Endocrine involvement in pediatric-onset Langerhans' cell histiocytosis: a population-based study.
To document the frequency and outcome of endocrine involvement in pediatric-onset Langerhans' cell histiocytosis (LCH), and the association with other types of organ involvement. This retrospective nationwide multicenter study involved 589 patients with pediatric-onset LCH, 148 of whom had endocrine dysfunction. Median follow-up was 11.6 years. Pituitary dysfunction was present in 145 patients, and 141 had diabetes insipidus (DI). The estimated 10-year risks of pituitary involvement were 24.2% +/- 1.8%. GH deficiency occurred in 61 patients. Median age at onset was 2.8 years for LCH, 3.9 years for DI, and 7.7 years for GH deficiency. The risk of cranial involvement; ear, nose, and throat involvement; pneumothorax; and cholangitis was significantly higher in patients with endocrinopathy. The chronology of episodes did not support a causal link between pituitary involvement and involvement of other organs. Systemic treatment of LCH did not prevent pituitary involvement. The most severe complication was a neurodegenerative syndrome, which affected 4.3% and 10.8% of patients, respectively, 5 and 15 years after initial diagnosis, and appeared to be linked to pituitary involvement. Patients who develop endocrine LCH disorders are at a high risk of neurodegenerative LCH and require long-term follow-up.


Aging accelerates dietary lard-induced increase in blood pressure in rats.
We investigated whether the dietary lard-induced increase in blood pressure (BP) is accelerated in aged rats compared to young ones. Three-month-old (young group), 10-month-old (middle-age group), and 18-month-old (older group) F344/N male rats were used. The rats were fed either chow alone or chow in which 50% of the energy content was from substituted lard. Systolic BP (SBP) and body weights (BW) were determined weekly during each 7-week feeding period. A Steady-state plasma glucose (SSPG) method was used to determine the insulin sensitivity. Bilateral testicular fat mass (epididymal fat; Epi-F) was removed in order to evaluate weight (Epi-FW). SBP began to increase at 2 weeks in the older lard-fed group, at 4 weeks in the middle-age lard-fed group, and at 5 weeks in the young lard-fed group after feeding was begun. There was no significant difference in the basal values of SBP among any ages-groups of the rats. After 4 weeks of lard feeding, increases in SBP, plasma insulin, leptin level, SSPG and Epi-FW/BW were observed in the older lard-fed group. In the younger rats, however, only hyperinsulinemia developed. At 7 weeks, increased BP in the younger rats was accompanied by increased plasma leptin level, SSPG and Epi-FW/BW. In summary, aging accelerates development of a dietary lard-induced increase in BP, which may be caused by the hyperleptinemia that may be the result of increased susceptibility to insulin resistance and/or visceral adiposity in older rats.


Evaluating the efficiency of different natural clay sediments for the removal of chlortetracycline from aqueous solutions.
Natural clay sediments were collected from ten different localities in Saudi Arabia (S-1 from eastern, S-2 to S-4 from middle and S-5 to S-10 from western regions), characterized and evaluated for their efficiency towards chlortetracycline (CTC) removal from aqueous solutions. Sediment S-4 exhibited highest surface area (288.5 m2 g-1), followed by S-5, S-9, and S-1 (252.1, 249.6, and 110.4 m2 g-1, respectively). Sediments S-5, S-9, S-2, and S-4 showed the highest cation exchange capacities (CEC) (62.33, 56.54, 52.72, and 46.85 cmol kg-1, respectively). The pH range of 3.5-5.5 was optimum for the highest CTC removal. Freundlich model was best fitted to CTC sorption data (R2 = 0.96-0.99), followed by Dubinin-Radushkevich model (R2 = 0.89-0.97). The sediments S-4, S-5, and S-9 exhibited the highest CTC removal efficiency (98.80-99.05%), which could be due to higher smectite and kaolinite contents, CEC, surface area and layered structure. Post-sorption XRD patterns shown new peaks and peak shifts confirming the sorption of CTC. Electrostatic interactions, interlayer sorption and H-π bonding were the potential CTC sorption mechanisms. Therefore, natural clay sediments with high sorption capacities could efficiently remove CTC from contaminated aqueous media.


Bromobenzene-induced lethal toxicity in mouse is prevented by pretreatment with zinc sulfate.
In the current study, we evaluated the protective effect of zinc (Zn) against bromobenzene (BB) -induced lethal toxicity. We used Zn because this element is known to be an inducer of metallothionein (MT), which is in turn known to serve as an endogenous scavenger of free radicals. We administered Zn (as ZnSO4) at 50 mg/kg subcutaneously once-daily for 3 successive days prior to a single intraperitoneal administration of 1.2 g/kg BB in male ddY mice. Our results showed that pretreatment with Zn completely abolished the BB-induced mortality of mice until 48 h. We also found that pretreatment of mice with Zn significantly decreased the functional marker levels and reduced the histological damage both in liver and kidney as assessed at 18 h post-BB. We also showed that pretreatment with Zn enhanced antioxidative activity, resulting in decreased lipid peroxidation in both liver and kidney. Moreover, BB-induced calcium levels were downregulated by pretreatment with Zn. In addition, Zn-induced MT was decreased in Zn + BB-treated animals, implying that MT was consumed by BB-induced radicals. These findings suggest that prophylaxis with Zn protects mice from BB-induced lethal toxicity by decreasing oxidative stress in liver and kidney, presumably by induction of MT, which scavenges radicals induced by BB exposure.


Histology of the porcine mandibular distraction wound.
The purpose of this study was to document the progression and pattern of endosteal bone formation in a porcine mandibular distraction wound. Bone formation was assessed in a 0-day latency model (n=24 pigs) using distraction rates of 1, 2, or 4 mm/day to create a 12-mm gap. Macro-radiographs and sagittal histologic sections, from the center of the mandible, were evaluated by computer morphometrics (% bone fill) and by a semi-quantitative bone formation score. Mean percent area of new bone was 12.4% (0-25.9%), 7.5% (0-21.3%) and 3.8% (0-10.5%) in mandibles distracted at 1, 2 or 4 mm/day respectively. At all time points, percent area of new bone was highest in mandibles distracted at 1 mm/day. Bone was deposited from the margins of the osteotomy toward the center of the wound and occurred first around the inferior alveolar canal and tooth bud regions. New bone formed by intramembranous ossification alone. The results of this experiment document the contribution of endosteal bone formation in this model of distraction osteogenesis.


Convergent synthesis of 3-arm star polymers from RAFT-prepared poly(N,N-diethylacrylamide) via a thiol-ene click reaction.
A novel convergent route to 3-arm star polymers is described that takes advantage of RAFT-synthesized homopolymers serving as masked macromolecular terminal thiol-containing materials capable of undergoing thiol-ene click reactions.


Detection of dithiocarbamate, chloronicotinyl and organophosphate pesticides by electrochemical activation of SERS features of screen-printed electrodes.
Enhancement of Raman intensity due to the electrochemical surface-enhanced Raman scattering (EC-SERS) effect is an interesting alternative to overcome the lack of sensitivity traditionally associated with Raman spectroscopy. Furthermore, activation of metallic screen-printed electrodes (SPEs) by electrochemical route leads to the reproducible generation of nanostructures with excellent SERS properties. EC-SERS procedure proposed in this work for the detection of several pesticides (thiram, imidacloprid and chlorpyrifos) with different nature, uses gold SPEs as SERS substrates, but also includes a preconcentration step as the initial and essential stage. Taking into account the small volume of solution employed, only 60 µL, the preconcentration cannot be performed for more than 15 min in order to ensure the proper contact of the solution with WE, RE and CE. Furthermore, selected temperature, 34 °C, is not very high to allow the exhaustive control of the drop volume. Optimization of preconcentration parameters (time and temperature) displays a crucial step, particularly in the detection of low concentrations of pesticides, because it will provide higher Raman intensity in EC-SERS experiments. After the initial step, gold SPEs were electrochemically activated by cyclic voltammetry, allowing the detection of very low concentration (µg·L-1) of pesticides due to the generation of fresh nanostructures with SERS effect.


Poly-ICLC preconditioning protects the blood-brain barrier against ischemic injury in vitro through type I interferon signaling.
Preconditioning with a low dose of harmful stimulus prior to injury induces tolerance to a subsequent ischemic challenge resulting in neuroprotection against stroke. Experimental models of preconditioning primarily focus on neurons as the cellular target of cerebral protection, while less attention has been paid to the cerebrovascular compartment, whose role in the pathogenesis of ischemic brain injury is crucial. We have shown that preconditioning with polyinosinic polycytidylic acid (poly-ICLC) protects against cerebral ischemic damage. To delineate the mechanism of poly-ICLC protection, we investigated whether poly-ICLC preconditioning preserves the function of the blood-brain barrier (BBB) in response to ischemic injury. Using an in vitro BBB model, we found that poly-ICLC treatment prior to exposure to oxygen-glucose deprivation maintained the paracellular and transcellular transport across the endothelium and attenuated the drop in transendothelial electric resistance. We found that poly-ICLC treatment induced interferon (IFN) β mRNA expression in astrocytes and microglia and that type I IFN signaling in brain microvascular endothelial cells was required for protection. Importantly, this implicates a potential mechanism underlying neuroprotection in our in vivo experimental stroke model, where type I IFN signaling is required for poly-ICLC-induced neuroprotection against ischemic injury. In conclusion, we are the first to show that preconditioning with poly-ICLC attenuates ischemia-induced BBB dysfunction. This mechanism is likely an important feature of poly-ICLC-mediated neuroprotection and highlights the therapeutic potential of targeting BBB signaling pathways to protect the brain against stroke.


Practitioner use of and attitudes towards videoconferencing for the delivery of evidence-based telemental health interventions: A mixed methods study.
The implementation of evidence-based psychosocial interventions using video-conference delivery (VCD) has the potential to increase accessibility to effective treatments, although its use remains limited and understudied. This study employed a mixed methods approach in surveying mental health practitioners about their attitudes regarding VCD of interventions that are considered evidence-based (i.e., have been shown to improve targeted outcomes in rigorous research). One hundred and eleven practitioners were sampled from several national and regional U.S. practice organizations and were administered quantitative surveys about their use of and attitudes towards VCD of evidence-based interventions (EBI). We examined the relationship between practitioner-level technology access, experience, and training with technology fluency and acceptability of using VCD. Quantitative results indicated the most frequently used adaptation for VCD was Tailoring and that practitioner education predicted attitudes towards EBIs. A subset (n = 20) of respondents were then purposively selected for qualitative interviews to further investigate accessibility, appropriateness, and feasibility of delivering EBIs via video conference. A conventional content analysis revealed that VCD was appropriate and acceptable for EBIs; however, many practitioners also described barriers related to feasibility of implementation. The results of this study have important implications for telemental health dissemination efforts which seek to extend services to populations not served well by traditional, in-person mental health services.


