Time trends in hospital-referred stroke and transient ischemic attack: results of a 7-year nationwide survey in France.
Nationwide evaluations of the burden of stroke are scarce. We aimed to evaluate trends in stroke and transient ischemic attack (TIA) hospitalization, in-hospital case fatality rates (CFRs) and mortality rates in France during 2000-2006. Hospitalizations for stroke and TIA were determined from National Hospital Discharge Diagnosis Records that used the International Classification of Disease, 10th revision, codes I60, I61, I63, I64, G45, G46. CFRs and mortality rates were estimated from the national death certificates database. The total number of stays for stroke increased between 2000 and 2006 (88,371 vs. 92,118) contrasting with a decrease in that for TIA. The age-standardized (European population) hospitalization rates for TIA decreased in men (52.2 vs. 44.5/100,000/year, p = 0.002), whereas they remained stable in women (32.4 vs. 31.0/ 100,000/year). Concerning stroke, a decrease in hospitalization rates was observed in both men (from 135.3 to 123.4/ 100,000/year, p < 0.001) and women (from 85.1 to 80.7, p < 0.001). Whatever the age group and the sex, a sharp decrease in in-hospital stroke CFRs was noted. In addition, a 23% decrease in mortality rates was observed. This decrease was greater in patients >65 years. Our results demonstrate a decline in hospitalization rates for stroke, and in both stroke CFRs and mortality rates between 2000 and 2006. Improvements in stroke prevention and acute stroke care may have contributed to these results, and may have been initiated by recent advances in health policy with regard to this disease in France.


The adaptive origins of uniquely human sociality.
Humans possess some unique social-cognitive skills and motivations, involving such things as joint attention, cooperative communication, dual-level collaboration and cultural learning. These are almost certainly adaptations for humans' especially complex sociocultural lives. The common assumption has been that these unique skills and motivations emerge in human infancy and early childhood as preparations for the challenges of adult life, for example, in collaborative foraging. In the current paper, I propose that the curiously early emergence of these skills in infancy--well before they are needed in adulthood--along with other pieces of evidence (such as almost exclusive use with adults not peers) suggests that aspects of the evolution of these skills represent ontogenetic adaptations to the unique socio-ecological challenges human infants face in the context of a regime of cooperative breeding and childcare. This article is part of the theme issue 'Life history and learning: how childhood, caregiving and old age shape cognition and culture in humans and other animals'.


Comparative Study of Different Drills for Bone Drilling: A Systematic Approach.
The performance of the drilling process depends on the characteristics of the drilling equipment and surgeon's skill. To our knowledge, no research has focused on multi-parameter analysis of the dynamic behaviour of drills during the drilling process. This study aimed to characterise the physical changes and effects of different drills attached to a robotic arm during drilling of artificial bones in a standardised experimental setup. Drilling processes using three brands of drills attached to a robotic arm were compared in terms of thrust force, vibration, noise level, speed deviation, and temperature. A standardised experimental setup was constructed, and measurement data were analysed statistically. Identical artificial bones were drilled 10 times with each drill. Thrust force measurements, which varied through the cortex and medulla, showed expressive differences for each drill for maximum and mean values (p<0.001). Meaningful differences were obtained for mean vibration values and noise level (p<0.001). Speed variation measurements in drilling showed conspicuous differences with confident statistics (p<0.001). Induced temperature values were measured statistically for Drill 1, Drill 2, and Drill 3 as 78.38±11.49°C, 78.11±7.79°C, and 89.77±7.79°C, respectively. Thrust force and drill bit temperature were strongly correlated for each drill. Vibration values and noise level, which also had an influential relationship, were in the acceptable range for all experiments. Both thrust force and speed deviation information could be used to detect the drill bit status in the bone while drilling.


Mechanisms of ferroptosis in hypoxic-ischemic brain damage in neonatal rats.
This study was to explore the mechanism of ferroptosis and hypoxic-ischemic brain damage in neonatal rats. The neonatal rat hypoxic-ischemic brain damage (HIBD) model was established using the Rice-Vannucci method and treated with the ferroptosis inhibitor liproxstatin-1. Cognitive assessment was performed through absentee field experiments to confirm the successful establishment of the model. Brain tissue damage was evaluated by comparing regional cerebral blood flow and quantifying tissue staining. Neuronal cell morphological changes in the rats' cortical and hippocampal regions were observed using HE and Nissl staining. ELISA was performed to determine GPX4, GSH and ROS expression levels in the rats' brain tissues, and Western blotting to assess the expression levels of 4-HNE, GPX4, GSS, ACSL4, SLC7A11, SLC3A2, TFRC, FHC, FLC, HIF-1α, and Nrf2 proteins in rat brain tissues. Compared to the Sham group, the HIBD group exhibited a significant decrease in cerebral blood perfusion, reduced brain nerve cells, and disordered cell arrangement. The use of the ferroptosis inhibitor effectively improved brain tissue damage and preserved the shape and structure of nerve cells. The oxidative stress products ROS and 4-HNE in the brain tissue of the HIBD group increased significantly, while the expression of antioxidant indicators GPX4, GSH, SLC7A11, and GSS decreased significantly. Furthermore, the expression of iron metabolism-related proteins TFRC, FHC, and FLC increased significantly, whereas the expression of the ferroptosis-related transcription factors HIF-1α and Nrf2 decreased significantly. Treatment with liproxstatin-1 exhibited therapeutic effects on HIBD and downregulated tissue ferroptosis levels. This study shows the involvement of ferroptosis in hypoxic-ischemic brain damage in neonatal rats through the System Xc--GSH-GPX4 functional axis and iron metabolism pathway, with the HIF-1α and Nrf2 transcription factors identified as the regulators of ferroptosis involved in the HIBD process in neonatal rats.


Differential effects of defibrillation on systemic and cardiac sympathetic activity.
To assess the effect of defibrillation shocks on cardiac and circulating catecholamines. Prospective examination of myocardial catecholamine balance during dc shock by simultaneous determination of arterial and coronary sinus plasma concentrations. Internal countershocks (10-34 J) were applied in 30 patients after initiation of ventricular fibrillation for a routine implantable cardioverter defibrillator test. Another 10 patients were externally cardioverted (50-360 J) for atrial fibrillation. Transcardiac noradrenaline, adrenaline, and lactate gradients immediately after the shock. After internal shock, arterial noradrenaline increased from a mean (SD) of 263 (128) pg/ml at baseline to 370 (148) pg/ml (p = 0.001), while coronary sinus noradrenaline fell from 448 (292) to 363 (216) pg/ml (p = 0.01), reflecting a shift from cardiac net release to net uptake. After external shock delivery, there was a similar increase in arterial noradrenaline, from 260 (112) to 459 (200) pg/ml (p = 0.03), while coronary sinus noradrenaline remained unchanged. Systemic adrenaline increased 11-fold after external shock (p = 0.01), outlasting the threefold rise following internal shock (p = 0.001). In both groups, a negative transmyocardial adrenaline gradient at baseline decreased further, indicating enhanced myocardial uptake. Cardiac lactate production occurred after ventricular fibrillation and internal shock, but not after external cardioversion, so the neurohumoral changes resulted from the defibrillation process and not from alterations in oxidative metabolism. A dc shock induces marked systemic sympathoadrenal and sympathoneuronal activation, but attenuates cardiac sympathetic activity. This might promote the transient myocardial depression observed after electrical discharge to the heart.


Zygomatic implants as a rehabilitation approach for a severely deficient maxilla.
A gunshot injury is one of the main trauma injuries that affect the head and neck region. Severe esthetic, functional, and psychologic deficiencies are consequences of gunshot injuries. The use of implants anchored in the zygomatic bone has been advocated as an approach to the prosthetic rehabilitation of a severely deficient maxilla. This approach provides the patient with an immediate, high-quality, esthetic, and functional complete fixed prosthesis and eliminates the need for bone grafting. In this case report, a patient with a severely deficient maxilla caused by a gunshot injury was rehabilitated by placement of four zygomatic and two pterygomaxillary implants, which were immediately loaded with a complete fixed all-acrylic resin interim prosthesis. The definitive CM Prosthesis (CM Prosthetics) was constructed using computer-aided design/computer-assisted manufacture (CAD/CAM) technology.


Differentiation at the MHCIIα and Cath2 loci in sympatric Salvelinus alpinus resource morphs in Lake Thingvallavatn.
Northern freshwater fish may be suitable for the genetic dissection of ecological traits because they invaded new habitats after the last ice age (∼10.000 years ago). Arctic charr (Salvelinus alpinus) colonizing streams and lakes in Iceland gave rise to multiple populations of small benthic morphotypes, often in sympatry with a pelagic morphotype. Earlier studies have revealed significant, but subtle, genetic differentiation between the three most common morphs in Lake Thingvallavatn. We conducted a population genetic screen on four immunological candidate genes Cathelicidin 2 (Cath2), Hepcidin (Hamp), Liver expressed antimicrobial peptide 2a (Leap-2a), and Major Histocompatibility Complex IIα (MHCIIα) and a mitochondrial marker (D-loop) among the three most common Lake Thingvallavatn charr morphs. Significant differences in allele frequencies were found between morphs at the Cath2 and MHCIIα loci. No such signal was detected in the D-loop nor in the other two immunological genes. In Cath2 the small benthic morph deviated from the other two (FST = 0.13), one of the substitutions detected constituting an amino acid replacement polymorphism in the antimicrobial peptide. A more striking difference was found in the MHCIIα. Two haplotypes were very common in the lake, and their frequency differed greatly between the morphotypes (from 22% to 93.5%, FST = 0.67). We then expanded our study by surveying the variation in Cath2 and MHCIIα in 9 Arctic charr populations from around Iceland. The populations varied greatly in terms of allele frequencies at Cath2, but the variation did not correlate with morphotype. At the MHCIIα locus, the variation was nearly identical to the variation in the two benthic morphs of Lake Thingvallavatn. The results are consistent with a scenario where parts of the immune systems have diverged substantially among Arctic charr populations in Iceland, after colonizing the island ∼10.000 years ago.


