In situ phytoplankton photosynthetic characteristics and their controlling factors in the eastern Indian Ocean.
Photosynthesis is the most important bioenergy conversion process on Earth. Capturing instantaneous changes in in situ photosynthesis in open ocean ecosystems remains a major challenge. In this study, fast repetition rate fluorometry (FRRF), which can obtain nondestructive, real-time and in situ estimates of photosynthetic parameters, was used for the first time to continuously observe the spatial variation in in situ photosynthetic parameters in the eastern Indian Ocean (EIO). We further formulated new insights regarding abiotic and biotic factors of potential importance in determining photosynthetic performance. First, we found that the distributions of micro/nano- and picophytoplankton were opposite under the control of nutrient concentrations. Micro/nanophytoplankton had higher cell abundances in the nearshore and upwelling regions, while picophytoplankton had higher abundances in the open ocean, and Prochlorococcus was the dominant group. Second, based on the FRRF technology, we obtained the high-precision and high-density vertical profile map of photosynthetic parameters in the euphotic layer. It was observed that values of the maximum photochemical efficiency (Fv/Fm; 0.14-0.55, unitless) and the functional absorption cross-section of PSII (σPSII; 1.71-4.90 nm2 RCII-1) increased with increasing depth, while high values of the photosynthetic electron transfer rates (ETRRCII; 0.0019-17.0292 mol e- mol RCII-1 s-1) and the nonphotochemical quenching (NPQNSV; 0.35-7.26, unitless) occurred in the shallow 50 m layer, and the values decreased as the depth increased. Finally, we discussed limiting factors that regulated the distribution of photosynthetic parameters and concluded that optical properties varied significantly with changes in the ocean physico-chemical parameters and taxonomic composition of phytoplankton assemblages in the EIO. Picophytoplankton (especially cyanobacteria), rather than the micro/nanophytoplankton community, was the dominant factor influencing photosynthesis. Among abiotic factors, photosynthetically active radiation (PAR) was the proximal limiting factor affecting photosynthetic efficiency, followed by temperature and dissolved inorganic nitrogen (DIN). Consequently, phytoplankton photosynthetic parameters exhibited great variability, allowing rapid responses to environmental condition changes. In this study, we established the basis for detecting future changes in primary production in this oligotrophic area.


Pharmacokinetics of tetra(m-hydroxyphenyl)chlorin in human plasma and individualized light dosimetry in photodynamic therapy.
The pharmacokinetics of the photosensitizer 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (mTHPC) was investigated in the plasma of 20 patients by absorption and fluorescence spectroscopy. The temporal behavior was characterized by a rapid decrease in concentration during the first minutes after intravenous injection of 0.15 mg/kg mTHPC. A minimum concentration in the plasma was reached after about 45 min. The drug concentration then increased again, attaining a maximum after about 10 h, after which it decreased again with a halflife of about 30 h. Irradiation tests in the oral cavity at different time intervals after the injection revealed that the tissue reaction was only partially correlated with the mTHPC plasma level. The tissue response was stronger at later drug-light intervals (1-4 days) than during the first hours after injection even though the mTHPC plasma concentration was higher at the shorter times. Relative mTHPC concentrations were also measured in the mucosae of the oral cavity, the esophagus and the bronchi of 27 patients by light-induced fluorescence spectroscopy using an optical fiber-based spectrometer. These measurements were performed prior to photodynamic therapy (PDT), 4 days after injection of the photosensitizer. Highly significant linear correlations were found between the relative mTHPC concentrations in the mucosae of these three organs. Likewise, the plasma levels of mTHPC measured just before PDT were significantly correlated with the mTHPC concentrations in the three types of mucosae mentioned above. These results indicate that mTHPC plasma levels measured just before PDT can be used for PDT light dosimetry.