Effects of surface treatments and abutment shades on the final color of high-translucency self-glazed zirconia crowns.
Achieving excellent esthetics with monolithic self-glazed zirconia crowns in anterior teeth is challenging, and the impact of different surface treatments and abutment shades on the final color is unclear. The purpose of this in vitro study was to evaluate the effects of different external surface treatments (self-glazed, milled, polished, and glazed), different intaglio surface treatments (milled and airborne-particle abraded), and different abutment shades on the color difference of high-translucency self-glazed zirconia crowns. Sixty shade A1 and 60 shade A3 crowns were fabricated with a thickness of 0.80 ±0.02 mm and randomly divided into 12 groups (n=10). Different external and intaglio surface treatments were applied. Shade A1 and A3 abutments were made with composite resin. Color was measured with a spectrophotometer and expressed in CIELab coordinates, and color differences (ΔE00) between specimens and references were calculated. The data were analyzed with ANOVA and the Tukey post hoc test. The impact of different surface treatments and abutment shades on the color difference were compared by using multiple linear regression (α=.05). The effects of external surface treatments, intaglio airborne-particle abrasion, and abutment shades on the L∗, a∗, b∗ and ΔE00 values of the final color of the crowns were significantly different (P<.001). Polishing resulted in the greatest ΔE00 value among all external surface treatments (P<.001). The average ΔE00 values of all crowns on the A3 abutment were higher than those of all crowns on the A1 abutment (P<.001). The influence on the color difference was abutment>external surface treatment>intaglio surface treatment. Different surface treatments affected the final color of zirconia crowns, and a greater impact was seen with external surface treatments than with intaglio surface treatments. External polishing resulted in the greatest color difference. The abutment shade had the most effect on the color difference, as the darker the abutment color, the greater the color difference.


Automated Structured Reporting for Thyroid Ultrasound: Effect on Reporting Errors and Efficiency.
To compare the effectiveness of different reporting templates using the ACR Thyroid Imaging Reporting and Data System (TI-RADS) for thyroid ultrasound. In this retrospective study, four radiologists implemented ACR TI-RADS while dictating 20 thyroid ultrasounds for each of four different templates: free text, minimally structured, fully structured, fully structured and automated (embedded software automatically sums TI-RADS points, correlates with nodule size, and inserts appropriate recommendation into report impression). In total, 80 reports were constructed per template type. Frequencies of different errors related to ACR TI-RADS were recorded: errors in point assignment, point addition, risk-level assignment, and recommendation. Reporting times were recorded, and a survey about using the template was administered. Differences in error rates were compared using χ2 and Fisher's exact tests, and differences in reporting times were compared using Kruskal-Wallis tests. Across all readers, errors were identified in 27.5% of reports (22 of 80) for the free text template, 28.8% (23 of 80) for the minimally structured template, 18.8% (15 of 80) for the fully structured template, and 0% (0 of 80) for the fully structured and automated template (P < .0001). Frequency of each error type (number assignment, addition, TR categorization, recommendation) decreased across the four templates (P < .0005 to P < .005). Median reporting times for the less complex templates were 210 to 240 seconds, whereas the median automated template reporting time was 180 seconds (P = .41). Radiologists subjectively preferred using the automated template. A structured reporting template for thyroid ultrasound that automatically executed steps of ACR TI-RADS resulted in fewer reporting errors for radiologists.


Arthrography of the knee: a comparative study of the accuracy of single and double contrast techniques.
Single and double contrast arthrographic techniques were compared in 951 patinets with suspected meniscal injuries. Exploratory surgery of the knee was performed in 384 of these patients and good clinical follow-up was obtained in 135 patients. In the latter two groups of patients, the single contrast technique was 97% accurate in assessing the medial meniscus and 96% accurate in assessing the lateral meniscus. Double contrast arthrography was 97% accurate in assessing the medial meniscus and 93% accurate in assessing the lateral meniscus. Numerical differences in the results from the two techniques were not statistically significant. Therefore both techniques can be considered equally effective diagnostically.


Absence of correlation between radiation-induced CD8 T-lymphocyte apoptosis and sequelae in patients with prostate cancer accidentally overexposed to radiation.
454 patients with prostate adenocarcinoma were accidentally overexposed to radiation in Epinal hospital, France, between August 1999 and January 2007. We aimed toevaluate whether radiation-induced CD4 or CD8 T-lymphocyte apoptosis (RILA) correlates with the severity of radiation toxicity. Between 2007 and 2013, all patients who received more than 108% of the prescribed radiation dose, after correction of the treatment plan, were convened, and blood was sampled at 6-months follow-up. Maximal Digestive toxicity (MDT) and maximal urinary toxicity (MUT) were graded using the Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0 scale. RILA was assessed using flow cytometry. 245 patients were included in our study. After a median follow-up of 4.8 years, the MDT and MUT reached grade 3-4 in 37 patients and 56 patients, respectively. Patients with prostatectomy exhibited a statistically higher grade of MUT compared with those treated with definitive radiotherapy (p=0.03). The median RILA values were 11.8% and 15.3% for CD4 and CD8 T-lymphocytes, respectively. We found no significant correlation between CD4 or CD8 RILA and either MDT or MUT. RILA does not correlate with the inter-individual variation in MDT or MUT in the largest cohort of patients overexposed to radiation. The magnitude of the overdosage probably overrides biological predictors of toxicity, including individual radiosensitivity.


Tunable mechanical behavior of synthetic organogels as biofidelic tissue simulants.
Solvent-swollen polymer gels can be utilized as mechanical simulants of biological tissues to evaluate protective systems and assess injury mechanisms. However, a key challenge in this application of synthetic materials is mimicking the rate-dependent mechanical response of complex biological tissues. Here, we characterize the mechanical behavior of tissue simulant gel candidates comprising a chemically crosslinked polydimethylsiloxane (PDMS) network loaded with a non-reactive PDMS solvent, and compare this response with that of tissue from murine heart and liver under comparable loading conditions. We first survey the rheological properties of a library of tissue simulant candidates to investigate the effects of solvent loading percentage, reactive functional group stoichiometry, and solvent molecular weight. We then quantify the impact resistance, energy dissipation capacities, and energy dissipation rates via impact indentation for the tissue simulant candidates, as well as for the murine heart and liver. We demonstrate that by tuning these variables the silicone gels can be engineered to match the impact response of biological tissues. These experiments inform the design principles required for synthetic polymer gels that are optimized to predict the response of specific biological tissues to impact loading, providing insight for further tuning of this gel system to match the impact response of other "soft tissues".


American Society of Microbiology - 100th General Meeting.
Symposium sessions on genomics, surveillance, and pharmaceutical intervention opportunities were highlights of this annual ASM meeting. Two-component signal transduction was highlighted by both academic and industrial representatives, as was prokaryotic genomics. Recurring themes throughout the meeting were the contribution of efflux mechanisms to worldwide resistance, target modifications responsible for fluoroquinolone resistance, and the role of structural biology in the discovery and exploitation of bacterial targets.


Feasibility of a portable X-ray fluorescence device for bone lead measurements of condor bones.
Lead based ammunition is a primary source of lead exposure, especially for scavenging wildlife. Lead poisoning remains the leading cause of diagnosed death for the critically endangered California condors, which are annually monitored via blood tests for lead exposure. The results of these tests are helpful in determining recent exposure in condors and in defining the potential for exposure to other species including humans. Since condors are victim to acute and chronic lead exposure, being able to measure both would lend valuable information on the rates of exposure and accumulation through time. A commercial portable X-ray fluorescence (XRF) device has been optimized to measure bone lead in vivo in humans, but this device could also be valuable for field measurements of bone lead in avian species. In this study, we performed measurements of bone Pb in excised, bare condor bones using inductively coupled plasma mass spectrometry (ICP-MS), a cadmium 109 (Cd-109) K-shell X-ray fluorescence (KXRF) system, and a portable XRF system. Both KXRF and portable XRF bone Pb measurement techniques demonstrated good correlations with ICP-MS results (r=0.93 and r=0.92 respectively), even with increasing skin thickness (r=0.86 between ICP-MS and portable XRF at 1.54mm of soft tissue). In conclusion, our results suggest that a portable XRF could be a useful option for measurement of bone Pb in avian species in the field.


Concizumab: First Approval.
Concizumab (Alhemo™), a subcutaneously administered humanised monoclonal IgG4 antibody against tissue factor pathway inhibitor (TFPI), binds to the Kunitz-2 domain of TFPI and prevents TFPI from binding to activated Factor X. Concizumab is being developed by Novo Nordisk for the treatment of hemophilia A and B with and without inhibitors. In March 2023, concizumab was approved in Canada for the treatment of adolescent and adult patients (12 years of age or older) with hemophilia B who have FIX inhibitors and require routine prophylaxis to prevent or reduce the frequency of bleeding episodes. This article summarizes the milestones in the development of concizumab leading to this first approval for the treatment of hemophilia B.


Bladder and cutaneous sensory neurons of the rat express different functional P2X receptors.
The expression and functional responses of P2X receptors in bladder and cutaneous sensory neurons of adult rats and mice have been studied using immunohistochemistry and patch clamp techniques. Cell bodies of bladder pelvic afferents were identified in L6 and S1 dorsal root ganglia (DRG), following Fast Blue injection into the muscle wall of the urinary bladder. Similarly, cutaneous sensory neurons were identified in L3 and L4 DRG, following Fast Blue injection into the saphenous nerve innervating the skin. Bladder sensory neurons contained only weak to moderate P2X(3)-immunoreactivity (IR), in contrast to strong P2X(3)-IR observed in a sub-population of cutaneous afferents. Whole-cell patch-clamp recordings revealed that approximately 90% of bladder afferent neurons responded to alpha beta-methylene ATP (alpha beta meATP) and ATP (30 microM) with persistent currents, which were inhibited by 2',3'-O-trinitrophenyl-ATP (TNP-ATP) (0.3 microM) to 6.4+/-1.9% and 8.0+/-2.6% of control, respectively (n=8). The remaining bladder sensory neurons demonstrated biphasic, transient or no response to P2X agonists. In contrast, only 24% of cutaneous afferent neurons gave persistent currents to alpha beta meATP (30 microM), with 66% of cells giving transient or biphasic currents and the remaining 10% being non-responsive. Our results suggest that, in contrast to DRG neurons in general, bladder sensory neurons projecting via pelvic nerves express predominantly P2X(2/3) heteromeric receptors, which are likely to mediate the important roles of ATP as a signaling molecule of urinary bladder filling and nociception.


