease the costs associated with diagnosis while having no detrimental impact on the ability to accurately diagnose the illness.


Survival of grafted fetal neural cells in kainic acid lesioned CA3 region of adult hippocampus depends upon cell specificity.
We hypothesize that the degree of graft cell survival within the damaged CNS correlates with the specificity of donor cells to the region of grafting. We investigated graft cell survival following transplantation of fetal micrografts into the CA3 region of the adult rat hippocampus at a time-point of 4 days after an intracerebroventricular administration of kainic acid (KA). Grafts consisted of 5'-bromodeoxyuridine (BrdU) labeled embryonic day (E) 19 cells from hippocampal fields CA3 and CA1 and E15 and E19 cells from the striatum. Absolute cell survival in these grafts was quantitatively analyzed at 1 month postgrafting, using BrdU immunostaining of serial sections and three-dimensional reconstruction of grafts. Absolute graft cell survival in lesioned CA3 was dramatically greater for cells having hippocampal origin (CA3 cells, 69% cell survival; CA1 cells, 42% cell survival) than those having nonhippocampal origin, such as striatal cells (E15 cells, 12% cell survival; E19 cells, 4% cell survival). This difference is in sharp contrast to survival of these cells in culture, where E19 cells from both hippocampal and nonhippocampal origins exhibited similar survival. Comparison of survival among hippocampal cell types indicated significantly greater survival for cells that are specific to the lesioned area (i.e., CA3 cells) than for those that are nonspecific to the lesioned area (i.e., CA1 cells). Graft cell survival in the intact CA3 region (contralateral to KA administration), however, did not differ either between cells having hippocampal and nonhippocampal origins or between CA3 and CA1 cells (CA3 cells, 26% cell survival; CA1 cells, 33% cell survival; and E15 striatal cells, 20% cell survival). These results underscore the finding that enhanced survival of fetal cell grafts in the lesioned CNS is critically dependent upon the specificity of donor fetal cells to the region of transplantation. Thus, grafting of cells that are specific to the lesioned area is a prerequisite for achieving maximal graft cell survival and integration in the lesioned host CNS.


Sc20C60: a volleyballene.
An exceptionally stable hollow cage containing 20 scandium atoms and 60 carbon atoms has been identified. This Sc20C60 molecular cluster has a Th point group symmetry and a volleyball-like shape that we refer to below as "Volleyballene". Electronic structure analysis shows that the formation of delocalized π bonds between Sc atoms and the neighboring pentagonal rings made of carbon atoms is crucial for stabilizing the cage structure. A relatively large HOMO-LUMO gap (∼1.4 eV) was found. The results of vibrational frequency analysis and molecular dynamics simulations both demonstrate that this Volleyballene molecule is exceptionally stable.


Investigation of solid surfaces modified by Langmuir-Blodgett monolayers using sum-frequency vibrational spectroscopy and X-ray photoelectron spectroscopy.
Langmuir-Blodgett (LB) monomolecular layers of alkylhydroxamic acids and alkylphosphonic acids on copper and iron substrates have been studied by X-ray photoelectron spectroscopy (XPS) and sum-frequency vibrational spectroscopy. According to the XPS results, the structures of the hydroxamic acid and phosphonic acid Langmuir-Blodgett films are very similar: the thickness of the layer of the hydrocarbon tails is typically 1.9-2.1 nm, while the layer of headgroups is about 0.3-0.35 nm thick. The tilt angle of the carbon chains is estimated to be 20-30 degrees with respect to the sample surface normal, and the molecules are connected to the substrate via their headgroups. Analysis of the P 2p and N 1s lines indicates the presence of deprotonated headgroups. The substrate Cu 2p line includes a component which can be assigned to Cu(2+) ions in a thin Cu(OH)(2) layer. The deposition of LB layers led to significant decrease of the hydroxide-related signal, which indicates that binding of the headgroups to the surface is accompanied by the elimination of water molecules. The sum-frequency spectra also clearly indicate that well-ordered monolayers can be formed by the Langmuir-Blodgett technique. Since the non-resonant background from the metal substrates renders the analysis of the spectra more difficult, model system samples on glass were prepared. It was found that the alkyl chains of the adsorbed acids predominantly adopt the all-trans conformation and form an ordered structure. Upper limits for the mean tilt angle of the terminal methyl groups are approximately 10-20 degrees.