Endovascular aortic repair: first twenty years.
Endovascular aortic/aneurysm repair (EVAR) was introduced into clinical practice at the beginning of the nineties. Its fast development had a great influence on clinicians, vascular surgeons and interventional radiologists, educational curriculums, patients, industry and medical insurance. The aim of this paper is to present the contribution of clinicians and industry to the development and advancement of endovascular aortic repair over the last 20 years. This review article presents the development of EVAR by focusing on the contribution of physicians, surgeons and interventional radiologists in the creation of the new field of vascular surgery termed hybrid vascular surgery, and also the contribution of technological advancement by a significant help of industrial representatives--engineers and their counselors. This article also analyzes studies conducted in order to compare the successfulness of EVAR with up-to-now applied open surgical repair of aortic aneurysms, and some treatment techniques of other aortic diseases. During the first two decades of its development the EVAR method was rapidly progressing and was adopted concurrently with the expansion of technology. Owing to large randomized studies, early and long-term results indicate specific complications of this method, thus influencing further technological improvement and defining risk patients groups in whom the use of the technique should be avoided. Good results are insured only in centers, specialized in vascular surgery, which have on their disposal adequate conditions for solving all complications associated with this method.


Predicting Development of Chronic Obstructive Pulmonary Disease and its Risk Factor Analysis.
Chronic Obstructive Pulmonary Disease (COPD) is an irreversible airway obstruction with a high societal burden. Although smoking is known to be the biggest risk factor, additional components need to be considered. In this study, we aim to identify COPD risk factors by applying machine learning models that integrate sociodemographic, clinical, and genetic data to predict COPD development.Clinical relevance- This study assessed the risk factors of COPD in sociodemographic, clinical, and genetic data. We have determined that sociodemographic factors are highly associate to the development of COPD.


In utero growth restriction and catch-up adipogenesis after developmental di (2-ethylhexyl) phthalate exposure cause glucose intolerance in adult male rats following a high-fat dietary challenge.
Phthalates impact adipocyte morphology in vitro, but the sex-specific adipogenic signature immediately after perinatal di(2-ethylhexyl) phthalate (DEHP) exposure and adulthood physiology following a high-fat (HF) dietary challenge are unknown. In the current study, pregnant and lactating dams received DEHP (300 mg/kg body weight) or oil. At weaning [postnatal day (PND) 21], adipose tissue was sampled for real-time polymerase chain reaction. The remaining offspring consumed a control or HF diet. DEHP decreased % fat in males at birth from 13.9%±0.2 to 11.8%±0.6 (mean±S.E.M.), representing a 15.1% decrease in fat by DEHP, and these males caught up in adiposity to controls by PND21. Adult DEHP-exposed males had a 27.5% increase in fat (12.5%±0.9% in controls vs. 15.9%±1.5% in the DEHP group); adipocyte perimeter was increased as well, with fewer small/medium-sized adipocytes, and decreased cell number compared to oil controls. HF diet intake in DEHP-exposed males further increased male energy intake and body weight and led to glucose intolerance. In PND21 males, DEHP increased the expression of adipogenic markers (Pparg1, Cebpa, Adipoq, Ppard, Fabp4, Fasn, Igf1), decreased Lep, and decreased markers of mesenchymal stem cell commitment to the adipogenic lineage (Bmp2, Bmp4, Stat1, Stat5a) compared to oil controls. These data suggest that DEHP may decrease the adipocyte pool at birth, which initially increases adaptive adipocyte maturation and lipid accumulation, but leads to adipose tissue dysfunction in adulthood, decreasing the capacity to adapt to a HF diet, and leading to systemic glucose intolerance.


Neuroprotection mediated by glial cell line-derived neurotrophic factor: involvement of a reduction of NMDA-induced calcium influx by the mitogen-activated protein kinase pathway.
The glial cell line-derived neurotrophic factor (GDNF) is first characterized for its trophic activity on dopaminergic neurons. Recent data suggested that GDNF could modulate the neuronal death induced by ischemia. The purpose of this study was to characterize the influence of GDNF on cultured cortical neurons subjected to two paradigms of injury (necrosis and apoptosis) that have been identified during cerebral ischemia and to determine the molecular mechanisms involved. First, we demonstrated that both neurons and astrocytes express the mRNA and the protein for GDNF and its receptor complex (GFRalpha-1 and c-Ret). Next, we showed that the application of recombinant human GDNF to cortical neurons and astrocytes induces the activation of the MAP kinase (MAPK) pathway, as visualized by an increase in the phosphorylated forms of extracellular signal-regulated kinases (ERKs). Thereafter, we demonstrated that GDNF fails to prevent apoptotic neuronal death but selectively attenuates slowly triggered NMDA-induced excitotoxic neuronal death via a direct effect on cortical neurons. To further characterize the neuroprotective mechanisms of GDNF against NMDA-mediated neuronal death, we showed that a pretreatment with GDNF reduces NMDA-induced calcium influx. This effect likely results from a reduction of NMDA receptor activity rather than an enhanced buffering or extrusion capacity for calcium. Finally, we also demonstrated that an ERKs activation pathway is necessary for GDNF-mediated reduction of the NMDA-induced calcium response. Together, these results describe a novel mechanism by which the activation of MAPK induced by GDNF modulates NMDA receptor activity, a mechanism that could be responsible for the neuroprotective effect of GDNF in acute brain injury.