The protective effect of Nigella sativa against liver injury: a review.
Nigella sativa (Family Ranunculaceae) is a widely used medicinal plant throughout the world. N. sativa is referred in the Middle East as a part of an overall holistic approach to health. Pharmacological properties of N. sativa including immune stimulant, hypotensive, anti-inflammatory, anti-cancer, antioxidant, hypoglycemic, spasmolytic and bronchodilator have been shown. Reactive oxygen species (ROS) and oxidative stress are known as the major causes of many diseases such as liver injury and many substances and drugs can induce oxidative damage by generation of ROS in the body. Many pharmacological properties of N. sativa are known to be attributed to the presence of thymoquinone and its antioxidant effects. Thymoquinone protects liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and glutathione level, radical scavengering, increasing the activity of quinone reductase, catalase, superoxide dismutase and glutathione transferase, inhibition of NF-κB activity and inhibition of both cyclooxygenase and lipoxygenase. Therefore, this review aimed to highlight the roles of ROS in liver diseases and the mechanisms of N. sativa in prevention of liver injury.


Exploring the relationship between threat-related changes in anxiety, attention focus, and postural control.
Individuals report directing attention toward and away from multiple sources when standing under height-related postural threat, and these changes in attention focus are associated with postural control modifications. As it is unknown whether these changes generalize to other types of threat situations, this study aimed to quantify changes in attention focus and examine their relationship with postural control changes in response to a direct threat to stability. Eighty young adults stood on a force plate fixed to a translating platform. Three postural threat conditions were created by altering the expectation of, and prior experience with, a postural perturbation: no threat of perturbation, threat without perturbation experience, and threat with perturbation experience. When threatened, participants were more anxious and reported directing more attention to movement processes, threat-related stimuli, and self-regulatory strategies, and less to task-irrelevant information. Postural sway amplitude and frequency increased with threat, with greater increases in frequency and smaller increases in amplitude observed with experience. Without experience, threat-related changes in postural control were accounted for by changes in anxiety; larger changes in anxiety were related to larger changes in sway amplitude. With experience, threat-related postural control changes were accounted for by changes in attention focus; increases in attention to movement processes were related to greater forward leaning and increases in sway amplitude, while increases in attention to self-regulatory strategies were related to greater increases in sway frequency. Results suggest that relationships between threat-related changes in anxiety, attention focus, and postural control depend on the context associated with the threat.


In vitro and in vivo evaluation of ferric-hyaluronate implants for delivery of amikacin sulfate to the tarsocrural joint of horses.
To assess the antimicrobial elution characteristics, toxicity, and antimicrobial activity of amikacin-impregnated ferric-hyaluronate implants (AI-FeHAI) for amikacin delivery to the tarsocrural joint of horses. Experimental study. AI-FeHAI implants, equine cartilage, and synovium, and horses (n=6). In vitro study: Five AI-FeHAI were placed in saline solution with daily replacement until implant degradation. Eluent was tested for amikacin concentration and bioactivity. Synovial and cartilage explants were incubated in the presence or absence of AI-FeHAI for 72 hours and subsequently assessed for morphology, viability, and composition. Synovial explants were incubated with Staphylococcus aureus in the presence or absence of AI-FeHAI. Spent medium was cultured daily and explants were assessed for morphology and viability after 96 hours. In vivo study: AI-FeHAI were placed in 6 tarsocrural joints. Standard cytologic analysis and amikacin concentration (SFAC) were determined in synovia obtained regularly for 28 days thereafter. Similar analyses were conducted after a single intra-articular injection of amikacin 6 months later. In vitro study: Amikacin concentrations exceeded 16 microg/mL and inhibited S. aureus growth for 8 days. AI-FeHAI had no effect on cartilage explants. AI-FeHAI eliminated bacteria from synovial explants. In vitro study: After AI-FeHAI placement, SFAC was highest (140.78+63.81 microg/mL) at first sampling time. By 24 hours SFAC was <16 microg/mL. After intra-articular injection, SFAC was the highest (377.91 +/- 40.15 microg/mL) at first sampling time. By 48 hours SFAC was <16 microg/mL. A single intra-articular amikacin injection demonstrated superior pharmacokinetics than AI-FeHAI prepared as described. AI-FeHAI cannot be recommended for clinical use.


Endothelin type A receptor inhibition normalises intrarenal hypoxia in rats used as a model of type 1 diabetes by improving oxygen delivery.
Intrarenal tissue hypoxia, secondary to increased oxygen consumption, has been suggested as a unifying mechanism for the development of diabetic nephropathy. Increased endothelin-1 signalling via the endothelin type A receptor (ETA-R) has been shown to contribute to the development of chronic kidney disease, but its role in kidney oxygen homeostasis is presently unknown. The effects of acute ETA-R inhibition (8 nmol/l BQ-123 for 30-40 min directly into the left renal artery) on kidney function and oxygen metabolism were investigated in normoglycaemic control and insulinopenic male Sprague Dawley rats (55 mg/kg streptozotocin intravenously 2 weeks before the main experiment) used as a model of type 1 diabetes. Local inhibition of ETA-R in the left kidney did not affect BP in either the control or the diabetic rats. As previously reported, diabetic rats displayed increased kidney oxygen consumption resulting in tissue hypoxia in both the kidney cortex and medulla. The inhibition of ETA-Rs restored normal kidney tissue oxygen availability in the diabetic kidney by increasing renal blood flow, but did not affect oxygen consumption. Furthermore, ETA-R inhibition reduced the diabetes-induced glomerular hyperfiltration and increased the urinary sodium excretion. Kidney function in normoglycaemic control rats was largely unaffected by BQ-123 treatment, although it also increased renal blood flow and urinary sodium excretion in these animals. Acutely reduced intrarenal ETA-R signalling results in significantly improved oxygen availability in the diabetic kidney secondary to elevated renal perfusion. Thus, the beneficial effects of ETA-R inhibition on kidney function in diabetes may be due to improved intrarenal oxygen homeostasis.


Ethnicity and breast cancer characteristics in Kenya.
There are no published data from specific regions of sub-Saharan Africa describing the clinical and pathological characteristics and molecular subtypes of invasive breast cancer by ethnic group. The purpose of this study was to investigate these characteristics among the three major ethno-cultural groupings in Kenya. The study included women with pathologically confirmed breast cancer diagnosed between March 2012 and May 2015 at 11 hospitals throughout Kenya. Sociodemographic, clinical, and reproductive data were collected by questionnaire, and pathology review and immunohistochemistry were performed centrally. The 846 cases included 661 Bantus (78.1%), 143 Nilotes (16.9%), 19 Cushites (2.3%), and 23 patients of mixed ethnicity (2.7%). In analyses comparing the two major ethnic groups, Bantus were more educated, more overweight, had an older age at first birth, and had a younger age at menopause than Nilotes (p < 0.05 for all comparisons). In analyses restricted to definitive surgery specimens, there were no statistically significant differences in tumor characteristics or molecular subtypes by ethnicity, although the Nilote tumors tended to be larger (OR for ≥ 5 cm vs. < 2 cm: 3.86, 95% CI 0.77, 19.30) and were somewhat more likely to be HER2 enriched (OR for HER2 enriched vs. Luminal A/B: 1.41, 95% CI 0.79, 2.49). This case series showed no significant differences in breast cancer tumor characteristics or molecular subtypes, but significant differences in sociodemographic characteristics and reproductive factors, among the three major ethnic groups in Kenya. We suggest further evaluation of ethnic differences in breast cancer throughout the genetically and culturally diverse populations of sub-Saharan Africa.


The effect of perceived insufficient milk on transition to supplementary food and factors affecting it during the first six months postpartum in Turkey: A cross-sectional study.
The researchers' aims were to determine the effect of perceived insufficient milk supply on the transition to supplementary food and the factors affecting it. This is a cross-sectional design study, we were conducted between April and August 2019 and included 335 mothers and their babies in a baby-friendly hospital in Turkey. It was shown that mothers with perceived insufficient milk switched to supplementary food 6.538 times more frequently (p < 0.05). It was shown that some maternal, lactational, and infant (baby's age) factors affected the perception of insufficient milk (p < 0.05). The perception of insufficient milk is an important factor contributing to the transition to supplementary food.


Interleukin-22 Secreted by NKp44+ Natural Killer Cells Promotes Proliferation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis.
Although CD3-CD56+NKp44+ natural killer (NKp44+NK) cells have been linked to autoimmune diseases including inflammatory bowel disease, ankylosing spondylitis, and primary Sjogren syndrome, the expansion and role of those cells in patients with rheumatoid arthritis (RA) remain less defined. Here, we investigate the proportion and pathogenesis of NKp44+NK cells in patients with RA. The results show NKp44+NK cells significantly expanded in RA peripheral blood and synovial fluid, which were correlated positively with RA disease activity. They also highly expressed in RA synovial tissues and secreted a high concentration of interleukin-22 (IL-22) in vitro. Further, NKp44+NK cells culture supernatant promoted the proliferation of fibroblast-like synoviocytes (FLS) which was blocked by IL-22 antagonist and AG490. Treated with recombination human IL-22, the proliferation and phosphorylation-STAT3 on RA-FLS increased in a dose-dependent manner and time-dependent manner; the progress of which could be blocked by AG490. The present study clarifies the expansion of NKp44+NK cells in the peripheral blood and synovial fluid of patients with RA, especially in the synovial tissues of RA for the first time. STAT3 is an essential pathway in mediating the effects of IL-22 secreted by NKp44+NK cells on the proliferation of FLS in patients with RA.


Theoretical studies of HIV-1 reverse transcriptase inhibition.
Computational methods for accurately calculating the binding affinity of a ligand for a protein play a pivotal role in rational drug design. We herein present a theoretical study of the binding of five different ligands to one of the proteins responsible for the human immunodeficiency virus type 1 (HIV-1) cycle replication; the HIV-1 reverse transcriptase (RT). Two types of approaches are used based on molecular dynamics (MD) simulations within hybrid QM/MM potentials: the alchemical free energy perturbation method, FEP, and the pathway method, in which the ligand is physically pulled away from the binding site, thus rendering a potential of mean force (PMF) for the binding process. Our comparative analysis stresses their advantages and disadvantages and, although the results are not in quantitative agreement, both methods are capable of distinguishing the most and the less potent inhibitors of HIV-1 RT activity on an RNase H site. The methods can then be used to select the proper scaffold to design new drugs. A deeper analysis of these inhibitors through molecular electrostatic potential (MEP) and calculation of the binding contribution of the individual residues shows that, in a rational design, apart from the strong interactions established with the two magnesium cations present in the RNase H site, it is important to take into account interactions with His539 and with those residues that are anchoring the metals; Asp443, Glu478, Asp498 and Asp549. The MEPs of the active site of the protein and the different ligands show a better complementarity in those inhibitors that present higher binding energies, but there are still possibilities of improving the favourable interactions and decreasing those that are repulsive in order to design compounds with higher inhibitory activity.


Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity.
Inflammasomes are a family of cytosolic multiprotein complexes that initiate innate immune responses to pathogenic microbes by activating the caspase 1 protease. Although genetic data support a critical role for inflammasomes in immune defence and inflammatory diseases, the molecular basis by which individual inflammasomes respond to specific stimuli remains poorly understood. The inflammasome that contains the NLRC4 (NLR family, CARD domain containing 4) protein was previously shown to be activated in response to two distinct bacterial proteins, flagellin and PrgJ, a conserved component of pathogen-associated type III secretion systems. However, direct binding between NLRC4 and flagellin or PrgJ has never been demonstrated. A homologue of NLRC4, NAIP5 (NLR family, apoptosis inhibitory protein 5), has been implicated in activation of NLRC4 (refs 7-11), but is widely assumed to have only an auxiliary role, as NAIP5 is often dispensable for NLRC4 activation. However, Naip5 is a member of a small multigene family, raising the possibility of redundancy and functional specialization among Naip genes. Here we show in mice that different NAIP paralogues determine the specificity of the NLRC4 inflammasome for distinct bacterial ligands. In particular, we found that activation of endogenous NLRC4 by bacterial PrgJ requires NAIP2, a previously uncharacterized member of the NAIP gene family, whereas NAIP5 and NAIP6 activate NLRC4 specifically in response to bacterial flagellin. We dissected the biochemical mechanism underlying the requirement for NAIP proteins by use of a reconstituted NLRC4 inflammasome system. We found that NAIP proteins control ligand-dependent oligomerization of NLRC4 and that the NAIP2-NLRC4 complex physically associates with PrgJ but not flagellin, whereas NAIP5-NLRC4 associates with flagellin but not PrgJ. Our results identify NAIPs as immune sensor proteins and provide biochemical evidence for a simple receptor-ligand model for activation of the NAIP-NLRC4 inflammasomes.


Correction of a lower eyelid deformity caused by multiple extrusions of alloplastic orbital floor implants.
The case of a young woman is presented in whom a silicone orbital floor implant became extruded into the maxillary sinus 8 years after its insertion for an orbital floor fracture. Two subsequent attempts at correction using silicone only compounded the problem. Ultimate correction, in two stages, required (1) an iliac bone graft to the infraorbital rim and orbital floor defects, along with a temporal muscle flap and nasal antrostomy; and (2) an upper lateral cartilage chondromucosal graft and a full-thickness postauricular skin graft. A warning is sounded against the use of alloplastic materials for major orbital floor defects, particularly when there have been problems with these materials.


Ankyrin-G palmitoylation and βII-spectrin binding to phosphoinositide lipids drive lateral membrane assembly.
Ankyrin-G and βII-spectrin colocalize at sites of cell-cell contact in columnar epithelial cells and promote lateral membrane assembly. This study identifies two critical inputs from lipids that together provide a rationale for how ankyrin-G and βII-spectrin selectively localize to Madin-Darby canine kidney (MDCK) cell lateral membranes. We identify aspartate-histidine-histidine-cysteine 5/8 (DHHC5/8) as ankyrin-G palmitoyltransferases required for ankyrin-G lateral membrane localization and for assembly of lateral membranes. We also find that βII-spectrin functions as a coincidence detector that requires recognition of both ankyrin-G and phosphoinositide lipids for its lateral membrane localization. DHHC5/8 and βII-spectrin colocalize with ankyrin-G in micrometer-scale subdomains within the lateral membrane that are likely sites for palmitoylation of ankyrin-G. Loss of either DHHC5/8 or ankyrin-G-βII-spectrin interaction or βII-spectrin-phosphoinositide recognition through its pleckstrin homology domain all result in failure to build the lateral membrane. In summary, we identify a functional network connecting palmitoyltransferases DHHC5/8 with ankyrin-G, ankyrin-G with βII-spectrin, and βII-spectrin with phosphoinositides that is required for the columnar morphology of MDCK epithelial cells.


Specificity, induction, and absorption of pesticin.
Irradiation of pesticinogenic (Pst(+)) cells of Yersinia pestis with ultraviolet light resulted in a five- to eightfold increase in titer of intracellular pesticin. Extracellular activity in irradiated or control cultures never approached that found within the bacteria. Upon chromatography of crude extracts of Pst(+) cells on columns of diethylaminoethyl-cellulose, Sephadex G200, and calcium hydroxyapatite, fractions were recovered which inhibited the growth of indicator cells of Escherichia coli, Y. pseudotuberculosis, Y. enterocolitica, and Pst(-)Y. pestis. By means of these methods, in conjuntion with fractional precipitation with ammonium sulfate, the antibacterial activity was purified to homogeneity (as judged by disc gel electrophoresis and analysis by double diffusion in agar). The relative sensitivity of each cell type was constant and not affected by the state of purification. These findings indicate that the pesticin molecule alone accounts for lethality. Cells of E. coli and Y. pseudotuberculosis were about 100 and 10 times more sensitive to pesticin, respectively, than were those of Pst(-)Y. pestis. Activity directed against sensitive cells of these three species was enhanced by 0.1% ethylenediaminetetraacetate (EDTA) and completely inhibited by 0.01 m hemin or 0.001 m Fe(3+). The response of Y. enterocolitica to pesticin was variable in the presence of EDTA and was not influenced by Fe(3+). Attempts to detect common surface structures responsible for absorption of pesticin by the four cell types were not successful.


Utricular Dysfunction in Refractory Benign Paroxysmal Positional Vertigo.
To determine the prevalence of otolith dysfunction in patients with refractory benign paroxysmal positional vertigo (BPPV). Unmatched case control. Tertiary care institution. Patients included were diagnosed with BPPV, failed initial in-office canalith repositioning maneuvers (CRMs), and completed vestibular testing and vestibular rehabilitation (n = 40). Refractory BPPV (n = 19) was defined in patients whose symptoms did not resolve despite vestibular rehabilitation. These patients were compared with a control group of those with nonrefractory BPPV (n = 21) for results of a caloric test, cervical vestibular evoked myogenic potential (cVEMP), and subjective visual vertical (SVV). Forty-six of 251 patients failed initial treatment with in-office CRM. Forty patients met inclusion criteria. There was no significant difference between the cases (refractory BPPV) (n = 19) and controls (nonrefractory BPPV) (n = 21) in terms of age, duration of symptoms, laterality of BPPV, and BPPV symptoms. There was no difference in the prevalence of caloric weakness and cVEMP abnormalities (P > .05), with odds ratios (ORs [95% confidence interval (CI)]) of having abnormal results among cases vs controls of 1.1818 (0.3329-4.1954) and 4.3846 (0.7627-25.2048), for caloric and cVEMP, respectively. Abnormal eccentric SVV was more prevalent in refractory BPPV cases (58%) than in controls (14%) (P < .0072). The OR (95% CI) of having abnormal SVV was 8.25 (1.7967-37.8822) higher among patients with refractory BPPV than those with nonrefractory BPPV. Patients with refractory BPPV are more likely to have abnormal eccentric SVV and thus underlying utricular dysfunction. This finding is important to take into account when designing rehabilitation strategies for patients with BPPV who fail CRM.


Regiospecificity in the metabolism of the homologous cyclic nitrosamines, N'-nitrosonornicotine and N'-nitrosoanabasine.
We compared the metabolism in the F-344 rat of the moderately potent esophageal carcinogen N'-nitrosonornicotine (NNN, 2'-(3-pyridyl)-N-nitrosopyrrolidine) and its weakly active homologue N'-nitrosoanabasine (NAB, 2'-(3-pyridyl)-N-nitrosopiperidine). Urine was the major pathway of excretion for both nitrosamines. The major urinary metabolites of dl-NNN resulted from 2'-hydroxylation (8.1% of the dose), 5'-hydroxylation (37.6%), and pyridine N-oxidation (10.8%). The percentages of the dose of the corresponding metabolites of dl-NAB were: 2'-hydroxylation (not detected), 6'-hydroxylation (9.8%), pyridine-N-oxidation (30.0%). Similar results were obtained when the urinary metabolites of l-NNN and l-NAB were compared. In 48 h cultures of rat esophagus, the major metabolites of [2'-14C]dl-NNN resulted from 2'-hydroxylation (47%) and to a lesser extent from 5'-hydroxylation (15%). In contrast the major metabolite of [2'-14C]dl-NAB resulted from 6'-hydroxylation (35%) with lesser amounts from 2'-hydroxylation (8%). 6'-Hydroxylation of [2'-14C]dl-NAB also exceeded 2'-hydroxylation in cultures of 3, 6, 12 or 24 h duration. Pyridine-N-oxidation was not observed in the esophagus for either nitrosamine. These results demonstrate a high degree of regiospecificity in the metabolism of these structurally related nitrosamines. Among the identified urinary metabolites the ratio of alpha-hydroxylation to N-oxidation was 4.2 for NNN and 0.3 for NAB. Among the 48 h esophageal metabolites the ratio of 2'-hydroxylation to 5'- or 6'-hydroxylation was 3.1 for NNN and 0.2 for NAB. The results also suggest a basis for the weak carcinogenicity of NAB: facile excretion as its pyridine-N-oxide and detoxification in the esophagus by 6'-hydroxylation.


Biomass, Morphology, and Dynamics of the Fine Root System Across a 3,000-M Elevation Gradient on Mt. Kilimanjaro.
Fine roots (≤2 mm) consume a large proportion of photosynthates and thus play a key role in the global carbon cycle, but our knowledge about fine root biomass, production, and turnover across environmental gradients is insufficient, especially in tropical ecosystems. Root system studies along elevation transects can produce valuable insights into root trait-environment relationships and may help to explore the evidence for a root economics spectrum (RES) that should represent a trait syndrome with a trade-off between resource acquisitive and conservative root traits. We studied fine root biomass, necromass, production, and mean fine root lifespan (the inverse of fine root turnover) of woody plants in six natural tropical ecosystems (savanna, four tropical mountain forest types, tropical alpine heathland) on the southern slope of Mt. Kilimanjaro (Tanzania) between 900 and 4,500 m a.s.l. Fine root biomass and necromass showed a unimodal pattern along the slope with a peak in the moist upper montane forest (~2,800 m), while fine root production varied little between savanna and upper montane forest to decrease toward the alpine zone. Root:shoot ratio (fine root biomass and production related to aboveground biomass) in the tropical montane forest increased exponentially with elevation, while it decreased with precipitation and soil nitrogen availability (decreasing soil C:N ratio). Mean fine root lifespan was lowest in the ecosystems with pronounced resource limitation (savanna at low elevation, alpine heathland at high elevation) and higher in the moist and cool forest belt (~1,800-3,700 m). The variation in root traits across the elevation gradient fits better with the concept of a multi-dimensional RES, as root tissue density and specific root length showed variable relations to each other, which does not agree with a simple trade-off between acquisitive and conservative root traits. In conclusion, despite large variation in fine root biomass, production, and morphology among the different plant species and ecosystems, a general belowground shift in carbohydrate partitioning is evident from 900 to 4,500 m a.s.l., suggesting that plant growth is increasingly limited by nutrient (probably N) shortage toward higher elevations.


