Angiotensin II receptor subtypes and angiotensin-converting enzyme in the fetal rat brain.
Angiotensin II (ANG II) receptor subtypes (AT1, displaced by losartan, and AT2, displaced by CGP 42112A) were characterized by quantitative autoradiography after incubation with the ANG II agonist [125I]Sar1-ANG II, in specific brain nuclei of 19-day-old rat embryos. Binding to AT1 receptors, located in the subfornical organ, paraventricular nucleus, nucleus of the solitary tract and choroid plexus, was sensitive to incubation with GTP gamma S. The sensitivity of AT2 receptors to GTP gamma S was heterogeneous. In the ventral thalamic, rostral hypoglossal and medial geniculate nuclei, and in the locus coeruleus, binding to AT2 receptors was sensitive to GTP gamma S and these areas belong to the AT2A subgroup. Conversely, in the inferior olive, medial (fastigial) cerebellar nucleus and caudal part of the hypoglossal nucleus, areas belonging to the AT2B subgroup, binding was insensitive to GTP gamma S. AT2 receptors were also present in cerebral arteries. In the fetal anterior pituitary, AT1 receptors predominated. The angiotensin-converting enzyme (ACE; EC 18.104.22.168) was studied by autoradiography with the selective inhibitor [125I]351A. In 19-day-old embryos, ACE was highly expressed in choroid plexus, with high concentrations in subfornical organ, posterior pituitary and cerebral arteries. No ACE binding was detected in extrapyramidal structures or anterior pituitary in 19-day-old embryos.


Respondent-driven sampling among gay and bisexual men: experiences from a New Zealand pilot study.
Respondent-driven sampling (RDS) is a method of approximating random sampling of populations that are difficult to locate and engage in research such as gay, bisexual and other men who have sex with men (GBM). However, its effectiveness among established urban gay communities in high-income countries is largely unexplored outside North America. We conducted a pilot study of RDS among urban GBM in Auckland, New Zealand to assess its local applicability for sexual health research. Pre-fieldwork formative assessment explored RDS suitability among local GBM. Highly-networked initial participants ("seeds") and subsequent participants completed a questionnaire, took a rectal swab for chlamydia and gonorrhoea testing, and were asked to recruit up to three eligible peers over the subsequent 2 weeks using study coupons. Compensation was given for participating and for each peer enrolled. Feedback on the pilot was obtained through questionnaire items, participant follow-up, and a focus group. Nine seeds commenced recruitment, directly enrolling 10 participants (Wave One), who in turn enrolled a further three (Wave Two). Two of the 22 participants (9 %) had undiagnosed rectal chlamydia. The coupon redemption rate (23 %) was lower than the expected rate (33 %) for this population. Participants were motivated by altruism above financial incentives; however, time, transport and reluctance recruiting peers were perceived as barriers to enrolment. Slow recruitment in our pilot study suggests that RDS might not be an effective or efficient method of sampling gay men in all high-income urban settings. However those who participated in the pilot were willing to provide anal swabs and information on their sexual behaviour, and also on the size of their GBM social network which is necessary to weight data in RDS. Refinements and adaptations such as reducing the transaction costs of taking part (e.g. offering online participation) could improve responses but these have their own drawbacks (higher set-up costs, difficulty collecting biological specimens).


Determination of glabridin in human plasma by solid-phase extraction and LC-MS/MS.
Glabridin is a major flavonoid included specifically in licorice (Glycyrrhiza glabra L.), and has various physiological activities including antioxidant and anti-inflammatory effects. We have developed and validated an analytical method for determination of glabridin in human plasma by solid-phase extraction (SPE) and LC-MS/MS. Glabridin was extracted from plasma by SPE using a C8 cartridge and analyzed by LC-MS/MS using mefenamic acid as an internal standard (IS). The analyte were separated by a C18 column on LC, and monitored with a fragment ion of m/z 201 formed from a molecular ion of m/z 323 for glabridin and that of m/z 196 from m/z 240 for IS during negative ion mode with tandem MS detection. The lower limit of quantitation (LLOQ) of glabridin was 0.1 ng/mL in plasma, corresponding to 1.25 pg injected on-column. The calibration curves exhibited excellent linearity (r>0.997) between 0.1 and 50 ng/mL. Precision and accuracy were <17 and <+/-7% at LLOQ, and <11 and <+/-5% at other concentrations. Glabridin was recovered >90%, and was stable when kept at 10 degrees C for 72 h, at -20 degrees C until 12 weeks, and after three freeze-thaw cycles. This is the first report on determination of glabridin in body fluids by the selective, sensitive, and reproducible method.


Associations between cardiorespiratory fitness and cardiometabolic risk factors in children and adolescents with obesity.
It is unclear if associations between cardiorespiratory fitness (CRF) and cardiometabolic risk factors are independent of degree of obesity, in children with obesity. The aim of this cross-sectional study on 151 children (36.4% girls), 9-17 years, from a Swedish obesity clinic, was to investigate associations between CRF and cardiometabolic risk factors, adjusted for body mass index standard deviation score (BMI SDS), in children with obesity. CRF was objectively assessed with the Åstrand-Rhyming submaximal cycle ergometer test, and blood samples (n = 96) and blood pressure (BP) (n = 84) according to clinical routine. Obesity specific reference values for CRF were used to create CRF levels. CRF was inversely associated with high-sensitivity C-reactive protein (hs-CRP), independent of BMI SDS, age, sex, and height. The inverse associations between CRF and diastolic BP did not remain significant when adjusted for BMI SDS. CRF and high-density lipoprotein cholesterol became inversely associated when adjusted for BMI SDS. Independent of degree of obesity, lower CRF is associated with higher levels of hs-CRP, as a biomarker of inflammation, in children with obesity and regular assessment of CRF should be encouraged. Future research in children with obesity should investigate if low-grade inflammation decreases when CRF is improved.


Design and approval of the nutritional warnings' policy in Peru: Milestones, key stakeholders, and policy drivers for its approval.
Nutritional warnings are used as a public health strategy to address obesity. Peru approved in 2013 and implemented in 2019 a law requiring nutritional warnings on the marketing and packaging of processed foods high in sugar, sodium, saturated fat, and containing trans-fat. The complexity behind the design and approval of these policies over six years provides unique learnings, that inform the obesity prevention context, especially when proposed policies face strong opposition from powerful stakeholders. Our study aims to describe the milestones and key stakeholders' roles and stances during the nutritional warnings policy design in Peru, and to identify and analyze the main drivers of policy change that explain its approval. In 2021, interviews were conducted with 25 key informants closely involved in its design. Interviews were analyzed using the Kaleidoscope Model as a theoretical framework. Relevant policy documents and news were also analyzed. Milestones for this policy included the approval of the Law, Regulation, and Manual. Policy supporters were mainly from Congress, civil society advocates, and Health Ministers. Opponents came from Congress, ministries linked to the economic sector, the food industry, and media. Across the years, warnings evolved from a single text, to traffic lights, to the approved black octagons. Main challenges included the strong opposition of powerful stakeholders, the lack of agreement for defining the appropriate evidence supporting nutritional warning parameters and design, and the political instability of the country. Based on the Kaleidoscope Model, the policy successfully targeted a relevant problem (unhealthy eating decisions) and had powerful advocates who effectively used focusing events to reposition the warnings in the policy agenda across the years. Negotiations weakened the policy but led to its approval. Importantly, government veto players were mostly in favor of the policy, which enabled its final approval despite the strong opposition.


Impact of spinal imbalance and BMI on lumbar spinal canal stenosis determined by a diagnostic support tool: cohort study in community‑living people.
The Japanese Society for Spine Surgery and Related Research (JSSR) developed a diagnostic support tool (score range −2 to 16) for lumbar spinal canal stenosis (LSS). It is well known that patients with LSS have a forward-bending posture while walking. We could find only one study which examined sagittal alignment of LSS patients. The objectives of this study were to screen community-living people with LSS, and to investigate the association between LSS and spinal sagittal alignment, range of motion (ROM), and other spinal or physical factors. We enrolled 286 subjects ≥50 years old in the study. We regarded those with a JSSR diagnostic risk score ≥7 as having LSS. We measured and evaluated lateral lumbar radiographs, sagittal parameters, sagittal balance, and spinal mobility as determined with SpinalMouse®, back muscle strength (BMS), and body mass index (BMI). Spinal inclination angle (SIA) was used as an index of sagittal balance. Multivariate logistic regression analysis indicated that increased BMI (OR 1.121, p < 0.05) and SIA (OR 1.144, p < 0.05) were important relevant factors for LSS. BMI had significant positive correlations with SIA (r = 0.214), and thoracic and lumbar kyphosis angles (r = 0.283, 0.131), and negative correlations with sacral slope angle (r = −0.166), and lumbar and total spinal ROMs (r = −0.270, −0.166). SIA had significant positive correlations with age (r = 0.334), BMI (r = 0.214) and lumbar kyphosis angle (r = 0.525), and negative correlations with BMS (r = −0.268), and lumbar and total spinal ROMs (r = −0.184, −0.171). Increased SIA and BMI might be the most relevant risk factors for LSS.


A fluorogenic active-site titrant for serine proteases.
The synthesis of 3'-(4-guanidinobenzoyloxy)-spiro(isobenzofuran-1(3H),9H-[9H]xan then]-3-one or 3HFGB, an active-site titrant for serine proteases, is described. 3HFGB has two advantages over previously described titrants. It is very sensitive (it can measure serine proteases at the 10(-11)-10(-12) M level), and it can be used at stoichiometric ratios of titrant to protease of unity or less. Moreover, the fluorogenic leaving group, 3'-hydroxyspiro[isobenzofuran-1(3H),9'-[9H]xanthen]-3- one, is suitable for use in a range of esteropeptidase substrates. The use of 3HFGB in the active-site titration of trypsin is described.


Reversal of lorazepam delirium by physostigmine.
Two adult patients suffered postoperative delirium following administration of lorazepam, a new benzodiazepine sedative. Physostigmine was found effective in reversing all untoward central nervous system effects.


