Responses of blood pressure and renal sympathetic nerve activity to colorectal distension in anesthetized rats.
We investigated the effects of visceral stimulation by colorectal distension (CRD) on mean arterial blood pressure (MAP) and renal sympathetic nerve activity (RSNA), the latter being an index of vasoconstrictor activity, in anesthetized central nervous system (CNS)-intact and C2 spinalized rats. The CRD stimulation was induced by the distention of a balloon inserted into the colorectum. In CNS-intact rats, there were significant reductions in MAP and RSNA in response to intraballoon pressures of 60 and 80 mmHg, but not to 20 and 40 mmHg. However, spinalized rats demonstrated significant increases in MAP in response to intraballoon pressures of 60 and 80 mmHg and increases in RSNA in response to intraballoon pressures of 40, 60, and 80 mmHg. These results suggest that noxious visceral stimulation at lower spinal levels reduces MAP by inhibiting sympathetic output in CNS-intact anesthetized rats. On the other hand, noxious visceral stimulation results in an increase in sympathetic-induced MAP in spinalized anesthetized rats.


[Repair of nasal septal perforation with different intranasal flap techniques and their outcomes].
The aim of this study was to reveal the efficacy of different nasal mucosal flap techniques in the repair of nasal septal perforation. Between April 2006 and May 2009 21 patients (12 males, 9 females; mean age 36.6+/-12.7 years; range 17 to 60 years) with the complaints of nasal obstruction, bleeding, crusting, whistling during inspiration, and pain and in whom septum perforation was detected were operated on and they were included in this study. The patients were followed-up for an average of 16.9 months (3 to 35 months). Cross-stealing technique was performed on 11 patients while advancement flap was performed on three patients and rotation flap was performed on seven patients. Patients were followed-up for at least three months before the evaluation of the postoperative results. Complete closure was observed in 16 out of 21 patients (76.2%) and partial closure in one patient (4.8%). In four patients (19%) perforation was not closed and its size remained unchanged. In the literature, many different surgical techniques have been described for the repair of nasal septal perforation. The main aim of the repair is not only the closure of perforation but also the restoration of normal function and physiology in the nose. In order to achieve this, the most physiologically and anatomically suitable method is the closure of nasal septal perforation with three layers composed of two mucoperichondrial flaps and one interpositional graft. Although cross-stealing technique may be an anatomically and physiologically feasible option for the closure of small-middle sized perforation located anteriorly, the highest success rates are obtained with advancement and rotation flaps when the location and size of perforation are considered.


A prospective, randomised, double blind placebo-controlled trial to evaluate the efficacy and safety of tocilizumab in patients with severe COVID-19 pneumonia (TOC-COVID): A structured summary of a study protocol for a randomised controlled trial.
SARS-CoV2 infection leads to a concomitant pulmonary inflammation. This inflammation is supposed to be the main driver in the pathogenesis of lung failure (Acute Respiratory Distress Syndrome) in COVID-19. Objective of this study is to evaluate the efficacy and safety of a single dose treatment with Tocilizumab in patients with severe COVID-19. We hypothesize that Tocilizumab slows down the progression of SARS-CoV-2 induced pneumonia and inflammation. We expect an improvement in pulmonary function compared to placebo-treated patients. Desirable outcomes would be that tocilizumab reduces the number of days that patients are dependent on mechanical ventilation and reduces the invasiveness of breathing assistance. Furthermore, this treatment might result in fewer admissions to intensive care units. Next to these efficacy parameters, safety of a therapy with Tocilizumab in COVID-19 patients has to be monitored closely, since immunosuppression could lead to an increased rate of bacterial infections, which could negatively influence the patient's outcome. Multicentre, prospective, 2-arm randomised (ratio 1:1), double blind, placebo-controlled trial with parallel group design. Inclusion criteria 1.Proof of SARS-CoV2 (Symptoms and positive polymerase chain reaction (PCR))2.Severe respiratory failure: a.Ambient air SpO2 ≤ 92% orb.Need of ≥ 6l O2/min orc.NIV (non-invasive ventilation) ord.IMV (invasive mechanical ventilation)3.Age ≥ 18 years Exclusion criteria 1.Non-invasive or invasive mechanical ventilation ≥ 48 hours2.Pregnancy or breast feeding3.Liver injury or failure (AST/ALT ≥ 5x ULN)4.Leukocytes < 2 × 103/μl5.Thrombocytes < 50 × 103/μl6.Severe bacterial infection (PCT > 3ng/ml)7.Acute or chronic diverticulitis8.Immunosuppressive therapy (e.g. mycophenolate, azathioprine, methotrexate, biologicals, prednisolone >10mg/d; exceptions are: prednisolone ≤ 10mg/d, sulfasalazine or hydroxychloroquine)9.Known active or chronic tuberculosis10.Known active or chronic viral hepatitis11.Known allergic reactions to tocilizumab or its ingredients12.Life expectation of less than 1 year (independent of COVID-19)13.Participation in any other interventional clinical trial within the last 30 days before the start of this trial14.Simultaneous participation in other interventional trials (except for participation in COVID-19 trials) which could interfere with this trial; simultaneous participation in registry and diagnostic trials is allowed15.Failure to use one of the following safe methods of contraception: female condoms, diaphragm or coil, each used in combination with spermicides; intra-uterine device; hormonal contraception in combination with a mechanical method of contraception. The data collection of the primary follow up (28 days after randomisation) takes place during the hospital stay. Subsequently, a telephone interview on the quality of life is conducted after 6 and 12 months. Participants will be recruited from inpatients at ten medical centres in Germany. Intervention arm: Application of 8mg/kg body weight (BW) Tocilizumab i.v. once immediately after randomisation (12 mg/kg for patients with <30kg BW; total dose should not exceed 800 mg) AND conventional treatment. Control arm: Placebo (NaCl) i.v. once immediately after randomisation AND conventional treatment. Primary endpoint is the number of ventilator free days (d) (VFD) in the first 28 days after randomisation. Non-invasive ventilation (NIV), Invasive mechanical ventilation (IMV) and extracorporeal membrane oxygenation (ECMO) are defined as ventilator days. VFD's are counted as zero if the patient dies within the first 28 days. The randomisation code will be generated by the CTU (Clinical Trials Unit, ZKS Freiburg) using the following procedure to ensure that treatment assignment is unbiased and concealed from patients and investigator staff. Randomisation will be stratified by centre and will be performed in blocks of variable length in a ratio of 1:1 within each centre. The block lengths will be documented separately and will not be disclosed to the investigators. The randomisation code will be produced by validated programs based on the Statistical Analysis System (SAS). Participants, caregivers, and the study team assessing the outcomes are blinded to group assignment. 100 participants will be randomised to each group (thus 200 participants in total). Protocol Version: V 1.2, 16.04.2020. Recruitment began 27th April 2020 and is anticipated to be completed by December 2020. The trial was registered before trial start in trial registries (EudraCT: No. 2020-001408-41, registered 21st April 2020, and DRKS: No. DRKS00021238, registered 22nd April 2020). The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Mechanisms and dynamics of orphan gene emergence in insect genomes.
Orphan genes are defined as genes that lack detectable similarity to genes in other species and therefore no clear signals of common descent (i.e., homology) can be inferred. Orphans are an enigmatic portion of the genome because their origin and function are mostly unknown and they typically make up 10% to 30% of all genes in a genome. Several case studies demonstrated that orphans can contribute to lineage-specific adaptation. Here, we study orphan genes by comparing 30 arthropod genomes, focusing in particular on seven recently sequenced ant genomes. This setup allows analyzing a major metazoan taxon and a comparison between social Hymenoptera (ants and bees) and nonsocial Diptera (flies and mosquitoes). First, we find that recently split lineages undergo accelerated genomic reorganization, including the rapid gain of many orphan genes. Second, between the two insect orders Hymenoptera and Diptera, orphan genes are more abundant and emerge more rapidly in Hymenoptera, in particular, in leaf-cutter ants. With respect to intragenomic localization, we find that ant orphan genes show little clustering, which suggests that orphan genes in ants are scattered uniformly over the genome and between nonorphan genes. Finally, our results indicate that the genetic mechanisms creating orphan genes-such as gene duplication, frame-shift fixation, creation of overlapping genes, horizontal gene transfer, and exaptation of transposable elements-act at different rates in insects, primates, and plants. In Formicidae, the majority of orphan genes has their origin in intergenic regions, pointing to a high rate of de novo gene formation or generalized gene loss, and support a recently proposed dynamic model of frequent gene birth and death.


Adiabatic density perturbations and matter generation from the minimal supersymmetric standard model.
We propose that the inflaton is coupled to ordinary matter only gravitationally and that it decays into a completely hidden sector. In this scenario both baryonic and dark matter originate from the decay of a flat direction of the minimal supersymmetric standard model, which is shown to generate the desired adiabatic perturbation spectrum via the curvaton mechanism. The requirement that the energy density along the flat direction dominates over the inflaton decay products fixes the flat direction almost uniquely. The present residual energy density in the hidden sector is typically shown to be small.


Soil microbial population dynamics following bioaugmentation with a 3-chlorobenzoate-degrading bacterial culture. Bioaugmentation effects on soil microorganisms.
Changes in microbial populations were evaluated following inoculation of contaminated soil with a 3-chlorobenzoate degrader. Madera sandy loam was amended with 0, 500, or 1,000 microg 3-chlorobenzoate g(-1) dry soil. Selected microcosms were inoculated with the degrader Comamonas testosteroni BR60. Culturable bacterial degraders were enumerated on minimal salts media containing 3-chlorobenzoate. Culturable heterotrophic bacteria were enumerated on R2A. Isolated degraders were grouped by enterobacterial repetitive intergenic consensus sequence-polymerase chain reaction fingerprints and identified based on 16S ribosomal-DNA sequences. Bioaugmentation increased the rate of degradation at both levels of 3-chlorobenzoate. In both the 500 and 1,000 microg 3-chlorobenzoate g(-1) dry soil inoculated microcosms, degraders increased from the initial inoculum and decreased following degradation of 3-CB. Inoculation delayed the development of indigenous 3-chlorobenzoate degrading populations. It is unclear if inoculation altered the composition of indigenous degrader populations. In the uninoculated soil, degraders increased from undetectable levels to 6.6 x 10(7) colony-forming-units g(-1) dry soil in the 500 microg 3-chlorobenzoate g(-1) dry soil microcosms, but none were detected in the 1,000 microg 3-chlorobenzoate g(-1) dry soil microcosms. Degraders isolated from uninoculated soil were identified as one of two distinct Burkholderia species. In the uninoculated soil, numbers of culturable heterotrophic bacteria initially decreased following addition of 1,000 microg 3-chlorobenzoate g(-1) dry soil. Inoculation with C. testosteroni reduced this negative impact on culturable bacterial numbers. The results indicate that bioaugmentation may not only increase the rate of 3-chlorobenzoate degradation but also reduce the deleterious effects of 3-chlorbenzoate on indigenous soil microbial populations.