Immigration and hybridization patterns of yellow and anubis baboons in and around Amboseli, Kenya.
In 1986, Samuels and Altmann reported evidence for a hybrid zone between Papio anubis and Papio cynocephalus in Amboseli, Kenya, in a baboon population that has been the subject of long-term study since 1971 [Samuels & Altmann, International Journal of Primatology 7:131-138, 1986]. In the current report we document ongoing patterns of hybridization in Amboseli between anubis and yellow baboons. In July 2000, we exhaustively scored living members of study groups for their degree of hybridity, using seven phenotypic characteristics (five in juveniles). We also scored all former members of study groups on the basis of photographic records, field notes, and observer recollections. A total of five anubis males and 11 males with hybrid phenotypes have immigrated into study groups over the course of the long-term study, and immigrations by hybrid males have increased in frequency over time. Further, the increasing frequency of hybrid phenotypes among animals born into study groups indicates that anubis and hybrid males have successfully reproduced in study groups. However, hybrid phenotypes and anubis immigrations were limited to groups in the southwestern portion of the Amboseli basin, with no hybrids occurring in the six eastern groups. Finally, we present evidence that anubis and hybrid males in Amboseli exhibit patterns of natal dispersal that are different from those of yellow males in Amboseli: males with anubis or hybrid phenotypes were significantly more likely to immigrate as juveniles or young subadults than were yellow males.


A novel mechanism for mechanosensory-based rheotaxis in larval zebrafish.
When flying or swimming, animals must adjust their own movement to compensate for displacements induced by the flow of the surrounding air or water. These flow-induced displacements can most easily be detected as visual whole-field motion with respect to the animal's frame of reference. Despite this, many aquatic animals consistently orient and swim against oncoming flows (a behaviour known as rheotaxis) even in the absence of visual cues. How animals achieve this task, and its underlying sensory basis, is still unknown. Here we show that, in the absence of visual information, larval zebrafish (Danio rerio) perform rheotaxis by using flow velocity gradients as navigational cues. We present behavioural data that support a novel algorithm based on such local velocity gradients that fish use to avoid getting dragged by flowing water. Specifically, we show that fish use their mechanosensory lateral line to first sense the curl (or vorticity) of the local velocity vector field to detect the presence of flow and, second, to measure its temporal change after swim bouts to deduce flow direction. These results reveal an elegant navigational strategy based on the sensing of flow velocity gradients and provide a comprehensive behavioural algorithm, also applicable for robotic design, that generalizes to a wide range of animal behaviours in moving fluids.


Nanoantennas for ultrabright single photon sources.
We propose to use nanoantennas (NAs) coupled to incoherently pumped quantum dots for ultrabright single photon emission. Besides fully quantum calculations, we analyze an analytical expression for the emitted photon rate. From these analytical considerations, it turns out that the Purcell factor and the pumping rate are the main quantities of interest. We also disclose a trade-off between the emitted photon rate and the nonclassical nature of the emitted light. This trade-off has to be considered while designing suitable NAs, which we also discuss in depth.