Zagreb Amblyopia Preschool Screening Study: near and distance visual acuity testing increase the diagnostic accuracy of screening for amblyopia.
To present and evaluate a new screening protocol for amblyopia in preschool children. Zagreb Amblyopia Preschool Screening (ZAPS) study protocol performed screening for amblyopia by near and distance visual acuity (VA) testing of 15 648 children aged 48-54 months attending kindergartens in the City of Zagreb County between September 2011 and June 2014 using Lea Symbols in lines test. If VA in either eye was >0.1 logMAR, the child was re-tested, if failed at re-test, the child was referred to comprehensive eye examination at the Eye Clinic. 78.04% of children passed the screening test. Estimated prevalence of amblyopia was 8.08%. Testability, sensitivity, and specificity of the ZAPS study protocol were 99.19%, 100.00%, and 96.68% respectively. The ZAPS study used the most discriminative VA test with optotypes in line as they do not underestimate amblyopia. The estimated prevalence of amblyopia was considerably higher than reported elsewhere. To the best of our knowledge, the ZAPS study protocol reached the highest sensitivity and specificity when evaluating diagnostic accuracy of VA tests for screening. The pass level defined at ≤0.1 logMAR for 4-year-old children, using Lea Symbols in lines missed no amblyopia cases, advocating that both near and distance VA testing should be performed when screening for amblyopia.


Comparative analysis of DNA loop length in nontransformed and transformed hamster cells.
The size of the looped, matrix-attached DNA domains was estimated in both nontransformed and transformed hamster cells. In BHK cells it was observed that in interphase as well as during mitosis, transformed cells, on the average, have shorter loops than nontransformed cells. In CHO cells, however, no alteration of the length of the looped DNA domains was found to accompany transformation. The implications of these observations are discussed in relation to the process of the process of transformation.


Superior hybrid hydrogels of polyacrylamide enhanced by bacterial cellulose nanofiber clusters.
Hybrid polyacrylamide/bacterial cellulose nanofiber clusters (PAM/BC) hydrogels with high strength, toughness and recoverability were synthesized by in situ polymerization of acrylamide monomer in BC nanofiber clusters suspension. The hybrid gels exhibited an extremely large elongation at break of 2200%, and a high fracture stress of 1.35MPa. Additionally, the original length of hydrogels could be recovered after releasing the tensile force. Compressive results showed that the PAM/BC hybrid gels could reach a strain of about 99% without break, and was able to completely recover its original shape immediately after releasing the compression force. The compressive stress at 99% reached as high as 30MPa. Nearly no hysteresis in cyclic compressive tests was observed with these hybrid gels. The FT-IR, XRD and TGA analysis showed that hydrogen bonds between the PAM chains and BC nanofiber clusters mainly contributed to the superior mechanical properties of hybrid hydrogels. The cell viability results suggested that PAM/BC hybrid hydrogel was benign for biomedical application. These PAM/BC hydrogels offer a great promise as biomaterials such as bone and cartilage repair materials.


Global forebrain ischemia results in decreased immunoreactivity of calcium/calmodulin-dependent protein kinase II.
Previous studies utilizing crude brain homogenates have shown that forebrain ischemia results in inhibition of calcium/calmodulin-dependent protein kinase II (CaM kinase II) activity without large-scale proteolysis of the enzyme. In this report, a monoclonal antibody (1C3-3D6) directed against the beta- (60-kDa) subunit of CaM kinase II that does not recognize ischemically altered enzyme was utilized to further investigate the ischemia-induced inhibition of CaM kinase II. Immunohistochemical investigations showed that the ischemia-induced decreased immunoreactivity of CaM kinase II occurred immediately following ischemic insult in ischemia-sensitive cells such as pyramidal cells of the hippocampus. No decrease in CaM kinase II immunoreactivity was observed in ischemia-resistant cells such as granule cells of the dentate gyrus. The decreased immunoreactivity was observed for CaM kinase II balanced for protein staining and calmodulin binding in vitro. In addition, autophosphorylation of CaM kinase II in the presence of low (7 microM) or high (500 microM) ATP did not alter immunoreactivity of the enzyme with 1C3-3D6. The data demonstrate the production of a monoclonal antibody that recognizes the beta-subunit of CaM kinase II in a highly specific manner, but does not recognize ischemic enzyme. Together with previous studies, the data support the hypothesis that rapid, ischemia-induced inhibition of CaM kinase II activity may be involved in the cascade of events that lead to selective neuronal cell loss in stroke.


Motivation Predicts Change in Nurses' Physical Activity Levels During a Web-Based Worksite Intervention: Results From a Randomized Trial.
Low physical activity levels can negatively affect the health of nurses. Given the low physical activity levels reported by nurses, there is a clear need for brief and economical interventions designed to increase physical activity levels in this population. We developed a web-based intervention that used motivational strategies to increase nurses' physical activity levels. The intervention provided the nurses with feedback from an activity monitor coupled with a web-based individual, friend, or team physical activity challenge. In this parallel-group randomized trial, we examine whether nurses' motivation at baseline predicted changes in objectively measured physical activity levels during the 6-week intervention. The participants were 76 nurses (n=74, 97% female; mean age 46, SD 11 years) randomly assigned to 1 of 3 physical activity challenge conditions: (1) individual, (2) friend, or (3) team. The nurses completed a web-based questionnaire designed to assess motivational regulations for physical activity levels before the intervention and wore a Tractivity activity monitor before and during the 6-week intervention. We analyzed data using multilevel modeling for repeated measures. The nurses' physical activity levels increased (linear estimate=10.30, SE 3.15; P=.001), but the rate of change decreased over time (quadratic estimate=-2.06, SE 0.52; P<.001). External and identified regulations (ß=-2.08 to 11.55; P=.02 to .04), but not intrinsic and introjected regulations (ß=-.91 to 6.29; P=.06 to .36), predicted changes in the nurses' physical activity levels. Our findings provide evidence that an intervention that incorporates self-monitoring and physical activity challenges can be generally effective in increasing nurses' physical activity levels in the short term. They also suggest that drawing solely on organismic integration theory to predict changes in physical activity levels among the nurses participating in web-based worksite interventions may have been insufficient. Future research should examine additional personal (eg, self-efficacy) and occupational factors (eg, shift length and shift type) that influence physical activity levels to identify potential targets for intervention among nurses. ClinicalTrials.gov NCT04524572; https://clinicaltrials.gov/ct2/show/NCT04524572.


Current dilemmas in Down syndrome clinical care: celiac disease, thyroid disorders, and atlanto-axial instability.
This study will discuss our current understanding of celiac disease (CD), thyroid disorders, and atlanto-axial instability, three important areas of medical management in individuals with Down syndrome (DS). In this study, we highlight our current knowledge, as well as what we need to study in order to gather the necessary data to refine the empirically based screening protocols which are now in place.


Creation of a national resource with linked genealogy and phenotypic data: the Veterans Genealogy Project.
Creation of a genealogy of the United States and its ancestral populations is under way. When complete, this US genealogy will be record linked to the National Veteran's Health Administration medical data representing more than 8 million US veterans. Genealogical data are gathered from public sources, primarily the Internet. Record linking using data from relatives is accomplished to integrate multiple data sources and then to link genealogical data to the veteran's demographic data. This resource currently includes genealogy for more than 22 million individuals representing the Intermountain West and the East Coast. The demographic data for more than 40,000 veteran patients using Veterans Hospital Administration services in Utah and Massachusetts have already been record linked. The resource is only in its second year of creation and already represents the largest such combination of genealogy and medical data in the world. The data sources, the creation of the genealogy, record-linking methods and results, proposed genetic analyses, and future directions are discussed.


Asymmetry currents and admittance in squid axons.
The complex admittance of squid (Loligo pealei) axon was measured rapidly (within 1 s) with pseudo-random small signals and discrete Fourier transform techniques under guarded, "space-clamp" conditions and during suppression of ion conduction. Asymmetry currents were measured by paired step clam pulses of +/-70 mV from a holding potential of -97 mV and gave an apparent capacitance of 0.36 muF/cm2. However, the admittance data showed no change in capacitance at holding potentials from -97 to -67 mV and gave a decrease of 0.07 of 0.15 muF/cm2 at -37 mV. The failure to observe a capacitance increase at low membrane potentials suggests the following possibilities: (a) the asymmetry current is a displacement current that inactivates completely with time, and (b) the asymmetry current is not a displacement current and arises from large signal effects (i.e., delayed nonlinearity in ionic current) on the membrane.


Percutaneous CT-guided lung biopsy for the diagnosis of persistent pulmonary consolidation.
The primary objective of this study was to determine the diagnostic accuracy of percutaneous computed tomography (CT)-guided biopsy of persistent pulmonary consolidations. The secondary objective was to determine the complication rate and identify factors affecting diagnostic yield. Two radiologists retrospectively reviewed 98 percutaneous CT-guided biopsies performed in 93 patients (60 men, 33 women; mean age, 62±14.0 (SD) years; range: 18-88 years) with persistent pulmonary consolidations. Final diagnoses were based on surgical outcomes or 12 months clinical follow-up findings. Biopsy results were compared to the final diagnosis to estimate diagnostic yield. A final diagnosis was obtained for all patients: 51/93 (54.8%) had malignant lesions, 12/93 (12.9%) specific definite benign lesions (including 9 infections, two pneumoconiosis and one lipoid pneumonia) and 30/93 (32.3%) non-specific benign lesions. CT-guided biopsy had an overall diagnostic yield of 60% (59/98) with a correct diagnosis for 50/51 malignant lesions (diagnostic yield of 98% for malignancy) and for 9/47 benign lesions (diagnostic yield of 19% for benign conditions). Major complications occurred in 4/98 (4%) of lung biopsies (four pneumothoraxes requiring chest tube placement). Percutaneous CT-guided biopsy is an alternative to endoscopic or surgical biopsy for the diagnosis of persistent consolidation with a low risk of severe complication.


[Microbiological evaluation of cefoxitin, a new beta-lactamase resistant cephamycin antibiotic, compared to cephalothin, cephaloridine and cefazolin].
Cefoxitin (Mefoxitin), Cephaloridin, Cephalothin and Cefazolin were tested in vitro against 380 clinical isolates of Staph. aureus and Enterobacteriaceae using the tube dilution procedure. Of the gramnegative microorganisms a selection of 150 strains was examined regarding susceptibility to the antibiotic combinations cefoxitin/gentamicin and cefoxitin/sisomicin in comparison to cephalothin/gentamicin and cephalothin/sisomicin. Cefoxitin has a broad antimicrobial spectrum and a high beta-lactamase-resistance. Cefoxitin was more active than the other antibiotics tested against E. coli, Klebsiella, Serratia, Enterobacter, indole-negative and -positive Proteus species. The high effectiveness of cefoxitin against anaerobic bacteria such as Bacteroides fragilis and Clostridium perfringens is discussed. Cefoxitin has an excellent bactericidal potency. Among the combinations tested cefoxitin/sisomicin was most active and obtained synergistic effects in most species. The resistance rate of cefoxitin of 8.7% was reduced to 0.7% with cefoxitin/sisomicin.