Extracellular DNA plays a key role in the structural stability of sulfide-based denitrifying biofilms.
Sulfide-based biofilm processes are increasingly used for wastewater denitrification, yet little is known about the extracellular polymeric substance (EPS) composition of sulfide-oxidizing biofilms. This can have an important impact on biofilm mechanical strength and stability. In this research, the properties and roles of EPS components in biofilm stability were investigated. Weak biofilm stability characterized by high roughness and numerous "needle" structures was visualized by optical coherence tomography (OCT) and microscopy. A high abundance of extracellular DNA (eDNA) and a low protein to polysaccharide ratio were found in the biofilm. The roles of eDNA, protein and polysaccharide in biofilm cohesion and adhesion were identified through enzyme treatment and atomic force microscopy (AFM). The enzymatic hydrolysis of eDNA increased the elastic modulus of biofilms by 57 times and reduced the adhesion energy by 96%. The hydrolysis of proteins led to an increase of elastic modulus by 27 times and a loss of adhesion energy by 95.5%. The enzymatic hydrolysis of polysaccharides caused minimal changes in elastic modulus and adhesion energy. These results suggest that eDNA was the key EPS component for biofilm cohesion and adhesion, possibly because it provided special binding sites and can form strong cross-linking with magnesium or other multivalent cations. This study provided new insights into the role of eDNA in biofilm stability and shed light on the development of sulfide-based denitrifying biofilms.


Genomic signatures reveal selection in Lingxian white goose.
Lingxian white goose (LXW) is a goose breed indigenous to China that is famous for its meat quality and fast growth. However, the genomic evidence underlying such excellent breeding characteristics remains poorly understood. Therefore, we performed whole-genome resequencing of 141 geese from 3 indigenous breeds to scan for selection signatures and detect genomic regions related to breed features of LXW. We identified 5 reproduction-related genes (SYNE1, ESR1, NRIP1, CCDC170, and ARMT1) in highly differentiated regions and 11 notable genes in 26 overlapping windows, some of which are responsible for meat quality (DHX15), growth traits (LDB2, SLIT2, and RBPJ), reproduction (KCNIP4), and unique immunity traits (DHX15 and SLIT2). These findings provide insights into the genetic characteristics of LXW and identify genes affecting important traits in LXW, which extends the genetic resources and basis for facilitating genetic improvement in domestic geese breeds.


Complexity of early and middle successional stages in a rocky intertidal surfgrass community.
A variety of simple models have been proposed to describe ecological succession (e.g., Connell and Slatyer 1977), but these models do not address some agents that may increase complexity. To determine the complexity of a natural sequence, four null hypotheses were tested: (1) seasonality of growth, recruitment, and mortality does not influence succession; (2) the interspecific interactions that produce successional change are the same throughout the sequence; (3) consumers have no influence on succession, and (4) small scale spatial variation in establishment and mortality does not occur. These hypotheses were tested in a low zone rocky intertidal community normally dominated by the surfgrass Phyllospadix scouleri on the Oregon coast.Succession experiments initiated in different seasons and an herbivore exclusion experiment falsified each of these hypotheses. At two sites (Boiler Bay and Squaw Island) experimental plots that were cleared in the spring were first colonized by Ulva sp., but those cleared in other seasons were first colonized by Phaeostrophion irregulare. Ulva appears adapted to colonize space made available by winter storms, whereas Phaeostrophion takes advantage of space made available by sand movement in the fall. Another seasonal pattern was the sharp decline in total algal cover in the fall, when wave action increased. At Squaw Island, the presence of Phaeostrophion established in fall and winter significantly inhibited the summer establishment of Ulva, though Ulva occupied some space epiphytically. In contrast, at Boiler Bay, a different, stronger type of interspecific interaction occurred: Phaeostrophion totally inhibited the establishment of filamentous diatoms. The cover of Ulva in the summer was also influenced by herbivores, but Ulva cover declined in the fall in both herbivore exclusions and controls, suggesting that herbivores were not solely responsible for its replacement. Local variation was demonstrated, because after three years of succession, replicate plots often differed. The early colonists, Phaeostrophion and Ulva, continued to dominate some plots; in other plots they had been replaced by middle successional species, including Cryptosiphonia woodii and Odonthalia floccosa. In still other plots Rhodomela larix had replaced other species. Similarly complex successional sequences occur in many natural communities. Thus, the features that simple models do not address may add complexity to succession, and for some communities different approaches must be developed.


Child sexual abuse in KwaZulu-Natal, South Africa.
This paper discusses child sexual abuse in a hospital serving a largely rural population in Eshowe, KwaZulu-Natal, South Africa during a period of 9 years and 2 months. Child sexual abuse was a significant problem. The incidence of sexually transmitted diseases at presentation was high (65.9%). The abuser, when identified, was more commonly an acquaintance or stranger than a family member. The shortage of resources in 'third world' countries means that medical personnel must take the lead in identifying and managing children with sexual abuse. Frequently they must assume additional roles, such as that of social worker, if management is to be successful. However, high patient case loads in these situations make this difficult and therefore child sexual abuse may not be adequately dealt with. A possible solution to this problem is the use of outside agencies to research the problem and the establishment of regional special units to manage child abuse.


Polymetacrylate and hybrid interparticle monolithic columns for fast separations of proteins by capillary liquid chromatography.
Preparation of organic polymer monolithic columns in fused silica capillaries was aimed at fast gradient separation of proteins. For this purpose, polymerization in situ procedure was optimized, using ethylene dimetacrylate and butyl metacrylate monomers with azobisisobutyronitrile as initiator of the polymerization reaction in presence of non-aqueous porogen solvent mixtures composed of 1-propanol and 1,4-butanediol. The separation of proteins in totally monolithic capillary columns was compared with the chromatography on a new type of "hybrid interparticle monolithic" capillary columns, prepared by in situ polymerization in capillary packed with superficially porous spherical beds, 37-50 microm. The "hybrid" columns showed excellent stability and improved hydrodynamic flow properties with respect to the "totally" monolithic capillary columns. The separation selectivity is similar in the two types of columns. The nature of the superficially porous layer (bare silica or bonded C18 ligands) affects the separation selectivity less significantly than the porosity (density) of the monolithic moiety in the interparticle space, controlled by the composition of the polymerization mixture. The retention behaviour of proteins on all prepared columns is consistent with the reversed-phase gradient elution theory.


Effect of cholesteryl hemisuccinate on the interfacial properties of phosphatidylcholine bilayers.
Cholesteryl hemisuccinate (CHEMS) is an amphipathic lipid that can regulate cell growth. A comparison of the effects of CHEMS and cholesterol on 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) bilayers was investigated using fluorescence techniques. In liquid-crystalline phase POPC bilayers, CHEMS increased the interfacial surface charge, but was less effective than cholesterol in reducing acyl chain mobility and interfacial hydration. In liquid-crystalline phase DPPC bilayers, CHEMS and cholesterol were equally effective in reducing acyl chain mobility. Similar to the POPC matrix, CHEMS increased the interfacial surface charge and cholesterol decreased the surface hydration. The different effect of cholesterol and CHEMS on acyl chain mobility may be due to a preferential interaction of cholesterol with POPC. In gel phase DPPC bilayers, CHEMS and a succinylated pyrenyl cholesterol analog exhibited different effects on membrane physical-chemical properties than cholesterol. Succinylation also increased the rate of transfer of the pyrenyl cholesterol analog between single unilamellar vesicles approximately seven fold. This process demonstrated first-order kinetics which indicated that transbilayer migration was not a rate-limiting step. The succinylation of cholesterol places a carboxyl group at the lipid-water interface and the sterol ring deeper in the bilayer. For a structural model to explain its biological properties, CHEMS should be considered a bulky fatty acid.


In vitro crosslinking of DNA by 8-methoxypsoralen visualized by electron microscopy.
By electron microscopic visualisation of totally denatured DNA, we have detected photochemically induced 8-methoxypsoralen crosslinks in vitro after irradiation at 360 nm. The amount of crosslinks was expressed as the percentage of DNA length which was kept in double-stranded appearance by closely situated crosslinks. This percentage correlated well with irradiation time, irradiation intensity, and the concentration of 8-methoxypsoralen. These parameters have also been correlated with the mean size and the size distribution of non-crosslinked regions of DNA, so called bubbles. For a comparison with another psoralen type, we have carried out a similar set of experiments using 4,5,8-trimethylpsoralen.


Ferritin accumulation and uroporphyrin crystal formation in hepatocytes of C57BL/10 mice: a time-course study.
To establish the time-sequence relationship between ferritin accumulation and uroporphyrin crystal formation in livers of C57BL/10 mice, a biochemical, morphological and morphometrical study was performed. Uroporphyria was induced by the intraperitoneal administration of hexachlorobenzene plus iron dextran and of iron dextran alone. Uroporphyrin crystal formation started in hepatocytes of mice treated with hexachlorobenzene plus iron dextran at 2 weeks and in mice treated with iron dextran alone a 9 weeks. In the course of time, uroporphyrin crystals gradually increased in size. Uroporphyrin crystals were initially formed in hepatocytes in the periportal areas of the liver, in which also ferric iron staining was first detected. The amount and the distribution of the main storage form of iron in hepatocytes, ferritin, did not differ between the two treatment groups. Ferritin accumulation preceded the formation of uroporphyrin crystals in hepatocytes in both treatment groups. Moreover, uroporphyrin crystals were nearly always found close to ferritin iron. We conclude that uroporphyrin crystals are only formed in hepatocytes in which also iron (ferritin) accumulates. Hexachlorobenzene accelerates the effects of iron in porphyrin metabolism, but does not influence the accumulation of iron into the liver.


Bridging Social Capital and Individual Earnings: Evidence for an Inverted U.
Based on data on a cross section of individuals surveyed in the 1999-2002 wave of World and European Values Surveys, we investigate the multilateral associations between bridging social capital, individuals' earnings, as well as social trust and employment status. Our analysis provides robust evidence that the relationship between bridging social capital and earnings is inverted-U shaped. We carry out a range of tests in order to ascertain that this result is not driven by regressor endogeneity or omitted variables bias. We also identify significant interaction effects between bridging social capital, social trust, and employment status.