Vibroplasty in Severe Congenital or Acquired Meatal Stenosis by Coupling an Active Middle Ear Implant to the Short Process of the Incus.
To evaluate the safety and effectiveness of coupling an active middle ear implant to the short process of the incus in subjects with meatal pathologies. Retrospective study. Tertiary referral center. Twelve patients suffering from either congenital aural atresia or acquired meatal fibrosis. Implantation of an active middle ear implant with coupling of the actuator to the short process of the incus. Evaluation of the air conduction and bone conduction hearing thresholds pre- and postoperatively, aided warble-tone hearing thresholds, unaided and aided speech recognition in quiet and noise. Questionnaires on subjective benefit and quality of life. Mean unaided postoperative air conduction and bone conduction thresholds did not vary significantly from preoperative values (p = 0.55 and 0.082, respectively). The mean functional gain amounted to 42.1 ± 8.8 dB, the mean aided sound field threshold of the implanted ear was 28.6 ± 8.6 dB. No significant difference in functional gain but a close to significant difference in postoperative aided thresholds (p = 0.053) were found between subjects with congenital atresia and acquired fibrosis. Subjective benefit assessed by the global score of the Abbreviated Profile of Hearing Aid Benefit questionnaire revealed an improvement of 31 to 42%. Coupling of the actuator to the short process of the incus is a safe and clinically promising procedure in cases where the standard application to the long process is not feasible. In pure conductive hearing loss the benefit is comparable to long incus process coupling, whereas in mixed hearing loss slightly worse results were observed.


Gli1 Regulates the Postnatal Acquisition of Peripheral Nerve Architecture.
Peripheral nerves are organized into discrete compartments. Axons, Schwann cells (SCs), and endoneurial fibroblasts (EFs) reside within the endoneurium and are surrounded by the perineurium, a cellular sheath comprised of layers of perineurial glia (PNG). SC secretion of Desert Hedgehog (Dhh) regulates this organization. In Dhh nulls, the perineurium is deficient and the endoneurium is subdivided into small compartments termed minifascicles. Human Dhh mutations cause a neuropathy with similar defects. Here we examine the role of Gli1, a canonical transcriptional effector of hedgehog signaling, in regulating peripheral nerve organization in mice of both genders. We identify PNG, EFs, and pericytes as Gli1-expressing cells by genetic fate mapping. Although expression of Dhh by SCs and Gli1 in target cells is coordinately regulated with myelination, Gli1 expression unexpectedly persists in Dhh null EFs. Thus, Gli1 is expressed in EFs noncanonically (i.e., independent of hedgehog signaling). Gli1 and Dhh also have nonredundant activities. Unlike Dhh nulls, Gli1 nulls have a normal perineurium. Like Dhh nulls, Gli1 nulls form minifascicles, which we show likely arise from EFs. Thus, Dhh and Gli1 are independent signals: Gli1 is dispensable for perineurial development but functions cooperatively with Dhh to drive normal endoneurial development. During development, Gli1 also regulates endoneurial extracellular matrix production, nerve vascular organization, and has modest, nonautonomous effects on SC sorting and myelination of axons. Finally, in adult nerves, induced deletion of Gli1 is sufficient to drive minifascicle formation. Thus, Gli1 regulates the development and is required to maintain the endoneurial architecture of peripheral nerves.SIGNIFICANCE STATEMENT Peripheral nerves are organized into distinct cellular/ECM compartments: the epineurium, perineurium, and endoneurium. This organization, with its associated cellular constituents, is critical for the structural and metabolic support of nerves and their response to injury. Here, we show that Gli1, a transcription factor normally expressed downstream of hedgehog signaling, is required for the proper organization of the endoneurium but not the perineurium. Unexpectedly, Gli1 expression by endoneurial cells is independent of, and functions nonredundantly with, Schwann Cell-derived Desert Hedgehog in regulating peripheral nerve architecture. These results further delineate how peripheral nerves acquire their distinctive organization during normal development, and highlight mechanisms that may regulate their reorganization in pathologic settings, including peripheral neuropathies and nerve injury.


No change in N-acetyl aspartate in first episode of moderate depression after antidepressant treatment: (1)H magnetic spectroscopy study of left amygdala and left dorsolateral prefrontal cortex.
The role of brain metabolites as biological correlates of the intensity, symptoms, and course of major depression has not been determined. It has also been inconclusive whether the change in brain metabolites, measured with proton magnetic spectroscopy, could be correlated with the treatment outcome. Proton magnetic spectroscopy was performed in 29 participants with a first episode of moderate depression occurring in the left dorsolateral prefrontal cortex and left amygdala at baseline and after 8 weeks of antidepressant treatment with escitalopram. The Montgomery-Asberg Depression Rating Scale, the Hamilton Rating Scale for Depression, and the Beck Depression Inventory were used to assess the intensity of depression at baseline and at the endpoint of the study. At endpoint, the participants were identified as responders (n=17) or nonresponders (n=12) to the antidepressant therapy. There was no significant change in the N-acetyl aspartate/creatine ratio (NAA/Cr) after treatment with antidepressant medication. The baseline and endpoint NAA/Cr ratios were not significantly different between the responder and nonresponder groups. The correlation between NAA/Cr and changes in the scores of clinical scales were not significant in either group. This study could not confirm any significant changes in NAA after antidepressant treatment in the first episode of moderate depression, or in regard to therapy response in the left dorsolateral prefrontal cortex or left amygdala. Further research is necessary to conclude whether NAA alterations in the first episode of depression could possibly be different from chronic or late-onset depression, and whether NAA alterations in stress-induced (reactive) depression are different from endogenous depression. The potential role of NAA as a biomarker of a treatment effect has yet to be established.


Applying time-frequency analysis to assess cerebral autoregulation during hypercapnia.
Classic methods for assessing cerebral autoregulation involve a transfer function analysis performed using the Fourier transform to quantify relationship between fluctuations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV). This approach usually assumes the signals and the system to be stationary. Such an presumption is restrictive and may lead to unreliable results. The aim of this study is to present an alternative method that accounts for intrinsic non-stationarity of cerebral autoregulation and the signals used for its assessment. Continuous recording of CBFV, ABP, ECG, and end-tidal CO2 were performed in 50 young volunteers during normocapnia and hypercapnia. Hypercapnia served as a surrogate of the cerebral autoregulation impairment. Fluctuations in ABP, CBFV, and phase shift between them were tested for stationarity using sphericity based test. The Zhao-Atlas-Marks distribution was utilized to estimate the time-frequency coherence (TFCoh) and phase shift (TFPS) between ABP and CBFV in three frequency ranges: 0.02-0.07 Hz (VLF), 0.07-0.20 Hz (LF), and 0.20-0.35 Hz (HF). TFPS was estimated in regions locally validated by statistically justified value of TFCoh. The comparison of TFPS with spectral phase shift determined using transfer function approach was performed. The hypothesis of stationarity for ABP and CBFV fluctuations and the phase shift was rejected. Reduced TFPS was associated with hypercapnia in the VLF and the LF but not in the HF. Spectral phase shift was also decreased during hypercapnia in the VLF and the LF but increased in the HF. Time-frequency method led to lower dispersion of phase estimates than the spectral method, mainly during normocapnia in the VLF and the LF. The time-frequency method performed no worse than the classic one and yet may offer benefits from lower dispersion of phase shift as well as a more in-depth insight into the dynamic nature of cerebral autoregulation.


Phylogenomics and classification of Notropis and related shiners (Cypriniformes: Leuciscidae) and the utility of exon capture on lower taxonomic groups.
North American minnows of the Shiner Clade, within the family Leuciscidae, represent one of the most taxonomically complex clades of the order Cypriniformes due to the large number of taxa coupled with conserved morphologies. Species within this clade were moved between genera and subgenera until the community decided to lump many of the unclassified taxa with similar morphologies into one genus, Notropis, which has held up to 325 species. Despite phylogentic studies that began to re-elevate some genera merged into Notropis, such as Cyprinella, Luxilus, Lythrurus, and Pteronotropis, the large genus Notropis remained as a taxonomic repository for many shiners of uncertain placement. Recent molecular advances in sequencing technologies have provided the opportunity to re-examine the Shiner Clade using phylogenomic markers. Using a fish probe kit, we sequenced 90 specimens in 87 species representing 16 genera included in the Shiner Clade, with a resulting dataset of 1,004 loci and 286,455 base pairs. Despite the large dataset, only 32,349 bp (11.29%) were phylogenetically informative. In our maximum likelihood tree, 78% of nodes are 100% bootstrap supported demonstrating the utility of the phylogenomic markers at lower taxonomic levels. Unsurprisingly, species within Notropis as well as Hudsonius, Luxilus, and Alburnops are not resolved as monophyletic groups. Cyprinella is monophyletic if Cyprinella callistia is excluded, and Pteronotropis is monophyletic if it includes Hudsonius cummingsae. Taxonomic changes we propose are: restriction of species included in Alburnops and Notropis, elevation of the subgenus Hydrophlox, expansion of species included in Miniellus, movement of Hudsonius cummingsae to Pteronotropis, and resurrection of the genera Coccotis and Paranotropis. We additionally had two specimens of three species, Notropis atherinoides, Ericymba amplamala, and Pimephales vigilax and found signficant differences between the localities (1,086, 1,424, and 845 nucleotides respectively).