Comparative clinical pharmacology of bacampicillin and high oral doses of ampicillin.
Ampicillin is often used in high oral doses due to its incomplete absorption. The objective of this study was to compare the bioavailability of bacampicillin, a new prodrug of ampicillin which is nearly completely absorbed, to that of high doses of oral ampicillin. Single oral doses of bacampicillin 400 mg or 800 mg and ampicillin 500 mg, 1 g, or 2 g were given to 12 male subjects according to a cross-over design after overnight fasting. The median time after administration till the peak serum level was 0.75 and 1.0 hour with bacampicillin 400 mg and 800 mg respectively, as compared to 1.5, 2.0 and 1.5 hours for the ampicillin doses. The mean of the individual peak serum level after bacampicillin 400 mg, was 7.7 mg/l, which is higher than that after ampicillin 500 mg, 5.2 mg/l, and about the same as that after ampicillin 1 g, 7.6 mg/l. A slightly higher mean peak level was seen after bacampicillin 800 mg, 12.2 mg/l, as compared to ampicillin 2 g, 10.5 mg/l. The absorption rate was highest with bacampicillin, for which 90% of the absorption had occurred 1 hour after administration as compared to 2.5 hours after administration of ampicillin. The relative bioavailability was about 2--3 times higher after bacampicillin as compared to ampicillin. The data imply dose-dependent absorption of oral ampicillin in high doses as there seems to be a less than proportional increase in AUC. The urinary recovery after bacampicillin was 68--75% as compared to 25--41% after ampicillin. Higher doses gave a lower percentage recovery and this phenomenon was more pronounced with ampicillin.


Synthetic photoplethysmogram generation using two Gaussian functions.
Evaluating the performance of photoplethysmogram (PPG) event detection algorithms requires a large number of PPG signals with different noise levels and sampling frequencies. As publicly available PPG databases provide few options, artificially constructed PPG signals can also be used to facilitate this evaluation. Here, we propose a dynamic model to synthesize PPG over specified time durations and sampling frequencies. In this model, a single pulse was simulated by two Gaussian functions. Additionally, the beat-to-beat intervals were simulated using a normal distribution with a specific mean value and a specific standard deviation value. To add periodicity and to generate a complete signal, the circular motion principle was used. We synthesized three classes of pulses by emulating three different templates: excellent (systolic and diastolic waves are salient), acceptable (systolic and diastolic waves are not salient), and unfit (systolic and diastolic waves are noisy). The optimized model fitting of the Gaussian functions to the templates yielded 0.99, 0.98, and 0.85 correlations between the template and synthetic pulses for the excellent, acceptable, and unfit classes, respectively, with mean square errors of 0.001, 0.003, and 0.017, respectively. By comparing the heart rate variability of real PPG and randomly synthesized PPG for 5 min in 116 records from the MIMIC III database, strong correlations were found in SDNN, RMSSD, LF, HF, SD1, and SD2 (0.99, 0.89, 0.84, 0.89, 0.90 and 0.95, respectively).


Analysis of subgingival microbiome of periodontal disease and rheumatoid arthritis in Chinese: A case-control study.
Periodontitis (PD) and rheumatoid arthritis (RA) share similar pathogenesis. Evidences indicated that oral bacteria play an important role in the etiology of both diseases. For example, Porphyromonas gingvialis connect the two diseases through immune responses. We designed this study to compare bacterial diversity in RA, PD and healthy subjects and to investigate whether there are other oral bacteria play an potential role in linking the two diseases. This study included 3 groups of Chinese participants who visited Sichuan Provincial People's Hospital during August 2018 and March 2019. Subgingival plaques were collected from RA group (n = 54), PD group (n = 45) and normal group (n = 44). Illumina MiSeq was used to compare the composition of subgingival microbiota and analyze correlations between oral bacteria and both diseases. Alpha diversity Analysis reflected similar microbiome profile in RA, PD and healthy groups. But we found Treponema was significantly more abundant in the PD and RA groups than healthy group at each taxonomic level from the phylum down to the genus level. Porphyromonas, Prevotella, and Veilonella were significantly more abundant in RA while Streptococcus, Gemella, Planobacterium were verified the opposite results. We found no significant group differences referent to either microbial diversity or richness. But we picked out Spirochaetes which may link the two diseases. Upper/lower regulation of some microbia in RA may remind us a direction to explore the role they play in pathogenesis.


Hepatic adenoma: imaging with different radionuclides.
A case of a benign hepatic-cell adenoma studies with dynamic radionuclide angiography and static imaging with different tracers is presented.


Technical note: Personalized treatment gating thresholds in frameless stereotactic radiosurgery using predictions of dosimetric fidelity and treatment interruption.
Gamma Knife Icon (GKI) enables a user-defined gating threshold for intrafraction motion during stereotactic radiosurgery (SRS). An optimal threshold would ensure dosimetric fidelity of the planned distribution and minimize treatment time extension by gating. A prediction of motion characteristics for a patient based on a retrospective database of motion traces could be beneficial to evaluating the choice of gating threshold. A short acquisition of motion may help to define a personalized threshold that balances dosimetric accuracy and treatment length. This study aims to evaluate the performance of a prediction of motion and the resultant dosimetric consequences for a range of motion gating thresholds. A database of 2552 motion traces (776 patients) was analyzed using previously published methods to characterize patient intrafraction motion on the GKI. For a selection of six fractionated SRS patient cases (two patients with single brain metastasis, four vestibular schwannomas), a 10-min sample of motion was used to classify motion and identify traces in the database with similar metrics. The similar motion traces were used to perform a predictive reconstruction of the selected patient's delivered dose for a range of motion thresholds. The remaining fractions were reconstructed and compared to that predicted. From the six cases, 26 fractions were used to predict the number of interruptions (n = 26), change in target coverage (n = 26), and change in brainstem maximum dose (vestibular cases only, n = 20). The difference between mean predicted and reconstructed values was compared for accuracy. The difference between mean prediction and reconstructed values was 0.32 ± 0.38% in target coverage, 2.36 ± 5.06 interruptions, and 0.15 ± 0.24 Gy for the brainstem maximum dose. Sixty-seven of the 72 predictions (26 coverage, 26 interruptions, and 20 brainstem maximum dose) were within one standard deviation of the predicted mean. Large databases of motion traces were used to characterize patient performance and predict motion performance. Dosimetric deterioration due to motion and extension of treatment duration can be predicted in some cases using only a short acquisition of motion and the treatment plan. This reconstruction may provide benefit in generating a patient-specific motion threshold.


Perioperative considerations during implantation of the subcutaneous defibrillator: State-of-the-art review.
The subcutaneous implantable cardioverter-defibrillator (S-ICD) is an important tool in the armamentarium of an electrophysiologist. Multiple randomized trials over the last decade have shown that S-ICDs are as efficacious as the transvenous ICDs and eliminate complications related to vascular access. In this review, we highlight issues unique to S-ICD implantation, focusing not only on the surgical implantation procedure, but also the pre- and postimplant management of the patient.


Induction of apoptosis in macrophages by air oxidation of dioleoylphosphatidylglycerol.
Dioleoylphosphatidylglycerol (DOPG) containing unsaturated sites is the target of oxidation during preparation, storage, or in vivo use of anionic liposomes. We investigated the biological effect of air oxidation of DOPG on RAW 264.7 murine macrophage-like cells. Oxidation was induced by exposing DOPG to air for 24-72 h. The extent of air oxidation was confirmed using Matrix-Assisted Laser Desorption and Ionization with Time-of-Flight (MALDI-TOF) mass spectrometry. The product of the air oxidation of DOPG was identified as the addition of one oxygen atom to one of the symmetrical fatty moieties of DOPG at m/z 814.77. The treatment of DOPG with air oxidation produced dose-dependent cytotoxicity in macrophages. RAW 264.7 cells exposed to oxidized DOPG exhibited morphological features of apoptosis, such as chromatin condensation and cell shrinkage. Typical apoptotic ladders were observed in DNA extracted from RAW 264.7 cells treated with oxidized DOPG. Flow cytometric analysis demonstrated an increase in the hypodiploid DNA population (sub-G1), indicating that DNA cleavage occurred after treatment with oxidized DOPG. In addition, we showed that pretreating RAW 264.7 cells with zVAD-fmk, a general caspase inhibitor, did not prevent apoptosis induced by oxidized DOPG, suggesting that apoptosis in macrophage cells follows a caspase-independent pathway. These results point to a need for precaution in formulating DOPG liposomes for drug delivery and therapeutic purposes.


Evidence for self-association of prothrombin fragment 1 in the absence of calcium ions. Implications for the interpretation of cooperativity of calcium binding.
Sedimentation equilibrium studies have demonstrated that prothrombin fragment 1 from either human or bovine plasma reversibly dimerizes in the absence of Ca2+ with an equilibrium constant of 1,000 M-1. In the presence of 10 mM Ca2+ this association constant increased to 10,000 M-1. A model for preferential binding of Ca2+ to the pre-existing dimer has been found capable of accounting quantitatively for the cooperative Ca2+ binding to this prothrombin fragment, and for the dependence of its sedimentation coefficient on protein concentration in the presence and absence of metal ion. Sedimentation equilibrium studies of intact bovine and human prothrombins have confirmed previous reports that these prothrombins dimerize. For both prothrombins the association constant is 10,000 M-1, both in the absence and presence of Ca2+.


Comparison of neonatal outcomes of cesarean sections performed under primary or secondary general anesthesia: a retrospective study.
The conversion of neuraxial anesthesia (NA) to general anesthesia (GA) during a cesarean section (CS) may be associated with a higher risk of neonatal morbidity by adding the undesirable effects of both these anesthesia techniques. We aimed to compare the neonatal morbidity of non-elective CS performed after conversion from NA to GA (secondary GA) vs. that after GA from the outset (primary GA). We performed a monocentric retrospective study at the Angers University Hospital (France). All non-elective CSs performed under GA between January 2015 and December 2019 were included. The CSs were classified using a three-color coding system (green for non-urgent delivery, orange for urgent CS, and red for very urgent CS). The primary neonatal outcome was a composite of umbilical artery pH <7.10 or 5-min Apgar score <7. The crude and adjusted odds ratios (OR) for the risk of neonatal morbidity associated with secondary GA were estimated. We included 247 patients, of whom 101 (41.3%) had a secondary GA and 146 (58.7%) had primary GA. In the secondary GA group, 86.1% (87/101) had epidural anesthesia and 13.9% (14/101) had spinal anesthesia. Multivariate analysis showed no difference in neonatal morbidity between the two groups (adjusted odds ratio 1.18, 95% CI 0.56 to 2.51). Our study found insufficient evidence to identify a difference in neonatal outcomes between secondary compared with primary GA for CS, regardless of the level of emergency. However, our study is underpowered and additional studies are needed to confirm these data.