Open sharing of genomic data: Who does it and why?
We explored the characteristics and motivations of people who, having obtained their genetic or genomic data from Direct-To-Consumer genetic testing (DTC-GT) companies, voluntarily decide to share them on the publicly accessible web platform openSNP. The study is the first attempt to describe open data sharing activities undertaken by individuals without institutional oversight. In the paper we provide a detailed overview of the distribution of the demographic characteristics and motivations of people engaged in genetic or genomic open data sharing. The geographical distribution of the respondents showed the USA as dominant. There was no significant gender divide, the age distribution was broad, educational background varied and respondents with and without children were equally represented. Health, even though prominent, was not the respondents' primary or only motivation to be tested. As to their motivations to openly share their data, 86.05% indicated wanting to learn about themselves as relevant, followed by contributing to the advancement of medical research (80.30%), improving the predictability of genetic testing (76.02%) and considering it fun to explore genotype and phenotype data (75.51%). Whereas most respondents were well aware of the privacy risks of their involvement in open genetic data sharing and considered the possibility of direct, personal repercussions troubling, they estimated the risk of this happening to be negligible. Our findings highlight the diversity of DTC-GT consumers who decide to openly share their data. Instead of focusing exclusively on health-related aspects of genetic testing and data sharing, our study emphasizes the importance of taking into account benefits and risks that stretch beyond the health spectrum. Our results thus lend further support to the call for a broader and multi-faceted conceptualization of genomic utility.


Longitudinal health-related quality of life analysis in oncology with time to event approaches, the STATA command qlqc30_TTD.
Health-related quality of life (HRQoL) has become one relevant and available alternative endpoint of clinical trials in cancer research to evaluate efficiency of care both for the patient and health system. HRQoL in oncology is mainly assessed using the 30-item European Organisation for Research and Treatment of Cancer Quality of Life-Questionnaire Core 30 (EORTC QLQ-C30). The EORTC QLQ-C30 questionnaire is usually assessed at different times along the clinical trials in order to analyze the kinetics of HRQoL evolution and to fully assess the impact of the treatment on the patient's HRQoL level. In this perspective, the realization of a longitudinal HRQoL analysis is essential and the time to HRQoL score deterioration approach is a method which is more and more used in clinical trials. Using the Stata software, we developed a QLQ-C30 specific command, qlqc30_TTD, which implements longitudinal strategies based on the time to event methods by considering the time to HRQoL score deterioration. This user-written command providing automatic execution of the Time To Deterioration (TTD) and Time Until Definitive Deterioration (TUDD) methods. The program implements all published definitions and provides the Kaplan-Meier curves for each dimension (by group) and a table with the Hazard Ratio and Log-Rank test. The longitudinal analysis of HRQoL data in cancer clinical trials remains complex with only few programs like ours computed. This program will be of great help and will allow a more systematic and quicker analysis of the HRQoL data in clinical trials in oncology.


Age- and sex-related ABC transporter expression in pyrethroid-susceptible and -resistant Aedes aegypti.
Resistance mechanisms to synthetic insecticides often include point mutations and increased expression of genes encoding detoxification enzymes. Since pyrethroids are the main adulticides used against Aedes aegypti, which vectors pathogens such as Zika virus, understanding resistance to this insecticide class is of significant relevance. We focused on adenosine triphosphate (ATP)-binding cassette (ABC) transporters in the pyrethroid-resistant Puerto Rico (PR) strain of Ae. aegypti. We investigated the expression patterns of six ABC transporters previously characterized as differentially expressed in insecticide-challenged mosquitoes, or increased mRNA expression in pyrethroid-resistant Ae. aegypti, by comparing PR to the Rockefeller (Rock) susceptible strain. No constitutive differential expression between strains was detected, but expression differences for these genes was influenced by sex and age, suggesting that their role is independent from resistance in PR. Instead, ABC transporters may be induced after insecticide exposure. Challenging mosquitoes with deltamethrin, with or without ABC transporter modulators, showed that Rock and PR responded differently, but a contribution of ABC transporters to deltamethrin toxicity is suspected. Moreover, the effect of dexamethasone, which enhanced the inhibition of nerve firing by deltamethrin, was observed using a Drosophila central nervous system preparation, showing synergy of these two compounds through the potential inhibition of ABC transporters.