A facile one-carbon homologation of aryl aldehydes to amides.
The easily accessible 2-aryl-1,1-dibromo-1-alkenes can be converted to amides under unusually mild conditions in good to excellent yields. Both electron-donating and electron-withdrawing substitutions on the aromatic rings are tolerated, and the reaction works well with hindered alkylamines. This simple homologation could find broad applications. [reaction: see text]


Beyond mental health: an evolutionary analysis of development under risky and supportive environmental conditions: an introduction to the special section.
Evolutionary approaches to behavior have increasingly captured the attention and imagination of academics and laypeople alike. One part of this trend has been the increasing influence of evolutionary theory in developmental science. The articles in this special section of Developmental Psychology attempt to demonstrate why an evolutionary analysis is needed to more fully understand the contexts and contingencies of development. The 3 theoretical articles articulate the core evolutionary logic underlying conditional adaptation (and maladaptation) to both stressful and supportive environmental conditions over development. These theoretical articles are then followed by 9 empirical articles that test these evolutionary-developmental theories and hypotheses. Finally, 6 commentaries evaluate the prospects, pitfalls, and implications of this body of work.


Pro-fibrogenic role of alarmin high mobility group box 1 in HIV-hepatitis B virus coinfection.
Liver disease is accelerated in people with HIV (PWH) with hepatitis B virus (HBV) coinfection. We hypothesized that liver fibrosis in HIV-HBV is triggered by increased hepatocyte apoptosis, microbial translocation and/or HIV/HBV viral products. Sera from PWH with HBV coinfection versus from those with HBV only or putative mediators were used to examine the pathogenesis of liver disease in HIV-HBV. We applied sera from PWH and HBV coinfection versus HBV alone, or putative mediators (including HMGB1), to primary human hepatic stellate cells (hHSC) and examined pro-fibrogenic changes at the single cell level using flow cytometry. High mobility group box 1 (HMGB1) levels in the applied sera were assessed according to donor fibrosis stage. Quantitative flow cytometric assessment of pro-fibrogenic and inflammatory changes at the single cell level revealed an enhanced capacity for sera from PWH with HBV coinfection to activate hHSC. This effect was recapitulated by lipopolysaccharide, HIV-gp120, hepatocyte conditioned-media and the alarmin HMGB1. Induction of hepatocyte cell death increased their pro-fibrogenic potential, an effect blocked by HMGB1 antagonist glycyrrhizic acid. Consistent with a role for this alarmin, HMGB1 levels were elevated in sera from PWH and hepatitis B coinfection compared to HBV alone and higher in those with HIV-HBV with liver fibrosis compared to those without. Sera from PWH and HBV coinfection have an enhanced capacity to activate primary hHSC. We identified an increase in circulating HMGB1 which, in addition to HIV-gp120 and translocated microbial products, drove pro-fibrogenic changes in hHSC, as mechanisms contributing to accelerated liver disease in HIV-HBV.


Induction of peripheral CD8+ T-cell tolerance by cross-presentation of self antigens.
There is now convincing evidence that CD8+ T cells can be activated by professional antigen-presenting cells which present antigens derived from non-lymphoid tissues in association with MHC class I molecules in the draining lymph nodes. This mechanism, referred to as cross-presentation, enables the immune system to respond to those microorganisms that infect only non-lymphoid tissues. Consistent with this view, cross-presentation was found to focus on antigens expressed in high concentrations and those released from dying cells, which can be expected to result from viral infections. Recent evidence, however, demonstrates that high dose self antigens can be cross-presented constitutively, resulting in the activation of autoreactive CD8+ T cells. This does not lead to auto immunity under physiologic conditions, but to CD95-mediated deletion of the T cells. Cross-presentation can thus engage a well-defined pathway of antigen-induced T-cell death and purge the immune system of autoreactive CD8+ T cells. Low dose self antigens are not cross-presented and are consequently ignored. The immune system therefore uses two strategies to avoid CD8+ T-cell-mediated autoimmunity in the periphery: deletion of autoreactive CD8+ T cells responding to high dose self antigens and ignorance of self antigens expressed at low concentrations.


The clinical challenges of synthetic cathinones.
Within the new psychoactive substances (NPS) scenario, several hundred different molecules, mostly including synthetic cannabinoids and cathinones, have been identified so far. The aims of the paper were to: (i) identify the number of synthetic cathinones mentioned in a range of psychonaut, NPS-related, online sources; and (ii) describe the associated acute/long term clinical scenario and the related treatment/management plan. After about 18 months of operation and exclusion of false positives/duplicates, some 4204 unique NPS molecules were included in the NPSfinder® crawling/navigating software database. Most popular NPS included: 1265 psychedelic phenethylamines (30.1%; confidence interval [CI] 95%: 28.7-31.5%); 1253 synthetic cannabinoids (29.8%; CI 95%: 28.4-31.2%); 429 synthetic opioids (10.2%; CI 95%: 9.3-10.2%); and 171 synthetic cathinones (4.1%; CI 95% 3.5-4.7%). Conversely, the United Nations Office on Drugs and Crime and the European Monitoring Centre for Drugs and Drug Addiction databases respectively included 169 and 140 cathinones. Overall, the 3 databases reported some 222 synthetic cathinones, and 41 were uniquely identified by the NPSfinder®. In terms of clinical scenarios, synthetic cathinone ingestion is initially associated with stimulant effects; however, psychopathological disturbances, violence, suicidal behaviour, hyperthermia, coma and death have also been described. The proportion of cathinones commented on by psychonaut fora appeared to be relatively small, and similar to those reported by both the United Nations Office on Drugs and Crime and European Monitoring Centre for Drugs and Drug Addiction. This may be associated with a recent significant decline in both cathinone-related consumption and acute medical presentation. Due to their complex behavioural and medical toxicity issues, healthcare professionals should be, however, be educated to recognise the signs and symptoms of NPS, including synthetic cathinone, ingestion.


Counseling patients to quit smoking. What to say, when to say it, and how to use your time to advantage.
Helping patients stop smoking is one of the most important--and frustrating--services primary care physicians can provide. Many physicians are reluctant to spend time talking about tobacco use with patients who show little or no interest in changing their habits. Fortunately, specific technique have been identified that can make the task easier. This article from the distinguished Nicotine Dependence Center of the Mayo Clinic looks at the "best practices" for dealing with nicotine dependence.


A stepwise strategy for coronary risk assessment for noncardiac surgery.
Physicians should adapt a systematic approach to cardiac risk stratification for patients being considered for noncardiac surgery, involving clinical evaluation, functional assessment, and surgical risk assessment for all patients and then deciding which patient needs to undergo noninvasive testing, coronary angiography and revascularization, perioperative monitoring, and aggressive postoperative care.


Multicenter Next-Generation Sequencing Studies between Theory and Practice: Harmonization of Data Analysis Using Real-World Myelodysplastic Syndrome Data.
In the age of personalized medicine, genetic testing by means of targeted sequencing has taken a key role. However, when comparing different sets of targeted sequencing data, these are often characterized by a considerable lack of harmonization. Laboratories follow their own best practices, analyzing their own target regions. The question on how to best integrate data from different sites remains unanswered. Studying the example of myelodysplastic syndrome (MDS), we analyzed 11 targeted sequencing sets, collected from six different centers (n = 831). An intersecting target region of 43,076 bp (30 genes) was identified; whereas, the original target regions covered up to 499,097 bp (117 genes). Considering a region of interest in the context of MDS, a target region of 55,969 bp (31 genes) was identified. For each gene, coverage and sequencing data quality was evaluated, calculating a sequencing score. Analyses revealed huge differences between different data sets as well as between different genes. Analysis of the relation between sequencing score and mutation frequency in MDS revealed that most genes with high frequency in MDS could be sequenced without expecting low coverage or quality. Still, no gene appeared consistently unproblematic for all data sets. To allow for comparable results in a multicenter setting analyzing MDS, we propose to use a predefined target region of interest and to perform centralized data analysis using harmonized criteria.


Association of Albuminuria With Intraglomerular Hydrostatic Pressure and Insulin Resistance in Subjects With Impaired Fasting Glucose and/or Impaired Glucose Tolerance.
Little is known about the relationships between insulin resistance, intrarenal hemodynamics, and urinary albumin excretion (UAE) in humans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). The aim of the current study was to examine intrarenal hemodynamic abnormalities, insulin resistance, and UAE in subjects with IFG or IGT. We hypothesized that intrarenal hemodynamic abnormalities would be associated with insulin resistance. Fifty-four kidney donors underwent 75-g oral glucose tolerance and inulin and para-aminohippuric acid clearance testing. Insulin sensitivity index (ISI) was evaluated by the Matsuda index. Intrarenal hemodynamic parameters were calculated by the Gomez formulae. Of the 54 subjects, 33 exhibited IFG or IGT and 31 exhibited normal glucose tolerance (NGT). Glomerular hydrostatic pressure (Pglo) and UAE were significantly higher in the IFG or IGT subjects with obesity (P = 0.015 and 0.0001, respectively). Log ISI correlated significantly and negatively with Pglo (r = -0.351, P = 0.009) in all subjects. In multiple regression analyses among all subjects, log ISI was associated significantly and independently with Pglo (β = -0.316, P = 0.015), after adjustment for age, sex, and systolic blood pressure. Further, BMI (β = 0.517, P = 0.0004), Pglo (β = 0.420, P = 0.004), and log ISI (β = -0.366, P = 0.008) were each associated significantly and independently with UAE after adjustment. We demonstrated that increased insulin resistance is associated with increased Pglo and UAE in IFG or IGT subjects. These hemodynamic burdens and insulin resistance may cause injury to the glomeruli even in subjects with IFG or IGT.


Growth of postnatal rat retina in vitro. Development of neurotransmitter systems.
In this study, we demonstrate that explanted neonatal rat retina can be maintained in culture for periods up to 3 weeks. The cultured retinas displayed a distinct layering that was almost identical to litter-matched retinas of the same age, but the majority of the ganglion cells did not survive and photoreceptor outer segments did not develop properly. Distinct synaptophysin immunoreactivity was expressed in both the inner and outer plexiform layers of cultured retina and the pattern mimicked that one observed in vivo. After 2-3 weeks in vitro, the inner retina expressed immunoreactivities to various components of the cholinergic and nitrergic transmitter systems, including nitric oxide activated cyclic GMP immunoreactivity. The investigated cell populations displayed similar distribution patterns as in situ, but morphological differences appeared in vitro. Such differences were mainly observed as irregularities in the arborization patterns in the inner part of the inner plexiform layer. We suggest that these discrepancies may arise as a result of reduced ganglion cell survival. Our observations demonstrate that some neurotransmitter systems develop in vitro and their neural circuitry appears similar to the in vivo situation. The presence of synapses, receptor proteins and transmitter substances implies that neural communication can occur in cultured retinas.