Dose-dependent relationship between SGLT2 inhibitor hold time and risk for postoperative anion gap acidosis: a single-centre retrospective analysis.
Use of sodium-glucose transporter-2 (SGLT2) inhibitors has dramatically increased over the past decade. This medication class predisposes patients to euglycaemic diabetic ketoacidosis, particularly during times of physiologic stress, including fasting and surgery. Beyond case reports and series, a systematic description of perioperative metabolic effects of SGLT2 inhibitors is lacking. We examined the degree of anion gap acidosis, controlling for non-ketone anions, in patients undergoing surgery at Massachusetts General Hospital in 2016-22. We constructed a multivariable regression model incorporating known non-ketone contributors to the postoperative anion gap (albumin, lactate, estimated glomerular filtration rate, and preoperative anion gap), hold time, and interaction terms between hold time and three previously suggested risk factors for euglycaemic diabetic ketoacidosis: emergency surgery, cardiac surgery, and insulin use. In 463 patients on SGLT2 inhibitors, we observed a strong association between decreased hold time and postoperative anion gap (P<0.001 in a univariable analysis; -0.43, 95% confidence interval [-0.76 to -0.11] change in anion gap per day held, P=0.01 in a multivariable analysis). A significant interaction between hold time and emergency surgery was observed, whereas there was no apparent interaction with insulin use or cardiac surgery. These findings provide the first evidence that an anion gap acidosis, likely from ketoacids, develops in all patients who do not hold SGLT2 inhibitors before surgery rather than in an idiosyncratic few. If an SGLT2 inhibitor is unable to be stopped, postoperative monitoring of anion gap and serum ketones can help detect clinically significant euglycaemic diabetic ketoacidosis, particularly in those undergoing emergency surgery.


[Diagnosis and indication for aortic valve replacement in asymptomatic and symptomatic patients with aortic regurgitation].
Chronic volume overload is associated with dilatation and eccentric hypertrophy of the left ventricle (= ventricular remodeling). With the dilatation of the left ventricle and the shift of the pressure-volume-relationship to the right, the filling pressures can be kept normal despite severe regurgitation. Therefore, the patient with aortic regurgitation can remain asymptomatic over many years. Thus, the indication for aortic valve replacement in patients with severe aortic regurgitation is sometimes difficult and may lead to problems to choose the optimal time point for operation. As a general rule, symptomatic patients with severe aortic regurgitation should be operated as soon as possible. In asymptomatic patients with significant dilatation of the left ventricle and reduction of systolic pump function the therapy of choice is aortic valve replacement. Asymptomatic patients with normal left ventricular function have usually a good prognosis with a yearly mortality rate of approximately 0.04%. However, in the presence of significant dilatation of the left ventricle, i.e. enddiastolic chamber diameter more than 70 mm respectively endsystolic diameter more than 50 mm, patients have to be checked on a regular basis, i.e. in yearly intervals to detect left ventricular dysfunction in due time. According to the literature, asymptomatic patients with severe aortic regurgitation develop left ventricular dysfunction in a yearly rate of 4%. However, approximately 50% of all patients are even after 10 years asymptomatic. The indication for aortic valve replacement is given when the patient shows a deterioration of left ventricular function or becomes symptomatic. Valve replacement is also indicated in patients with an ejection fraction below 50% and/or endsytolic chamber diameter of more than 55 mm. Therapy of choice in symptomatic patients with severe aortic regurgitation is aortic valve replacement. In asymptomatic patients, operation depends on the degree of chamber dilatation respectively the severity of left ventricular dysfunction. In patients with severe aortic regurgitation but without clinical symptoms and moderate enlargement of the left ventricle regular check-ups in yearly intervals are indicated. In the presence of severe left ventricular dilatation check-ups should be performed on a half-year basis to prevent irreversible damage to the heart muscle.


Longitudinal Pure-Tone Threshold Changes in the Same Subjects: Analysis of Factors Affecting Hearing.
To investigate the change of hearing threshold over time and analyze factors that could affect hearing, this longitudinal study of pure-tone threshold changes in the same subjects at a 9-year interval was performed. Retrospective longitudinal study in a single center (n = 1,978). A total of 1,978 subjects were included; they received pure-tone audiometry at a 9-year interval. The degree of the threshold changes was examined and compared between age groups. The subjects' data, such as the level of cholesterol, were analyzed to find risk factors on hearing. The average of the threshold changes was 3.35 dB in the 20s to 30s; 4.38 dB in the 30s to 40s; 5.75 dB in the 40s to 50s; 7.21 dB in the 50s to 60s; and 10.00 dB in the 60s to 70s (all P < 0.05). If the low-density lipoprotein cholesterol (LDL-C) was maintained below 100 mg/dl, the difference in the weighted four-frequency average was 5.45 dB, whereas it was 6.15 dB in the subjects whose LDL-C was over 100 mg/dl (P = 0.032, age-adjusted). In current smokers, the thresholds increased more than in never- or ex-smokers (P = 0.026 in the weighted four-frequency average and P = 0.011 at 8,000 Hz, age-adjusted). The degree of the threshold changes exhibited an exponential increase with age. Cessation of smoking is advisable to prevent increased aggravation of hearing. Strict management of the low-density lipoprotein cholesterol may have a positive effect on hearing. 3 Laryngoscope, 129:470-476, 2019.


Effectiveness of motor control exercises versus other musculoskeletal therapies in patients with pelvic girdle pain of sacroiliac joint origin: A systematic review with meta-analysis of randomized controlled trials.
Pelvic girdle pain represents a group of musculoskeletal pain disorders associated with the sacroiliac joint and/or the surrounding musculoskeletal and ligamentous structures. Its physical management is still a serious challenge as it has been considered the primary cause of low back pain. This review sought to determine the effectiveness of motor control exercises for two clinically relevant measures; i.e., pain and disability, on patients with pelvic girdle pain of sacroiliac joint origin. This review covered only randomized controlled studies. Online databases, such as PubMed, Embase, Scopus, and Cochrane Library, were searched from January 1, 1990, to December 31, 2019. PEDro scale was used to assess the methodological quality of included studies, while Review Manager was employed to synthesize data in view of meta-analysis. The PRISMA guidelines were applied for this review. Twelve randomized controlled trials of moderate-to-high quality were included in this review. The studies involved 1407 patients with a mean age ranging from 25.5 to 42.1 years as well as intervention and follow-up durations from 1 week to 2 years. Motor control exercises alone for pelvic girdle pain of sacroiliac joint origin were not effective in terms of pain reduction (SMD = 0.29 [-0.64,1.22]) compared to control interventions whereas they were slightly effective in terms of disability reduction (SMD =-0.07 [-0.67, 0.53]) at short-term. The combination of motor control exercises with other musculoskeletal therapies, however, revealed to be more effective than control interventions in terms of pain reduction (SMD =-1.78 [-2.49, -1.07]; 95%CI) and lessened disability (SMD =-1.80 [-3.03, -0.56]; 95%CI) at short-term. Motor control exercises alone were not found to be effective in reducing pain at short-term. However, their combination with other musculoskeletal therapies revealed a significant and clinically-relevant decrease in pain and disability at short-term, especially in peripartum period.


An overview of targeted cancer therapy.
Cancer is a multifactorial disease and is one of the leading causes of death worldwide. The contributing factors include specific genetic background, chronic exposure to various environmental stresses and improper diet. All these risk factors lead to the accumulation of molecular changes or mutations in some important proteins in cells which contributes to the initiation of carcinogenesis. Chemotherapy is an effective treatment against cancer but undesirable chemotherapy reactions and the development of resistance to drugs which results in multi-drug resistance (MDR) are the major obstacles in cancer chemotherapy. Strategies which are in practice with limited success include alternative formulations e.g., liposomes, resistance modulation e.g., PSC833, antidotes/toxicity modifiers e.g., ICRF-187 and gene therapy. Targeted therapy is gaining importance due to its specificity towards cancer cells while sparing toxicity to off-target cells. The scope of this review involves the various strategies involved in targeted therapy like-monoclonal antibodies, prodrug, small molecule inhibitors and nano-particulate antibody conjugates.


Influence of nutrients on biomass evolution in an upflow anaerobic sludge blanket reactor degrading sulfate-laden organics.
This paper describes the effect of the nutrients iron (Fe), nickel (Ni), zinc (Zn), cobalt (Co), and molybdenum (Mo) on biomass evolution in an upflow anaerobic sludge blanket (UASB) reactor metabolizing synthetic sulfate-laden organics at varying operating conditions during a period of 540 days. A bench-scale model of a UASB reactor was operated at a temperature of 35 degrees C for a chemical oxygen demand-to-sulfate (COD/SO4(2-)) ratio of 8.59 to 2.0, a sulfate loading rate of 0.54 to 1.88 kg SO4(2-)/m3 x d, and an organic loading rate of 1.9 to 5.75 kg COD/m3 x d. Biomass was characterized in terms of total methanogenic activity, acetate-utilizing methanogenic activity, total sulfidogenic activity, acetate-utilizing sulfidogenic activity, and scanning electron microscopy (SEM). Nickel and cobalt limitation appears to affect the activity of hydrogen-utilizing methane-producing bacteria (HMPB) significantly without having an appreciable effect on the activity of acetate-utilizing methane-producing bacteria (AMPB). Nickel and cobalt supplementation resulted in increased availability and, consequently, restoration of biomass activity and process performance. Iron limitation and sulfidogenic conditions resulted in the growth of low-density, hollow, fragile granules that washed out, causing process instability and performance deterioration. Iron and cobalt supplementation indicated significant stimulation of AMPB with slight inhibition of HMPB. Examination of biomass through SEM indicated a population shift with dominance of sarcina-type organisms and the formation of hollow granules. Granule disintegration was observed toward the end of the study.