[Interneuronal relations in a dissociated sympathetic ganglion culture].
Structural and functional relations between sympathetic neurons in the long-term culture of a dissociated autonomic ganglion were studied with light and electron microscopic (scanning microscopy) and electrophysiological microelectrode techniques. Different patterns of functional interneuronal relations depending on the ultrastructural organization and features of unification of the cells in networks, are discussed.


Recent advances in understanding chronic rhinosinusitis endotypes.
Chronic rhinosinusitis (CRS) is a heterogeneous inflammatory disease with an as-yet-undefined etiology. The management of CRS has historically been phenotypically driven, and the presence or absence of nasal polyps has frequently guided diagnosis, prognosis, and treatment algorithms. Research over the last decade has begun to question the role of this distinction in disease management, and renewed attention has been placed on molecular and cellular endotyping and a more personalized approach to care. Current research exploring immunologic mechanisms, inflammatory endotypes, and molecular biomarkers has the potential to more effectively delineate distinct and clinically relevant subgroups of CRS. The focus of this review will be to discuss and summarize the endotypic characterization of CRS and the potential diagnostic and therapeutic implications of this approach to disease management.


The role of affect and reasoning in a patient with a delusion of misidentification.
This study investigated a patient with a delusion of misidentification (DM) resembling a Capgras delusion. Instead of the typical Capgras delusion--the false belief that someone has been replaced by an almost identical impostor--patient MF misidentified his wife as his former business partner. Detailed investigation of MF's face processing, affective response and affect perception, and ability to evaluate, and reject, implausible ideas was undertaken. MF's visual processing of identity, gender, and age of familiar and unknown faces was intact but he was unable to identify the facial expressions of anger, disgust, and fear, or to match faces across expressions. MF also showed a reduced affective responsiveness to his environment, and impaired reasoning ability. We propose that MF's delusion of misidentification resulted from a combination of affective deficits, including impairment of both affective response and affect perception, in addition to an inability to evaluate, and reject, implausible ideas. These deficits, in combination with specific life events at the time of onset of the delusion, may have contributed to the form and content of the delusion. In addition, the results raise the possibility that the processing of face identity and facial expression are not as independent as previously proposed in models of face processing.


Convex total variation denoising of Poisson fluorescence confocal images with anisotropic filtering.
Fluorescence confocal microscopy (FCM) is now one of the most important tools in biomedicine research. In fact, it makes it possible to accurately study the dynamic processes occurring inside the cell and its nucleus by following the motion of fluorescent molecules over time. Due to the small amount of acquired radiation and the huge optical and electronics amplification, the FCM images are usually corrupted by a severe type of Poisson noise. This noise may be even more damaging when very low intensity incident radiation is used to avoid phototoxicity. In this paper, a Bayesian algorithm is proposed to remove the Poisson intensity dependent noise corrupting the FCM image sequences. The observations are organized in a 3-D tensor where each plane is one of the images acquired along the time of a cell nucleus using the fluorescence loss in photobleaching (FLIP) technique. The method removes simultaneously the noise by considering different spatial and temporal correlations. This is accomplished by using an anisotropic 3-D filter that may be separately tuned in space and in time dimensions. Tests using synthetic and real data are described and presented to illustrate the application of the algorithm. A comparison with several state-of-the-art algorithms is also presented.