Novel treatment strategies in clear-cell metastatic renal cell carcinoma.
Metastatic renal-cell carcinoma (mRCC) is highly resistant to cytotoxic agents or hormones and is currently mainly treated with cytokine-based therapy. Transient responses and moderate survival advantages have been achieved in a subset of patients with these aspecific biological response modifiers. Side-effects are considerable, especially with high-dose interleukin (IL)-2. Efforts made in the field of specific immunotherapy have focused on optimization of dendritic cell vaccination and on administration of monoclonal antibodies, either cold (unconjugated) or hot (radioactively labeled). Furthermore, allogeneic bone marrow transplantation is able to induce remissions but, regrettably, is related to substantial morbidity and mortality. Neutralization of the biological activity of some immunosuppressive cytokines produced by RCC (IL-6 and tumor necrosis factor-alpha) with monoclonal antibodies is currently under investigation. Insights gained into the processes and pathways underlying carcinogenesis have led to the development of new treatment strategies. These treatments can be used for clear cell RCC, since they focus on blocking gene products that are upregulated by mutations in the von Hippel-Lindau gene. Specific strategies include anti-vascular endothelial growth factor monoclonal antibody (bevacizumab) or inhibition of its receptor kinases (oral SU11248 or PTK787), or targeting the Raf kinase pathway (by BAY 43-9006) or the mammalian target of rapamycin (mTOR) pathway (by CCI-779). Early clinical results are promising, but their place in the treatment of RCC has to be determined.


Variation of axillary temperature and its correlation with oral temperature.
Unilateral axillary temperature is recorded in unconscious patients and children due to its easy approach. To evaluate variation of axillary temperature on the two sides and its correlation with oral temperature. One hundred and 46 healthy men and women, aged 12 through 52 years. Axillary temperature from both sides and oral temperature were recorded using digital electronic thermometer in supine position with due precautions. Difference in temperature on the two sides of axilla was found to vary by as much as 0 degree F to 3.4 degrees F. Therefore, the data was grouped into higher and lower temperature ranges. The difference between mean oral and mean higher axillary temperature was found to be 0.5 degree F +/- 0.6 degree F (r = 0.564) while that in comparison to mean lower axillary temperature was 1.0 degree F +/- 0.89 degree F (r = 0.64). The difference between mean oral and mean axillary temperature was 1.0 degree F +/- 0.80 degree F (r = 0.84). Based on our observations, it is found that an average of temperature of both sides of axilla represents the axillary temperature more accurately and to get the correct oral equivalent of axillary temperature one should add 1 degree F to the mean axillary temperature.


Poly(beta-hydroxybutyrate) production in oilseed leukoplasts of brassica napus
Polyhydroxyalkanoates (PHAs) comprise a class of biodegradable polymers which offer an environmentally sustainable alternative to petroleum-based plastics. Production of PHAs in plants is attractive since current fermentation technology is prohibitively expensive. The PHA homopolymer poly(beta-hydroxybutyrate) (PHB) has previously been produced in leaves of Arabidopsis thaliana (Nawrath et al., 1994, Proc Natl Acad Sci USA 91: 12760-12764). However, Brassica napus oilseed may provide a better system for PHB production because acetyl-CoA, the substrate required in the first step of PHB biosynthesis, is prevalent during fatty acid biosynthesis. Three enzymatic activities are needed to synthesize PHB: a beta-ketothiolase, an acetoacetyl-CoA reductase and a PHB synthase. Genes from the bacterium Ralstonia eutropha encoding these enzymes were independently engineered behind the seed-specific Lesquerella fendleri oleate 12-hydroxylase promoter in a modular fashion. The gene cassettes were sequentially transferred into a single, multi-gene vector which was used to transform B. napus. Poly(beta-hydroxybutyrate) accumulated in leukoplasts to levels as high as 7.7% fresh seed weight of mature seeds. Electron-microscopy analyses indicated that leukoplasts from these plants were distorted, yet intact, and appeared to expand in response to polymer accumulation.


Fetal growth influences lymphocyte subset counts at birth: the Generation R Study.
Preterm born and low-birth-weight infants are at risk for severe infections in infancy. It has been suggested that these infants have an immature immune system. To assess the associations of gestational age, birth weight and fetal growth with absolute lymphocyte subset counts at birth. This study was conducted in 571 infants participating in the Generation R Study, a population-based prospective cohort study from fetal life onwards. Gestational age and birth weight were obtained from midwives and hospital registries. Fetal growth was defined as increase in weight between late pregnancy and birth. Lymphocytes and T lymphocyte subset counts in cord blood were determined by 6-color flow cytometry. Multivariate linear regression models with adjustment for gender, maternal education, smoking, alcohol use, fever and mode of delivery were applied. Per week increase of gestational age, T, B and NK lymphocyte counts increased with 3, 5 and 6%, respectively (p < 0.05). Helper, cytotoxic and naive T lymphocyte counts increased with 3, 4 and 5%, respectively (p < 0.05), but memory T lymphocyte counts did not. Increased birth weight and fetal growth were significantly associated with higher B lymphocyte counts, independent of gestational age, but not with the other lymphocyte subset counts. Lymphocyte subset counts increase with prolonged gestation, suggesting an ongoing development of the immune system. Birth weight and fetal growth seem to influence only B lymphocyte counts.


Posttransplant Lymphoproliferative Disorder: Otolaryngological Manifestations and Management.
Objective Posttransplant lymphoproliferative disorder (PTLD) is a unifying term for a spectrum of lymphoid expansion entities brought about by immunosuppression and is strongly associated with Epstein-Barr virus (EBV). Otolaryngological findings tend to present early in the clinical course; therefore, disease awareness among otolaryngologists is of utmost importance. This review synthesizes the body of literature pertaining to PTLD involving the head and neck, summarizes contemporary management, and highlights areas for future research. Data Sources PubMed/Medline. Review Methods Primary literature search of the Medline database was performed for all titles published in the past 10 years pertaining to PTLD. The database search included PTLD combined with a collection of otolaryngological MeSH terms. Full manuscripts were reviewed based on relevance of their title and abstract. Selection into this review was according to clinical and scientific relevance. Conclusion Adenotonsillar focus is common in children in whom adenotonsillectomy may be diagnostic and prevents potentially morbid airway obstruction. Sinonasal PTLD may mimic fungal infection. Laryngotracheal involvement predominately presents in children with symptoms of airway obstruction. PTLD limited to the esophagus is rare. Oral PTLD is rare and phenotypically varied. Cutaneous presentation of PTLD is infrequent, yet one-third of cases affects the head and neck. PTLD may present as cervical lymphadenopathy. Implications for Practice PTLD consideration is vital when evaluating posttransplant patients. Children and EBV-seronegative patients should receive otolaryngological follow-up after transplant. PTLD treatment is multidisciplinary and typically led by lymphoma specialists. Formal partnerships between otolaryngologists and transplant centers may improve patient care and research quality.


Cryotherapy, Sensation, and Isometric-Force Variability.
OBJECTIVE: To determine the changes in sensation of pressure, 2-point discrimination, and submaximal isometric-force production variability due to cryotherapy. DESIGN AND SETTING: Sensation was assessed using a 2 x 2 x 2 x 3 repeated-measures factorial design, with treatment (ice immersion or control), limb (right or left), digit (finger or thumb), and sensation test time (baseline, posttreatment, or postisometric-force trials) as independent variables. Dependent variables were changes in sensation of pressure and 2-point discrimination. Isometric-force variability was tested with a 2 x 2 x 3 repeated-measures factorial design. Treatment condition (ice immersion or control), limb (right or left), and percentage (10, 25, or 40) of maximal voluntary isometric contraction (MVIC) were the independent variables. The dependent variables were the precision or variability (the standard deviation of mean isometric force) and the accuracy or targeting error (the root mean square error) of the isometric force for each percentage of MVIC. SUBJECTS: Fifteen volunteer college students (8 men, 7 women; age = 22 +/- 3 years; mass = 72 +/- 21.9 kg; height = 183.4 +/- 11.6 cm). MEASUREMENTS: We measured sensation in the distal palmar aspect of the index finger and thumb. Sensation of pressure and 2-point discrimination were measured before treatment (baseline), after treatment (15 minutes of ice immersion or control), and at the completion of isometric testing (final). Variability (standard deviation of mean isometric force) of the submaximal isometric finger forces was measured by having the subjects exert a pinching force with the thumb and index finger for 30 seconds. Subjects performed the pinching task at the 3 submaximal levels of MVIC (10%, 25%, and 40%), with the order of trials assigned randomly. The subjects were given a target representing the submaximal percentage of MVIC and visual feedback of the force produced as they pinched the testing device. The force exerted was measured using strain gauges mounted on an apparatus built to measure finger forces. RESULTS: Sensation of pressure was less (ie, it took greater pressure to elicit a response) after ice immersion, thumbs were more affected than index fingers, and the decrease was greater in the right limb than the left. Two-point discrimination was not affected by cryotherapy but was higher in the finger than in the thumb under all conditions. Isometric-force variability (standard deviation of mean isometric force) was greater as percentage of force increased from 10% to 40% of MVIC. Targeting accuracy (root mean square error) was decreased at 40% of MVIC. Accuracy and force variability were not affected by cryotherapy. CONCLUSIONS: The application of cryotherapy and reduced sensation of pressure appear to have little effect on motor control of the digits. These results support the hypothesis that the use of cold is not contraindicated for use as an analgesic before submaximal rehabilitative exercise focusing on restoring neuromuscular control to injured tissues.