The role and mechanism of progesterone receptor activation of extra-nuclear signaling pathways in regulating gene transcription and cell cycle progression.
Human progesterone receptor (PR) contains a polyproline motif in the amino-terminal domain that interacts with the SH3 domain of Src and mediates rapid activation of c-Src and downstream MAPK (Erk-1/-2) independent of the transcriptional activity of PR. Forcedly target PR to different locations in the cell by use of mutations or tags for different cell compartments showed that progestin activation of Src/MAPK is mediated by PR outside the nucleus. No distinction could be made between the cytoplasm and cell membrane as the site of PR activation of Src. Therefore we can only conclude that this is an extra-nuclear action of PR. Interestingly, the B isoform of PR which is naturally distributed between cytoplasm and nucleus mediated progestin activation of Src/MAPK, whereas PR-A that is predominantly nuclear failed to do so indicating that the two PR isoforms have distinct abilities to mediate rapid activation of signaling pathways. Due to distinct cellular locations, progestin activation of Src/MAPK signaling can regulate selected target genes such as cyclin D1 (CCND1) that lack direct PR binding response elements (PREs). Progestin induction of CCND1 was observed in cells expressing PR-B but not PR-BDeltaSH3 or PR-A and induction in the presence of PR-B was dramatically reduced in the presence of inhibitors of Src or MAPK. In contrast progestin induction of Sgk (serum and glucocorticoid regulated kinase) gene, which contains a classical PRE, was observed with both PR isoforms as well as PR-BDeltaSH3 and was unaffected by Src and MAPK inhibitors. PR bound to enhancer region of Sgk in a progestin dependent manner as detected by chromatin co-immunoprecipitation (ChIP) whereas no PR binding to CCDN1 was observed. Consistent with CCND1 data, progestin stimulation of cell cycle progression was only observed in cells expressing PR-B but not cells expressing PR-BDeltaSH3 or PR-A. These results demonstrate the importance of PR activation of extra-nuclear signaling pathways in regulating selected target genes and cell cycle progression.


Effects of dietary thyme (Zataria multiflora) extract on antioxidant and immunological responses and immune-related gene expression of rainbow trout (Oncorhynchus mykiss) juveniles.
Effects of dietary hydroalcoholic extract of Zataria multiflora (ZE) on growth performance, plasma and hepatic antioxidant capacities, and humoral and skin mucus immune parameters were evaluated in rainbow trout (Oncorhynchus mykiss) juveniles. in vitro tests showed that ZE had antioxidant property comparable to butylated hydroxytoluene (BHT) at 100-200 μg/mL concentrations, although its antioxidant property was lower than BHT at concentration below 100 μg/mL. Moreover, ZE had anti-bacterial activity against Aeromonas hydrophila, which was 30-50% lower than that of tetracycline. After feeding the fish with diets supplemented with 0 (CT, 1 (ZE1), 2 (ZE2), and 3 (ZE3) g/kg ZE for eight weeks, there were no significant differences in growth performance and feed efficiency among the treatments; however, the fish in ZE2 and ZE3 treatments showed significantly higher survival than the fish in CT treatment. Blood leukocyte counts, plasma globulin, total immunoglobulin, lysozyme and bactericidal activity against A. hydrophila in ZE2 and ZE3 groups were significantly higher than that of CT group. All the ZE-treated groups had higher plasma complement activity compared to the CT group. Mucosal lysozyme and bactericidal activities of the ZE2 fish were significantly higher than the other treatments. Expression of tumor necrosis factor alpha, interleukin-1 beta, interleukin-6, and lysozyme genes increased in head kidney of the fish treated with ZE; the highest increases were related to the ZE2 treatment. Plasma total antioxidant (TA) activities of ZE2 and ZE3 treatments were significantly higher than that of the CT treatment. Plasma and hepatic superoxide dismutase (SOD) and catalase (CAT) activities of ZE2 group were significantly higher than the other treatments. Plasma malondialdehyde (MDA) levels were significantly lower in ZE2 treatment, compared to the other treatments. However, hepatic MDA level of ZE2 treatment was significantly lower than those of the ZE1 and CT treatments. In conclusion, dietary ZE supplementation level of 2 g/kg is suggested for rainbow trout feed supplementation to augment fish survival, antioxidant and immune strength.


Molecular and Cellular Mechanisms of Salt Taste.
Salt taste, the taste of sodium chloride (NaCl), is mechanistically one of the most complex and puzzling among basic tastes. Sodium has essential functions in the body but causes harm in excess. Thus, animals use salt taste to ingest the right amount of salt, which fluctuates by physiological needs: typically, attraction to low salt concentrations and rejection of high salt. This concentration-valence relationship is universally observed in terrestrial animals, and research has revealed complex peripheral codes for NaCl involving multiple taste pathways of opposing valence. Sodium-dependent and -independent pathways mediate attraction and aversion to NaCl, respectively. Gustatory sensors and cells that transduce NaCl have been uncovered, along with downstream signal transduction and neurotransmission mechanisms. However, much remains unknown. This article reviews classical and recent advances in our understanding of the molecular and cellular mechanisms underlying salt taste in mammals and insects and discusses perspectives on human salt taste.


Effects of HMW-GSs at Glu-B1 locus on starch-protein interaction and starch digestibility during thermomechanical processing of wheat dough.
The composition of glutenin protein significantly affects protein-starch interactions and starch digestion characteristics in wheat dough matrices. To elucidate the effects of high molecular weight glutenin subunits at the Glu-B1 locus on dough processing quality, the detailed structural changes of protein, starch, and their complexes were compared in Mixolab dough samples of two near isogenic lines 7 + 8 and 7 + 9. The results showed that the degree of protein aggregation increased continuously during dough processing, as did the destruction and rearrangement of the gluten network. Compared to 7 + 8, the stronger and more stable protein network formed in 7 + 9 dough induced intensive interactions between protein and starch, primarily through hydrogen bonds and isomeric glycosidic bonds. In 7 + 9 dough, the more compact and extensive protein-starch network significantly inhibited starch gelatinization during dough pasting, while during the dough cooling stage [from C4 (82.8 °C) to C5 (52.8 °C)], more protein-starch complexes composed of monomeric proteins and short-chain starch were generated, which remarkably inhibited starch retrogradation. All protein-starch interactions in the 7 + 9 dough improved the starch digestion resistance, as reflected by the high content of resistant starch. The more extensive and intensive protein-starch interactions in the 7 + 9 dough inhibited the gelatinization and enzymatic hydrolysis of starch, thereby producing more slowly digestible starch and resistant starch. These findings demonstrate the feasibility of optimizing the texture and digestibility of wheat-based food products by regulating the behavior and interactions of proteins and starch during dough processing. © 2022 Society of Chemical Industry.


Role of Physician Gender in the Modern Practice of Obstetrics and Gynecology: Do Obstetrician-Gynecologists Perceive Discrimination from their Sex?
It is unclear whether obstetrician-gynecologists (OBGYNs) experience gender discrimination as a result of patient and organizational gender preferences. Our objective was to evaluate whether the gender preference for OBGYNs resulted in perceptions of discrimination by the physician while simultaneously assessing their patients' views for choosing their OBGYN. A survey assessed whether OBGYNs' perceptions of patients and employers' preferences for gender in selecting an OBGYN affected their clinical practice and resulted in feelings of discrimination. Providers' patients simultaneously completed a survey to explore the role of gender in the selection of their OBGYN. The Mann-Whitney U test was used for comparisons. A P < 0.05 was considered statistically significant. Thirty-four physicians (97% response rate) and 803 patients (81% response rate) completed the survey. The majority of male physicians agreed that their gender negatively affects their patient practice volume (60%), whereas no female physicians agreed with this statement (0%, P < 0.01). Female physicians were more likely to agree (46%) that they are discriminated against because of gender in terms of salary as compared with male physicians (20%, P = 0.049), however. Although more women who see a female OBGYN (compared with those who see a male OBGYN) perceive that their physician's gender is important to them (62% versus 20%, P < 0.01), the most frequent reason all women chose their OBGYN is the "rating" of the physician. Female and male OBGYNs perceive bias because of their gender; however, the former is because of compensation and the latter is because of patient preferences. The majority of women choose their OBGYN based on the physician's rating and not on the physician's sex, however.


Congenic mice demonstrate the presence of QTLs conferring obesity and hypercholesterolemia on chromosome 1 in the TALLYHO mouse.
The TALLYHO (TH) mouse presents a metabolic syndrome of obesity, type 2 diabetes, and hyperlipidemia. Highly significant quantitative trait loci (QTLs) linked to adiposity and hypercholesterolemia were previously identified on chromosome (Chr) 1 in a genome-wide scan of F2 mice from C57BL/6J (B6) x TH. In this study, we generated congenic mouse strains that carry the Chr 1 QTLs derived from TH on a B6 background; B6.TH-Chr1-128Mb (128Mb in size) and B6.TH-Chr1-92Mb (92Mb in size, proximally overlapping). We characterized these congenic mice on chow and high fat (HF) diets. On chow, B6.TH-Chr1-128Mb congenic mice exhibited a slightly larger body fat mass compared with B6.TH-Chr1-92Mb congenic and B6 mice, while body fat mass between B6.TH-Chr1-92Mb congenic and B6 mice was comparable. Plasma total cholesterol levels were significantly higher in B6.TH-Chr1-128Mb congenics compared to B6.TH-Chr1-92Mb congenic and B6 mice. Again, there was no difference in plasma total cholesterol levels between B6.TH-Chr1-92Mb congenic and B6 mice. All animals gained more body fat and exhibited higher plasma total cholesterol levels when fed HF diets than fed chow, but these increases were greater in B6.TH-Chr1-128Mb congenics than in B6.TH-Chr1-92Mb congenic and B6 mice. These results confirmed the effect of the 128Mb TH segment from Chr 1 on body fat and plasma cholesterol values and showed that the distal segment of Chr 1 from TH is necessary to cause both phenotypes. Through bioinformatic approaches, we generated a list of potential candidate genes within the distal region of Chr 1 and tested Ifi202b and Apoa2. We conclude that Chr 1 QTLs largely confer obesity and hypercholesterolemia in TH mice and can be promising targets for identifying susceptibility genes. Congenic mouse strains will be a valuable resource for gene identification.


Chemotypic and genetic diversity in Epimedium sagittatum from different geographical regions of China.
Different geographical plant populations within a single species can exhibit variation, in the production of secondary metabolites. Genetic and environmental variations both contribute to differences between populations; however, the relative importance of these factors is unclear. Here, the extent of variation in the production of four flavonoid glycosides (epimedin A, B, C and icariin) were investigated in eleven wild populations of Epimedium sagittatum used in traditional Chinese medicine. Secondary metabolite profiles were classified into five chemotypes. A common garden experiment indicated this chemotype variation has a significant genetic basis. Extensive genetic variation among intraspecific populations was shown using a retrotransposon-based molecular marker system. These results will assist in development of strategies for conservation, utilization and domestication of E. sagittatum.