Association of Red Blood Cell Distribution Width With Mortality Risk in Hospitalized Adults With SARS-CoV-2 Infection.
Coronavirus disease 2019 (COVID-19) is an acute respiratory illness with a high rate of hospitalization and mortality. Biomarkers are urgently needed for patient risk stratification. Red blood cell distribution width (RDW), a component of complete blood counts that reflects cellular volume variation, has been shown to be associated with elevated risk for morbidity and mortality in a wide range of diseases. To investigate whether an association between mortality risk and elevated RDW at hospital admission and during hospitalization exists in patients with COVID-19. This cohort study included adults diagnosed with SARS-CoV-2 infection and admitted to 1 of 4 hospitals in the Boston, Massachusetts area (Massachusetts General Hospital, Brigham and Women's Hospital, North Shore Medical Center, and Newton-Wellesley Hospital) between March 4, 2020, and April 28, 2020. The main outcome was patient survival during hospitalization. Measures included RDW at admission and during hospitalization, with an elevated RDW defined as greater than 14.5%. Relative risk (RR) of mortality was estimated by dividing the mortality of those with an elevated RDW by the mortality of those without an elevated RDW. Mortality hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazards model. A total of 1641 patients were included in the study (mean [SD] age, 62[18] years; 886 men [54%]; 740 White individuals [45%] and 497 Hispanic individuals [30%]; 276 nonsurvivors [17%]). Elevated RDW (>14.5%) was associated with an increased mortality risk in patients of all ages. The RR for the entire cohort was 2.73, with a mortality rate of 11% in patients with normal RDW (1173) and 31% in those with an elevated RDW (468). The RR in patients younger than 50 years was 5.25 (normal RDW, 1% [n = 341]; elevated RDW, 8% [n = 65]); 2.90 in the 50- to 59-year age group (normal RDW, 8% [n = 256]; elevated RDW, 24% [n = 63]); 3.96 in the 60- to 69-year age group (normal RDW, 8% [n = 226]; elevated RDW, 30% [104]); 1.45 in the 70- to 79-year age group (normal RDW, 23% [n = 182]; elevated RDW, 33% [n = 113]); and 1.59 in those ≥80 years (normal RDW, 29% [n = 168]; elevated RDW, 46% [n = 123]). RDW was associated with mortality risk in Cox proportional hazards models adjusted for age, D-dimer (dimerized plasmin fragment D) level, absolute lymphocyte count, and common comorbidities such as diabetes and hypertension (hazard ratio of 1.09 per 0.5% RDW increase and 2.01 for an RDW >14.5% vs ≤14.5%; P < .001). Patients whose RDW increased during hospitalization had higher mortality compared with those whose RDW did not change; for those with normal RDW, mortality increased from 6% to 24%, and for those with an elevated RDW at admission, mortality increased from 22% to 40%. Elevated RDW at the time of hospital admission and an increase in RDW during hospitalization were associated with increased mortality risk for patients with COVID-19 who received treatment at 4 hospitals in a large academic medical center network.


Significance of small foci of Gleason score 7 or greater prostate cancer on needle biopsy.
With increased screening for prostate cancer, we have noted a greater number of patients with small foci of Gleason score 7 or greater prostate cancer on needle biopsy. The significance of these findings is unknown. We studied 57 men with small foci of Gleason score 7 or greater on needle biopsy. Tumor length was less than 1.5 mm in all but 2 cases. In those 2 cases, there were two minute (less than 0.5 mm) foci of cancer separated by 1.8 mm. The length of cancer ranged from 0.2 to 1.8 mm (mean 0.63 mm). In all cases, only one core was involved. Thirty-three men underwent radical prostatectomy (RP), 14 received radiation, 8 underwent surveillance, and 2 received hormonal therapy. Men who underwent RP were younger (62 years) than those who had radiotherapy (69.1 years), who were younger than those who underwent surveillance (74.5 years). The mean prostate-specific antigen (PSA) for men undergoing RP was 8.0 ng/mL (range 1.4 to 22). Preoperative serum PSA values did not predict organ-confined status. Needle biopsy grades were as follows: 3 + 4 = 7 (n = 30); 4 + 3 = 7 (n = 17); 4 + 4 = 8 (n = 7); 5 + 4 = 9 (n = 1); and 5 + 5 = 10 (n = 2). We were able to review slides in 27 of the RP specimens, of which 24 were well sampled. Of these 24 cases, 33% had positive margins and 33% were not organ confined; the median tumor volume was 0.5 cc (mean 1.04). No difference in RP tumor volume was found between tumors with needle biopsy Gleason primary grade 3 and those with 4 or greater. The percentage of Gleason pattern 4 on needle biopsy weakly correlated with the percentage of Gleason pattern 4 in the RP specimen (P = 0.04). However, the percentage of Gleason pattern 4 only in the RP specimen, but not in the biopsy, correlated with whether the tumor was organ confined. The likelihood of having organ-confined disease with small foci of Gleason score 7 or greater on needle biopsy appears to be equivalent to that calculated from the Partin Tables for greater amounts of Gleason score 6 cancer on needle biopsy. In men who are considering RP, small foci of Gleason score 7 or greater adenocarcinoma on needle biopsy should not necessarily be considered an adverse finding.