Pinning synchronization control for stochastic multi-layer networks with coupling disturbance.
The pinning synchronization scheme is investigated for stochastic multi-layer networks under the intra-layer coupling disturbance and stochastic noise. To save the control cost, a pinning control scheme is proposed. And some sufficient conditions in the form of the LMI are given, based on Lyapunov theory and stochastic analysis, to make sure that the multi-layer networks synchronize to a desired trajectory. Next, the selection scheme of pinned nodes is designed according to the structure of considered multi-layer networks. Finally, simulation examples are shown to illustrate the feasibility and availability of the designed pinning scheme.


Evidence that high mobility group protein 17 is not phosphorylated in human colon carcinoma cells.
The high mobility group proteins 14 and 17 were reported previously to be phosphorylated in murine and human tumor cell lines. Recently, it was suggested that subgroups of HMG-14, HMG-14a and 14b, but not HMG-17, were phosphorylated in situ in HeLa cells. In order to definitively determine whether HMG-17 is indeed phosphorylated or whether the protein previously identified as [32P]HMG-17 was a subgroup of HMG-14, we have used the technique of electroblotting in conjunction with an immunochemical procedure utilizing anti-HMG-17 IgG. Our results indicate that HMG-17 was not phosphorylated in human colon carcinoma cell line HT-29 incubated for 18 h with 32Pi, but that HMG-14a and HMG-14b were phosphorylated. In contrast, HMG-14a, -14b and -17 were phosphorylated in vitro in isolated nuclei incubated with [gamma-32P]ATP.


Simulated microgravity induces microvolt T wave alternans.
There are numerous anecdotal reports of ventricular arrhythmias during spaceflight; however, it is not known whether spaceflight or microgravity systematically increases the risk of cardiac dysrhythmias. Microvolt T wave alternans (MTWA) testing compares favorably with other noninvasive risk stratifiers and invasive electrophysiological testing in patients as a predictor of sudden cardiac death, ventricular tachycardia, and ventricular fibrillation. We hypothesized that simulated microgravity leads to an increase in MTWA. Twenty-four healthy male subjects underwent 9 to 16 days of head-down tilt bed rest (HDTB). MTWA was measured before and after the bed rest period during bicycle exercise stress. For the purposes of this study, we defined MTWA outcome to be positive if sustained MTWA was present with an onset heart rate<or=125 bpm. During various phases of HDTB, the following were also performed: daily 24-hour urine collections, serum electrolytes and catecholamines, and cardiovascular system identification (measure of autonomic function). Before HDTB, 17% of the subjects were MTWA positive [95%CI: (0.6%, 37%)]; after HDTB, 42% of the subjects were MTWA positive [95%CI: (23%, 63%)] (P=0.03). The subjects who were MTWA positive after HDTB compared with MTWA negative subjects had an increased versus decreased sympathetic responsiveness (P=0.03) and serum norepinephrine levels (P=0.05), and a trend toward higher potassium excretion (P=0.06) after bed rest compared to baseline. HDTB leads to an increase in MTWA, providing the first evidence that simulated microgravity has a measurable effect on electrical repolarization processes. Possible contributing factors include loss in potassium and changes in sympathetic function.


Cholera toxin augments the release of endothelium-derived relaxing factor evoked by bradykinin and the calcium ionophore A23187.
1. Experiments were designed to examine the effect of cholera toxin and forskolin on the release of relaxing factor(s) from superfused cultured endothelial cells under basal conditions and upon stimulation with bradykinin, adenosine diphosphate or the calcium ionophore A23187. 2. Exposure of cultured porcine aortic endothelial cells to cholera toxin (30 micrograms/ml, for 3 hr) and forskolin (10(-6) M, for 45 min) significantly increased the intracellular content in cyclic AMP. Cholera toxin but not forskolin stimulated the accumulation of cyclic GMP. 3. Exposure to cholera toxin did not modify the basal release of endothelium-derived relaxing factor nor that induced by adenosine diphosphate, but significantly increased that evoked by bradykinin and the calcium ionophore A23187. Forskolin did not significantly affect the basal or the stimulated release of endothelium-derived relaxing factor. 4. These results suggest that cholera toxin potentiates the release of endothelium-derived relaxing factor (presumably nitric oxide) from endothelial cells by a mechanism other than augmented production of cyclic AMP.


Botanical from the medicinal spice, Piper capense is safe as demonstrated by oral acute and subchronic toxicity investigations.
Piper capense Linn is a plant used in Cameroon to treat cancer and several other diseases such as urinary tract disorder, fever, stomach-ache and to improve appetite. The methanol extract of Piper capense has been reported for its antiproliferative activity towards several human cancer cell lines. The aim of this work was to evaluate the acute and subchronic oral toxicities of a methanol extract from P. capense fruits on rats. The acute oral toxicity assay was carried out by administration of a single dose of 5000 mg/kg body weight of methanol extract of the Piper capense to five female rats, after which the behavior of the animals and the number of deaths were noted after 48 h. The animals were then kept for observation for 14 days. On the 15th day, the rats were sacrificed and macroscopic observation of the organs was made. Concerning the subchronic toxicity study, the rats composed of males and females received three doses (250, 500 and 1000 mg/kg body weight/day) for a period of 28 days by oral gavage. General animal behavior, food intake, weight gain, organ weights, haematological parameters, serum, and urinary biochemical parameters, and histological sections of liver and kidneys, were evaluated. Methanol extract from the Piper capense fruits did not cause any death in rats that were administered a single dose of 5000 mg/kg body weight of extract and therefore, the letal dose 50 (LD50) of the extract is greater than 5000 mg/kg body weight. Subchronic administration of the methanol extract of Piper capense fruits showed significant variations (P > 0.05) after analysis of certain biochemical parameters: serum urea, urinary urea, alanine aminotransferase (ALAT), aspartate aminotransferase, (ASAT), serum protein; in both male and female rats that received the dose of 1000 mg/kg body weight/day. No major signs of toxicity were observed in the liver and kidneys of animals after analysis of the histological sections performed. Beside, some signs of toxicity were observed, including cell lysis and inflammation on the liver and kidney organs at a dose of 1000 mg/kg body weight/day. Finally, the methanol extract of Piper capense fruits is safe at lower doses, but could cause some damages at doses as high as 1000 mg/kg body weight/day. Consequently, it should be taken with caution when used in therapy.


Butanol and hexanol production in Clostridium carboxidivorans syngas fermentation: Medium development and culture techniques.
Clostridium carboxidivorans was grown on model syngas (CO:H2:CO2 [70:20:10]) in a defined nutrient medium with concentrations of nitrogen, phosphate and trace metals formulated to enhance production of higher alcohols. C. carboxidivorans was successfully grown in a limited defined medium (no yeast extract, no MES buffer and minimal complex chemical inputs) using an improved fermentation protocol. Low partial pressure of CO in the headspace, coupled with restricted mass transfer for CO and H2, was required for successful fermentation. In the absence of substrate inhibition (particularly from CO), growth limitation increased production of alcohols, especially butanol and hexanol. Concentrations of butanol (over 1.0g/L), hexanol (up to 1.0g/L) and ethanol (over 3.0g/L) were achieved in bottle fermentations. Minimal medium and controlled supply of CO and H2 should be used in characterizing candidate butanol and hexanol producing strains to select for commercial potential.


Wideband reflectance measurements in newborns: Relationship to otoscopic findings.
Newborn hearing screening includes testing with otoacoustic emissions and the auditory brainstem response. Unfortunately, both tests are affected by the presence of material in the ear canal and middle ear such as vernix, meconium, and amniotic fluid. The objective of this study was to determine to what extent occlusion of the ear canal as seen on otoscopy affects wideband energy reflectance measurements in newborns. A secondary objective was to obtain additional normative wideband reflectance data in newborns. Newborns from a well-baby nursery were enrolled. Wideband energy reflectance measurements and otoscopy were done immediately after the hearing screening. Occlusion of the ear canal as seen on otoscopy was described on a scale of 0-100%. A total of 156 babies were enrolled (mean age = 25 hours). A statistically significant difference in the reflectance at ambient pressure was found between the 0-70% and 80-100% occlusion groups. There was no significant difference in reflectance between the right and the left ears. The median reflectance pattern generally followed that of previous studies but in certain frequency regions the present reflectance values were higher. A significant increase in reflectance occurs when 70%-80% of the ear-canal diameter is occluded. Taking otoscopy findings into account may improve the interpretation of reflectance measurements. However, further studies are required to better establish the relationship between canal occlusion and reflectance.


New capabilities in determining the binding parameters for ligand-receptor interaction.
A new method for determining the binding parameters of ligand-receptor interaction is suggested. The method is based on the application of the so-called coordinate of dilution, suggested by us earlier. We demonstrated that it is possible to determine the binding characteristics of ligand-receptor interaction using either the measurement of the concentration of the ligand-receptor complex at a state of equilibrium or the concentration of free receptors at different dilutions of the studying ligand-receptor mixture. The method also allows the determination of the concentration of the ligand in a pre-existing ligand-receptor mixture without preliminary separation of the interacting counterparts. For this reason the suggested method could be especially useful when the studying very labile receptors for which purification from the corresponding ligand is very difficult or impossible.


[Tapering and termination of immunosuppressive treatment in spondyloarthritides (including psoriatic arthritis)].
Immunomodulatory long-term treatment has also become the standard treatment for spondyloarthritides (SpA), including psoriatic arthritis (PsA); however, uncertainty exists about dose reduction or termination of treatment after remission or low disease activity. When is it possible to reduce medication or terminate treatment for SpA? An extensive non-systematic literature search was performed focusing on practice guidelines, systematic meta-analyses and clinical trials on medicinal long-term treatment and voluntary medication reduction in axial and peripheral SpA, including PsA. The chances of drug-free remission after treatment with biologics for axial SpA and in PsA are low; however, in remission or a state of low disease activity reduction of the cumulative dosage of biologics can be successful in 53-100% of cases without a significant increase in disease activity. The current state and duration of remission, with or without comedication with nonsteroidal anti-inflammatory drugs (NSAID), extra-articular disease manifestations and the results of previous treatment attempts have to be carefully taken into consideration before elective dose reduction. Reduction of long-term treatment is an individualized decision made jointly by patients and physicians. The risk of flares and especially of extra-articular disease manifestations needs to be weighed against the possible advantages of reduced medication. Maintainenance of mediction-free disease remission is too rare in SpA or PsA patients carefully selected for biologics treatment, to allow a later voluntary termination of therapy, without at least a prior cautious attempt at dose reduction.