Epidermal growth factor receptor cooperates with Src family kinases in acquired resistance to cetuximab.
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that plays a major role in oncogenesis. Cetuximab is an EGFR-blocking antibody that is FDA approved for use in patients with metastatic colorectal cancer (mCRC) and head and neck squamous cell carcinoma (HNSCC). Although cetuximab has shown strong clinical benefit for a subset of cancer patients, most become refractory to cetuximab therapy. We reported that cetuximab-resistant NSCLC line NCI-H226 cells have increased steady-state expression and activity of EGFR secondary to altered trafficking/degradation and this increase in EGFR expression and activity lead to hyper-activation of HER3 and down stream signals to survival. We now present data that Src family kinases (SFKs) are highly activated in cetuximab-resistant cells and enhance EGFR activation of HER3 and PI(3)K/Akt. Studies using the Src kinase inhibitor dasatinib decreased HER3 and PI(3)K/Akt activity. In addition, cetuximab-resistant cells were resensitized to cetuximab when treated with dasatinib. These results indicate that SFKs and EGFR cooperate in acquired resistance to cetuximab and suggest a rationale for clinical strategies that investigate combinatorial therapy directed at both the EGFR and SFKs in patients with acquired resistance to cetuximab.


Context Dependent Effects of Chimeric Peptide Morpholino Conjugates Contribute to Dystrophin Exon-skipping Efficiency.
We have recently reported that cell-penetrating peptides (CPPs) and novel chimeric peptides containing CPP (referred as B peptide) and muscle-targeting peptide (referred as MSP) motifs significantly improve the systemic exon-skipping activity of morpholino phosphorodiamidate oligomers (PMOs) in dystrophin-deficient mdx mice. In the present study, the general mechanistic significance of the chimeric peptide configuration on the activity and tissue uptake of peptide conjugated PMOs in vivo was investigated. Four additional chimeric peptide-PMO conjugates including newly identified peptide 9 (B-9-PMO and 9-B-PMO) and control peptide 3 (B-3-PMO and 3-B-PMO) were tested in mdx mice. Immunohistochemical staining, RT-PCR and western blot results indicated that B-9-PMO induced significantly higher level of exon skipping and dystrophin restoration than its counterpart (9-B-PMO), further corroborating the notion that the activity of chimeric peptide-PMO conjugates is dependent on relative position of the tissue-targeting peptide motif within the chimeric peptide with respect to PMOs. Subsequent mechanistic studies showed that enhanced cellular uptake of B-MSP-PMO into muscle cells leads to increased exon-skipping activity in comparison with MSP-B-PMO. Surprisingly, further evidence showed that the uptake of chimeric peptide-PMO conjugates of both orientations (B-MSP-PMO and MSP-B-PMO) was ATP- and temperature-dependent and also partially mediated by heparan sulfate proteoglycans (HSPG), indicating that endocytosis is likely the main uptake pathway for both chimeric peptide-PMO conjugates. Collectively, our data demonstrate that peptide orientation in chimeric peptides is an important parameter that determines cellular uptake and activity when conjugated directly to oligonucleotides. These observations provide insight into the design of improved cell targeting compounds for future therapeutics studies.Molecular Therapy-Nucleic Acids (2013) 2, e124; doi:10.1038/mtna.2013.51; published online 24 September 2013.


Germline-specific expression of the Oct-4/green fluorescent protein (GFP) transgene in mice.
The Pic-1, Oct-1,2, Unc-86 (POU) transcription factor Oct-4 is specifically expressed in the germ cell line, and a previous study has indicated that the expression of the lacZ gene inserted into an 18 kb genomic fragment encompassing the Oct-4 gene can come close to mimicking the endogenous embryonic expression pattern of Oct-4 in transgenic mice. In the present study transgenic mice expressing green fluorescent protein (GFP) in the germ cell line were generated using the same Oct-4 genomic fragments and the expression pattern was analyzed in detail through all stages of germ cell development. The GFP expressing primordial germ cells were first detected as early as 8.0 days post-coitum (d.p.c.; early head fold stage) at the base of the allantois in living embryos. The GFP expression was thereafter found in both male and female germ cells at all developmental stages except in male germ cells after differentiating into type A spermatogonia in the postnatal testis. There was also a lower level of expression in female germ cells in the prophase of the first meiotic division. These transgenic mice therefore proved to be powerful tools for isolating living germ cells at various developmental stages to study their nature and to isolate new genes.