Augmentation of a Nonanatomical Repair of a Medial Meniscus Posterior Root Tear With Centralization Using Three Knotless Anchors May Be Associated With Less Meniscal Extrusion and Better Compressive Load Distribution in Mid-Flexion Compared With Non-Anatomical Root Repair Alone in a Porcine Knee Model.
To investigate the biomechanics of the centralization augmentation using knotless soft anchors to a nonanatomical transtibial pull-out root repair in a porcine medial meniscus posterior root tear (MMPRT) model. Porcine knee joints (N = 10) were used to perform one of the following procedures: (1) intact; (2) MMPRT; (3) nonanatomical root repair; (4) nonanatomical root repair with centralization using 2 anchors: anchors were inserted at the posterior medial collateral ligament (MCL) border and 10 mm anterior to the posterior MCL border; and (5) nonanatomical root repair with centralization using 3 anchors: another anchor was placed 10 mm posterior to the posterior MCL border. Contact area on the medial meniscus (MM), contact pressure in the MM and tibial cartilage, and MM extrusion were evaluated at 30°, 45°, 60°, and 90° knee flexions under 200 N compressive force. MM extrusion at the posterior MCL border was significantly reduced after root repair with centralization using 3 anchors than after root repair alone at 30° (-0.063 mm vs 1.5 mm, P = .017), 45° (0.21 mm vs 1.7 mm, P = .018), and 60° (0.78 mm vs 2.3 mm, P = .019). There were no significant differences in MM extrusion between the root repair alone and root repair with centralization using 2 anchors at all flexion angles. The contact area in the middle and posterior MM was significantly greater after centralization with 3 anchors than after root repair alone at all flexion angles (except the posterior MM at 90°). The mean contact pressure in the tibial cartilage was significantly lower after centralization with 3 anchors than after root repair at all angles. Augmentation of a nonanatomical repair of a medial meniscus posterior root tear with centralization using three knotless anchors may be associated with less meniscal extrusion and better compressive load distribution between 30° and 60° flexion compared with nonanatomical root repair alone in a porcine model. This biomechanical study at time zero suggests that the addition of centralization using 3 knotless anchors may reduce MM extrusion and restore the load-distributing function of the MM.


An update on pancreatic regeneration mechanisms: Searching for paths to a cure for type 2 diabetes.
Over the last decades, various approaches have been explored to restore sufficient β-cell mass in diabetic patients. Stem cells are certainly an attractive source of new β-cells, but an alternative option is to induce the endogenous regeneration of these cells. Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth. Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes.


The near complete tracheal ring deformity.
Congenital complete and near-complete tracheal rings are extremely rare tracheal deformities. There are fewer than 100 cases of congenital complete tracheal rings, and only four cases of near-complete described in the literature. Long-segment occurrences of these anomalies are usually incompatible with life. We describe the presentation of the long-segment near complete tracheal ring deformity and long-segment anterior fusion of cartilage rings (cartilage sleeve deformity) in a living infant. The literature is reviewed, and the embryology, presentation, and management of these extremely rare anomalies are discussed.


Genetic evidence for activation of the positive transcriptional regulator Xy1R, a member of the NtrC family of regulators, by effector binding.
The Xy1R protein positively controls expression from the Pseudomonas putida TOL plasmid sigma 54-dependent Pu and Ps promoters, in response to the presence of aromatic effectors such as m-xylene, m-methylbenzyl alcohol, and p-chlorobenzaldehyde in the culture medium. Xy1R also autoregulates its own synthesis. A mutant Xy1R regulator called Xy1R7 was isolated after nitrosoguanidine mutagenesis of the wild-type gene and phenotypic selection for mutants that had acquired the ability to recognize m-nitrotoluene, a nitroarene that is not an effector for the wild-type regulator. The mutant regulator exhibited a single point mutation that resulted in a change in codon 172 (GAA-->AAA), which should result in a Glu-->Lys change in the polypeptide chain. The effector profile of the mutant regulator was determined by measuring beta-galactosidase from a fusion of the Pu promoter to a promoterless lacZ gene. The results showed that the mutant regulator had acquired the ability to recognize m-nitrotoluene, and retained the wild-type regulator's ability to recognize most of the wild-type effectors. Full transcriptional activation of the Pu promoter by Xy1R7, as with the wild-type Xy1R protein, requires its full modular structure, namely the sigma 54 recognition site, the integration host factor binding site, and the upstream activation sequences. The Xy1R7 regulator did not stimulate transcription from the Ps promoter in response to the presence of its effectors, and autoregulated its own synthesis at low levels.


Growth inhibitory factor and zinc affect neural cell cultures in a tissue specific manner.
Deficiency of neuronal growth inhibitory factor (GIF) and abnormalities in zinc homeostasis have been suggested to play a role in the neuropathogenesis of Alzheimer's disease. We report here that embryonic chick cerebral cell cultures zinc and copper containing GIF in the presence of marmoset hippocampal extract reduces significantly and concentration dependently mitochondrial succinate dehydrogenase activity (MTT) and cell mass. In contrast, no indications could be found that GIF affected neural retina cell cultures. Our results suggest that the observed effects of GIF are not elicited by zinc.


Working together for the common good: cell-cell communication in bacteria.
The 4th ASM Conference on Cell-Cell Communication in Bacteria was held in Miami, FL, from 6 to 9 November 2011. This review highlights three key themes that emerged from the many exciting talks and poster presentations in the area of quorum sensing: sociomicrobiology, signal transduction mechanisms, and interspecies communication.


Uranium in sediments, mussels (Mytilus sp.) and seawater of the Krka river estuary.
The response of an aquatic environment to the decrease of phosphate discharges from a technologically improved transhipment terminal, situated at the Croatian Adriatic coast in the port of Sibenik, has been assessed based on uranium activity and concentration in sediment, seawater and mussels Mytilus sp. The highest 238U activities (485+/-16Bqkg(-1) dry weight) were found in the sediment sample collected from the sampling site closest to the terminal. The maximum concentrations in the sediment samples are above the natural ranges and clearly indicate the harbour activities' influence. The 238U/226Ra activity ratios in sediment samples demonstrate the decreasing trend of phosphate ore input. Mussel samples showed levels of 238U activities in the range from 12.1+/-2.9 to 19.4+/-7.2 Bqkg(-1) dry weight, thus being slightly higher than in normally consumed mussels. Only the seawater, taken just above the bottom sediment at the sampling site closest to the terminal, shows a slightly higher uranium concentration (3.1+/-0.2 microgL(-1)) when compared to the samples taken in upper seawater layers (2.1+/-0.2 microgL(-1)) but is in the range of the concentration level of uranium in natural seawater. Since the transhipment terminal in the port of Sibenik was modernised in 1988, discharge of phosphate ore into the seawater was drastically reduced and, consequently, uranium concentration levels in seawater have decreased. However, enhanced uranium activity levels are still found in deeper sediment layer samples and in mussel.


Multifocal high grade prostatic intraepithelial neoplasia is a risk factor for subsequent prostate cancer.
The risk of under diagnosed or development of subsequent prostate cancer and the treatment of patients diagnosed with high grade prostatic intraepithelial neoplasia remain controversial. We evaluated the relationship between high grade prostatic intraepithelial neoplasia on initial biopsy and the future presence of prostate cancer. From December 1997 to February 2008 a total of 328 men underwent a second prostate biopsy after being initially diagnosed with high grade prostatic intraepithelial neoplasia. Men with prostate cancer or atypia on initial biopsy were excluded from study. Another 335 men without high grade prostatic intraepithelial neoplasia, prostate cancer or atypia underwent a second prostate biopsy based on clinical suspicion alone. A Cox proportional hazards model was used to estimate the effect of high grade prostatic intraepithelial neoplasia on the subsequent diagnosis of prostate cancer after adjustment for prostate specific antigen, age, presence of inflammation, abnormal digital rectal examination and number of cores obtained at biopsy. High grade prostatic intraepithelial neoplasia was also stratified into multifocal disease and laterality. Adjusted Kaplan-Meier plots were generated to estimate the rates of prostate cancer. High grade prostatic intraepithelial neoplasia alone on initial prostate biopsy had a significant effect on the subsequent diagnosis of prostate cancer (HR 1.89; 95% CI 1.39, 2.55; p <0.0001). Stratifying high grade prostatic intraepithelial neoplasia into multifocal and bilateral disease significantly increased the hazard ratios to 2.56 (95% CI 1.83, 3.60) and 2.20 (95% CI 1.51, 3.21), respectively, resulting in estimated 3-year cancer rates of 29.0% and 37.0% compared to 12.5% and 18.9%, respectively, following benign biopsy. Multifocal and bilateral disease are adverse features of high grade prostatic intraepithelial neoplasia that significantly increase the risk of prostate cancer despite adjusting for other clinical indicators such as prostate specific antigen and abnormal digital rectal examination.


Working capacity and pulmonary gas exchange in children with exercise-induced asthma.
Sixteen children aged 10.1-14.3 years with a history of exercise-induced asthma (EIA) were evaluated as to their working capacity both during a maximal exercise test and during submaximal exercise. During submaximal exercise ventilation and alveolar gas exchange were measured. Working capacity was normal with respect to the oxygen uptake and to the maximal load. Arterial blood gases were normal before exercise but PaO2 decreased (p less than 0.01) during the submaximal exercise test. The values were, however, still within the normal limits in all but two of the children. The flow-volume data showed bronchial obstruction in the resting state, before exercise, with lower values of MEF50 and MEF25 (p less than 0.01) than in healthy children. Following exercise, 14 of the 16 children developed clinical symptoms of asthma with increased impairment of the flow-volume curves. Most of them recovered from asthmatic symptoms within 30 min. Flow-volume curves were found to be a sensitive measurement of bronchial obstruction during the symptom-free phase and during EIA although with larger individual variations than FEV1.


Biflavonoids from Brazilian pine Araucaria angustifolia as potentials protective agents against DNA damage and lipoperoxidation.
A biflavonoid fraction (BFF) obtained from Araucaria angustifolia needles was effective to quench singlet oxygen (1O2), to protect plasmid DNA against single strand break (ssb) caused by 1O2 or Fenton reaction and to inhibit Fenton or UV radiation-induced lipoperoxidation in phosphatidylcholine liposomes. The activity of the biflavonoid fraction (BFF) was compared with quercetin, rutin (flavonoids), ginkgetin, amentoflavone (biflavonoids), alpha-tocopherol and Trolox. The BFF displayed a higher quenching rate constant compared to flavonoids and biflavonoids and protected against ssb induced by 1O2. Although the BFF was not as efficient as either flavonoids, alpha-tocopherol or Trolox in protection against ssb induced by Fenton-reaction or lipoperoxidation, these scavenging properties suggest that BFF is still an excellent candidate for successful employment as an antioxidant and photoprotector.