Deferred consent. A new approach for resuscitation research on comatose patients.
Methodological constraints inherent in the rapidly growing field of resuscitation research have created an apparent conflict with newly promulgated federal regulations, especially those concerning informed consent requirements. We propose that two new concepts be applied to resuscitation research to satisfy the current federal regulations governing biomedical research. The first of these concepts is "minimal differential risk," ie, in resuscitation medicine, the difference between the risk of an undesirable outcome when standard, commonly accepted therapy may be used and the risk of an undesirable outcome with experimental therapy is minimal. The second concept is "deferred consent," ie, obtaining consent to continue with an experimental therapy after administration of that therapy has already begun. We believe that the emergency exception to informed consent applies to resuscitation research. Recognition of the applicability of these concepts to resuscitation research should allow compliance with federal and state regulations that otherwise might inhibit or preclude such research endeavors.


[Effect of acetate on the formation of the phyoeffector tentoxin by Alternaria alternata (Fr.) Keissler].
The effect of the cosubstrate acetate on the formation of the phytotoxic substance tentoxin by Alternaria alternata (Fr.) Keissler was investigated. Acetate was taken up and metabolized during growth. The added acetate stimulated considerably the biosynthesis of tentoxin depending on its concentration and time of introduction. There was an increased incorporation of (U-14C)-glucose into the toxin molecule in the presence of acetate in the medium. The results indicate an induction of the biosynthesis of tentoxin by the precursor acetate, probably mediated through the accumulation of the glycolytic intermediates pyruvate and phosphoenolpyruvate.


Reprogramming plant gene expression: a prerequisite to geminivirus DNA replication.
SUMMARY Geminiviruses constitute a large family of plant-infecting viruses with small, single-stranded DNA genomes that replicate through double-stranded intermediates. Because of their limited coding capacity, geminiviruses supply only the factors required to initiate their replication and use plant nuclear DNA polymerases to amplify their genomes. Many geminiviruses replicate in differentiated cells that no longer contain detectable levels of host DNA polymerases and associated factors. To overcome this barrier, geminiviruses induce the accumulation of DNA replication machinery in mature plant cells by reprogramming host gene expression. The mammalian DNA tumour viruses activate host genes required for DNA replication by binding to the retinoblastoma protein, a negative regulator of cell cycle progression, and relieving repression through the E2F family of transcription factors. In this review, we discuss recent experiments showing that geminiviruses also modulate components of the retinoblastoma/E2F transcription regulatory network to induce quiescent plant cells to re-enter the cell cycle and regain the capacity to support high levels of DNA replication. Regulation of the cell division cycle and its integration with developmental pathways is complex, with many factors, including hormones, sucrose and environmental signals, controlling re-entry into the plant cell cycle. Geminivirus interactions with these regulatory networks are likely to determine if and where they can replicate their genomes in different plant tissues and hosts.


Vesiculation from Pseudomonas aeruginosa under SOS.
Bacterial infections can be aggravated by antibiotic treatment that induces SOS response and vesiculation. This leads to a hypothesis concerning association of SOS with vesiculation. To test it, we conducted multiple analyses of outer membrane vesicles (OMVs) produced from the Pseudomonas aeruginosa wild type in which SOS is induced by ciprofloxacin and from the LexA noncleavable (lexAN) strain in which SOS is repressed. The levels of OMV proteins, lipids, and cytotoxicity increased for both the treated strains, demonstrating vesiculation stimulation by the antibiotic treatment. However, the further increase was suppressed in the lexAN strains, suggesting the SOS involvement. Obviously, the stimulated vesiculation is attributed by both SOS-related and unrelated factors. OMV subproteomic analysis was performed to examine these factors, which reflected the OMV-mediated cytotoxicity and the physiology of the vesiculating cells under treatment and SOS. Thus, SOS plays a role in the vesiculation stimulation that contributes to cytotoxicity.


Evaluating health risk models.
Interest in targeted disease prevention has stimulated development of models that assign risks to individuals, using their personal covariates. We need to evaluate these models and quantify the gains achieved by expanding a model to include additional covariates. This paper reviews several performance measures and shows how they are related. Examples are used to show that appropriate performance criteria for a risk model depend upon how the model is used. Application of the performance measures to risk models for hypothetical populations and for US women at risk of breast cancer illustrate two additional points. First, model performance is constrained by the distribution of risk-determining covariates in the population. This complicates the comparison of two models when applied to populations with different covariate distributions. Second, all summary performance measures obscure model features of relevance to its utility for the application at hand, such as performance in specific subgroups of the population. In particular, the precision gained by adding covariates to a model can be small overall, but large in certain subgroups. We propose new ways to identify these subgroups and to quantify how much they gain by measuring the additional covariates. Those with largest gains could be targeted for cost-efficient covariate assessment.


Combined effects of occupational exposure to hazardous operations and lifestyle-related factors on cancer incidence.
We aimed to examine whether the number of types of hazardous operations at work experienced through a lifetime is associated with cancer incidence, and additionally examined the combined effects with lifestyle-related factors. Using a nationwide, multicenter, hospital inpatient dataset (2005-2015), we conducted a matched case-control study with 1 149 296 study subjects. We classified the participants into those with none, 1, or 2 or more types of hazardous operation experience, based on information of special medical examinations taken, mandatory in Japan for workers engaged in hazardous operations. Using those with no experience as the reference group, we estimated the odds ratios for cancer incidence (all sites, lung, stomach, colon and rectum, liver, pancreas, bile duct, and bladder) by conditional logistic regression with multiple imputations. We also examined the effects of the combination with hazardous operations and lifestyle-related factors. We observed increased risks for cancer of all sites, and lung, pancreas, and bladder cancer associated with the experience of hazardous operations. Multivariable-adjusted ORs (95% CIs) of cancer incidence of all sites were 1 (reference), 1.16 (1.12, 1.21), and 1.17 (1.08, 1.27) for none, 1, and 2 or more types of hazardous operation experience, respectively (P for trend <.001). Potential combined associations of hazardous operations with smoking were observed for lung, pancreas, and bladder cancer, and with diabetes for pancreas cancer. Engaging in hazardous operations at work and in combination with lifestyle-related factors may increase the risk of cancer. We highlight the potential for those engaged in hazardous work to avoid preventable cancers.


Colonoscopy at a tertiary healthcare facility in Southwest Nigeria: Spectrum of indications and colonic abnormalities.
Colonoscopy is considered the gold standard for diagnosing structural colonic diseases. It is safe and effective both for diagnosis and therapeutic interventions. This study was carried out to evaluate the pattern of indications and spectrum of colonic disease at a tertiary healthcare facility in Southwest Nigeria. All consenting patients who were referred for colonoscopy were recruited into the study. A proforma was used to record information such as biodata of the patients, indications for the procedure, and the findings at colonoscopy. There were 250 patients, comprising 130 (52.0%) males and 120 (48.0%) females, with a male to female ratio of 1.1:1. The mean age of the patients was 57.9 ± 14.2 years with a range of 15-90 years. The most common indication for colonoscopy was hematochezia 85 (34.0%), others were abdominal pain 46 (18.4%), suspected colonic cancer 27 (10.8%), constipation 27 (10.8%), and chronic diarrhea 22 (8.8%). Sixty-five (26%) patients had normal colonoscopy while various abnormalities were detected in 185 (74%) patients. The most common abnormalities were colonic polyps (23.2%), hemorrhoids (20.8%), diverticulosis (14.8%), colorectal tumor (12.1%), and colitis (4.0%). Colonoscopy is an effective means of diagnosing colonic diseases and that the diagnostic yield could be high if the indication were appropriate. The most common indication in our practice was hematochezia, and the most frequent diagnosis was colonic polyps.


[Bone pain after long distance flight as first manifestation of HbSC disease].
A 7-year old Ghanese boy was admitted with repeated bone pain. Multiple bone marrow alterations were seen as the causal factor. HbSC disease was diagnosed by hemoglobin electrophorics. The onset of pain attacks appears to be linked to the long distance flight from Ghana to Austria. Due to severe bone marrow affection, beside symptomatic therapy a long-term treatment with hydroxyurea was started, leading to an HbF increase from 5.1 % to 19.3 %. After a follow-up of 8 months the patient has remained free of complaints.


[Syndromes and sequences].
In order to introduce a series of articles on syndromes, the differences between syndromes and diseases are discussed, their causes summarized, annotations are made with regard to genotype and phenotype, and the diagnosis and frequency are described.


B cell apoptosis triggered by antigen receptor ligation proceeds via a novel caspase-dependent pathway.
In contrast to positive signaling leading to proliferation, the mechanisms involved in negative signaling culminating in apoptosis after B cell Ag receptor (BCR) ligation have received little study. We find that apoptosis induced by BCR cross-linking on EBV-negative mature and immature human B cell lines involves the following sequential, required events: a cyclosporin A-inhibitable, likely calcineurin-mediated step; and activation of caspase-2, -3, and -9. Caspase-2 is activated early and plays a major role in the apoptotic pathway, while caspase-9 is activated later in the apoptotic pathway and most likely functions to amplify the apoptotic signal. Caspase-8 and -1, which are activated by ligation of the CD95 and TNF-R1 death receptors, are not involved. Apoptosis induced by BCR ligation thus proceeds via a previously unreported intracellular signaling pathway.


Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways.
Selective serotonin reuptake inhibitors (SSRIs) have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF)-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists. The effects of three SSRIs (fluvoxamine, sertraline, paroxetine) and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP), and dehydroepiandrosterone (DHEA)-sulfate) on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP(3)) receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine (but not sertraline or paroxetine) and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP(3) receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma), phosphatidylinositol 3-kinase (PI3K), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways blocked the potentiation of NGF-induced neurite outgrowth by SA4503. These findings suggest that stimulation of sigma-1 receptors and subsequent interaction with IP(3) receptors, PLC-gamma, PI3K, p38MAPK, JNK, and the Ras/Raf/MAPK signaling pathways are involved in the mechanisms of action of sigma-1 receptor agonists such as fluvoxamine and SA4503.


Characterizing HIV risk among cisgender men in Latin America who report transgender women as sexual partners: HIV risk in Latin America men.
Cisgender men (CM) who report transgender women (TW) as sexual partners are an understudied population in the HIV epidemic in Latin America. The current study sought to characterize this group in a 2012 cross-sectional online survey of Latin American CM who were members of a sexual networking website for men who have sex with men (N = 11,847). Multivariable logistic regression models were fit to estimate demographic, behavioral, and psychosocial correlates of having a TW sexual partner and engaging in condomless sex. Overall, 0.9% (n = 106) reported a TW sexual partner in the last 12 months; of these, 76.4% (n = 81) reported condomless sex in the last three months. Identifying as bisexual or heterosexual compared to gay, and specifying a versatile sexual role preference compared to insertive were associated with reporting a recent TW sex partner (all p < 0.05). HIV-negative serostatus, lifetime STI history, and alcohol dependence were associated with recent condomless sex (all p < 0.05). CM with TW sexual partners have distinct HIV-related vulnerabilities. Future research is needed to understand CM who report TW sexual partners, including their sexual preferences and practices, sexual networks, exposure to stigma, biomedical prevention interest and uptake, and acceptability of integrating alcohol abuse screening into sexual health services.