Large Vessel Stroke Following Multiple Other Strokes and Cardiomyopathy in a Forty-Nine-Year-Old COVID-19 Patient.
The novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made its presence known on the centerstage of worldwide healthcare in 2020. Although it is widely known about its pulmonary presence and ensuing complications, evidence is emerging that there are other organ systems including the cardiovascular and cerebrovascular systems that may be damaged by this virus. There have been reports of large vessel stroke occurring in coronavirus disease 2019 (COVID-19) positive patients, with very few reported in the age group less than 50 years. In this case, we describe a previously healthy 49-year-old male who presented with signs of stroke, and was found to have the novel coronavirus as he had been suffering from upper respiratory tract symptoms for 3 weeks. He subsequently developed further large vessel stroke while in the hospital despite being started on antiplatelet therapy. He was also found to have new onset cardiomyopathy. He was started on anticoagulation and discharged with follow-up for cardiomyopathy testing outpatient. This case begs the question on which anticoagulation to utilize in COVID-19 positive patients to be effective in preventing thrombotic events. It is postulated that a pro-inflammatory state induced by the virus and the virus' affinity for angiotensin converting enzyme-2 receptors in the cerebral vasculature are predispositions to cause a stroke. The virus also directly damages cardiac myocytes causing a number of cardiac complications including cardiomyopathy. It is crucial that guidelines on anticoagulation choice and indications for when to start anticoagulation be developed in order to prevent the more devastating consequences of thrombosis and embolism and their subsequent clinical sequelae.


Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells.
We sought to determine the location, expression, and characterization of cardiac stem cells (CSCs) in children with end-stage heart failure (ESHF). We hypothesized ESHF myocardium would contain an increased number of CSCs relative to age-matched healthy myocardium, and ESHF-derived CSCs would have diminished functional capacity as evidenced by reduced telomere length. Tissue samples were obtained from the explanted hearts of children undergoing heart transplantation with ESHF, defined as New York Heart Association class III or IV and ejection fraction less than 0.20, and from age-matched congenital heart disease patients with normal myocardium. The expression profile of cardiac-specific stem cell markers was determined using quantitative real time polymerase chain reaction and immunofluorescence. Cardiac stem cell growth reserve was assessed with telomere length. There were 15 ESHF and 15 age-matched congenital heart disease patients. End-stage heart failure myocardium demonstrated increased expression of c-kit(+) and islet-1(+) CSCs by 2.0- and 2.5-fold, respectively, compared with myocardium from congenital heart disease patients. There was no difference in expression of c-kit(+) CSCs with advancing age from infants to children in ESHF myocardium. The c-kit(+) CSCs isolated from ESHF patients demonstrated significantly reduced telomere length, suggesting a diminished functional capability in these cells (8.1 ± 0.6 kbp versus 6.3 ± 0.3 kbp; p = 0.015). End-stage heart failure myocardium demonstrated an age-independent increase in CSCs relative to healthy myocardium; however, these CSCs from ESHF patients may have diminished proliferative ability and reduced functionality as an autologous cell therapy candidate. Further investigation is necessary to determine the role of ESHF-derived CSCs within the myocardium.