Comparison of Efficacy Outcomes of Lidocaine Spray, Topical Lidocaine Injection, and Lidocaine General Anesthesia in Nasal Bone Fractures Surgeries: A Randomized, Controlled Trial.
BACKGROUND Lidocaine is widely used as a general and local anesthetic in minor or major surgeries. The objective of the study was to compare postoperative pain relief and adverse events using different forms of lidocaine administration in patients following closed nasal bone reduction surgery. MATERIAL AND METHODS A total of 381 patients with a solitary nasal fracture that could be managed with closed reduction were included in this study and divided into 3 groups of 127 patients in each group. Patients had received 1% lidocaine HCl with epinephrine (LL group), inserted a mesh impregnated with lidocaine spray (TL group), or 1 mg/kg/h lidocaine infusion (GL group) before surgeries. Patients also received morphine when the pain was not controlled. The postoperative pain was assessed at 6 hours and 48 hours after surgery. Postoperative vomiting and nausea were evaluated. Repeated ANOVA/Tukey-Kramer multiple comparisons test was performed at 95% confidence level. RESULTS At 6 hours after surgery, patients in the general lidocaine (GL) group reported decreased postoperative pain compared with those in the topical lidocaine (TL) group (P<0.001, q=6.633) and LL group (P<0.001, q=8.056). The morphine consumption within 48 hours was least in GL group than TL group (P<0.001, q=172.9) and LL group (P<0.001, q=226.42). Lidocaine infusion caused nausea (P<0.001, q=6.742) and vomiting (P<0.001, q=4.306). CONCLUSIONS Topical lidocaine anesthesia had the same postoperative pain relief and the least adverse events as local and general lidocaine anesthesia.


The participation of human peripheral blood lymphocytes with Fc receptors for IgG or IgM in the fetal bovine serum induction of amplifier cell activity.
The culture of human peripheral blood lymphocytes (PBL) in fetal bovine serum (FBS) supplemented media results in the activation of an amplifier activity for mitogen or antigen induced proliferative responses. T cells are required for the generation of amplifier cells. In addition, this amplifier activity was shown to require a cell with Fc receptors for IgG but lacked Fc receptors for IgM. Therefore, it appears that the FBS induced amplifier cells have the same characteristics as the FBS culture induced NK-like cytotoxic and proliferating cells, i.e. these cells are of T cell origin, Fc gamma positive, and Fc mu negative. These FBS-cultured PBL may be a useful model for studying cell interactions and regulatory phenomena in human lymphoid cells.


Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the Pediatric Preclinical Testing Program.
Many childhood malignancies including sarcomas, neuroblastoma, and Wilms tumor show the presence of both, active, type-1-insulin-like growth factor receptor (IGF-1R), and the autocrine production of its ligands IGF-1/IGF-2. IMC-A12 is a fully human IgG1 antibody that prevents ligand binding to the IGF-1R. IMC-A12 was evaluated against the 23 cell lines of the Pediatric Preclinical Testing Program (PPTP) in vitro panel using 96 hr exposure at concentrations ranging from 0.01 nM to 0.1 microM. IMC-A12 was tested in vivo at a dose of 1 mg/mouse administered intraperitoneally twice weekly for 6 weeks. In vitro, IMC-A12-induced T/C values <50% in only three cell lines, a rhabdomyosarcoma cell line (Rh41) and two Ewing sarcoma cell lines (TC-71 and CHLA-9). In vivo, IMC-A12 induced significant differences in EFS distribution compared to control in 24 of 34 (71%) evaluable solid tumor xenografts. Using the PPTP "time to event" activity measure, IMC-A12 induced intermediate (n = 13) or high (n = 1) activity in 33 xenografts evaluable for this activity measure, including 6 of 6 rhabdomyosarcoma xenografts, 3 of 5 osteosarcoma xenografts, 2 of 5 neuroblastoma xenografts, and 1 of 5 Ewing sarcoma xenografts. The only objective response observed was observed in a rhabdomyosarcoma xenograft (Rh28) that achieved a maintained complete response. IMC-A12 demonstrated broad antitumor activity against the PPTP's in vivo solid tumor panels, with the activity primarily being tumor growth inhibition rather than tumor regression. IMC-A12 showed its greatest activity in vivo against the PPTP's rhabdomyosarcoma xenografts.