The ribosomal RNA processing machinery is recruited to the nucleolar domain before RNA polymerase I during Xenopus laevis development.
Transcription and splicing of messenger RNAs are temporally and spatially coordinated through the recruitment by RNA polymerase II of processing factors. We questioned whether RNA polymerase I plays a role in the recruitment of the ribosomal RNA (rRNA) processing machinery. During Xenopus laevis embryogenesis, recruitment of the rRNA processing machinery to the nucleolar domain occurs in two steps: two types of precursor structures called prenucleolar bodies (PNBs) form independently throughout the nucleoplasm; and components of PNBs I (fibrillarin, nucleolin, and the U3 and U8 small nucleolar RNAs) fuse to the nucleolar domain before components of PNBs II (B23/NO38). This fusion process is independent of RNA polymerase I activity, as shown by actinomycin D treatment of embryos and by the lack of detectable RNA polymerase I at ribosomal gene loci during fusion. Instead, this process is concomitant with the targeting of maternally derived pre-rRNAs to the nucleolar domain. Absence of fusion was correlated with absence of these pre-rRNAs in nuclei where RNA polymerase II and III are inhibited. Therefore, during X. laevis embryogenesis, the recruitment of the rRNA processing machinery to the nucleolar domain could be dependent on the presence of pre-rRNAs, but is independent of either zygotic RNA polymerase I transcription or the presence of RNA polymerase I itself.


Implant Design and Effects on Patellofemoral Crepitus.
Background Patellofemoral crepitus is a known complication of posterior stabilized (PS) total knee arthroplasty (TKA). This study compared the incidence of patellofemoral crepitus between two femoral components designs. Materials and Methods Between January 2005 and August 2010, 1,120 patients with complete 2-year follow-up had a PS TKA with two different prosthetic designs (group A, 553 patients; group B, 567 patients). Records were reviewed to identify the incidence of total, symptomatic, and operative patellofemoral crepitus. Results No statistical differences were observed in the incidence of total patellofemoral crepitus (group A 14.1%, group B 14.5%; p = 0.932) or symptomatic patellofemoral crepitus (group A 5.6%, group B 4.2%; p = 0.334). The incidence of operative crepitus was greater in group A (3.3%) than in group B (1.3%; p = 0.026). Analysis of mobile versus fixed bearing designs showed a higher incidence of total patellofemoral crepitus in mobile bearing TKA (16.04 vs. 4.93%; p = 0.006) within group B only. Conclusion Femoral component design with a smoother intercondylar box transition zone resulted in a lower incidence of operative patellofemoral crepitus. No statistical differences were noted regarding the incidence of total and symptomatic patellofemoral crepitus. Mobile bearing TKA exhibited greater total crepitus within group B. Level of Evidence Level III.


Daily Context for Abusive and Neglectful Behavior in Family Caregiving for Dementia.
The purpose of this study was to identify risk and protective factors for abusive and neglectful behavior in the context of daily caregiving. Family caregivers who co-reside with a care recipient with Alzheimer's disease and related dementia, recruited from social media, completed 21-days of diaries. Multilevel modeling with days (n = 831) nested within caregivers (N = 50) was used to evaluate relationships between hypothesized risk and protective factors and the odds of an abusive or neglectful behavior on a given day. Disruptions in the daily routine and stress of the caregiver related to behavioral symptoms of the care recipient are significant risk factors for abusive and neglectful behavior. Participating in a meaningful activity with the care recipient when it occurs twice in a day is a significant protective factor against use of a neglect behavior (OR = 0.19; CI 0.06-0.64; p = .01), but not for abusive behavior. Hypotheses that spending the full day together would increase risk, and that receipt of instrumental support and caregiver participation in self-care would decrease risk, were not supported. Findings demonstrate that risk of an abusive or neglectful behavior varies from day-to-day in the presence and absence of contextual factors, and that the majority of the variance in the odds an abusive or neglectful behavior occurring is related to day-level factors. Findings demonstrate that diary surveys are critical to identifying ecologically valid modifiable risk and protective factors for abusive and neglectful behaviors that can be targeted in future interventions.


Altered gastric tone and motility response to brain-stem dopamine in a rat model of parkinsonism.
The majority of patients with Parkinson's disease (PD) experience gastrointestinal dysfunction. Recently, we described a nigro-vagal pathway that uses dopaminergic (DA) inputs to the dorsal motor nucleus of the vagus (DMV) and A2 area neurons to modulate gastric motility and tone. This pathway is disrupted in a rodent model of PD. The aim of the present study was to test the hypothesis that brain-stem DA modulation of gastric tone and motility is altered in a rodent model of PD. Male Sprague-Dawley rats received three weekly intraperitoneal injections of paraquat (10 mg/kg) or saline (control). In naive conditions, microinjection of DA into the DMV induced a gastroinhibitory response in 100% of animals. In 19 of 28 PQ-treated animals, however, microinjection of DA into the DVC induced a biphasic response, with an initial increase in gastric tone and motility followed by a profound gastroinhibition. The excitatory response to DA microinjection was attenuated by a combination of DA type 1 (DA1)- and DA2-like receptor antagonists. Conversely, the inhibitory response was reduced by the DA2-like receptor antagonist only. Pretreatment with the α2-adrenoceptor antagonist yohimbine did not modulate the response to DA, thus excluding involvement of the A2 area. At the end of the experiments, induction of the Parkinson phenotype was confirmed by the presence of α-synuclein immunoreactivity in the DMV and substantia nigra pars compacta. These data suggest a maladaptive neural plasticity in brain-stem vagal circuits regulating gastric motility in PQ-treated rats that may be responsible for the gastric dysfunction observed in PD models. NEW & NOTEWORTHY After paraquat treatment and induction of Parkinson's disease, brain-stem dopamine (DA) application induces a biphasic gastric response in the majority of rats, with an initial increase in tone and motility followed by gastroinhibition. The initial increase in gastric tone and motility is mediated via a combined activation of DA type 1 (DA1)- and DA2-like receptors. The inhibitory effects of DA are mediated by DA2-like receptors and are not affected by blockade of adrenergic inputs mediated by α2-adrenoceptors.


Implementing a Substance Use Screening Protocol in Rural Federally Qualified Health Centers.
In 2018, nearly 20% of Americans aged 12 years and older reported using illicit substances, with higher rates in rural areas. Federally Qualified Health Centers (FQHCs) provide health care to one in five rural Americans. However, estimates suggest that only 13.6% of patients in rural FQHCs receive substance use (SU) screening compared with 42.6% of patients in urban FQHCs. This quality improvement (QI) project aimed to improve patient quality and safety and meet Health Resources and Services Administration reporting requirements. These aims were achieved through the design and implementation of a new SU screening protocol in four FQHCs in rural Indiana. Deming's plan-do-study-act model was used to implement QI interventions to increase SU screening rates. A new SU screening tool, the National Institute on Drug Abuse -Modified Alcohol, Smoking, and Substance Involvement Screening Testwas implemented, and staff were trained on its use. the screening, brief intervention, and referral to treatment model was used as a guiding framework. Outcome measures included a comparison of SU screening rates from the first quarter of 2019 to the first quarter of 2020, as well a pretest-posttest designed to measure staff knowledge and attitudes regarding SU. Baseline SU screening rate in 2019 was 0.87%. This increased to 24.8% by March 2020. Additionally, posttest results demonstrated improvement from staff on all indices, and an approval rating of 77% of the new SU screening practices. This project demonstrated that a low-cost QI intervention can increase SU screening rates in rural FQHCs, as well as improve staff knowledge and attitudes regarding SU.


Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235.
The aim of our study is to evaluate the preclinical therapeutic activity and mechanism of action of BEZ235, a dual PI3K/mTOR inhibitor, in combination with dexamethasone in acute lymphoblastic leukemia (ALL). The cytotoxic effects of BEZ235 and dexamethasone as single agents and in combination were assessed in a panel of ALL cell lines and xenograft models. The underlying mechanism of BEZ235 and dexamethasone was evaluated using immunoblotting, TaqMan RT-PCR, siRNA, immunohistochemistry, and immunoprecipitation. Inhibition of the PI3K/AKT/mTOR pathway with the dual PI3K/mTOR inhibitor BEZ235 enhanced dexamethasone-induced anti-leukemic activity in in vitro (continuous cell lines and primary ALL cultures) and systemic in vivo models of T-ALL (including a patient-derived xenograft). Through inhibition of AKT1, BEZ235 was able to alleviate AKT1-mediated suppression of dexamethasone-induced apoptotic pathways leading to increased expression of the proapoptotic BCL-2 protein BIM. Downregulation of MCL-1 by BEZ235 further contributed to the modulation of dexamethasone resistance by increasing the amount of BIM available to induce apoptosis, especially in PTEN-null T-ALL where inhibition of AKT only partially overcame AKT-induced BIM suppression. Our data support the further investigation of agents targeting the PI3K/mTOR pathway to modulate glucocorticoid resistance in T-ALL.


Association between voiding lower urinary tract symptoms and findings on dynamic magnetic resonance imaging with regard to pelvic organs and their supportive structures.
Pelvic organ prolapse (POP) causes voiding lower urinary tract symptoms (vLUTS). In the present study, we investigated the association between vLUTS and pelvic organ mobility (POM), including relevant supportive structures, on dynamic magnetic resonance imaging (dMRI). We included 118 patients who had POP of stage II or less before straining and stage III or more when straining during dMRI. The presence of vLUTS and overactive bladder (OAB) was determined by a voiding subscore of the International Prostate Symptom Score (vIPSS) ≥5 and the OAB symptom score, respectively. POM was measured by dMRI before and during straining, and patients with and without vLUTS as well as patients with and without vLUTS and/or OAB were compared. p < .05 was considered to be statistically significant. According to vIPSS, 42 patients (35.6%) had vLUTS. On dMRI, patients with vLUTS showed a significantly more ventral position and/or movement of the bladder and cervix. Moreover, patients with vLUTS and OAB had significantly more ventral movement of the uterine cervix and a larger strain on imaginary uterosacral and cardinal ligaments than those without these symptoms. In addition, patients with vLUTS and OAB had significantly higher vIPSS than those with vLUTS alone. vLUTS may be associated with the proximity of the bladder and cervix to the pubic bone and consequent compression of the urethra by the prolapsed organs. vLUTS with OAB might indicate more advanced lower urinary tract dysfunction than vLUTS alone.