Thiopyronine and 8-methoxypsoralen sensitized photodynamic effect on DNA synthesis in yeast.
The synthesis of DNA in growing yeast cells was investigated after photodynamic treatment of the cells with thiopyronine (TP) and visible light or with 8-methoxypsoralen (8-MOP) and UVA light. DNA synthesis was inhibited after photodynamic treatment with 8-MOP but not after photodynamic treatment with TP. This result is further evidence that the photodynamic effect with TP does not attack nuclear DNA in eucaryotic cells.


Discovery of flat seismic reflections in the mantle beneath the young Juan de Fuca Plate.
Crustal properties of young oceanic lithosphere have been examined extensively, but the nature of the mantle lithosphere underneath remains elusive. Using a novel wide-angle seismic imaging technique, here we show the presence of two sub-horizontal reflections at ∼11 and ∼14.5 km below the seafloor over the 0.51-2.67 Ma old Juan de Fuca Plate. We find that the observed reflectors originate from 300-600-m-thick layers, with an ∼7-8% drop in P-wave velocity. They could be explained either by the presence of partially molten sills or frozen gabbroic sills. If partially molten, the shallower sill would define the base of a thin lithosphere with the constant thickness (11 km), requiring the presence of a mantle thermal anomaly extending up to 2.67 Ma. In contrast, if these reflections were frozen melt sills, they would imply the presence of thick young oceanic lithosphere (20-25 km), and extremely heterogeneous upper mantle.


Age- and sex-specific effects of stress on parvalbumin interneurons in preclinical models: Relevance to sex differences in clinical neuropsychiatric and neurodevelopmental disorders.
Stress is a major risk factor for neurodevelopmental and neuropsychiatric disorders, with the capacity to impact susceptibility to disease as well as long-term neurobiological and behavioral outcomes. Parvalbumin (PV) interneurons, the most prominent subtype of GABAergic interneurons in the cortex, are uniquely responsive to stress due to their protracted development throughout the highly plastic neonatal period and into puberty and adolescence. Additionally, PV + interneurons appear to respond to stress in a sex-specific manner. This review aims to discuss existing preclinical studies that support our overall hypothesis that the sex-and age-specific impacts of stress on PV + interneurons contribute to differences in individual vulnerability to stress across the lifespan, particularly in regard to sex differences in the diagnostic rate of neurodevelopmental and neuropsychiatric diseases in clinical populations. We also emphasize the importance of studying sex as a biological variable to fully understand the mechanistic and behavioral differences between males and females in models of neuropsychiatric disease.


Glutamate decarboxylase immunoreactivity in the rat interpeduncular nucleus: a light and electron microscope investigation.
The distribution of immunohistochemically demonstrable glutamate decarboxylase, the synthetic enzyme for GABA, was examined in the rat interpeduncular nucleus at the light and electron microscope levels. Immunoreactive perikarya were distributed in a characteristic pattern among the subnuclear divisions. The rostral, ventral and caudal portions of the nucleus possessed numerous immunoreactive perikarya, while few immunoreactive somata were observed in the subnuclei of the dorsal aspect. A dense field of immunostained axons and terminals was also present throughout. Ultrastructural examination of glutamate decarboxylase immunoreactivity revealed numerous labelled somata, dendritic processes, axons and boutons. Axodendritic and axosomatic synapses with immunoreactive postsynaptic profiles were numerous throughout those subnuclei with large numbers of immunoreactive somata. Immunostained terminals in contact with both immunoreactive and non-immunoreactive somatic and dendritic profiles were also present. An abundance of immunostained terminals was observed in the subnuclei that possessed a sparse population of immunoreactive somata. Immunoreactive myelinated axons of unknown origin were also present. This investigation demonstrates that the rat interpeduncular nucleus possesses a large population of glutamate decarboxylase-immunoreactive neurons coextensive with a plexus of immunostained axons and terminals. The results suggest that the immunoreactive neurons give rise to axons which contribute to an intrinsic circuit interconnecting the different subnuclear divisions. These immunoreactive neurons are in receipt of non-immunoreactive afferent inputs of variable morphology, as well as projections from intrinsic immunoreactive neurons.


Association of an Active Choice Intervention in the Electronic Health Record Directed to Medical Assistants With Clinician Ordering and Patient Completion of Breast and Colorectal Cancer Screening Tests.
Early cancer detection can lead to improved outcomes, but cancer screening tests are often underused. To evaluate the association of an active choice intervention in the electronic health record directed to medical assistants with changes in clinician ordering and patient completion of breast and colorectal cancer screening tests. A retrospective quality improvement study was conducted among 69 916 patients eligible for breast or colorectal cancer screening at 25 primary care practices at the University of Pennsylvania Health System between September 1, 2014, and August 31, 2017. Data analysis was conducted from January 21 to July 8, 2019. From 2016 to 2017, 3 primary care practices at the University of Pennsylvania Health System implemented an active choice intervention in the electronic health record that prompted medical assistants to inform patients about cancer screening during check-in and template orders for clinicians to review during the visit. The primary outcome was clinician ordering of cancer screening tests. The secondary outcome was patient completion of cancer screening tests within 1 year of the primary care visit. The sample eligible for breast cancer screening comprised 26 269 women with a mean (SD) age of 60.4 (6.9) years; 15 873 (60.4%) were white and 7715 (29.4%) were black. The sample eligible for colorectal cancer screening comprised 43 647 patients with a mean (SD) age of 59.4 (7.5) years; 24 416 (55.9%) were women, 19 231 (44.1%) were men, 29 029 (66.5%) were white, and 9589 (22.0%) were black. For breast cancer screening, the intervention was associated with a significant increase in clinician ordering of tests (22.2 percentage points; 95% CI, 17.2-27.6 percentage points; P < .001) but no change in patient completion (0.1 percentage points; 95% CI, -4.0 to 4.3 percentage points; P = .45). For colorectal cancer screening, the intervention was associated with a significant increase in clinician ordering of tests (13.7 percentage points; 95% CI, 8.0-18.9 percentage points; P < .001) but no change in patient completion (1.0 percentage points; 95% CI, -3.2 to 4.6 percentage points; P = .36). An active choice intervention in the electronic health record directed to medical assistants was associated with a significant increase in clinician ordering of breast and colorectal cancer screening tests. However, it was not associated with a significant change in patient completion of either cancer screening test during a 1-year follow-up.


A Golgi-resident GPR108 cooperates with E3 ubiquitin ligase Smurf1 to suppress antiviral innate immunity.
The regulation of antiviral immunity is crucial in maintaining host immune homeostasis, a process that involves dynamic modulations of host organelles. The Golgi apparatus is increasingly perceived as a host organelle functioning as a critical platform for innate immunity, but the detailed mechanism by which it regulates antiviral immunity remains elusive. Here, we identify the Golgi-localized G protein-coupled receptor 108 (GPR108) as a regulator of type Ι interferon responses by targeting interferon regulatory factor 3 (IRF3). Mechanistically, GPR108 enhances the ubiquitin ligase Smad ubiquitylation regulatory factor 1 (Smurf1)-mediated K63-linked polyubiquitination of phosphorylated IRF3 for nuclear dot 10 protein 52 (NDP52)-dependent autophagic degradation, leading to suppression of antiviral immune responses against DNA or RNA viruses. Taken together, our study provides insight into the crosstalk between the Golgi apparatus and antiviral immunity via a dynamic and spatiotemporal regulation of GPR108-Smurf1 axis, thereby indicating a potential target for treating viral infection.


The establishment, growth, phenology and longevity of two species of Helianthemum in the Negev Desert Highlands, Israel.
The hills of the Negev highlands, west of Sede Boqer, are typically covered by various half-shrub communities, including the deciduous species of Helianthemum vesicarium Boiss., an Irano-Turanian element that grows only on north facing slopes, and H. ventosum Boiss., a Saharo-Arabian element which grows on both slopes but mainly on those facing south. Upon irrigation, plants of H. vesicarium preserve their natural rhythm of activity during winter and remain deciduous throughout the summer. On the other hand, under a similar irrigation treatment, the growth and flowering season of H. ventosum is modified and is extended well into the summer. Thus, H. ventosum shows a high phenological plasticity, while H. vesicarium seems to be very conservative. The different response of the two species to an improved water regime may partly explain the differences in their natural habitats: H. vesicarium on the more humid north facing slopes and H. ventosum mostly on the more arid and extreme south facing ones. Plants of both species which grow near boulders attain larger sizes and denser stands than those on the slopes.Age analysis based on xylem ring counts of 859 plants of the two natural populations showed that the plants did not exceed 14 years and most of them reached the age of some 5 years only. In general more seedlings are established during rainy year-clusters than during dry ones. However, no direct correlation between seedling establishment and the annual rainfall of specific years could be found.The rapid turnover of plants in the stands of both species of Helianthemum resembles the behavior of desert annuals rather than that of most desert shrubs.


Environmental factors contributing to negative symptoms in youth at clinical high risk for psychosis and outpatients with schizophrenia.
A bioecosystem theory was recently proposed positing that negative symptoms of schizophrenia (SZ) are influenced by environmental factors. These environmental processes reflect sources of resource deprivation that manifest across multiple systems that impact individuals directly through microsystems and indirectly through the exosystem and macrosystem. As an initial test of this theory, the current study examined whether self-reported environmental resource deprivation was associated with anhedonia, avolition, and asociality. Two samples were collected: (1) outpatients with schizophrenia or schizoaffective disorder (SZ: n = 38) and matched psychiatrically heathy controls (CN: n = 31); (2) youth at clinical high risk for psychosis (CHR: n = 34) and matched CN (n = 30). Measures of negative symptoms and environmental factors influencing the frequency of recreational, goal-directed, and social activities were collected. Negative symptoms were associated with environmental deprivation factors in the microsystem (number of social and activity settings) and exosystem (economy, mass media, politics/laws, neighborhood crime). These associations did not appear due to depression and were greater among those with SZ than CHR. These findings provide preliminary support for the bioecosystem theory and highlight an under-recognized role for environmental factors underlying negative symptoms across phases of psychotic illness. Environmental systems-focused treatment approaches may offer a novel means of treating negative symptoms, which could be promising when coupled with person-level pharmacological and psychosocial treatments.