[Physiological and hygienic evaluation of combined effects of harmful factors in metallurgy].
The quantitative assessment of a compound action of hazardous industrial factors in combination with workload with the technique of multiple discrete correlative-regressive analysis, contributes to the evaluation of their relative hygienic involvement along the major functional state indices. The results proved to be indispensable for the substantiation and elaboration of preventive measures.


Emotion Regulation as a Mediator between Childhood Abuse and Neglect and Posttraumatic Stress Disorder in Women with Substance Use Disorders.
A history of childhood abuse and neglect (CAN) is significantly associated with psychopathologies in adulthood, including comorbid posttraumatic stress disorder (PTSD) and substance use disorders (SUD). Difficulties in emotion regulation (ER) might influence the association between CAN and PTSD. The aim of this study was to examine the relationship between CAN and PTSD symptom severity in women with SUD and to investigate the mediating role of general difficulties in ER and its specific dimensions. Method: We examined 320 women, with a current diagnosis of at least subsyndromal PTSD and SUD, using self-report measures of CAN, PTSD symptom severity, and ER difficulties. We conducted both simple and multiple bootstrapping-enhanced mediation analysis to investigate whether general difficulties in ER and its specific dimensions mediate the relationship between CAN and PTSD symptom severity. Results: General difficulties in ER mediated the association between CAN and PTSD symptom severity. CAN significantly predicted adult PTSD symptom severity, directly and indirectly, through ER difficulties. Difficulties engaging in goal directed behavior when distressed was the only ER dimension, which mediated the effect of CAN on PTSD symptoms. Conclusions: Our results suggest that difficulties in ER and specifically difficulties engaging in goal directed behavior when distressed might constitute an influential factor in the relationship between CAN and PTSD symptom severity in a sample of SUD patients, and highlight the importance of targeting ER as a potential treatment focus for patients with comorbid PTSD and SUD.


Ghost-Free Deep High-Dynamic-Range Imaging Using Focus Pixels for Complex Motion Scenes.
Multi-exposure image fusion inevitably causes ghost artifacts owing to inaccurate image registration. In this study, we propose a deep learning technique for the seamless fusion of multi-exposed low dynamic range (LDR) images using a focus-pixel sensor. For auto-focusing in mobile cameras, a focus-pixel sensor originally provides left (L) and right (R) luminance images simultaneously with a full-resolution RGB image. These L/R images are less saturated than the RGB images because they are summed up to be a normal pixel value in the RGB image of the focus pixel sensor. These two features of the focus pixel image, namely, relatively short exposure and perfect alignment are utilized in this study to provide fusion cues for high dynamic range (HDR) imaging. To minimize fusion artifacts, luminance and chrominance fusions are performed separately in two sub-nets. In a luminance recovery network, two heterogeneous images, the focus pixel image and the corresponding overexposed LDR image, are first fused by joint learning to produce an HDR luminance image. Subsequently, a chrominance network fuses the color components of the misaligned underexposed LDR input to obtain a 3-channel HDR image. Existing deep-neural-network-based HDR fusion methods fuse misaligned multi-exposed inputs directly. They suffer from visual artifacts that are observed mostly in saturated regions because pixel values are clipped out. Meanwhile, the proposed method reconstructs missing luminance with aligned unsaturated focus pixel image first, and thus, the luma-recovered image provides the cues for accurate color fusion. The experimental results show that the proposed method not only accurately restores fine details in saturated areas, but also produce ghost-free high-quality HDR images without pre-alignment.


A Recombinant of Bean common mosaic virus Induces Temperature-Insensitive Necrosis in an I Gene-Bearing Line of Common Bean.
The I gene is a single, dominant gene conferring temperature-sensitive resistance to all known strains of Bean common mosaic virus (BCMV) in common bean (Phaseolus vulgaris). However, the closely related Bean common mosaic necrosis virus (BCMNV) induces whole plant necrosis in I-bearing genotypes of common bean, and the presence of additional, recessive genes is required to prevent this severe whole plant necrotic reaction caused by BCMNV. Almost all known BCMNV isolates have so far been classified as having pathotype VI based on their interactions with the five BCMV resistance genes, and all have a distinct serotype A. Here, we describe a new isolate of BCMV, RU1M, capable of inducing whole plant necrosis in the presence of the I gene, that appears to belong to pathotype VII and exhibits B-serotype. Unlike other isolates of BCMV, RU1M was able to induce severe whole plant necrosis below 30°C in bean cultivar Jubila that carries the I gene and a protective recessive gene bc-1. The whole genome of RU1M was cloned and sequenced and determined to be 9,953 nucleotides long excluding poly(A), coding for a single polyprotein of 3,186 amino acids. Most of the genome was found almost identical (>98%) to the BCMV isolate RU1-OR (also pathotype VII) that did not induce necrotic symptoms in 'Jubila'. Inspection of the nucleotide sequences for BCMV isolates RU1-OR, RU1M, and US10 (all pathotype VII) and three closely related sequences of BCMV isolates RU1P, RU1D, and RU1W (all pathotype VI) revealed that RU1M is a product of recombination between RU1-OR and a yet unknown potyvirus. A 0.8-kb fragment of an unknown origin in the RU1M genome may have led to its ability to induce necrosis regardless of temperature in beans carrying the I gene. This is the first report of a BCMV isolate inducing temperature-insensitive necrosis in an I gene containing bean genotype.


Extreme blood pressure fluctuations in a patient with intact autonomic reflexes and intact sodium conservation.
A patient who had episodes of profound hypotension alternating with severe hypertension without an obvious precipitating cause is reported. The hypotensive episodes were accompanied by tiredness, syncope, bradycardia, and a low norepinephrine concentration while supine or standing. In contrast, the hypertensive episodes were associated with marked tachycardia, sweating, anxiety, abdominal pain, and very high levels of plasma norepinephrine concentration. Extensive investigations failed to support a diagnosis of pheochromocytoma. The testing of baroreceptor function and autonomic reflexes was normal. Blood pressure was not salt sensitive. It was concluded that this patient has a unique clinical syndrome of extreme fluctuation of blood pressure and sympathetic nervous activity yet intact cardiovascular reflexes and normal sodium conservation. The abnormal blood pressure regulation most likely has a central origin.


Activation of Akt and mTOR in CD34+/K15+ keratinocyte stem cells and skin tumors during multi-stage mouse skin carcinogenesis.
The goal of the present studies was to localize two proteins known to be involved in regulation of cell proliferation and survival in specific cell populations in normal SENCAR mouse skin and during multi-stage skin carcinogenesis. The proteins evaluated included activated Akt, as defined by phosphorylation of Akt at Serine-473 (pAkt) and mammalian target of rapamycin (pmTOR), defined by phosphorylation of mTOR at Serine-2448 (pmTOR). The cell populations examined included mouse keratinocyte stem cells (KSCs) within hair follicles and preneoplastic papilloma cells. Immunochemical staining analysis as well as triple color immunofluorescence in combination with confocal microscopy were used to evaluate the presence of activated Akt and mammalian target of rapamycin (mTOR) in KSCs within the bulge niche of hair follicles, as identified by expression of the specific markers of mouse KSCs, CD34 and cytokeratin 15 (K15). Western blot analysis was used to examine CD34 and K15 protein levels in dorsal skin isolated from SENCAR mice during multi-stage skin carcinogenesis. CD34+/K15+ KSCs were located only in the outer root sheath (ORS) of a specific niche within hair follicles defined as "the bulge". The location of CD34+/K15+ KSCs remained restricted to the bulge region throughout the 22-week time-period examined during which pre-malignant papillomas developed and rapidly expanded. There was a significant decrease in K15 protein levels at 24 h and 15 weeks in dorsal skin treated with DMBA/TPA compared to CD34 protein levels. CD34+ cells within the numerous hair follicles in hyperplastic skin were found to undergo proliferation during the process of multi-stage skin carcinogenesis based on their staining with antibodies directed against proliferating cell nuclear antigen (PCNA). While pAkt was present within the bulge region of hair follicles, pmTOR was present in cells in the ORS of the bulge region as well as the upper infundibulum of hair follicles in dorsal skin treated with acetone. Within papillomas tissues isolated at 15 weeks following DMBA/TPA treatment, pAkt was localized to suprabasal cells with nominal staining of pAkt in the basal cell layer. There were fewer cells within the basal cell layer that contained pmTOR, in addition to the presence of pmTOR in suprabasal cells within papillomas. These results provide first time evidence for pAkt and pmTOR in CD34+/K15+ KSCs localized to the outer root sheath niche of the bulge region of mouse hair follicles. Taken together, the present observations suggest that pAkt and pmTOR may allow this cell population to evade terminal differentiation and to persist for long periods of time in their specific niche. Strategies that target pAkt and pmTOR may deplete both cells within the CD34+/K]5+ KSCs compartment, as well as impacting the survival of nonproliferating suprabasal cells within pre-malignant papillomas.


Complex expression pattern of the CEF-4 cytokine in transformed and mitogenically stimulated cells.
The transformation of chicken embryo fibroblasts (CEF) by the Rous sarcoma virus leads to the constitutive expression of the cellular gene designated CEF-4. With specific antisera, we confirmed that transformed cells actively synthesize and secrete a 6 kDa polypeptide corresponding to the CEF-4 gene product. The expression of CEF-4 was investigated by Northern and immunoprecipitation analyses. Upon activation of pp60v-src in cells infected by a ts mutant of RSV, the expression of CEF-4 was biphasic with an early transient and a late constitutive period of expression. CEF-4 was expressed in cells transformed by a variety of oncogenes, but the level of constitutive expression differed quantitatively among transformed cells. Cells transformed by v-myc alone did not express CEF-4. Unlike other members of the interleukin 8 gene family, CEF-4 was induced in response to a broad spectrum of growth factors and inflammatory agents. Dexamethasone repressed the induction of CEF-4 by lipopolysaccharides but had little or no effect on the response to serum or pp60v-src. These data emphasize the complexity of CEF-4 expression and suggest the existence of multiple levels or pathways of CEF-4 regulation in normal and transformed cells.