A mercury-catalyzed, high-yield system for the oxidation of methane to methanol.
A homogeneous system for the selective, catalytic oxidation of methane to methanol via methyl bisulfate is reported. The net reaction catalyzed by mercuric ions, Hg(II), is the oxidation of methane by concentrated sulfuric acid to produce methyl bisulfate, water, and sulfur dioxide. The reaction is efficient. At a methane conversion of 50 percent, 85 percent selectivity to methyl bisulfate ( approximately 43 percent yield; the major side product is carbon dioxide) was achieved at a molar productivity of 10(-7) mole per cubic centimeter per second and Hg(II) turnover frequency of 10(-3) per second. Separate hydrolysis of methyl bisulfate and reoxidation of the sulfur dioxide with air provides a potentially practical scheme for the oxidation of methane to methanol with molecular oxygen. The primary steps of the Hg(II)-catalyzed reaction were individually examined and the essential elements of the mechanism were identified. The Hg(II) ion reacts with methane by an electrophilic displacement mechanism to produce an observable species, CH(3)HgOSO(3)H, 1. Under the reaction conditions, 1 readily decomposes to CH(3)OSO(3)H and the reduced mercurous species, Hg(2)(2+) The catalytic cycle is completed by the reoxidation of Hg(2)(2+) with H(2)SO(4) to regenerate Hg(II) and byproducts SO(2) and H(2)O. Thallium(III), palladium(II), and the cations of platinum and gold also oxidize methane to methyl bisulfate in sulfuric acid.


Attenuation of neural responses in primary visual cortex during the attentional blink.
Information-processing bottlenecks are characteristic of many cognitive and neural systems. One such bottleneck is revealed by tasks in which rapidly successive stimulus events must be reported. Here, observers missed the second of two visual targets if it occurred within 700 ms of the first [an "attentional blink" (AB)], even though this second target could be reported accurately when the first item was ignored. Isolating neural responses to such rapid events has proven difficult because current magnetic resonance imaging methods rely on relatively sluggish changes in the brain's physiological response to sensory inputs. Here, we overcame this limitation by presenting successive visual targets at different spatial locations, thereby exploiting the retinotopic organization of early cortical visual areas to distinguish neural activity associated with successive target events. We show that neural activity in primary visual cortex is significantly modulated during the AB, and that this activity mirrors behavioral measures of target identification accuracy. The findings suggest that the neural signature of perceptual suppression during processing of rapidly successive stimuli is evident at the earliest stages of cortical sensory processing.


Exploring the Effects of Liquid Marbles' Deformation on Their Rolling Resistance.
Liquid marbles (LMs) are nonwetting droplets manufactured by encapsulating droplets with micro- or nanoscale particles. These marbles are widely used as transport carriers for digital microfluidics due to their rapid displacement velocity and leak-free transport. An improved understanding of the resistance mechanism of rolling LMs is crucial for their transport and manipulation. In this study, we investigated the rolling resistance of LMs obtained with different powders and volumes using a high-speed camera. Our findings suggest that the deformation of liquid marbles would hinder their rolling by a resistance torque. To depict this resistance effect, we propose a theoretical model (f∼λ(ε-12Bo1/2ε2+14Boε3)), where f is the rolling resistance of marbles, λ is the deflection coefficient, Bo is the Bond number, and (ε is the contact surface deformation) that accurately predicts the relationship between deformation and rolling resistance, which is supported by our experimental results. To further validate our theoretical model, we conducted three independent experiments: shape detection of prepared LMs, measuring the elastic force of LMs, and detecting the diffusive motion of the encapsulating particles. Furthermore, we discuss three factors that affect the rolling resistance: the volume of the marbles, the type and size of the encapsulating particles, and the substrate roughness. This comprehensive study not only generalizes the mechanism of deformation hindering the rolling of liquid marbles but also provides a theoretical framework to predict the relationship between the deformation and rolling resistance. These findings have practical implications for improving the manipulation efficiency and advancing the use of LMs as microfluidic carriers.


Antitumor activity of the β-glucan paramylon from Euglena against preneoplastic colonic aberrant crypt foci in mice.
In the present study, the effects of β-glucans isolated from Euglena on the formation of preneoplastic aberrant crypt foci (ACF) in the colon were examined in mice. Mice were fed a semi-purified AIN-93M diet containing cellulose or the same diet but with the cellulose replaced with β-glucans in the form of Euglena, paramylon, or amorphous paramylon, for 11 weeks. After consuming these dietary supplements for 8 days, half of the mice were intraperitoneally administered 1,2-dimethylhydrazine (DMH) at a dose of 20 mg kg(-1) body weight every week for 6 weeks. Among the DMH-treated groups, the paramylon- and amorphous paramylon-fed mice displayed a significantly lower number of ACF than the control group. Also, the liver weight of the paramylon group was markedly decreased compared with those of the control and Euglena groups, whereas the cecal content weight and fecal volume of the paramylon group were significantly increased. As for the levels of organic acids in the cecal contents, the paramylon group displayed significantly increased lactic acid levels compared with the control and Euglena groups. From these findings, although the mechanism of the ACF-inhibiting effects of paramylon remains unclear, it is considered that β-glucans, such as paramylon and its isomer amorphous paramylon, have preventive effects against colon cancer and are more effective against the condition than Euglena.


The Targeted Impact of Flavones on Obesity-Induced Inflammation and the Potential Synergistic Role in Cancer and the Gut Microbiota.
Obesity is an inflammatory disease that is approaching pandemic levels, affecting nearly 30% of the world's total population. Obesity increases the risk of diabetes, cardiovascular disorders, and cancer, consequentially impacting the quality of life and imposing a serious socioeconomic burden. Hence, reducing obesity and related life-threatening conditions has become a paramount health challenge. The chronic systemic inflammation characteristic of obesity promotes adipose tissue remodeling and metabolic changes. Macrophages, the major culprits in obesity-induced inflammation, contribute to sustaining a dysregulated immune function, which creates a vicious adipocyte-macrophage crosstalk, leading to insulin resistance and metabolic disorders. Therefore, targeting regulatory inflammatory pathways has attracted great attention to overcome obesity and its related conditions. However, the lack of clinical efficacy and the undesirable side-effects of available therapeutic options for obesity provide compelling reasons for the need to identify additional approaches for the prevention and treatment of obesity-induced inflammation. Plant-based active metabolites or nutraceuticals and diets with an increased content of these compounds are emerging as subjects of intense scientific investigation, due to their ability to ameliorate inflammatory conditions and offer safe and cost-effective opportunities to improve health. Flavones are a class of flavonoids with anti-obesogenic, anti-inflammatory and anti-carcinogenic properties. Preclinical studies have laid foundations by establishing the potential role of flavones in suppressing adipogenesis, inducing browning, modulating immune responses in the adipose tissues, and hindering obesity-induced inflammation. Nonetheless, the understanding of the molecular mechanisms responsible for the anti-obesogenic activity of flavones remains scarce and requires further investigations. This review recapitulates the molecular aspects of obesity-induced inflammation and the crosstalk between adipocytes and macrophages, while focusing on the current evidence on the health benefits of flavones against obesity and chronic inflammation, which has been positively correlated with an enhanced cancer incidence. We conclude the review by highlighting the areas of research warranting a deeper investigation, with an emphasis on flavones and their potential impact on the crosstalk between adipocytes, the immune system, the gut microbiome, and their role in the regulation of obesity.


Pharmacological effects of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents.
Soybean transphosphatidylated phosphatidylserine (SB-tPS) was prepared from soybean phosphatidylcholine by transphosphatidylation using phospholipase D, and the fatty acids composition and pharmacological properties were compared with those of bovine brain cortex-derived phosphatidylserine (BC-PS) which was reported to improve cognitive disorders of senile dementia patients by oral administration (300 mg/day). The molecular species of SB-tPS are rich in linoleic and palmitic acids whereas those of BC-PS are stearic and oleic acids. Despite the differences in fatty acid composition, SB-tPS displayed significant activities on the increase in brain glucose concentrations in mice (79 mg/kg, i.v.) and the restoration of scopolamine-induced amnesia in rats (60 mg/kg, i.p.) as did BC-PS. These results suggest the possibility that SB-tPS may prevent and/or improve senile dementia by oral administration.


Definition and description of schizophrenia in the DSM-5.
Although dementia praecox or schizophrenia has been considered a unique disease for over a century, its definitions and boundaries have changed over this period and its etiology and pathophysiology remain elusive. Despite changing definitions, DSM-IV schizophrenia is reliably diagnosed, has fair validity and conveys useful clinical information. Therefore, the essence of the broad DSM-IV definition of schizophrenia is retained in DSM-5. The clinical manifestations are extremely diverse, however, with this heterogeneity being poorly explained by the DSM-IV clinical subtypes and course specifiers. Additionally, the boundaries of schizophrenia are imprecisely demarcated from schizoaffective disorder and other diagnostic categories and its special emphasis on Schneiderian "first-rank" symptoms appears misplaced. Changes in the definition of schizophrenia in DSM-5 seek to address these shortcomings and incorporate the new information about the nature of the disorder accumulated over the past two decades. Specific changes in its definition include elimination of the classic subtypes, addition of unique psychopathological dimensions, clarification of cross-sectional and longitudinal course specifiers, elimination of special treatment of Schneiderian 'first-rank symptoms', better delineation of schizophrenia from schizoaffective disorder, and clarification of the relationship of schizophrenia to catatonia. These changes should improve diagnosis and characterization of individuals with schizophrenia and facilitate measurement-based treatment and concurrently provide a more useful platform for research that will elucidate its nature and permit a more precise future delineation of the 'schizophrenias'.


[Ethological analysis of monkey behavior in biomedical research].
The importance of ethological analysis of primates behaviour during the medicobiologic research has been shown. The concrete examples of methods of differentiation and registration of behavioral patterns in the models of psychoemotional stress in primates are given. The systemic approach to the study of behaviour allows to determine the behavioral data of the individual state--the composition of functional spheres, the number of elements, the frequency of their appearance, the system of domination-subjection characteristics of the sequences of behavioral acts and to find out their dynamics in different stages of experiment. The comparison of these data with physiologicobiochemical data is necessary to obtain the integral picture of individual reaction to the experimental factors.