Neurodevelopmental outcomes of preterm infants after randomisation to initial resuscitation with lower (FiO2 <0.3) or higher (FiO2 >0.6) initial oxygen levels. An individual patient meta-analysis.
To determine the effects of lower (≤0.3) versus higher (≥0.6) initial fractional inspired oxygen (FiO2) for resuscitation on death and/or neurodevelopmental impairment (NDI) in infants <32 weeks' gestation. Meta-analysis of individual patient data from three randomised controlled trials. Neonatal intensive care units. 543 children <32 weeks' gestation. Randomisation at birth to resuscitation with lower (≤0.3) or higher (≥0.6) initial FiO2. Primary: death and/or NDI at 2 years of age.Secondary: post-hoc non-randomised observational analysis of death/NDI according to 5-minute oxygen saturation (SpO2) below or at/above 80%. By 2 years of age, 46 of 543 (10%) children had died. Of the 497 survivors, 84 (17%) were lost to follow-up. Bayley Scale of Infant Development (third edition) assessments were conducted on 377 children. Initial FiO2 was not associated with difference in death and/or disability (difference (95% CI) -0.2%, -7% to 7%, p=0.96) or with cognitive scores <85 (2%, -5% to 9%, p=0.5). Five-minute SpO2 >80% was associated with decreased disability/death (14%, 7% to 21%) and cognitive scores >85 (10%, 3% to 18%, p=0.01). Multinomial regression analysis noted decreased death with 5-minute SpO2 ≥80% (odds (95% CI) 09.62, 0.98 to 0.96) and gestation (0.52, 0.41 to 0.65), relative to children without death or NDI. Initial FiO2 was not associated with difference in risk of disability/death at 2 years in infants <32 weeks' gestation but CIs were wide. Substantial benefit or harm cannot be excluded. Larger randomised studies accounting for patient differences, for example, gestation and gender are urgently needed.


Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy.
To characterize microaneurysms in diabetic retinopathy (DR) depicted by spectral-domain optical coherence tomography (SD-OCT). Retrospective, observational case series. We surveyed a consecutive series of 76 eyes from 60 patients with DR (22 mild nonproliferative diabetic retinopathy [NPDR]; 43 moderate NPDR; 9 severe NPDR; 2 proliferative diabetic retinopathy [PDR]) who underwent Spectralis OCT, fluorescein angiography (FA), and color fundus photography on the same day. The microaneurysms on OCT were oval and well demarcated at the points where those on color fundus photographs and FA were delineated. The characteristics of microaneurysms were evaluated. Based on the status of the capsular structure shown in the sectional images of OCT (called ring sign), we classified 147 microaneurysms depicted by all of SD-OCT, FA, and color fundus photographs in 76 eyes: 28 with complete ring sign, 54 with incomplete one, and 65 with no structure. Microaneurysms with no ring sign had hyperreflective spots in the lumen and were accompanied by nearby cystoid spaces more frequently than other types (P = .033 and P = .007). Thirteen of 75 microaneurysms with nearby cystoid spaces protruded into the cystoid spaces, and 11 of those 13 microaneurysms presented with no ring sign. Microaneurysms resided mainly in the inner nuclear layer (INL) (80.3%), and 65 of such microaneurysms (55.1%) were accompanied by nearby cystoid spaces. SD-OCT delineated the capsular structure, hyperreflective spots, and location of microaneurysms, and microaneurysms with the ring sign were positively correlated with nearby cystoid spaces and protrusion into the cystoid spaces.


TB Treatment Delays in Odisha, India: Is It Expected Even after These Many Years of RNTCP Implementation?
In India, the Revised National TB Control Programme (RNTCP) envisages initiation of TB treatment within seven days of diagnosis among smear-positive patients. After nearly two decades of RNTCP implementation, treatment delays are usually not expected. To determine the proportion of sputum smear-positive TB patients who were initiated on treatment after seven days and their associated risk factors. The study was conducted in Cuttack and Rayagada districts of Odisha. It was a retrospective cohort study that involves review of TB treatment registers and laboratory registers for 2013. Among 1,800 pulmonary TB (PTB) patients, 1,074 (60%) had been initiated on treatment within seven days of diagnosis, 721 (40%) had been initiated on treatment more than seven days, and 354 (20%) had delays of more than 15 days. The mean duration between TB diagnosis and treatment initiation was 21 days with a range of 8-207 days (median = 14 days). Odds of treatment delay of more than seven days were 4.9 times (95% confidence interval [CI] 3.3-6.6) among those who had been previously treated, 6.2 times (95% CI 1.3-29.7) among those infected with HIV, and 1.8 times (95% CI 1.1-2.9) among those diagnosed outside district DMC. Delay in initiation of TB treatment occurred in majority of the smear-positive patients. The RNTCP should focus on core areas of providing quality TB services with time-tested strategies. To have real-time monitoring mechanisms for diagnosed smear-positive TB patients is expected to be the way forward.


Simultaneous up-regulation of neurofilament proteins during the postnatal development of the rat nervous system.
The expression of neurofilament (NF) proteins was examined during postnatal development of the rat nervous system in order to elucidate the nature of NF expression during the period of transition from the embryonic (immature) to the adult (mature) stages of NF expression. mRNAs to the light (NF-L), mid-sized (NF-M), and heavy (NF-H) NF proteins were compared by Northern blots and by in situ hybridizations, in NF-rich (i.e., DRG, spinal cord and brainstem) and in NF-poor (i.e., cerebellum and cerebral cortex) regions of the developing rat nervous system. NF proteins were analyzed by gel electrophoresis and by immunoblots. In each tissue, the expression of NF-H was delayed compared to that of NF-L and NF-M, as previously reported. The present study now shows that the delayed expression of NF-H is accompanied by parallel up-regulations in the expressions of NF-L and NF-M, both at the levels of mRNA and protein. Similar rates of increase of all three NF mRNAs occur between postnatal days 5 (P5) and 24 (P24) in rat spinal cord and DRG. Furthermore, the postnatal up-regulation of NF expression is characterized by a progressive accumulation of all three NF proteins in the tissues. The findings indicate that the adult pattern of NF expression (with high levels of expression of all three NF proteins) becomes established during the postnatal period of development, raising questions as to the nature of factors that coregulate the expression of NF subunits.


[Management and follow-up of renal injury-a 10-year experience at a Swiss level 1 trauma center].
The objective was to analyze patterns of injury, management, imaging, and follow-up care of renal trauma at a Swiss level 1 trauma center. We examined 138 patients (>16 years) with renal organ injuries who presented to our institution between January 2008 and March 2018. Data on demographics, patterns of injury, clinical presentation, management, and follow-up were recorded. The injury grade of the 142 injured kidneys was grade 1 in 25% (n = 36), grade 2 in 16% (n = 23), grade 3 in 32% (n = 46), grade 4 in 24% (n = 34), and grade 5 in 2% (n = 3). The predominant injury mechanism was winter sports (45%). Conservative management was successful in all grade 1 renal injuries, and 91%, 86%, 35%, and 33% of grade 2, 3, 4, and 5 injuries, respectively. Early follow-up with CT or MRI scan was performed in 23% of grade 1-3 injuries and 57% of grade 4-5 injuries with clinical signs of complications as the most frequent indication for grade 1-3 injuries and routine follow-up imaging for grade 4-5 injuries, respectively. In follow-up care (1-9 months after injury) imaging showed persistent pathologies in 39% of grade 1-3 renal injuries and 62% of grade 4-5 injuries. Most minor renal injuries (grade 1-3) can be successfully managed conservatively. Early follow-up imaging is indicated for patients showing clinical signs of complications. Routine repeat imaging may not be justified for high-grade renal injuries without clinical symptoms. Re-imaging in follow-up care still lacks evidence-based recommendations.


Why don't zebras have machine guns? Adaptation, selection, and constraints in evolutionary theory.
In an influential paper, Stephen Jay Gould and Richard Lewontin (1979) contrasted selection-driven adaptation with phylogenetic, architectural, and developmental constraints as distinct causes of phenotypic evolution. In subsequent publications Gould (e.g., 1997a,b, 2002) has elaborated this distinction into one between a narrow "Darwinian Fundamentalist" emphasis on "external functionalist" processes, and a more inclusive "pluralist" emphasis on "internal structuralist" principles. Although theoretical integration of functionalist and structuralist explanations is the ultimate aim, natural selection and internal constraints are treated as distinct causes of evolutionary change. This distinction is now routinely taken for granted in the literature in evolutionary biology. I argue that this distinction is problematic because the effects attributed to non-selective constraints are more parsimoniously explained as the ordinary effects of selection itself. Although it may still be a useful shorthand to speak of phylogenetic, architectural, and developmental constraints on phenotypic evolution, it is important to understand that such "constraints" do not constitute an alternative set of causes of evolutionary change. The result of this analysis is a clearer understanding of the relationship between adaptation, selection and constraints as explanatory concepts in evolutionary theory.


High maternal mortality rate associated with advanced maternal age in Japan.
This study aimed to clarify the relationship between maternal mortality and advanced maternal age in Japan and to provide useful information for future perinatal management. Maternal death rates by age group were investigated for all maternal deaths in Japan for an 11-year period, from 2010 to 2021. Maternal deaths among those aged ≥ 40 years were examined in detail to determine the cause, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated. The maternal mortality rates were 0.8 (95% confidence interval [CI] 0.3-4.7) for < 20 years, 2.6 (95% CI 1.7-3.8) for 20-24 years, 2.9 (95% CI 2.3-3.6) for 25-29 years, 3.9 (95% CI 3.3-4.5) for 30-34 years, 6.8 (95% CI 5.9-7.9) for 35-39 years, and 11.2 (95% CI 8.8-14.3) for ≥ 40 years of age. Patients who were ≥ 40 years of age had a significantly higher mortality rate compared to that in other age groups. Hemorrhagic stroke was the most common cause of death in patients aged ≥ 40 years (15/65 [23%]), and preeclampsia (8/15 [54%]) was the most common cause of hemorrhagic stroke. Maternal mortality is significantly higher in older than in younger pregnant women in Japan, with hemorrhagic stroke being the most common cause of maternal death among women > 40 years of age. More than half of hemorrhagic strokes are associated with hypertension disorder of pregnancy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.