Eradication rates of helicobacter pylori infection with second-line treatment: non-ulcer dyspepsia compared to peptic ulcer disease.
Initial proton pump inhibitor (PPI)-based triple therapy for Helicobacter pylori (H. pylori) infection is less effective in patients with nonulcer dyspepsia (NUD) than those with peptic ulcer disease (PUD). To date, there have been no studies on the difference in eradication rates in NUD compared to PUD with regard to second-line therapy. Therefore, we retrospectively analyzed the difference in eradication rates of a second-line quadruple therapy for NUD and PUD patients. Between June 2003 and December 2005, patients who failed to respond to initial PPI-based triple therapy, received 7 days of quadruple therapy (PPI b.i.d., bismuth 300mg q.i.d., metronidazole 500mg t.i.d., tetracycline 500mg q.i.d.) as a second-line treatment regimen. Four weeks after the completion of the course of medication, a 13C-urea breath test was performed for detection of H. pylori. A total of 87 patients received second-line quadruple therapy. Of these, 43 patients had NUD and 44 patients had PUD (19 gastric ulcers, 23 duodenal ulcers, 2 both ulcers). The eradication rates were 76.7% (33/43) in the NUD group and 90.9% (40/44) in the PUD group by per-protocol analysis. Therefore, the eradication rates in the NUD group were significantly lower than those in the PUD group (p = 0.034). A 7-day bismuth-based second-line quadruple therapy for H. pylori infection was less effective in patients with NUD than those with PUD. Therefore, a more potent second-line treatment regimen or extension of treatment duration of quadruple therapy should be considered for the eradication of H. pylori in patients with NUD.


Impacts of land disturbance on aquatic ecosystem health: quantifying the cascade of events.
The impacts of land disturbance on streams have been studied extensively, but a quantitative mechanism of stream degradation is still lacking. Small changes in land use result in changes in physical and chemical characteristics in the stream, which significantly alter biotic integrity. The objective of this study was to quantify the mechanisms of aquatic ecosystem degradation in streams impacted by watershed urbanization. By quantifying the development level and the changes in the physical parameters of receiving streams, the effects of land use change can be illustrated in a conceptual model and evaluated using a traditional ecological risk assessment framework. Three 1st-order streams draining catchments undergoing varying stages of land development were examined in the upper Piedmont physiographic province of South Carolina, U.S.A. A disturbance index was developed to quantify the changes in land use on a monthly basis. This normalized disturbance index (NDI) was quantitatively linked to an increase in the percentage of impervious cover, stormwater runoff, storm-event total suspended solid (TSS) concentrations, and the North Carolina biotic index (NCBI). The NDI was inversely related to a decline in habitat, median bed-sediment particle size, and benthic index of biotic integrity (BIBI). Unlike the percentage of impervious cover, the NDI facilitated the development of strategies for multiple scales of regulation. Predictive multivariate regressions were developed for storm-event TSS concentrations, the BIBI, and the NCBI. These regressions can be used to develop improved regulations for the effects of development and can lead to better implementation of best management practices, improved monitoring of land use change, and more sustainable development.