High repetition rate atmospheric pressure matrix-assisted laser desorption/ionization in combination with liquid matrices.
One major drawback of matrix-assisted laser desorption/ionization (MALDI) is still the relatively poor pulse-to-pulse reproducibility of the signal intensity. This problem, caused by insufficient homogeneity in the matrix/analyte co-crystallization, is usually circumvented by averaging the detected ion intensity over several shots. However, during the consecutive laser pulses, the applied matrix gets depleted and only a number of subsequent experiments can be done on the same sample spot. In order to achieve the desired long-term stability in combination with a sufficient pulse-to-pulse reproducibility, recently liquid MALDI matrices have been introduced. This contribution demonstrates the promising combination of liquid matrices with high repetition rate lasers for atmospheric pressure MALDI (AP-MALDI). To demonstrate the robustness of the new approach, two different kinds of liquid matrices were used in combination with both a typical flashlamp pumped 15 Hz laser and a diode pumped solid state laser operated at 5 kHz. The latter showed a stable ion signal over more than 3,500,000 consecutive laser pulses.


[Objective assessment of hearing in neonates by registration of brain stem evoked potentials].
A detailed analysis of the findings of registration of short-latent evoked acoustic potentials (SLEP) in neonates with symptoms of ante- and postnatal affection of the central nervous system (CNS) and in healthy children has shown that some SLEP parameters (latent periods, interpeak intervals) in neonates with impaired CNS and healthy infants differ.


Numerical response of a mammalian specialist predator to multiple prey dynamics in Mediterranean farmlands.
The study of rodent population cycles has greatly contributed, both theoretically and empirically, to our understanding of the circumstances under which predator-prey interactions destabilize populations. According to the specialist predator hypothesis, reciprocal interactions between voles and small predators that specialize on voles, such as weasels, can cause multiannual cycles. A fundamental feature of classical weasel-vole models is a long time-lag in the numerical response of the predator to variations in prey abundance: weasel abundance increases with that of voles and peaks approximately 1 yr later. We investigated the numerical response of the common weasel (Mustela nivalis) to fluctuating abundances of common voles (Microtus arvalis) in recently colonized agrosteppes of Castilla-y-Léon, northwestern Spain, at the southern limit of the species' range. Populations of both weasels and voles exhibited multiannual cycles with a 3-yr period. Weasels responded quickly and numerically to changes in common-vole abundance, with a time lag between prey and weasel abundance that did not exceed 4 months and occurred during the breeding season, reflecting the quick conversion of prey into predator offspring and/or immigration to sites with high vole populations. We found no evidence of a sustained, high weasel abundance following vole abundance peaks. Weasel population growth rates showed spatial synchrony across study sites approximately 60 km apart. Weasel dynamics were more synchronized with that of common voles than with other prey species (mice or shrews). However, asynchrony within, as well as among sites, in the abundance of voles and alternative prey suggests that weasel mobility could allow them to avoid starvation during low-vole phases, precluding the emergence of prolonged time lag in the numerical response to voles. Our observations are inconsistent with the specialist predator hypothesis as currently formulated, and suggest that weasels might follow rather than cause the vole cycles in northwestern Spain. The reliance of a specialized predator on a functional group of prey such as small rodents does not necessarily lead to a long delay in the numerical response by the predator, depending on the spatial and interspecific synchrony in prey dynamics.


Culture and cooperation.
Does the cultural background influence the success with which genetically unrelated individuals cooperate in social dilemma situations? In this paper, we provide an answer by analysing the data of Herrmann et al. (2008a), who studied cooperation and punishment in 16 subject pools from six different world cultures (as classified by Inglehart & Baker (2000)). We use analysis of variance to disentangle the importance of cultural background relative to individual heterogeneity and group-level differences in cooperation. We find that culture has a substantial influence on the extent of cooperation, in addition to individual heterogeneity and group-level differences identified by previous research. The significance of this result is that cultural background has a substantial influence on cooperation in otherwise identical environments. This is particularly true in the presence of punishment opportunities.


Toll-like receptors in skin infections and inflammatory diseases.
The skin is the ultimate example of the function of innate immunity, it alerts the host of danger by many systems including sensing pathogen-associated molecule patterns (PAMPs) through Toll-like receptors and other pattern recognition receptors (PRRs), yet normally provides defense without inflammation. The skin responds rapidly to invading microbes by producing antimicrobial peptides or other antimicrobial intermediates before cytokine release results in inflammation. To achieve maximal immune responses for clearing invading microbes, the activation of select PRRs in skin then initiates and shapes adaptive immune responses through the activation of dendritic cells and recruitment of T cell subsets. Importantly, cross-talk between TLRs can influence this system in several ways including augmenting or suppressing the immune response. As a consequence of their pivotal role, TLR responses need to be tightly controlled by associated negative regulators or negative feedback loops to prevent detrimental effects from TLRs overactivation. This review focuses on describing the involvement of TLRs in the development of skin infections and inflammatory diseases, and highlights the potential application of TLR agonists or antagonists in these skin diseases.


A Bayesian approach for mixed effects state-space models under skewness and heavy tails.
Human immunodeficiency virus (HIV) dynamics have been the focus of epidemiological and biostatistical research during the past decades to understand the progression of acquired immunodeficiency syndrome (AIDS) in the population. Although there are several approaches for modeling HIV dynamics, one of the most popular is based on Gaussian mixed-effects models because of its simplicity from the implementation and interpretation viewpoints. However, in some situations, Gaussian mixed-effects models cannot (a) capture serial correlation existing in longitudinal data, (b) deal with missing observations properly, and (c) accommodate skewness and heavy tails frequently presented in patients' profiles. For those cases, mixed-effects state-space models (MESSM) become a powerful tool for modeling correlated observations, including HIV dynamics, because of their flexibility in modeling the unobserved states and the observations in a simple way. Consequently, our proposal considers an MESSM where the observations' error distribution is a skew-t. This new approach is more flexible and can accommodate data sets exhibiting skewness and heavy tails. Under the Bayesian paradigm, an efficient Markov chain Monte Carlo algorithm is implemented. To evaluate the properties of the proposed models, we carried out some exciting simulation studies, including missing data in the generated data sets. Finally, we illustrate our approach with an application in the AIDS Clinical Trial Group Study 315 (ACTG-315) clinical trial data set.


Missense Variant c.3301C>T (p.R1101W) in von Willebrand Factor A Sequence in a Patient with Recessive Dystrophic Epidermolysis Bullosa Pruriginosa with Compound Heterozygous COL7A1 Variants.
Dystrophic epidermolysis bullosa (DEB) pruriginosa is a rare subtype of DEB characterized by multiple, violaceous, and severe pruritic lichenified nodules along with blisters. Here, we report the case of a Korean male who, since the age of 3 years, had multiple pruritic nodules with blisters on both lower extremities. Genetic testing is required to diagnose DEB pruriginosa because its clinical and histologic features are inconclusive. We identified compound heterozygous COL7A1 variants of c.5797C>T (p.R1933*) and c.3301C>T (p.R1101W) in the patient, leading to a diagnosis of recessive DEB pruriginosa. Among the variants identified, c.3301C>T is a novel missense variant that has not been reported previously. This variant is in exon 26, which encodes von Willebrand factor A (vWFA) in collagen type VII. vWFA is known to preserve normal dermal structures by interacting with dermal collagens and basement membranes. Considering that this variant contradicts the general concept that autosomal dominant inheritance is more common and that variants typically occur in the triple helical collagenous domain of COL7A1 in DEB pruriginosa, we focus on the rarity of this case and the possible pathogenic role of the c.3301C>T (p.R1101W) variant.


Choline acetyltransferase activity in rat heart after transplantation.
Choline acetyltransferase (CAT) catalyzes the biosynthesis of acetylcholine according to the chemical equation: Acetyl-CoA + Choline in equilibrium Acetylcholine + CoA. To demonstrate the neuronal relationship of this enzyme, CAT activity was measured in hearts to which the extrinsic innervation was completely interrupted by extirpation of the heart from a donor animal and transplantation in a heterotopic position into the recipient's abdominal cavity. After the animals were killed at 8 days, enzyme activity in the transplanted hearts was measured and compared with that of the recipient. Choline acetyltransferase activity decreased 98% in the right atrium of the transplanted denervated hearts, 94% in the SA node, 87% in the left atrium, 80% in the right ventricle, and about 50% in the interventricular septum and left ventricle. These data show that sectioning the extrinsic parasympathetic innervation to the heart results in variable decreases in CAT activity, a finding which confirms that CAT activity is related to the extrinsic cholinergic innervation. The extrinsic (preganglionic) component of the parasympathetic system is nonuniform and supplies predominantly the specialized regions of the heart with conduction tissue. The residual enzyme activity is related to intrinsic (postganglionic) parasympathetic neurons. The intrinsic component is uniformly distributed to both specialized and contractile regions of the heart.


[Treatment strategy for POEMS syndrome].
POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is a paraneoplastic disease associated with an underlying plasma cell dyscrasia. This syndrome usually progresses slowly and can be life-threatening. No large-scale controlled study providing convincing evidence for the treatment of this rare condition has thus for been conducted. However, several lines of evidence have shown the efficacy of conventional therapies such as radiation, alkylator-based treatment, and corticosteroid therapy. Recent studies have also proposed novel therapeutic strategies such as autologous peripheral blood stem cell transplantation (auto-PBSCT) and thalidomide, lenalidomide, and bevacizumab therapies. We reviewed the current treatment strategies for POEMS syndrome and summarized them as follows; 1) Radiotherapy or surgical resection is highly effective for isolated plasmacytoma. 2) Melphalan-predonisolone administration may be a treatment option for the patients with widespread bone lesions. 3) High dose chemotherapy with auto-PBSCT is a promising novel approach that can lead to dramatic improvement particularly in patients with good systemic condition. 4) Plasma exchange and immunoglobulin treatment are not recommended. 5) Administration of thalidomide and lenalidomide may ameliorate the clinical conditions of the patients who are unable to undergo auto-PBSCT; however, this needs further confirmation. Finally, we emphasized that the efficacy of these therapies largely depends on the appropriate early diagnosis of POEMS syndrome.