Acetylcholinesterase Inhibitor Improves Learning and Memory Impairment Induced by Toxoplasma gondii Infection.
Here, we established the mouse models of chronic toxoplasmosis by T. gondii Tehran strain to provide a good understanding about defining the possible association between T. gondii exposure and learning and memory impairments. Moreover, as secondary objective of the present study, we hypothesized whether administration of an acetylcholinesterase (AChE) inhibitor could reduce learning and memory impairments induced by T. gondii infection. Twenty-four male BALB/c mice were used to establishment of latent toxoplasmosis. The animal model of Toxoplasma infection was established by the intraperitoneal inoculation of 20-25 tissue cysts from Tehran strain of T. gondii. Donepezil (2 mg/kg) an AChE inhibitor to treat Alzheimer disease was injected intraperitoneally once a day for two weeks starting from post-infection day 90. Morris water maze (MWM) task was used to assay spatial learning and short term spatial memory in all groups. One-way ANOVA with Tukey's post-hoc test was used to assess differences between experimental groups. P<0.05 was considered statistically significant. Toxoplasma infection impaired spatial leaning and short term spatial memory of the infected BALB/c mice, whereas donepezil, an AChE inhibitor, improved impairments induced by Toxoplasma infection. T. gondii infection through increasing AChE reduces the level of Acetylcholine (Ach) and consequently affects learning and memory activity in infected hosts, whereas, donepezil as an AChE inhibitor improves these impairments by restoring ACh levels at synapses of neurons in brain.


Development and validation of a symptom-based activity index for adults with eosinophilic esophagitis.
Standardized instruments are needed to assess the activity of eosinophilic esophagitis (EoE) and to provide end points for clinical trials and observational studies. We aimed to develop and validate a patient-reported outcome (PRO) instrument and score, based on items that could account for variations in patient assessments of disease severity. We also evaluated relationships between patient assessment of disease severity and EoE-associated endoscopic, histologic, and laboratory findings. We collected information from 186 patients with EoE in Switzerland and the United States (69.4% male; median age, 43 y) via surveys (n = 135), focus groups (n = 27), and semistructured interviews (n = 24). Items were generated for the instruments to assess biologic activity based on physician input. Linear regression was used to quantify the extent to which variations in patient-reported disease characteristics could account for variations in patient assessment of EoE severity. The PRO instrument was used prospectively in 153 adult patients with EoE (72.5% male; median age, 38 y), and validated in an independent group of 120 patients with EoE (60.8% male; median age, 40.5 y). Seven PRO factors that are used to assess characteristics of dysphagia, behavioral adaptations to living with dysphagia, and pain while swallowing accounted for 67% of the variation in patient assessment of disease severity. Based on statistical consideration and patient input, a 7-day recall period was selected. Highly active EoE, based on endoscopic and histologic findings, was associated with an increase in patient-assessed disease severity. In the validation study, the mean difference between patient assessment of EoE severity (range, 0-10) and PRO score (range, 0-8.52) was 0.15. We developed and validated an EoE scoring system based on 7 PRO items that assess symptoms over a 7-day recall period. Clinicaltrials.gov number: NCT00939263.


The impact of ankylosing spondylitis/axial spondyloarthritis on work productivity.
Ankylosing spondylitis (AS) is a chronic inflammatory condition that has a significant impact on the quality of life and work productivity. New classification criteria have enabled earlier diagnosis of this condition. However, work productivity is an important issue that is still often overlooked during clinical assessments and consultations. This article focusses on the relationship between axial spondyloarthritis (axial SpA) and work productivity. It summarises the impact of this condition on work productivity, and it highlights the tools available to assess this. It also highlights the increasing role and potential of employers, health professionals and new treatments for enhancing work productivity for people with this condition.


Benchmarking multi-rate codon models.
The single rate codon model of non-synonymous substitution is ubiquitous in phylogenetic modeling. Indeed, the use of a non-synonymous to synonymous substitution rate ratio parameter has facilitated the interpretation of selection pressure on genomes. Although the single rate model has achieved wide acceptance, we argue that the assumption of a single rate of non-synonymous substitution is biologically unreasonable, given observed differences in substitution rates evident from empirical amino acid models. Some have attempted to incorporate amino acid substitution biases into models of codon evolution and have shown improved model performance versus the single rate model. Here, we show that the single rate model of non-synonymous substitution is easily outperformed by a model with multiple non-synonymous rate classes, yet in which amino acid substitution pairs are assigned randomly to these classes. We argue that, since the single rate model is so easy to improve upon, new codon models should not be validated entirely on the basis of improved model fit over this model. Rather, we should strive to both improve on the single rate model and to approximate the general time-reversible model of codon substitution, with as few parameters as possible, so as to reduce model over-fitting. We hint at how this can be achieved with a Genetic Algorithm approach in which rate classes are assigned on the basis of sequence information content.