Design, synthesis, and biological evaluation of trizole-based heteroaromatic derivatives as Bcr-Abl kinase inhibitors.
Bcr-Abl is a key driver in the pathophysiology of CML. Broadening the chemical diversity of Bcr-Abl kinase inhibitors to overcome drug resistance is a current medical demand for CML treatment. As a continuation to our research, a series of compounds with heteroaromatics-trizole scaffold as hinge binding moiety (HBM) were developed as Bcr-Abl inhibitors based on in silico modeling analysis. Biological results indicated that these compounds exhibited a significantly enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in leukemia cell assays, compared with previous disclosed compounds. In particular, compounds 9f, 28c, 31, and 44c displayed comparable even better potency with that of Imatinib in enzymatic assay and cell assays including K562 cells and adriamycin-resistant K562/A cells. Moreover, compounds 9f, 28c, and 44c exhibited potent inhibition activities against K562R cells bearing T315I mutant with IC50 of 13.35 μM, 40.14 μM, and 1.91 μM, respectively, outperforming that of Imatinib. Meanwhile, the inhibition of Bcr-Abl activity in Ba/F3 cells demonstrated that these compounds exerted effects mainly by acting on Bcr-Abl. Additionally, compounds 9f, 28c, and 44c effectively induced apoptosis, arrest the cell cycle at S or G2/M phase, and inhibited phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies indicated that trizole indeed retained the hydrophobic interaction of aromatic heterocycles with hinge region, and ADME prediction suggested that tested compounds had a favorable safety profile. Therefore, aromatic heterocycles incorporated with trizole could serve as a promising HBM for Bcr-Abl inhibitors with proline as fexibile linker, and compounds 9f, 28c, especially 44c could be served as a starting point for further optimization.


[Chronotropic vago-sympathetic interactions during electric stimulation of cardiac nerves in the cat].
It is demonstrated that sympathetic nerves may strengthen or depress the synchronizing or tonic components of vagal chronotropic effect, but the former was absent if extracardiac nerves were cut bilaterally.


A novel multi-domain mucin-like glycoprotein of Cryptosporidium parvum mediates invasion.
Cryptosporidium parvum is a protozoan parasite which produces self-limited disease in immunocompetent hosts and devastating, persistent diarrhea in immunocompromised individuals. There is no effective treatment for cryptosporidiosis and little is known about the basic biology of the organism. Cloning and sequence analysis of the gene encoding GP900, a previously identified > 900 kDa glycoprotein, predicts a mucin-like glycoprotein composed of distal cysteine-rich domains separated by polythreonine domains and a large membrane proximal N-glycosylated core region. A trinucleotide repeat composed predominantly of the triplet ACA encodes the threonine domains. GP900 is stored in micronemes prior to appearance on the surface of invasive forms. The concentration of native GP900 which inhibits 50% (IC50) of invasion in vitro is low picomolar; the IC50 for a recombinant cysteine rich-domain is low nanomolar. These observations indicate that GP900 is a parasite ligand for a host receptor involved in attachment/invasion and suggest that immunotherapy or chemotherapy directed against GP900 may be feasible.


[Chronic inflammatory demyelinating polyneuropathy: Diagnosis and therapeutic update].
Chronic inflammatory demyelinating polyradiculoneuropathies are acquired demyelinating neuropathies belonging to the group of autoimmune neuropathies. Since specific biological markers are present in less than 10% of cases, the diagnosis is based on the clinical and electrophysiological analysis of each patient. Furthermore, a decision-making algorithm ranking all other available paraclinical tools will guide the physician to the diagnosis of atypical forms. In nearly 80% of cases, these dysimmune neuropathies are responsive to first-line treatments, namely intravenous immunoglobulins, corticosteroids and plasma exchanges. A second line treatment may be proposed in case of no response, intolerance or inaccessibility to the three reference treatments. While some immunosuppressants or monoclonal antibodies can sometimes be very effective, there is currently no predictive marker or recommendation available to determine which treatment will be most appropriate for which patient.


The binding of very low density lipoprotein remnants to the low density lipoprotein receptor in familial defective apolipoprotein B-100.
We have compared the affinity for low density lipoprotein (LDL) receptors of LDL and very low density lipoprotein (VLDL) remnants from patients with familial defective apo B-100 (FDB) with that of LDL and VLDL remnants from normal subjects. The binding affinity of FDB LDL was markedly reduced in all 14 FDB patients examined, hut the affinity of FDB remnants did not differ significantly from that of remnants prepared from normal subjects. Since the mutant form of apo B-100 present in FDB is recognized by LDL receptors with greatly reduced efficiency, we suggest that apo B plays only a minor role in the receptor-mediated uptake of VLDL remnants by the liver in man. These results are consistent with our previous suggestion that the ability of drugs that stimulate hepatic receptor activity to lower the plasma LDL level in FDB is due in part to increased hepatic uptake of lipoprotein precursors of LDL, including remnant particles with normal apo B-100 and those with mutant apo B-100.


The harm done by tests of significance.
Three historical episodes in which the application of null hypothesis significance testing (NHST) led to the mis-interpretation of data are described. It is argued that the pervasive use of this statistical ritual impedes the accumulation of knowledge and is unfit for use.


Comparison of prostacyclin production of human gastroepiploic artery and saphenous vein.
The prostacyclin production of the gastroepiploic artery (GEA) and saphenous vein (SV) were studied in 5 patients undergoing coronary artery revascularization. The GEA produced 90.0 +/- 11.9, 132.4 +/- 13.7, and 191.1 +/- 21.8 pg/mg tissue (mean +/- standard error of the mean) of 6-keto-prostaglandin F1 alpha (prostacyclin metabolite) after 2.5, 5.0, and 10.0 minutes, respectively, of incubation in Krebs-Henseleit buffer at 37 degrees C. The SV produced 39.8 +/- 7.0, 66.7 +/- 9.1, and 123.6 +/- 15.1 pg/mg tissue of 6-keto prostaglandin F1 alpha after 2.5, 5.0, and 10.0 minutes, respectively, of incubation. The GEA produced significantly more 6-keto-prostaglandin F1 alpha than SV at all three sampling times up to ten minutes of incubation (p less than 0.01). Prostacyclin is a potent vasodilator and an inhibitor of platelet aggregation. Prostacyclin production by the internal mammary artery was reported to be much higher than that of SV, and the patency rate of internal mammary artery grafts is reported to be better than that of SV grafts in coronary artery revascularization. Therefore, our results suggest that the patency rate of GEA grafts may be better than that of SV grafts in coronary artery revascularization. The GEA is a promising and excellent graft from the biochemical point of view.


Slide review in gynecologic oncology ensures completeness of reporting and diagnostic accuracy.
We reviewed patient records in our tertiary care teaching hospital to assess the value of the mandatory slide review policy in gynecologic oncology with emphasis on completeness of reports. Cases reviewed between October 2001 to September 2002 were studied. Clinical information was gathered from discussions at the weekly tumor board and from chart review. The standardized reporting guidelines in benchmark surgical pathology textbooks were used to assess the completeness of original pathology reports of excisional specimens. Diagnostic discrepancies were classified as major if the resultant change led to alteration of management or minor if it did not. Three hundred fifty-one cases were reviewed; 173 biopsies and 178 excisional specimens. Only 140 (78.7%) of the original pathology reports of the latter group conformed to standardized reporting guidelines. Of the 38 incomplete reports, 18 were missing critical information necessary for planning of further therapy, representing 10.1% of reports of all excisional specimens. We agreed with the original diagnosis in 252 cases (71.8%). Minor discrepancies were noted in 70 (19.9%) and major discrepancies in 29 cases (8.3%). No major discrepancy resulted from reviewing any of the vulvar specimens or cases that were already reviewed by gynecologic pathologists of other academic institutes. Mandatory slide review in gynecologic oncology is an important component in the management of gynecologic cancer patients because it completes reporting on missing parameters required for planning subsequent therapy in 10.1% of cases and recognizes discrepancies altering management in 8.3% of patients.


Characterization of a CNS penetrant, selective M1 muscarinic receptor agonist, 77-LH-28-1.
M1 muscarinic ACh receptors (mAChRs) represent an attractive drug target for the treatment of cognitive deficits associated with diseases such as Alzheimer's disease and schizophrenia. However, the discovery of subtype-selective mAChR agonists has been hampered by the high degree of conservation of the orthosteric ACh-binding site among mAChR subtypes. The advent of functional screening assays has enabled the identification of agonists such as AC-42 (4-n-butyl-1-[4-(2-methylphenyl)-4-oxo-1-butyl]-piperidine), which bind to an allosteric site and selectively activate the M(1) mAChR subtype. However, studies with this compound have been limited to recombinantly expressed mAChRs. In this study, we have compared the pharmacological profile of AC-42 and a close structural analogue, 77-LH-28-1 (1-[3-(4-butyl-1-piperidinyl)propyl]-3,4-dihydro-2(1H)-quinolinone) at human recombinant, and rat native, mAChRs by calcium mobilization, inositol phosphate accumulation and both in vitro and in vivo electrophysiology. Calcium mobilization and inositol phosphate accumulation assays revealed that both AC-42 and 77-LH-28-1 display high selectivity to activate the M1 mAChR over other mAChR subtypes. Furthermore, 77-LH-28-1, but not AC-42, acted as an agonist at rat hippocampal M1 receptors, as demonstrated by its ability to increase cell firing and initiate gamma frequency network oscillations. Finally, 77-LH-28-1 stimulated cell firing in the rat hippocampus in vivo following subcutaneous administration. These data suggest that 77-LH-28-1 is a potent, selective, bioavailable and brain-penetrant agonist at the M1 mAChR and therefore that it represents a better tool than AC-42, with which to study the pharmacology of the M1 mAChR.


Neuropathic Pain and Spinal Cord Injury: Management, Phenotypes, and Biomarkers.
Chronic neuropathic pain after a spinal cord injury (SCI) continues to be a complex condition that is difficult to manage due to multiple underlying pathophysiological mechanisms and the association with psychosocial factors. Determining the individual contribution of each of these factors is currently not a realistic goal; however, focusing on the primary mechanisms may be more feasible. One approach used to uncover underlying mechanisms includes phenotyping using pain symptoms and somatosensory function. However, this approach does not consider cognitive and psychosocial mechanisms that may also significantly contribute to the pain experience and impact treatment outcomes. Indeed, clinical experience supports that a combination of self-management, non-pharmacological, and pharmacological approaches is needed to optimally manage pain in this population. This article will provide a broad updated summary integrating the clinical aspects of SCI-related neuropathic pain, potential pain mechanisms, evidence-based treatment recommendations, neuropathic pain phenotypes and brain biomarkers, psychosocial factors, and progress regarding how defining neuropathic pain phenotypes and other surrogate measures in the neuropathic pain field may lead to targeted treatments for neuropathic pain after SCI.