Cigarette and e-cigarette use trajectories and prospective prescription psychotherapeutic drug misuse among adolescents and young adults.
This study aimed to determine the potential longitudinal impact of different cigarette and e-cigarette use trajectories among people aged 10-24 on prescription drug misuse of psychotherapeutic drugs. Data came from waves 1-5 of the Population Assessment of Tobacco and Health (PATH) Study (2013-2019; n = 14,454). Group-based trajectory modeling identified groups of adolescents and young adults based on cigarette and e-cigarette use across the five waves. Weighted logistic regression models were fit to examine the association of group membership with two outcomes at all waves: 1) misuse of opioids, sedatives, and/or tranquilizers, and 2) misuse of Ritalin and/or Adderall, adjusting for background characteristics. Five trajectory groups emerged: (1) non-use (77.7 %); (2) early-onset cigarette use with reducing use (4.6 %); (3) ever-increasing e-cigarette use (6.1 %); (4) stable dual use of cigarettes and e-cigarettes (3.2 %); and (5) accelerating dual use of cigarettes and e-cigarettes (8.4 %). In comparison to the non-use group, all other groups had significantly higher odds of misuse of opioids, tranquilizers, and/or sedatives and all but the early-onset cigarette use with reducing use group had significantly higher odds of misuse of Ritalin and/or Adderall by the end of wave 5. Patterns of cigarette and e-cigarette use in adolescent and young adult populations may serve as important indicators for concurrent and prospective prescription psychotherapeutic drug misuse. Findings highlight the need for cigarette and e-cigarette use prevention, harm reduction, and/or cessation efforts among adolescents and young adults.


Characteristics of concanavalin A-resistant Chinese hamster ovary cells and certain revertants.
Clones of Chinese hamster ovary (CHO) cells were isolated by single-step selection for resistance to killing Concanavalin A (ConA) and certain cellular and membrane properties were examined. The ConA-resistant isolates were only about 2-fold more resistant than wild type cells to the selecting lectin, but exhibited pleiotropic temperature-sensitivity for growth, markedly altered morphology and adherence, and significant difference in susceptibility to other agents such as colchicine. Two revertants to full temperature-resistance were isolated from different ConA-resistant mutants. One revertant clone had reacquired wild type sensitivity to ConA while the other revertant remained ConA-resistant. The two series of wild typed, ConA-resistant, and temperature revertant clones were analyzed for altered mobility of cell surface glycoproteins using lactoperoxidase/125I and galactose oxidase/(3H) borohydride labelling procedures. The ConA-resistant clones showed increased mobility on polyacrylamide gels of three classes of labelled proteins, in the molecular weight ranges 225,000, 200,000, and 130,000 daltons. These changes persisted in the temperature-revertant that remained ConA-resistant, while two of the altered protein closses were restored to wild type mobility in the revertant that regained ConA-sensitivity. Cell hybridization experiments indicated that the temperature-sensitivity phenotypes of different ConA-resistant isolates are recessive and noncomplementing, implying that the same gene is affected in each case. The reversions to temperature resistance appear to be recessive suppressor mutation in different genes.


Historical biogeography of Drosophila simulans based on Y-chromosomal sequences.
Y-chromosomal sequences have been used for phylogeographic studies in humans and other mammals, but so far have been ignored as a source of historical information in Drosophila and other insects with X/Y sex determination. Here, we present the first phylogeographic study of Drosophila simulans based on the Y chromosome. Geographic distribution of Y-chromosomal haplotypes suggests a high degree of population subdivision within Africa, as well as between the African and cosmopolitan groups of populations. Consistent with earlier studies based on autosomal and X-linked loci, our results suggest that D. simulans originated in Madagascar or East Africa, and that the South and West African populations of this species are derived.


Nano-sized polystyrene plastic particles affect many cancer-related biological processes even in the next generations; zebrafish modeling.
With the ever-increasing plastic pollution, the nano-sized plastic particles that are constantly released from the main materials have a greater potential threat. Studies continue on how to eliminate plastic waste, which has become a global problem, from nature. We are aware that complete elimination is not easy at all, but it is not known clearly that even if it is successful, its effects on organisms will also disappear completely. In this study, zebrafish injected with 20 nm-sized polystyrene particles (PS) only during the embryonic period were grown in an environment without plastic exposure. The effects of PS on their offspring embryo/larvae were examined at morphological, molecular and metabolomic levels. Results showed that parental PNP exposure caused significant malformations, decreased survival rate, increased heart rate and blood flow rate, as well as decreased eye size, height and locomotor activity, which were attributed to growth retardation in the offspring. According to the results of whole-mount immunofluorescence larval staining, cell death and reactive oxygen species were significantly increased, while lipid accumulation was decreased in new generation larvae from zebrafish injected with PNP. In order to elucidate the mechanisms underlying these morphological, physiological and molecular damages, the metabolome analyses were performed by evaluating the Q-TOF MS/MS spectra with chemometric analyses in the offspring larvae. According to the metabolomics results, 28 annotated metabolomes suggested by the OPLS-DA analysis that may vary significantly through a variable in projection scores were detected. In addition, it was detected that the significantly increased histopathological findings and immunopositivity of JNK, H2A.X, PI3 and NOP10 in new generation larvae. In conclusion, it has been shown that exposure to PS, even only during the embryonic period, may affect many cancer-related biological processes in the next generation.


Behavior-related alterations of striatal neurochemistry in a mouse model of stereotyped movement disorder.
Motor stereotypy is a common component of several developmental, genetic, and neuropsychiatric disorders. In animals, these behaviors can be induced or attenuated via pharmacological manipulation of specific neural loci comprising cortico basal ganglia-cortical feedback circuits, including the striatum. The present study employed the deer mouse model of spontaneous and persistent stereotypy to assess the involvement of several endogenous neurotransmitters and neuromodulators in mediating the expression of the stereotypic behaviors (i.e., repetitive hindlimb jumping) exhibited by these mice. This was accomplished by employing a microdialysis sampling system coupled on-line to capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection apparatus. Given the 13-s temporal resolution for analyte measurement afforded by this system, discrete behavior-related alterations in striatal neurochemical concentrations were detected. Rearing behavior was found to be associated with significant and selective elevations of striatal glutamate (Glu) and aspartate (Asp) concentrations. Moreover, rearing was found to most frequently precede repetitive jumping. The results also indicated that alterations in striatal serine (Ser) concentrations were involved in the modulation of locomotor activity. The present findings support a role of the striatal glutamatergic system in the mediation of spontaneous stereotypic behavior and suggest a potential neuronal mechanism by which transition to stereotypy occurs in these mice. Moreover, the present findings demonstrate the usefulness of the microdialysis system employed in studying the neurochemical substrates of rapidly transitioning behavior.


Modifiable socio-cultural beliefs and practices influencing early and adequate utilisation of antenatal care in rural Bangladesh: A qualitative study.
Our objective was to explore the socio-cultural factors that influence women's early and adequate utilisation of antenatal care (ANC) in rural Bangladesh. A qualitative study was conducted in two rural settings of Bangladesh, including 32 in-depth interviews with pregnant or recently delivered women, husbands whose wives were pregnant or had a recent birth, mothers-in-law whose daughters-in-law were pregnant or had a recent birth; 2 focus group discussions with husbands; and 4 key-informant interviews with community health workers. We used thematic analysis to analyse the data. ANC initiation in the first trimester was not a priority for most women. Women's lack of awareness about the appropriate timing of the first ANC contact, lack of decision-making autonomy and fear of caesarean section were the major barriers to the early and adequate ANC utilisation. There were many superstitions around pregnancy in rural settings which prevented women seeking early and adequate antenatal care and led them to seek care from traditional care providers instead of formal care providers. ANC utilisation in rural Bangladesh was associated with several socio-cultural beliefs which are modifiable with interventions that have been used in similar settings. Targeting these socio-cultural barriers with context- and community-specific interventions is important to improve overall ANC utilisation at the community-level which can lead to significant improvements in perinatal outcomes.


How accurate are pressure ulcer grades? An image-based survey of nurse performance.
We report a descriptive study using a questionnaire and twelve digital photographs classified by a consensus panel of experts using the European Pressure Ulcer Advisory Panel and Stirling plus digits classifications. The expert panel comprised 5 tissue viability specialists/clinical lecturers in tissue viability with many years of collective experience and examined 30 images over 2 1/2 hours. In general consensus on wound grading was good; in only 2 images was there insoluble disagreement. Two hundred subjects were recruited from a Tissue Viability Society (N = 50), the European Pressure Ulcer Advisory Panel (N = 50), five Community Trusts (N = 50) and five Acute Trust (N = 50) in England and Wales. The subjects were asked for demographic details (qualifications achieved, number of years qualified, employment grade and how their knowledge of classification of pressure ulcers has been obtained). The second part of the questionnaire asked them to classify twelve digital photographs of pressure ulcers using the European Pressure Ulcer Advisory Panel (EPUAP) and the Stirling plus digits systems. The study demonstrated that there is considerable lack of consensus when pressure ulcers are graded using the Stirling plus digit grading system and less disagreement when the EPUAP scale is used. The study also demonstrates that the statistical returns from different hospital and community units cannot be considered to be directly comparable. Furthermore, the study showed that the nurses most educated in pressure ulcer care (Clinical Nurse Specialists in Tissue Viability) were the most keen to receive extra education, whilst ward nurses were happy with their current knowledge and did not believe further education on pressure ulcer grading was necessary.


Efficacy of Truncal Plane Blocks in Pediatric Patients Undergoing Subcutaneous Implantable Cardioverter-Defibrillator Placement.
Pediatric patients undergoing subcutaneous implantable cardioverter-defibrillator (S-ICD) placement usually have substantial postoperative pain. The aim of this study was to investigate the effect of the transversus thoracic muscle plane (TTMP) block combined with serratus anterior plane block (SAPB) in patients undergoing S-ICD placement. A double-blind, randomized controlled study. First Affiliated Hospital of Nanchang University. Patients aged nine-to-18 years undergoing S-ICD placement were included. A group of 102 patients randomly were allocated to either receive combined nerve blocks (NER group) or no nerve block (CON group). The primary endpoint was perioperative fentanyl consumption. The secondary outcome measures included pain at rest and after movement at two, four, six, 12, 24, and 48 hours after extubation; 48-hour acetaminophen administration; time to extubation; length of stay in the postanesthesia care unit (PACU); length of hospital stay; codeine tablet consumption; and percentage of patients who had codeine tablets after discharge. The NER group reported significantly less intraoperative (4.1 μg/kg v 3.1 μg/kg, p = 0.04) and postoperative fentanyl consumption (3.8 μg/kg v 1.5 μg/kg, p = 0.006) than the CON group. Compared with the NER group, the CON group had higher Numerical Rating Scale (NRS) pain scores at 24 hours after surgery both at rest and after movement. The time to extubation (20.5 minutes v 12.6 minutes, p = 0.03) and length of stay in the PACU (30.5 minutes v 15.6 minutes, p = 0.02) were significantly decreased in the NER group compared with the CON group. The CON group had a significantly higher postoperative acetaminophen requirement than did the NER group (32 mg/kg v 16 mg/kg, p = 0.01). TTMP block combined with SAPB in pediatric S-ICD placement could provide effective analgesia.