Functional stability of a mixed microbial consortium producing PHA from waste carbon sources.
Polyhydroxyalkanoates (PHAs) represent an environmentally effective alternative to synthetic thermoplastics; however, current production practices are not sustainable. In this study, PHA production was accomplished in sequencing batch bioreactors utilizing real wastewaters and mixed microbial consortia from municipal activated sludge as inoculum. Polymer production reached 85, 53, and 10% of the cell dry weight from methanol-enriched pulp and paper mill foul condensate, fermented municipal primary solids, and biodiesel wastewater, respectively. Using denaturing gradient gel electrophoresis of 16S-rDNA from polymerase chain reaction-amplified DNA extracts, distinctly different communities were observed between and within wastewaters following enrichment. Most importantly, functional stability was maintained despite differing and contrasting microbial populations.


Expression profile of the human IDO1 protein, a cancer drug target involved in tumoral immune resistance.
Tryptophan catabolism by indoleamine 2,3-dioxygenase (IDO1) is a physiological immunoregulatory mechanism often hijacked by tumors. Our recent extensive study of IDO1 protein expression in human tissues showed expression in mature dendritic cells and in pulmonary and placental endothelial cells. IDO1 was also expressed in 56% of tumors, either by tumoral, stromal, or endothelial cells. These results and reagent will guide the clinical development of IDO1 inhibitors for cancer therapy.


Solid variant of aneurysmal bone cyst of the heel: a case report.
An aneurysmal bone cyst is a benign but often rapidly expanding osteolytic multi-cystic osseous lesion that occurs as a primary, secondary, intra-osseous, extra-osseous, solid or conventional lesion. It frequently coexists with other benign and malignant bone tumors. Although it is considered to be reactive in nature, there is evidence that some aneurysmal bone cysts are true neoplasms. The solid variant of aneurysmal bone cyst is a rare subtype of aneurysmal bone cyst with a preponderance of solid to cystic elements. Such a case affecting the heel, an unusual site, is reported. A 26-year-old Caucasian man presented with pain and swelling in his left lower extremity. A plain radiograph demonstrated an intra-osseous, solitary, eccentric mass in the front portion of the left heel. Computed tomography and magnetic resonance imaging scans showed that the lesion appeared to be sub-cortical, solid with a small cystic portion without the characteristic fluid-fluid level detection but with distinct internal septation. Bone images containing fluid-fluid levels are usually produced by aneurysmal bone cysts. The fluid-fluid level due to bleeding within the tumor followed by layering of the blood components based density differences, but it was not seen in our case. An intra-lesional excision was performed. Microscopic examination revealed fibrous septa with spindle cell fibroblastic proliferation, capillaries and extensive areas of mature osteoid and reactive woven bone formation rimmed by osteoblasts. The spindle cells had low mitotic activity, and atypical forms were absent. The histological features of the lesion were consistent with the solid variant of an aneurysmal bone cyst. Solid aneurysmal bone cysts have been of great interest to pathologists because they may be mistaken for malignant tumors, mainly in cases of giant cell tumors or osteosarcomas, because of cellularity and variable mitotic activity. It is rather obvious that the correlation of clinical, radiological and histological findings is necessary for the differential diagnosis. The eventual diagnosis is based on microscopic evidence and is made when a predominance of solid to cystic elements is found. The present case is of great interest because of the nature of the neoplasm and the extremely unusual location in which it developed. Pathologists must be alert for such a diagnosis.