Slide-free imaging of hematoxylin-eosin stained whole-mount tissues using combined third-harmonic generation and three-photon fluorescence microscopy.
Intraoperative margin assessment of surgical tissues during cancer surgery is clinically important, especially in the case of tissue conserving surgery like Mohs micrographic surgery in which minimization of the surgical area is considered crucial. Frozen pathology is the gold standard of assessing excised tissues for signs of remaining cancerous lesions. The current protocol, however, is time-consuming and labor-intensive. Instead of the complex frozen sectioning, staining, and traditional white light microscopy imaging protocol, optically sectioned histopathological imaging of hematoxylin-eosin stained whole-mount skin tissues with a subfemtoliter resolution is demonstrated by using nonlinear microscopy in this study. With our proposed method, the reagents of staining and the contrast of imaging are fully consistent with the current clinical standard of frozen pathology, thus facilitating rapid intraoperative assessment of surgical tissues for future applications. Image: Slide-free nonlinear microscopy imaging of H&E stained whole-mount skin tissue showing the morphology of sweat glands.


GSA-1/ARG1 protects root gravitropism in Arabidopsis under ammonium stress.
Gravitropism plays a critical role in plant growth and development, plant stability and acclimation to changes in water and nutrient availability. Ammonium (NH4(+)) is well known to have profound effects on root growth, but its impacts on gravitropism are poorly understood. To determine which genes are essential for the maintenance of root gravitropism under NH4(+) stress, we isolated and identified an NH4 (+)-sensitive mutant, gsa-1 (gravitropism sensitive to ammonium-1), in Arabidopsis thaliana, using an agar plate root reorientation assay. We found that, under NH4(+) stress, gsa-1 displayed increased loss of root gravitropism. Gene cloning and sequencing revealed that gsa-1 contains a G to C transversion mutation at the highly conserved 5'-GT splice position of intron 10 of ARG1 (ALTERED RESPONSE TO GRAVITY1), known to participate in the transduction of the root gravity signal. Genetic complement tests established the locus of GSA-1/ARG1 and its role in resistance to NH4 (+) inhibition on root gravitropism. GSA-1/ARG1 is required for normal AUX1 expression and basipetal auxin transport in root apices. In addition, PIN-FORMED2 (PIN2) is proposed as a target in the reduction of root gravitropism under NH4(+) stress, a response which can be antagonized by the GSA-1/ARG1-dependent pathway. These results suggest that GSA-1/ARG1 protects root gravitropism in Arabidopsis thaliana under ammonium stress.


An update on prostate cancer.
Consideration of the number of prostate biopsy samples found to be positive for cancer may add clinically useful information to T stage, Gleason score, and prostate-specific antigen level in predicting outcome after radical prostatectomy. Higher radiation doses and neoadjuvant hormone therapy has been applied successfully to patients with higher risk disease. Brachytherapy has emerged as a modality for localized prostate cancer with outcomes and toxicity being further defined. Efforts to measure and improve quality of life are an important part of prostate cancer research. Standard management of metastatic disease remains androgen ablation, with long-term side effects being recognized. Newer hormonal and chemotherapeutic agents are being explored for patients with metastatic disease.


[An account of a strange instance of disease--Stengel-Batten-Spielmayer-Vogt disease].
Otto Christian Stengel's (1794-1890) description of four siblings suffering from probable neuronal ceroid lipofuscinosis (Batten disease or Spielmeyer-Vogt disease) is one of the few Norwegian primary reports of neurological disease. Dr. Stengel was a physician in the copper mining town of Roeros in Norway from 1821 to 1883. His report was published in Norwegian in the first volume of the first Norwegian medical journal "Eyr" in 1826, 77 years before Frederick E. Batten (1865-1918) through his publication in 1903 became internationally renowned for giving the first report of the disease. This article presents the life of Dr. Stengel and reviews the findings in his report.


Quantitative analysis of maturational changes in EEG background activity in very preterm infants with a normal neurodevelopment at 1 year of age.
The electroencephalographic (EEG) background pattern of preterm infants changes with postmenstrual age (PMA) from discontinuous activity to continuous activity. However, changes in discontinuity have been investigated by visual analysis only. To investigate the maturational changes in EEG discontinuity in healthy preterm infants using an automated EEG detection algorithm. Weekly 4h EEG recordings were performed in preterm infants with a gestational age (GA)<32weeks and normal neurological follow-up at 1year. The channel C3-C4 was analyzed using an algorithm which automatically detects periods of EEG inactivity (interburst intervals). The interburst-burst ratio (IBR, percentage of EEG inactivity during a moving time window of 600s) and mean length of the interburst intervals were calculated. Using the IBR, discontinuous background activity (periods with high IBR) and continuous background activity (periods with low IBR) were automatically detected and their mean length during each recording was calculated. Data were analyzed with regression and multivariate analysis. 79 recordings were performed in 18 infants. All recordings showed a cyclical pattern in EEG discontinuity. With advancing PMA, IBR (R(2)=0.64; p<0.001), interburst interval length (R(2)=0.43; p<0.001) and length of discontinuous activity (R(2)=0.38; p<0.001) decreased, while continuous activity increased (R(2)=0.50; p<0.001). Multivariate analysis showed that all EEG discontinuity parameters were equally influenced by GA and postnatal age. Analyzing EEG background activity in preterm infants is feasible with an automated algorithm and shows maturational changes of several EEG derived parameters. The cyclical pattern in IBR suggests brain organisation in preterm infant.


Discrepancy between social and nonsocial decision-making under uncertainty following prefrontal lobe damage: the impact of an interactionist approach.
Deficits in decision-making are thought to contribute significantly to socio-behavioral impairments of patients with frontal lobe damage. The purpose of this study was to test the hypothesis of whether the inappropriate social behavior of patients with frontal lesions can be viewed as the product of a general failure of decision-making ability or as the result of socio-cognitive impairment. We studied a group of patients with prefrontal lesions (FL patients, n = 15) and a group of matched healthy controls (n = 30) on the Iowa Gambling task (IGT) of nonsocial decision-making, environmental dependency phenomena (EDP) during social interaction, and the "reading the mind in the eyes" and "character intention task" of theory of mind (TOM) tasks. The FL patients were impaired in both TOM and EDP protocols but, surprisingly, they behaved appropriately in the IGT. In addition, FL patients with EDP did not differ in executive functioning, IGT and TOM measures from those who did not demonstrate these behavioral disorders. The right orbitofrontal cortex was associated with social decision-making deficits. By adopting an interactionist approach, this study raises the possibility of identifying components of social and nonsocial decision-making, which could be helpful in understanding the behavioral disorders of FL patients.


Chronic Obstructive Pulmonary Disease is Not Associated with In-Hospital Mortality in COVID-19: An Observational Cohort Analysis.
Chronic obstructive pulmonary disease (COPD) is associated with worsened outcomes in COVID-19 (coronavirus disease 2019). However, data remain fraught with heterogeneity and bias from comorbid conditions. Additionally, data on the impact of COPD-specific factors, such as pre-hospital medications and pulmonologist involvement, remain sparse. We report a single-center analysis of COPD patients hospitalized with COVID-19 compared to those without COPD. Primary outcomes include ICU admission, mechanical ventilation, and in-hospital mortality. We evaluated all patients ≥40 years admitted with PCR-confirmed COVID-19 between February 2020 and February 2021. COPD was defined by documented ICD-10 diagnosis of COPD, confirmed smoking history, and active bronchodilator use. We compared outcomes between COPD patients and the remainder of the COVID-19 cohort. Multivariable analyses were adjusted for age, sex, smoking status, and comorbid conditions. Of 1537 hospitalized COVID-19 patients, 122 (7.9%) carried a diagnosis of COPD. The COPD cohort was older (74 ± 13 vs 66 ± 15 years, P < 0.001) and more often former smokers (P < 0.001). Comorbid conditions including diabetes, cardiovascular disease, and kidney disease were more prevalent in the COPD group (P < 0.001). After adjusting for comorbid conditions, the COPD cohort had higher severity scores and trended towards fewer hospital-free days. Among patients with COPD, pre-hospital use of aspirin was associated with decreased ICU admissions (aHR 0.56, P = 0.049) and mechanical ventilation (aHR 0.25, P = 0.008), while LAMAs (long-acting muscarinic antagonists) were associated with decreased in-hospital mortality (aHR 0.34, P = 0.047). Involvement of pulmonology in pre-hospital management of COPD was not found to significantly affect outcomes. When corrected for comorbid illnesses, COPD was associated with more severe disease but not with increased ICU admission, mechanical ventilation, or in-hospital mortality rates. Among COPD patients, prehospital treatment with aspirin and COPD-directed therapies were associated with improved outcomes.


[The efferent therapy of Raynaud's phenomenon].
The method of discrete plasmacytapheresis was applied for the treatment of 8 patients with primary and 18 with secondary Raynaud's phenomenon. The incorporation of this method in the therapeutic complex have promoted the achievement of clinical improvement in the whole of the patients with primary and in 13 with secondary Raynaud's phenomenon. Remission lasted from 1.5 months till 4.5 years. Positive effect is caused by the improvement of blood rheological properties on the hemodilution background, the excretion of pathological substances from blood flow.


A heterogeneous single-atom palladium catalyst surpassing homogeneous systems for Suzuki coupling.
Palladium-catalysed cross-coupling reactions, central tools in fine-chemical synthesis, predominantly employ soluble metal complexes despite recognized challenges with product purification and catalyst reusability1-3. Attempts to tether these homogeneous catalysts on insoluble carriers have been thwarted by suboptimal stability, which leads to a progressively worsening performance due to metal leaching or clustering4. The alternative application of supported Pd nanoparticles has faced limitations because of insufficient activity under the mild conditions required to avoid thermal degradation of the substrates or products. Single-atom heterogeneous catalysts lie at the frontier5-18. Here, we show that the Pd atoms anchored on exfoliated graphitic carbon nitride (Pd-ECN) capture the advantages of both worlds, as they comprise a solid catalyst that matches the high chemoselectivity and broad functional group tolerance of state-of-the-art homogeneous catalysts for Suzuki couplings, and also demonstrate a robust stability in flow. The adaptive coordination environment within the macroheterocycles of ECN facilitates each catalytic step. The findings illustrate the exciting opportunities presented by nanostructuring single atoms in solid hosts for catalytic processes that remain difficult to heterogenize.