Interaction of the metalloprotease disintegrins MDC9 and MDC15 with two SH3 domain-containing proteins, endophilin I and SH3PX1.
Metalloprotease disintegrins (a disintegrin and metalloprotease (ADAM) and metalloprotease, disintegrin, cysteine-rich proteins (MDC)) are a family of membrane-anchored glycoproteins that function in diverse biological processes, including fertilization, neurogenesis, myogenesis, and ectodomain processing of cytokines and other proteins. The cytoplasmic domains of ADAMs often include putative signaling motifs, such as proline-rich SH3 ligand domains, suggesting that interactions with cytoplasmic proteins may affect metalloprotease disintegrin function. Here we report that two SH3 domain-containing proteins, endophilin I (SH3GL2, SH3p4) and a novel SH3 domain- and phox homology (PX) domain-containing protein, termed SH3PX1, can interact with the cytoplasmic domains of the metalloprotease disintegrins MDC9 and MDC15. These interactions were initially identified in a yeast two-hybrid screen and then confirmed using bacterial fusion proteins and co-immunoprecipitations from eukaryotic cells expressing both binding partners. SH3PX1 and endophilin I both preferentially bind the precursor but not the processed form of MDC9 and MDC15 in COS-7 cells. Since rat endophilin I is thought to play a role in synaptic vesicle endocytosis and SH3PX1 has sequence similarity to sorting nexins in yeast, we propose that endophilin I and SH3PX1 may have a role in regulating the function of MDC9 and MDC15 by influencing their intracellular processing, transport, or final subcellular localization.


Congenital Chagas Disease in the Ecuadorian Amazon: Maternal Screening at Delivery and Evaluation of Risk Factors Associated with Vector Exposure.
Congenital infection with Trypanosoma cruzi remains a major route for Chagas disease transmission in endemic and non-endemic regions. We evaluated an intervention strategy aimed to detect congenital Chagas disease cases at a major hospital in the Ecuadorian Amazon via cord blood analysis at the time of delivery. All women giving birth at the hospital during the study period (191) were invited to participate. Among them, two (1.0%) did not adjust to the inclusion criteria and four (2.1%) declined to participate in the study, showing the intervention had good acceptability among the mothers. It was possible to obtain cord blood samples during 146 of the deliveries, and only one woman was found to be seropositive, without evidence of transmission to the newborn at delivery or 8 months later. In addition, sociodemographic and economic characterization of the study population revealed that few women had previous knowledge about Chagas disease (16.1%) whereas more than half (62.5%) recognized the vector. Recognizing the vector and having seen it indoors were associated with women from rural families, involved in agriculture, and hunting in the forest. Interestingly, most women (87.3%) reported having easy access to Ecuador's national health system, suggesting serological screening during prenatal visits would be of value in this province. With a proper prenatal screening system in place, cord blood screening would allow for timely detection of T. cruzi infection in newborns from both seropositive women and the minority (2.1%) of women who do not comply with prenatal care visits.


Little to no inbreeding depression in a tapeworm with mixed mating.
Meta-studies on hermaphrodites have found a negative relationship between primary selfing rates and levels of inbreeding depression (ID) and, thus, generally support purging in inbred systems. However, in plants, high among-taxa variance in ID results in no difference in the mean ID between outcrossing and mixed-mating taxa. Selective interference likely explains high ID among mixed-mating taxa, whereas low levels of ID among mixed-mating taxa are not as stressed. Among animal hermaphrodites, primarily molluscs, there are little data on mixed-mating systems. To fill a taxonomic and mating system gap, we tested for ID in a mixed-mating tapeworm, Oochoristica javaensis. We provide a direct estimate of ID across infection of an intermediate host by comparing selfing rates at two life history stages. We found little to no evidence for ID, and the level of ID falls in line with what is reported for highly selfing species even though O. javaensis has mixed mating. We discuss this result within the context of kin mating in O. javaensis. Our results emphasize that primary selfing rates alone may be insufficient to classify the inbreeding history in all species when testing for a relationship to ID. Mixed-mating taxa, and possibly some outcrossing taxa, may exhibit low levels of ID if biparental inbreeding is also driving purging. We advocate that ID studies report estimates of inbreeding history (e.g. FIS or identity disequilibrium) from nature-derived adult samples to provide context rather than relying on primary selfing rates alone.


Enhanced reinstatement of naturalistic event memories due to hippocampal-network-targeted stimulation.
Episodic memory involves the reinstatement of distributed patterns of brain activity present when events were initially experienced. The hippocampus is thought to coordinate reinstatement via its interactions with a network of brain regions, but this hypothesis has not been causally tested in humans. The current study directly tested the involvement of the hippocampal network in reinstatement using network-targeted noninvasive stimulation. We measured reinstatement of multi-voxel patterns of functional magnetic resonance imaging (fMRI) activity during encoding and retrieval of naturalistic video clips depicting everyday activities. Reinstatement of video-specific activity patterns was robust in posterior parietal and occipital areas previously implicated in event reinstatement. Theta-burst stimulation targeting the hippocampal network increased video-specific reinstatement of fMRI activity patterns in occipital cortex and improved memory accuracy relative to stimulation of a control out-of-network location. Furthermore, stimulation targeting the hippocampal network influenced the trial-by-trial relationship between hippocampal activity during encoding and later reinstatement in occipital cortex. These findings implicate the hippocampal network in the reinstatement of spatially distributed patterns of event-specific activity and identify a role for the hippocampus in encoding complex naturalistic events that later undergo cortical reinstatement.


Is N-methylacetazolamide a possible new therapy against ischemia-reperfusion injury?
The increase of intracellular Ca2+ concentration, produced principally by its influx through the L-type Ca2+ channels, is one of the major contributors to the ischemia-reperfusion injury. The inhibition of those channels in different experimental models was effective to ameliorate the post-ischemic damage. However, at a clinical level, the results were contradictory. Recent results of our group obtained in an ¨ex vivo¨ heart model demonstrated that a chemical derived from acetazolamide, the N-methylacetazolamide (NMA) protected the heart against ischemia-reperfusion injury, diminishing the infarct size and improving the post-ischemic recovery of myocardial function and mitochondrial dynamic. A significant inhibitory action on L-type Ca2+ channels was also detected after NMA treatment, suggesting this action as responsible for the beneficial effects on myocardium exerted by this compound. Although these results were promising, the effectiveness of NMA in the treatment of ischemic heart disease in humans as well as the advantages or disadvantages in comparison to the classic calcium antagonists needs to be investigated.


Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice.
Angiotensin II (Ang II)-mediated activation of its type I receptor (AT1R) in the central nervous system promotes glial proliferation, local inflammation, and a decrease of cerebral blood flow. Angiotensin-(1-7) (Ang-(1-7))-an Ang II derivative peptide-signals through the Mas receptor (MasR) in opposition to Ang II/AT1R, promoting anti-inflammatory, vasodilatory, and neuroprotective effects. As our laboratory has previously demonstrated beneficial effects of AT1R inhibition following controlled cortical impact (CCI) in mice, we asked whether activation of Ang-(1-7)/MasR signaling would also be beneficial in this model. Adult male C57BL/6 mice were injured by CCI. Ang-(1-7) or vehicle was administered subcutaneously (S.Q.) at 1 mg/kg/day at 1 or 6 h post-injury, until animals were sacrificed at 3 or 29 days post-injury (dpi). Ang-(1-7) attenuated motor deficits at 3 dpi and improved performance in the Morris Water Maze at 28 dpi. Brain histology or magnetic resonance imaging (MRI) indicated that Ang-(1-7)-treated mice had smaller lesion volumes at 3, 10, 24, and 29 dpi. Pre-treatment with A779, a MasR antagonist, prevented Ang-(1-7) from reducing lesion volume at 3 dpi, suggesting that the benefits of Ang-(1-7) were MasR-dependent. Immunohistochemistry revealed that Ang-(1-7) reduced microgliosis at 3 and 29 dpi, and astrogliosis at 29 dpi. Ang-(1-7) decreased neuronal and capillary loss at 29 dpi. In summary, S.Q. administration of Ang-(1-7) after injury had anti-inflammatory, neuroprotective, and cerebrovascular-protective actions leading to improved functional and pathological recovery in a mouse model of traumatic brain injury (TBI). These data show for the first time that Ang-(1-7) has potential therapeutic use for TBI.


Enhanced staging and all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma.
Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma. All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m(2)/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m(2)/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed. All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma (>/= 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity. It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.


Examining the immunotoxicity of oil sands process affected waters using a human macrophage cell line.
Oil sands process affected water (OSPW) is produced during the surface mining of the oil sands bitumen deposits in Northern Alberta. OSPW contains variable quantities of organic and inorganic components causing toxic effects on living organisms. Advanced Oxidation Processes (AOPs) are widely used to degrade toxic organic components from OSPW including naphthenic acids (NAs). However, there is no established biological procedure to assess the effectiveness of the remediation processes. Our previous study showed that human macrophage cells (THP-1) can be used as a bioindicator system to evaluate the effectiveness of OSPW treatments through examining the proinflammatory gene transcription levels. In the present study, we investigated the immunotoxicological changes in THP-1 cells following exposure to untreated and AOP-treated OSPW. Specifically, using proinflammatory cytokine protein secretion assays we showed that AOP treatment significantly abrogates the ability of OSPW to induce the secretion of IL-1β, IL-6, IL-8, TNF-α, IL-1Ra and MCP-1. By measuring transcriptional activity as well as surface protein expression levels, we also showed that two select immune cell surface markers, CD40 and CD54, were significantly elevated following OSPW exposure. However, AOP treatments abolished the immunostimulatory properties of OSPW to enhance the surface expression of these immune proteins. Finally, a transcriptome-based approach was used to examine the proinflammatory effects of OSPW as well as the abrogation of immunotoxicity following AOP treatments. Overall, this research shows how a human macrophage cell-based biomonitoring system serves as an effective in vitro tool to study the immunotoxicity of OSPW samples before and after targeted remediation strategies.