Precortical Phase of Alzheimer's Disease (AD)-Related Tau Cytoskeletal Pathology.
Alzheimer's disease (AD) represents the most frequent progressive neuropsychiatric disorder worldwide leading to dementia. We systematically investigated the presence and extent of the AD-related cytoskeletal pathology in serial thick tissue sections through all subcortical brain nuclei that send efferent projections to the transentorhinal and entorhinal regions in three individuals with Braak and Braak AD stage 0 cortical cytoskeletal pathology and fourteen individuals with Braak and Braak AD stage I cortical cytoskeletal pathology by means of immunostainings with the anti-tau antibody AT8. These investigations revealed consistent AT8 immunoreactive tau cytoskeletal pathology in a subset of these subcortical nuclei in the Braak and Braak AD stage 0 individuals and in all of these subcortical nuclei in the Braak and Braak AD stage I individuals. The widespread affection of the subcortical nuclei in Braak and Braak AD stage I shows that the extent of the early subcortical tau cytoskeletal pathology has been considerably underestimated previously. In addition, our novel findings support the concept that subcortical nuclei become already affected during an early 'pre-cortical' evolutional phase before the first AD-related cytoskeletal changes occur in the mediobasal temporal lobe (i.e. allocortical transentorhinal and entorhinal regions). The very early involved subcortical brain regions may represent the origin of the AD-related tau cytoskeletal pathology, from where the neuronal cytoskeletal pathology takes an ascending course toward the secondarily affected allocortex and spreads transneuronally along anatomical pathways in predictable sequences.


[Physicochemical properties of some antibiotics].
Some physico-chemical properties of 3 antibiotics, i.e. kanamycin, neomycin and monomycin dried in the evaporating-drying apparatus IDA-ITE-6 constructed at the Institute of Technical Thermophysics of the UkSSR Academy of Sciences were studied. The properties of their 6 and 18 percent solutions and sorption properties of the antibiotic powders were described. It was found that the properties of the 3 antibiotics were close.


Posterior-draining dural carotid cavernous fistulae: a possible cause of computed tomographic angiography negative isolated third nerve palsy.
Computed tomographic angiography (CTA) is a well-established non-invasive investigation for this neurological presentation to exclude intracranial aneurysms. However, dural arteriovenous fistulae with anterograde venous drainage only can be missed by CTA. Here we reported two patients with painful complete third nerve palsy and dural carotid cavernous fistulae with anterograde venous drainage only missed by CTA. The natural history and management option are discussed. In patients with persistent symptoms or without vasculopathic risk factors, magnetic resonance angiography (MRA) or digital subtraction angiography (DSA) should be considered to exclude the diagnosis.


An analog of a dipeptide-like structure of FK506 increases glial cell line-derived neurotrophic factor expression through cAMP response element-binding protein activated by heat shock protein 90/Akt signaling pathway.
Glial cell line-derived neurotrophic factor (GDNF) is an important neurotrophic factor that has therapeutic implications for neurodegenerative disorders. We previously showed that leucine-isoleucine (Leu-Ile), an analog of a dipeptide-like structure of FK506 (tacrolimus), induces GDNF expression both in vivo and in vitro. In this investigation, we sought to clarify the cellular mechanisms underlying the GDNF-inducing effect of this dipeptide. Leu-Ile transport was investigated using fluorescein isothiocyanate-Leu-Ile in cultured neurons, and the results showed the transmembrane mobility of this dipeptide. By liquid chromatography-mass spectrometry and quartz crystal microbalance assay, we identified heat shock cognate protein 70 as a protein binding specifically to Leu-Ile, and molecular modeling showed that the ATPase domain is the predicted binding site. Leu-Ile stimulated Akt phosphorylation, which was attenuated significantly by heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA). Moreover, enhanced interaction between phosphorylated Akt and Hsp90 was detected by immunoprecipitation. Leu-Ile elicited an increase in cAMP response element binding protein (CREB) phosphorylation, which was inhibited by GA, indicating that CREB is a downstream target of Hsp90/Akt signaling. Leu-Ile elevated the levels of GDNF mRNA and protein expression, whereas inhibition of CREB blocked such effects. Leu-Ile promoted the binding activity of phosphorylated CREB with cAMP response element. These findings show that CREB plays a key role in transcriptional regulation of GDNF expression induced by Leu-Ile. In conclusion, Leu-Ile activates Hsp90/Akt/CREB signaling, which contributes to the upregulation of GDNF expression. It may represent a novel lead compound for the treatment of dopaminergic neurons or motoneuron diseases.