Hyoid bone tumour mass presenting with cervical nodal metastasis.
This paper presents a quite unique case report of a patient presenting with the combination of cervical metastatic lymphadenopathy and a hyoid bone tumour mass. The differential diagnosis and treatment is discussed, with emphasis on the importance of immunohistochemistry and electron microscopy in the management of such a case.


Tricyclic 2'-C-modified nucleosides as potential anti-HCV therapeutics.
Promising biological activity in a number of therapeutic areas has been reported for both tricyclic nucleosides and 2'-modified nucleosides. In particular, disubstitution at the C-2' position of nucleosides has resulted in significant activity against the hepatitis C virus (HCV). Combining this with the observation that tricyclic nucleosides developed in our laboratory have been shown to inhibit the RNA-dependent RNA polymerase NS5B led to the design of a series of 2'-modified tricyclic nucleosides. Details of the synthesis, structural characterization, and preliminary biological results are reported.


The partition of glycosaminoglycan-quaternary ammonium complexes, II. The effects of polymer molecular weight and sulfation.
Previous results have shown the possibility for obtaining high-resolution separations of glycosaminoglycans by partition in butanol/aqueous two-phase systems containing quaternary ammonium salts. In this paper, the effects on partition behavior of both polymer molecular weight and sulfation were examined. Two series of fractionated chondroitin sulfate polymers were isolated in which the molecular weight and sulfation varied systematically. In the molecular weight series the six samples, spanned the range from 3200 +/- 300 to 19 700 +/- 500 and each sample carried 0.8 sulfate groups per uronic acid residue. In the sulfation series, each sample had an essentially constant molecular weight of 13 000, but the sulfation varied from 0.58 to 0.88 sulfate groups per uronic acid. The C50 of each of these samples was determined in the 1-butanol/aqueous NaCl phase system containing 1% hexadecylpyridinium chloride. In the series wherein the molecular weight varied, the C50 increased with molecular weight up to 12 000 where a limiting value was reached. In the series wherein the sulfation varied, a linear relationship was found between the C50 and the square of the number of anionic substituents per disaccharide. These results show that fractionation by partition techniques will be sensitive to the anionic nature of the polymer, but for the common connective tissue glycosaminoglycan, there will be no fractionation according to molecular weight.


Disordered spatiotemporal processing in schizophrenics.
Schizophrenics have been observed to process information slower than normal individuals. The present study evaluated spatiotemporal information processing by schizophrenics and normal controls by means of a contrast sensitivity task. Spatial frequency gratings (0.9, 3.8, 15 cycles/degree), temporally modulated at 0.0 stationary, 0.8, 3.25, 6.5, and 26.0 Hz, were presented to evaluate whether or not schizophrenics are deficient in processing patterns or temporal information. While the patterns were increasing linearly from 0% to 30% contrast, the subjects were required to discern when pattern or temporal changes first occurred. A multivariate Analysis of Variance revealed that schizophrenics were poorer at detecting temporal changes between 3.25 and 6.5 Hz, whereas they were able to detect patterns better on the low and poorer on the high spatial frequencies compared to normals. No differences were obtained for the stationary pattern. These results are discussed in terms of abnormal sensory gating occurring during the critical duration of temporal integration.


A Tale of Two Elabela Null Mice.
Elabela (ELA), the second peptide ligand for the apelin receptor, APLNR, was previously found in lower vertebrates to be crucial for endoderm and cardiac development. Two new studies report on the phenotypes of Ela null mice, ranging from defective embryogenesis to preeclampsia, providing new insights and raising greater intrigue on this cardiometabolic pathway.


Co-treatment of fruit and vegetable waste in sludge digesters: Chemical and spectroscopic investigation by fluorescence and Fourier transform infrared spectroscopy.
In a previous work co-digestion of food waste and sewage sludge was performed in a pilot apparatus reproducing operating conditions of an existing full scale digester and processing waste mixed sludge (WMS) and fruit and vegetable waste (FVW) at different organic loading rates. An analysis of the relationship among bio-methane generation, process stability and digestate phytotoxicity was conducted. In this paper we considered humification parameters and spectroscopic analysis. Humification parameters indicated a higher not humified fraction (NH) and a lower degree of humification (DH) of FVW with respect to WMS (NH=19.22 and 5.10%; DH=36.65 and 61.94% for FVW and WMS, respectively) associated with their different chemical compositions and with the stabilization process previously undergone by sludge. FVW additions seemed to be favourable from an agronomical point of view since a lower percentage of organic carbon was lost. Fourier transform infrared spectra suggested consumption of aliphatics associated with rising in bio-methane generation followed by accumulation of aliphatics and carboxylic acids when the biogas production dropped. The trend of peaks ratios can be used as an indicator of the process efficiency. Fluorescence intensity of peak B associated with tryptophan-like substances and peak D associated with humic-like substances observed on tridimensional Excitation Emission Matrix maps increased up to sample corresponding to the highest rate of biogas production. Overall spectroscopic results provided evidence of different chemical pathways of anaerobic digestion associated with increasing amount of FVW which led to different levels of biogas production.


Cytostatic effect of xanthone-loaded mPEG-b-p(HPMAm-Lac2) micelles towards doxorubicin sensitive and resistant cancer cells.
Xanthone exhibits several medicinal activities and especially it inhibits the growth of cancer cells. However, the use of xanthone is limited because of its low aqueous solubility and systemic toxicity. In the present study xanthone was loaded into poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl) methacrylamide-dilactate] mPEG-b-p(HPMAm-Lac(2)) micelles in order to overcome these drawbacks. It was shown that xanthone could be loaded in these micelles up to 2 mg/mL with ~100% entrapment efficiency and ~20% loading capacity. The average particle diameter of the xanthone loaded mPEG-b-p(HPMAm-Lac(2)) micelles as determined by dynamic light scattering ranged from 84 to 112 nm. In vitro assays showed that xanthone in its free form as well as loaded in polymeric micelles had a high cytotoxicity towards both doxorubicin sensitive and, importantly, resistant cancer cells. On the other hand empty mPEG-b-p(HPMAm-Lac(2)) micelles did not show any cytotoxicity towards normal cells (PBMCs). Interestingly, the cytostatic effect of xanthone towards normal cells was masked when loaded in the micelles. The mechanism of cell growth inhibition by xanthone-loaded polymeric micelles was mediated through induction of apoptosis, as evidenced from a subdiploid peak of propidium iodide stained cells using flow cytometric analysis. From the results of this study it can be concluded that xanthone has potent anticancer activity not only on sensitive but also on doxorubicin resistant cancer cell lines. mPEG-b-p(HPMAm-Lac(2)) micelles are therefore attractive delivery systems of xanthone for the treatment of cancer.


Immunohistochemical analysis of colorectal cancer with gastric phenotype: claudin-18 is associated with poor prognosis.
Claudin-18 plays a key role in constructing tight junctions, and altered claudin-18 expression has been documented in various human malignancies; however, little is known about the biological significance of claudin-18 in colorectal cancer (CRC). The aim of this study is to investigate the significance of claudin-18 expression in CRC and its association with clinicopathological factors. We performed clinicopathological analysis of claudin-18 expression in a total of 569 CRCs by immunohistochemistry. Moreover, we investigated the association between claudin-18 and various markers including gastric/intestinal phenotype (MUC5AC, MUC6, MUC2 and CD10), CDX2, claudin-3, claudin-4, p53 and Ki-67. Claudin-18 expression was detected in 21 of the 569 CRCs (4%) and was seen exclusively on the cell membrane. Positive expression of claudin-18 showed a significant correlation with positive expression of MUC5AC (P < 0.0001) and negative expression of CDX2 (P= 0.0013). The prognosis of patients with positive claudin-18 expression was significantly poorer than in negative cases (P= 0.0106). Multivariate analysis revealed that T grade, M grade and claudin-18 expression were independent predictors of survival in patients with CRC. We revealed that claudin-18 expression correlates with poor survival in patients with CRC and is associated with the gastric phenotype.


Deep genealogical analysis of a large cohort of participants in the CARTaGENE project (Quebec, Canada).
Genealogical analysis helps to better understand the genetic structure of populations. The population of Quebec (Canada) often serves as a model for this type of analysis, having one of the world's most complete genealogical databases. The main objective of this study was to reconstruct, analyse and compare the ascending genealogies of participants to CARTaGENE, a project that aims at building a database on various aspects of public health. In total, 5110 genealogies from four Quebec regions were reconstructed. Distribution of ancestors, completeness and depth of the genealogies, characteristics of immigrant ancestors and kinship and inbreeding coefficients were analysed. Most genealogies go back to the 17th century, with a mean genealogical depth of 10 generations. Origins of immigrant ancestors are more diverse in the Montreal region, resulting in lower inbreeding and kinship among the participants from this region. Inbreeding and kinship values are mainly explained by remote genealogical links (from 6 to 11 generations). Deep genealogies allowed for a precise measurement of the geographic origins of the participants' immigrant ancestors, as well as inbreeding and kinship ties in the population, which may be crucial for studies aiming to identify genetic variations associated with Mendelian or complex diseases.


Giant cell arteritis associated with acute Q fever - A case report.
Q fever is a worldwide spread zoonotic disease, caused by the gram-negative intracellular bacillus Coxiella burnetii. Apart from its most common manifestations, Q fever has been reported to occasionally mimic autoimmune diseases. We herein present a case of acute Q fever in a 69-year-old man, manifesting as prolonged fever with pneumonitis, in whom biopsy of the temporal artery revealed giant cell arteritis. Moreover, PCR testing of the biopsy specimen was positive for Coxiella burnetii, thus further supporting the possibly infectious etiology of some cases of biopsy proven giant cell arteritis, with implications for treatment.