Structure and dynamics of cylindrical micelles at equilibrium and under shear flow.
The dynamics and rheology of semidilute unentangled micellar solutions are investigated by Langevin dynamics mesoscopic simulations coupled to a microreversible kinetic model for scissions and recombinations. Two equilibrium state points, differing by the scission energy and therefore by the corresponding average micelle length, have been examined. The kinetic rates are tuned by an independent parameter of the model, whose range is chosen in such a way that the kinetics always strongly couple to the chain dynamics. Our results confirm, as predicted by Faivre and Gardissat, that the stress relaxation, as well as the monomer diffusion, is characterized by a time tauLambda, defined by the lifetime of a segment Lambda, whose Rouse relaxation time is equal to its lifetime. Moreover, the power-law dependence of the zero-shear viscosity versus tauLambda was evidenced. Under stationary shear, the chains are deformed and their average bond length is increased, which enhances the overall scission frequency. In turn, this induces an overall shortening of the chains in order to increase the overall corresponding chain-end recombination frequency, as required by the stationary conditions. Nonequilibrium simulations show that the chain deformation and orientation, as well as the rheology of the system, can be expressed as universal functions of a single reduced shear rate betaLambda=gammatauLambda (with gamma the bare shear rate). Furthermore, local analysis of the kinetics under stationary shear gives insights on the variation of the average length with shear rate.


β2 integrin-mediated crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed blood-brain barrier.
In acute neuroinflammatory states such as meningitis, neutrophils cross the blood-brain barrier (BBB) and contribute to pathological alterations of cerebral function. The mechanisms that govern neutrophil migration across the BBB are ill defined. Using live-cell imaging, we show that LPS-stimulated BBB endothelium supports neutrophil arrest, crawling, and diapedesis under physiological flow in vitro. Investigating the interactions of neutrophils from wild-type, CD11a(-/-), CD11b(-/-), and CD18(null) mice with wild-type, junctional adhesion molecule-A(-/-), ICAM-1(null), ICAM-2(-/-), or ICAM-1(null)/ICAM-2(-/-) primary mouse brain microvascular endothelial cells, we demonstrate that neutrophil arrest, polarization, and crawling required G-protein-coupled receptor-dependent activation of β2 integrins and binding to endothelial ICAM-1. LFA-1 was the prevailing ligand for endothelial ICAM-1 in mediating neutrophil shear resistant arrest, whereas Mac-1 was dominant over LFA-1 in mediating neutrophil polarization on the BBB in vitro. Neutrophil crawling was mediated by endothelial ICAM-1 and ICAM-2 and neutrophil LFA-1 and Mac-1. In the absence of crawling, few neutrophils maintained adhesive interactions with the BBB endothelium by remaining either stationary on endothelial junctions or displaying transient adhesive interactions characterized by a fast displacement on the endothelium along the direction of flow. Diapedesis of stationary neutrophils was unchanged by the lack of endothelial ICAM-1 and ICAM-2 and occurred exclusively via the paracellular pathway. Crawling neutrophils, although preferentially crossing the BBB through the endothelial junctions, could additionally breach the BBB via the transcellular route. Thus, β2 integrin-mediated neutrophil crawling on endothelial ICAM-1 and ICAM-2 is a prerequisite for transcellular neutrophil diapedesis across the inflamed BBB.


Regiodivergent Baeyer-Villiger oxidation of fused ketones by recombinant whole-cell biocatalysts.
Recombinant Escherichia coli cells expressing monooxygenases of different bacterial origin were evaluated in microbial Baeyer-Villiger oxidations of racemic fused ketones. During the enzymatic oxidation process, both the "normal" lactone generated by migration of the more-substituted carbon atom and/or the "abnormal" lactone resulting from migration of the less-substituted carbon atom can be formed. Depending on the nature of the Baeyer-Villiger monooxygenase, either a regiodivergent biooxygenation to both lactones in high optical purities was observed or essentially racemic "normal" rearrangement product was formed. The complementary behavior of enzymes was found to correlate with our previous observation of clustering of cycloketone-oxidizing proteins into two distinct clusters based on phylogenetic relationship and biocatalyst performance.


[Clinical and X-ray characteristics of first detected intrathoracic lymph node tuberculosis in children].
Sixty-two case histories of Moscow children aged 4-12 years, treated at the Central Research Institute of Tuberculosis, Russian Academy of Medical Sciences, for first detected intrathoracic lymph node tuberculosis (ITLNT), were studied. Planned and prophylactic studies revealed the disease in 95.1% (including 66.1% after mass tuberculin diagnosis and 29% on examination for their contact). The disease was more commonly asymptomatic. Mild or moderate signs of the total disorder syndrome were prevalent in the clinical picture. In 56.5% of cases, a tuberculous process was detected in the phase of consolidation and calcinations. Among the patients with intrathoracic lymph nodal changes in the infiltration phase, the children with minor forms of ITLNT whose diagnosis was verified by computed tomography were 72.7%. The use of computed tomography in the diagnosis of ITLNT allowed one to make the fullest evaluation of changes in intrathoracic lymph nodes, including the groups of the anterior and posterior mediastinum.


Investigation of optical absorptance of one-dimensionally periodic silicon gratings as solar absorbers for solar cells.
A rigorous design using periodic silicon (Si) gratings as absorbers for solar cells in visible and near-infrared regions is numerically presented. The structure consists of a subwavelength Si grating layer on top of an Si substrate. Ranges of grating dimensions are preliminary considered satisfying simple and feasible fabrication techniques with an aspect ratio defined as the ratio of the grating thickness (d) and the grating lamella width (w), with 0 < d/w < 1.0. The subwavelength grating structure (SGS) is assumed to comprise different lamella widths and slits within each period in order to finely tune the grating profile such that the absorptance is significantly enhanced in the whole wavelength region. The results showed that the compound SGS yields an average absorptance of 0.92 which is 1.5 larger than that of the Si plain and conventional grating structures. It is shown that the absorptance spectrum of the proposed SGS is insensitive to the angle of incidence of the incoming light. The absorptance enhancement is also investigated by computing magnetic field, energy density, and Poynting vector distributions. The results presented in this study show that the proposed method based on nanofabrication techniques provides a simple and promising solution to design solar energy absorbers or other energy harvesting devices.


DNA double-strand breaks associated with replication forks are predominantly repaired by homologous recombination involving an exchange mechanism in mammalian cells.
DNA double-strand breaks (DSB) represent a major disruption in the integrity of the genome. DSB can be generated when a replication fork encounters a DNA lesion. Recombinational repair is known to resolve such replication fork-associated DSB, but the molecular mechanism of this repair process is poorly understood in mammalian cells. In the present study, we investigated the molecular mechanism by which recombination resolves camptothecin (CPT)-induced DSB at DNA replication forks. The frequency of homologous recombination (HR) was measured using V79/SPD8 cells which contain a duplication in the endogenous hprt gene that is resolved by HR. We demonstrate that DSB associated with replication forks induce HR at the hprt gene in early S phase. Further analysis revealed that these HR events involve an exchange mechanism. Both the irs1SF and V3-3 cell lines, which are deficient in HR and non-homologous end joining (NHEJ), respectively, were found to be more sensitive than wild-type cells to DSB associated with replication forks. The irs1SF cell line was more sensitive in this respect than V3-3 cells, an observation consistent with the hypothesis that DSB associated with replication forks are repaired primarily by HR. The frequency of formation of DSB associated with replication forks was not affected in HR and NHEJ deficient cells, indicating that the loss of repair, rather than the formation of DSB associated with replication forks is responsible for the increased sensitivity of the mutant strains. We propose that the presence of DSB associated with replication forks rapidly induces HR via an exchange mechanism and that HR plays a more prominent role in the repair of such DSB than does NHEJ.


Nonlinear photonics on-a-chip in III-V semiconductors: quest for promising material candidates.
We propose several designs of nonlinear optical waveguides based on quaternary III-V semiconductors AlGaAsSb and InGaAsP. These semiconductor materials have been widely used for laser sources. Their nonlinear optical properties, however, yet remain unexplored, while the materials definitely hold promise for nonlinear photonics on-a-chip. The latter argument is based on the fact that III-V compounds tend to exhibit high values of the nonlinear optical susceptibilities, while the nonlinear absorption in these materials can be minimized in the wavelength range of interest through a proper selection of the material composition. We present the modal analysis for the designed waveguide structures and show that the effective mode area much less than 1 μm2 can be achieved through a design optimization in each of the two compounds. We also present specific waveguide designs that demonstrate zero dispersion at the wavelengths of interest. The designed AlGaAsSb and InGaAsP waveguides are thus expected to demonstrate high values of the nonlinear coefficient and efficient nonlinear optical interactions.


Physical fitness, muscle morphology, and insulin-stimulated limb blood flow in normal subjects.
The response of limb blood flow to insulin is highly variable even in normal subjects. We examined whether physical fitness or differences in muscle morphology contribute to this variation. Maximal aerobic power, muscle fiber composition and capillarization, and the response of forearm glucose extraction and blood flow to a sequential hyperinsulinemic euglycemic clamp (serum insulin 374 +/- 10, 816 +/- 23, and 2,768 +/- 78 pmol/l) were determined in 16 normal males (age 25 +/- 1 yr, body mass index 24 +/- 1 kg/m2). Maximal aerobic power correlated positively with the proportion of type I fibers (r = 0.67, P < 0.01) and negatively with the proportion of type IIb fibers (r = -0.73, P < 0.01). Fiber composition but not blood flow correlated significantly with forearm and whole body glucose uptake. All doses of insulin significantly increased forearm blood flow, maximally by 123 +/- 21%. The ratio of capillaries per fiber was significantly correlated with basal and insulin-stimulated blood flow (0.58- 0.76, P < 0.05-0.01). Mean arterial blood pressure and the insulin-induced increase in blood flow were inversely correlated (r = -0.59, P < 0.05). We conclude that variation in glucose extraction is significantly determined by muscle fiber composition, whereas variation in insulin-stimulated blood flow is closely associated with muscle capillarization.


Altered physiology of acid secretion in depression-prone Flinders rats results in exacerbated NSAID and stress-induced gastric damage.
Flinders Sensitive Line (FSL) rats are characterized by hypersensitivity to cholinergic stimuli and have been extensively used for studying depressive disorders. A link between depression and peptic ulcers has long been established; however, there is a lack of data from animal models. We studied the physiology of acid secretion in FSL and Flinders Resistant Line (FRL) rats in vivo and in vitro. We also examined the susceptibility of Flinders rats to water immersion restraint stress (WIRS) or NSAID-induced gastric damage and explored the effect of an anticholinergic agent, atropine, in reversing this effect. Basal acid output was more than twofold greater in FSL compared with FRL rats in vivo, 213.5 and 92.8 μEq/3 h/100 g (P = 0.02), respectively. Carbachol was a more potent secretagog in vitro, and somatostatin was a less potent inhibitory agent, while paradoxically stimulating acid secretion over and above the carbachol response in gastric glands from FSL rats. The FSL rats were more susceptible to indomethacin and WIRS-induced gastric mucosal damage compared with FRL rats. Atropine reduced acid output, which resulted in a reduction in indomethacin and stress-induced gastric damage in FSL rats. Our study, for the first time, demonstrates that the altered vagally mediated physiology of acid secretion in depression-prone FSL rats contributes to gastric hypersecretion and, consequently, results in exacerbated stress and NSAID-induced gastric damage. Flinders rats may be a useful animal model for studying acid-related and also gastrointestinal functional disorders in depression.


Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: a global systematic review and meta-analysis.
People with severe mental illness (schizophrenia, bipolar disorder or major depressive disorder) die up to 15 years prematurely due to chronic somatic comorbidities. Sedentary behavior and low physical activity are independent yet modifiable risk factors for cardiovascular disease and premature mortality in these people. A comprehensive meta-analysis exploring these risk factors is lacking in this vulnerable population. We conducted a meta-analysis investigating sedentary behavior and physical activity levels and their correlates in people with severe mental illness. Major electronic databases were searched from inception up to April 2017 for articles measuring sedentary behavior and/or physical activity with a self-report questionnaire or an objective measure (e.g., accelerometer). Random effects meta-analyses and meta-regression analyses were conducted. Sixty-nine studies were included (N=35,682; 39.5% male; mean age 43.0 years). People with severe mental illness spent on average 476.0 min per day (95% CI: 407.3-545.4) being sedentary during waking hours, and were significantly more sedentary than age- and gender-matched healthy controls (p=0.003). Their mean amount of moderate or vigorous physical activity was 38.4 min per day (95% CI: 32.0-44.8), being significantly lower than that of healthy controls (p=0.002 for moderate activity, p<0.001 for vigorous activity). People with severe mental illness were significantly less likely than matched healthy controls to meet physical activity guidelines (odds ratio = 1.5; 95% CI: 1.1-2.0, p<0.001, I2 =95.8). Lower physical activity levels and non-compliance with physical activity guidelines were associated with male gender, being single, unemployment, fewer years of education, higher body mass index, longer illness duration, antidepressant and antipsychotic medication use, lower cardiorespiratory fitness and a diagnosis of schizophrenia. People with bipolar disorder were the most physically active, yet spent most time being sedentary. Geographical differences were detected, and inpatients were more active than outpatients and those living in the community. Given the established health benefits of physical activity and its low levels in people with severe mental illness, future interventions specifically targeting the prevention of physical inactivity and sedentary behavior are warranted in this population.


Dual oxidase 2 is essential for house dust mite-induced pro-inflammatory cytokine production in human keratinocytes.
House dust mites (HDMs) are known to trigger chronic inflammation through Toll-like receptors (TLRs) and their signalling cascades. In this study, we found that TLR2 ligation by HDMs induced the activation of dual oxidase 2 (Duox2) and nuclear factor-κB (NF-κB), leading to the production of pro-inflammatory cytokines in human keratinocytes. Stimulation of human keratinocytes with HDMs resulted in increases in interleukin-8 (IL-8) and chemokine (C-C motif) ligand 20 (CCL20) levels. However, pro-inflammatory cytokine production was abolished in keratinocytes transfected with TLR2 siRNA, indicating that HDM-induced cytokine production was mediated via TLR2 signalling. We also examined the function of Duox1/2 isozymes, which are primarily expressed in keratinocytes, in HDM-mediated pro-inflammatory cytokine production. Human keratinocytes transfected with control siRNA or Duox1 siRNA showed no inhibition of IL-8 or CCL20 production in response to HDMs, whereas the silencing of Duox2 expression resulted in a failure to induce cytokine production. Moreover, the phosphorylation and nuclear localization of RelA/p65, a component of NF-κB, were induced by HDMs in human keratinocytes. Transfection of human keratinocytes with TLR2 siRNA or Duox2 siRNA resulted in the complete abolishment of RelA/p65 nuclear localization in response to HDMs. Taken together, these results indicate that the HDM-dependent TLR2-Duox2 signalling axis indeed promotes NF-κB activation, which induces IL-8 and CCL20 production and mediates epidermal keratinocyte inflammation.


Maternal serum folate and vitamin B12 concentrations in pregnancies associated with neural tube defects.
Serum folate and vitamin B12 concentrations in early pregnancy were compared for 32 mothers with pregnancies affected by neural tube defects and 395 randomly selected pregnant control women from the same maternity hospitals. No significant differences were found between the affected mothers and the controls in the median values and frequency distributions of either vitamin. Sixteen of the samples from mothers whose infants had neural tube defects were taken between 9 and 13 weeks' gestation and 11 of these had both serum folate and vitamin B12 concentrations within the normal ranges for our laboratory. These findings are discussed in relation to the concept of folate deficiency as a major factor in the aetiology of neural tube defects.


Capecitabine induces both cardiomyopathy and multifocal cerebral leukoencephalopathy.
Chemotherapy for malignant tumors has diversified, and recognizing its side effects has become more important than ever. Both cardiotoxicity and neurotoxicity are rare, but they are among the most serious side effects caused by 5-fluorouracil (5-FU). Capecitabine is an orally administered prodrug that converts preferentially to 5-FU within tumors, resulting in enhanced concentrations of 5-FU in tumor tissue. Given that it targets tumor tissue, capecitabine was expected to reduce the risk of side effects associated with fluoropyrimidine. Here, we present the case of a 62-year-old man with colorectal adenocarcinoma who simultaneously experienced cardiomyopathy with cardiogenic shock and cerebral leukoencephalopathy during treatment with capecitabine. During emergency coronary angiography, ST-segment elevation and severely reduced left ventricular wall motion were observed; however, no severe coronary stenosis or spasm was revealed. Furthermore, we present a review of the literature on capecitabine-induced cardiotoxicity. As of April 2013, 39 case reports on capecitabine-induced cardiotoxicity have been published; however, cardiomyopathy was very rare, with only 3 cases reported. It is important for physicians to be aware of the various rare, but potentially serious, adverse effects associated with capecitabine chemotherapy and to inform patients about the possibility of these side effects, including cardiotoxicity and neurotoxicity.


Introducing a Clinical Summary Template From the Adult Day Center to Support Decision Making by Primary Care Providers.
CareMOBI (Mhealth for Organizations to Bolster Interconnectedness) is a mobile application designed to facilitate information exchange between primary care providers (PCPs) and adult day centers (ADCs). A key function of CareMOBI is to synthesize information collected outside of the provider's office (ie,: in the ADC or at home) and distill the most relevant data points into an exportable clinical summary that can help inform clinical decision making by the PCP with information from outside providers who are not formally embedded within health systems. In this study, we used a qualitative approach to understand the acceptability and utility of the clinical summary template within CareMOBI. Purposive sampling, followed by snowball sampling, was used to recruit PCPs from a variety of primary care practice settings (i.e. home-based, academic). Semi-structured interviews were conducted virtually to elicit feedback on the user-experience after interaction with a prototype template. Interviews were recorded, transcribed, and analyzed using content analysis. Our sample (n = 10) consisted of physicians and nurse practitioners in a variety of settings. Feedback suggested that the summary template facilitates interdisciplinary, bidirectional, succinct, and relevant information exchange across care teams. The summary template effectively integrates observations and assessments from team members, centralizes them, and allows PCPs to hone in on the most salient components to inform clinical decision making for the geriatric patient. The summary gave PCPs "live texture" about what was happening outside the office and represented a significant improvement over other methodologies of information exchange. Prior to implementation into clinical practice, several refinements are necessary based on feedback including integration into the PCP's workflow. The template was viewed by PCPs as a concise and actionable record, in contrast to current communication which is characterized as "bloated"-containing too many pages on nonessential information. The summary could potentially save PCP's time in locating and analyzing historical data to enable rapid patient assessment and prompt more ready and informed action.


Survey of the levels of satisfaction with pharmacy practice among third-year students in the Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido--influence of experience in voluntary training at a community pharmacy and plans after graduation.
Pharmacy practice, which is executed in the taught of pharmaceutical sciences in Japan, has been assessed and improved student questionnaires. The levels of student satisfaction with the practice are expected to be influenced by their plans after graduation and their experience of training in pharmacies. However, there are few reports analyzing the information in the questionnaires from these viewpoints. In this report, we surveyed the levels of satisfaction of 148 third-year students in the Faculty of Pharmaceutical Sciences of the Health Sciences University of Hokkaido using questionnaires and analyzed the influence of the students' background on the levels of satisfaction with pharmacy practice. Almost half of the students had received voluntary training in hospital and/or community pharmacies. Concerning plans after graduation, 36.5%, 27.7%, and 21.6% wanted to become community pharmacists, hospital pharmacists, and graduate students, respectively. More than 70% of the students were well satisfied with all the programs of practice. The levels of satisfaction with the overall practice and prescription analysis were significantly higher among students who had experienced training in pharmacies than among those who had not. Students who planned to become hospital pharmacists were more satisfied with manners seminars, one-dose package practice, and practice in a simulated pharmacy than the students who planned to enter the other field. Such surveys are useful for finding points for improvement and the development of new curricula when the assessment of pharmacy practice takes student background into consideration.


Genomic priorities and public health.
Given the continuing difficulty of identifying genes for complex disorders in a robust, replicable manner, and the extensive resources devoted to this effort, it is becoming increasingly important to analyze the relative benefits of genomics research for public health applications and for the understanding of disease pathogenesis. To establish priorities for genetics research, we review and evaluate several characteristics of selected exemplary complex diseases, including phenotypic accuracy, knowledge of specific and nonspecific genetic and environmental risk factors, and population prevalence and impact. We propose that complex diseases with the strongest evidence for genetic etiology, limited ability to modify exposure or risk factors, and high public health impact should have the highest priority for genetics research.