Urinary biomarkers of exposure to insecticides, herbicides, and one insect repellent among pregnant women in Puerto Rico.
There are potential adverse health risks to the mother and fetus from exposure to pesticides. Thus, studies of exposure to pesticides among pregnant women are of interest as they will assist with understanding the potential burden of exposure globally, identifying sources of exposure, and designing epidemiology studies. We measured urinary concentrations of the insect repellent N-N-diethyl-meta-toluamide (DEET) and two of its metabolites [3-diethyl-carbamoyl benzoic acid (DCBA) and N,N-diethyl-3-hydroxymethylbenzamide (DHMB)], four pyrethroid insecticide metabolites [4-fluoro-3-phenoxybenzoic acid (4-F-3-PBA); 3-phenoxybenzoic acid (3-PBA); trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA); and cis-3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane carboxylic acid (cis-DBCA)], and two chlorophenoxy herbicides [2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)] in 54 pregnant women from Puerto Rico at three separate time points (20 ± 2 weeks, 24 ± 2 weeks, and 28 ± 2 weeks of gestation). We calculated the distributions of the biomarker concentrations and compared them to those of women of reproductive age from the general U.S. population where available, and estimated the within-subject temporal variability of these repeated measurements. We also collected questionnaire data on demographics, consumption of select fruits, vegetables, and legumes in the past 48-hr, and pest-related issues, and associations between these variables and biomarker concentrations were examined. We found that 95th percentile urinary concentrations of DEET, 3-PBA, trans-DCCA, and 2,4-D were lower than women of reproductive age on the U.S. mainland, whereas 95th percentile urinary concentrations of 4-F-3-PBA, cis-DBCA, and 2,4,5-T were similar. DCBA, the only urinary biomarker detected in >50% of the samples, showed fair to good reproducibility across pregnancy (intraclass correlation coefficient: 0.60). Women were more likely (p <0.05) to have greater urinary concentrations of pesticide biomarkers if they were less educated (DCBA and trans-DCCA), unemployed (DHMB), or married (2,4-D), had consumed collards or spinach in past 48-hr (2,4-D) or had been using insect repellent since becoming pregnant (DCBA), or were involved with residential applications of pesticides (trans-DCCA). We identified concentrations and predictors of several pesticides among pregnant women in Puerto Rico. Further research is needed to understand what aspects of the predictors identified lead to greater exposure, and whether exposure during pregnancy is associated with adverse health.


Activation of Nrf2 pathways correlates with resistance of NSCLC cell lines to CBP501 in vitro.
CBP501 is an anticancer drug candidate that was investigated in two randomized phase II clinical trials for patients with nonsquamous non-small cell lung cancer (NSCLC) and malignant pleural mesothelioma (MPM). CBP501 has been shown to have two mechanisms of action, namely calmodulin modulation and G2 checkpoint abrogation. Here, we searched for a biomarker to predict sensitivity to CBP501. Twenty-eight NSCLC cell lines were classified into two subgroups, CBP501-sensitive and -insensitive, by quantitatively analyzing the cis-diamminedichloro-platinum (II) (CDDP)-enhancing activity of CBP501 through treatments with short-term (1 hour) coexposure to CDDP and CBP501 or to either alone. Microarray analysis was performed on these cell lines to identify gene expression patterns that correlated with CBP501 sensitivity. We found that multiple nuclear factor erythroid-2-related factor 2 (Nrf2) target genes showed high expression in CBP501-insensitive cell lines. Western blot and immunocytochemical analysis for Nrf2 in NSCLC cell lines also indicated higher protein level in CBP501-insensitive cell lines. Moreover, CBP501 sensitivity is modulated by silencing or sulforaphane-induced overexpression of Nrf2. These results indicate that Nrf2 transcription factor is a potential candidate as a biomarker for resistance to CBP501. This study might help to identify those subpopulations of patients who would respond well to the CBP501 and CDDP combination treatment of NSCLC.