Eosinophilia-myalgia syndrome, eosinophilic fasciitis, and related fibrosing disorders.
Clinically distinct fibrosing processes affecting the skin, selected internal organs, or both in a characteristic pattern are a common cause of morbidity. In addition to systemic sclerosis, the prototype idiopathic fibrosing disorder, these conditions include the eosinophilia-myalgia syndrome, epidemic toxic oil syndrome, eosinophilic fasciitis, localized forms of scleroderma, keloid, and the newly described entity of fibrosing colonopathy. The pathogenesis of these disorders, although still incompletely understood, appears to share similarities with that of systemic sclerosis. Insights into these diseases have recently emerged from epidemiologic and toxicoepidemiologic investigations, in situ hybridization and polymerase chain reaction amplification of target genomes, and in vivo and in vitro experimental research. Minor contaminants in food supplements, activation and degranulation of eosinophils, altered expression of CD34 antigen on dendritic cells, disordered regulation of fibroblast apoptosis and proliferation, infection with Borrelia organisms, and cytokines such as transforming growth factor-beta, interleukin-4, and connective tissue growth factor are implicated in inducing an accentuated and persistent fibrogenic host response to injury, resulting in tissue fibrosis. In addition, humoral and cellular autoimmunity may also be implicated.


Study of the Therapeutic Effects of Intercessory Prayer (STEP) in cardiac bypass patients: a multicenter randomized trial of uncertainty and certainty of receiving intercessory prayer.
Intercessory prayer is widely believed to influence recovery from illness, but claims of benefits are not supported by well-controlled clinical trials. Prior studies have not addressed whether prayer itself or knowledge/certainty that prayer is being provided may influence outcome. We evaluated whether (1) receiving intercessory prayer or (2) being certain of receiving intercessory prayer was associated with uncomplicated recovery after coronary artery bypass graft (CABG) surgery. Patients at 6 US hospitals were randomly assigned to 1 of 3 groups: 604 received intercessory prayer after being informed that they may or may not receive prayer; 597 did not receive intercessory prayer also after being informed that they may or may not receive prayer; and 601 received intercessory prayer after being informed they would receive prayer. Intercessory prayer was provided for 14 days, starting the night before CABG. The primary outcome was presence of any complication within 30 days of CABG. Secondary outcomes were any major event and mortality. In the 2 groups uncertain about receiving intercessory prayer, complications occurred in 52% (315/604) of patients who received intercessory prayer versus 51% (304/597) of those who did not (relative risk 1.02, 95% CI 0.92-1.15). Complications occurred in 59% (352/601) of patients certain of receiving intercessory prayer compared with the 52% (315/604) of those uncertain of receiving intercessory prayer (relative risk 1.14, 95% CI 1.02-1.28). Major events and 30-day mortality were similar across the 3 groups. Intercessory prayer itself had no effect on complication-free recovery from CABG, but certainty of receiving intercessory prayer was associated with a higher incidence of complications.


Apoptosis as a Mechanism of the Cancer Chemopreventive Activity of Glucosinolates: a Review
Cruciferous vegetables are a rich source of glucosinolates that have established anti-carcinogenic activity. Naturally-occurring glucosinolates and their derivative isothiocyanates (ITCs), generated as a result of their enzymatic degradation catalysed by myrosinase, have been linked to low cancer incidence in epidemiological studies, and in animal models isothiocyanates suppressed chemically-induced tumorigenesis. The prospective effect of isothiocyanates as anti-carcinogenic agent has been much explored as cytotoxic against wide array of cancer cell lines and being explored for the development of new anticancer drugs. However, the mechanisms of isothiocyanates in inducing apoptosis against tumor cell lines are still largely disregarded. A number of mechanisms are believed to be involved in the glucosinolate-induced suppression of carcinogenesis, including the induction of apoptosis, biotransformation of xenobiotic metabolism, oxidative stress, alteration of caspase activity, angiogenesis, histone deacytylation and cell cycle arrest. The molecular mechanisms through which isothiocyanates stimulate apoptosis in cancer cell lines have not so far been clearly defined. This review summarizes the underlying mechanisms through which isothiocyanates modify the apoptotic pathway leading to cell death.


Personality disorders and criminal law: an international perspective.
At the International War Crimes Tribunal for the Former Yugoslavia (ICTY), a detention camp guard, charged with acts of murder and torture, advanced a plea of diminished responsibility. Defense psychiatrists testified that he had a personality disorder that influenced his ability to control his behavior, but a prosecution expert testified that the guard did not meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. Thus, the unresolved question of how the law defines a mental disease or defect for purposes of mitigation or excuse was transposed to an international setting. It has been argued in a variety of jurisdictions and national legal systems that exculpatory mental disorders must be serious, and personality disorders should not qualify. In fact, it has been proposed that the volitional aspect of excuse defenses be eliminated, and definitions of mental disease or defect narrowed. Others have argued that such exclusions are too restrictive and arbitrary. This article examines the criminal defense at ICTY and traces its origin in national jurisdictions. Mental incapacity defenses based on personality disorders are more often used in The Netherlands, England, Germany and Belgium, but seldom in Canada and rarely in the United States and Sweden.


Effect of primary empty sella syndrome on pituitary surgery for Cushing's disease.
Primary empty sella syndrome (ESS) results from herniation of arachnoid mater into the pituitary fossa. It has been suggested to have a negative effect on pituitary surgery; however, outcomes in this cohort have not been defined. This study was performed to determine the effect of ESS on immediate and long-term biochemical outcome after pituitary surgery for Cushing's disease (CD). Using a matched cohort study design, the authors followed patients treated with pituitary surgery for CD with and without ESS. Complete ESS was defined as pituitary gland height ≤ 2 mm, whereas partial ESS was defined as pituitary gland height > 2 mm but less than three-quarters of the total sellar depth. The primary end points were immediate and long-term biochemical outcome. Cerebrospinal fluid leaks were recorded as a secondary end point. Seventy-eight patients with CD and primary ESS were identified and matched with 78 patients with CD without ESS. After surgical management, immediate biochemical remission was achieved in 69 patients (88%) with ESS and 75 controls (96%, p = 0.10). Long-term remission was achieved in most patients in both groups (5-year cure: 85% vs 92%, p = 0.10). Among patients with ESS, the presence of complete ESS predicted a worse long-term outcome (p = 0.04). Intraoperative CSF leaks were significantly more frequent with ESS (54% vs 24%, p < 0.001), and despite sellar floor repair, the rate of postoperative CSF leaks was also increased (6% vs 3%, p = 0.27). Biochemical outcome after pituitary surgery for CD was worse in patients with complete ESS, and the risk of a CSF leak was increased with both partial and complete ESS. However, as outcome remains superior to those following alternative therapies and the biology of these tumors is unchanged in the setting of ESS, pituitary surgery should remain the initial treatment of choice.


Long-Term Outcomes of Liver Transplantation for the Management of Neuroendocrine Neoplasms: A Systematic Review.
Liver transplantation is an uncommonly used, controversially debated therapeutic approach for highly selected individuals with neuroendocrine liver metastases. Synthesising evidence regarding outcomes from this approach is crucial to understand its position within the broad neuroendocrine liver metastases armamentarium. In this narrative systematic review of studies published in PubMed, Scopus and OVID until 1 July 2021, we summarise and critically appraise the existing literature regarding this modality, with a special focus on long-term outcomes data where possible. Fourteen studies were identified that reported outcomes from the use of liver transplantation for metastatic neuroendocrine neoplasms. No randomised trials were identified. Generally, indications and selection criteria were poorly articulated, with the notable exception of studies using the Milan criteria. The median 5-year overall survival was 65% (ranging from 36% to 97.2%, 11 studies), and the median 10-year overall survival was 50% (ranging from 46.1% to 88.8%, 3 studies). One additional study focussed on treatments and outcomes following post-transplant recurrence. No studies reported outcomes past 10 years. Further follow-up of the largest series with explicit selection criteria will deepen our understanding of the role that transplantation has to play in this setting.


RNA interference in Histoplasma capsulatum demonstrates a role for alpha-(1,3)-glucan in virulence.
Histoplasma capsulatum is a fungal pathogen that causes respiratory and systemic disease by proliferating within macrophages. While much is known about histoplasmosis, only a single virulence factor has been defined, in part because of the inefficiency of Histoplasma reverse genetics. As an alternative to allelic replacement, we have developed a telomeric plasmid-based system for silencing gene expression in Histoplasma by RNA interference (RNAi). Episomal expression of long RNAs that form stem-loop structures triggered gene silencing. To test the effectiveness of RNAi in Histoplasma, we depleted expression of a gfp transgene as well as two endogenous genes, ADE2 and URA5, and showed significant reductions in corresponding gene function. Silencing was target gene specific, stable during macrophage infection and reversible. We used RNAi targeting AGS1 (encoding alpha-(1,3)-glucan synthase) to deplete levels of alpha-(1,3)-glucan, a cell wall polysaccharide. Loss of alpha-(1,3)-glucan by RNAi yielded phenotypes indistinguishable from an AGS1 deletion: attenuation of the ability to kill macrophages and colonize murine lungs. This demonstrates for the first time that alpha-(1,3)-glucan is an important contributor to Histoplasma virulence.


Effects of simulated pulmonary surfactant on the cytotoxicity and DNA-damaging activity of respirable quartz and kaolin.
Respirable-sized quartz and kaolin dusts were pretreated with simulated pulmonary surfactant dispersions of dipalmitoyl phosphatidylcholine (DPPC) in saline to model the conditioning of particles depositing in alveolar regions of the lung. DPPC-treated and untreated dusts were used to challenge lavaged rat pulmonary alveolar macrophages in vitro. Cytotoxicity was determined over a 5-d period using both total and viable cell counts from a fluorescence-based viability assay. DNA damage, as an indication of genotoxicity, was determined over a 7-d period by the single-cell gel electrophoresis assay. Untreated quartz and kaolin both expressed a significant and potent cytotoxicity, which increased with concentration and time. DPPC-surfactant pretreatment delayed significant expression of this cytotoxicity until 3 to 5 d after challenge. Untreated quartz also caused DNA damage, which increased with concentration and time. DPPC-surfactant treatment of quartz delayed most DNA damage expression to 5 and 7 d. Untreated kaolin expressed weaker activity for DNA damage, significant at the highest concentration through 5 d, and at the higher concentrations on d 7. Surfactant treatment delayed most kaolin activity for DNA damage to 7 d after challenge.