Depth dose and off-axis characteristics of TLD in therapeutic pion beams.
The thermoluminescent (TL) response of LiF (TLD-100, TLD-600, TLD-700) and Li2B4O7 (TLD-800) has been measured as a function of depth and off-axis position in a therapeutic negative-pion beam in order to evaluate their usefulness in pion radiotherapy. TLD-100, TLD-600, and TLD-800 have been shown to be of little use as in vivo dosemeters because the neutron kerma relative to that in tissue changes grossly with depth. The neutron source comes primarily from pion absorption in the lead-alloy collimator. The 200 degrees C TLD-700 response agrees well with the depth dose spectra, except for small changes due to the varying linear energy transfer (LET) distributions. This variation can be partially accounted for by incorporating the known LET response of LiF. The 260 degrees C peak of TLD-700 has been found to be approximately four times more sensitive than the 200 degrees C peak to high LET dose. Using a simple model of the LET responses, the measured 200 degrees C and 260 degrees C peaks predict total dose within +/- 4% and high LET dose within +/- 50%, therefore indicating TLD-700 to be a good in vivo dosemeter for total dose but only an indicator of high LET dose.


1 alpha,25-Dihydroxycholecalciferol and a human myeloid leukaemia cell line (HL-60).
Human promyelocytic leukaemia cells (HL-60) can be induced to differentiate into mature granulocytes in vitro by 1 alpha,25-dihydroxycholecalciferol [1 alpha,25(OH)2D3], the active form of cholecalciferol. The differentiation-associated properties, such as phagocytosis and C3 rosette formation, were induced by as little as 0.12 nM-1 alpha,25(OH)2D3, and, at 12 nM, about half of the cells exhibited differentiation on day 3 of incubation. Concomitantly the viable cell number was decreased to less than half of the control. Among various derivatives of cholecalciferol examined, 1 alpha,25(OH)2D3 and 1 alpha,24R-dihydroxycholecalciferol were the most potent in inducing differentiation, followed successively by 1 alpha,24S-dihydroxycholecalciferol, 1 alpha-hydroxycholecalciferol, 25-hydroxycholecalciferol and 24R,25-dihydroxycholecalciferol. A cytosol protein specifically bound to 1 alpha,25 (OH)2D3 was found in HL-60 cells. Its physical properties closely resembled those found in such target tissues as intestine and parathyroid glands. 1 alpha,25(OH)2D3 bound to the cytosol receptor was transferred quantitatively to the chromatin fraction. The specificity of various derivatives of cholecalciferol in inducing differentiation was well correlated with that of their association with the cytosol receptor. These results are compatible with the hypothesis that the active form of cholecalciferol induces differentiation of human myeloid leukaemia cells by a mechanism similar to that proposed for the classical concept of steroid hormone action.


Ubiquitous points of control over regulatory T cells.
Posttranslational modification by ubiquitin tagging is crucial for regulating the stability, activity and cellular localization of many target proteins involved in processes including DNA repair, cell cycle progression, protein quality control, and signal transduction. It has long been appreciated that ubiquitin-mediated events are important for certain signaling pathways leading to leukocyte activation and the stimulation of effector function. Now it is clear that the activities of molecules and pathways central to immune regulation are also modified and controlled by ubiquitin tagging. Among the mechanisms of immune control, regulatory T cells (or Tregs) are themselves particularly sensitive to such regulation. E3 ligases and deubiquitinases both influence Tregs through their effects on the signaling pathways pertinent to these cells or through the direct, posttranslational regulation of Foxp3. In this review, we will summarize and discuss several examples of ubiquitin-mediated control over multiple aspects of Treg biology including the generation, function and phenotypic fidelity of these cells. Fully explored and exploited, these potential opportunities for Treg modulation may lead to novel immunotherapies for both positive and negative fine-tuning of immune restraint.


Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern threatens the efficacy of existing vaccines and therapeutic antibodies and underscores the need for additional antibody-based tools that potently neutralize variants by targeting multiple sites of the spike protein. We isolated 216 monoclonal antibodies targeting SARS-CoV-2 from plasmablasts and memory B cells collected from patients with coronavirus disease 2019. The three most potent antibodies targeted distinct regions of the receptor binding domain (RBD), and all three neutralized the SARS-CoV-2 Alpha and Beta variants. The crystal structure of the most potent antibody, CV503, revealed that it binds to the ridge region of SARS-CoV-2 RBD, competes with the angiotensin-converting enzyme 2 receptor, and has limited contact with key variant residues K417, E484, and N501. We designed bispecific antibodies by combining nonoverlapping specificities and identified five bispecific antibodies that inhibit SARS-CoV-2 infection at concentrations of less than 1 ng/ml. Through a distinct mode of action, three bispecific antibodies cross-linked adjacent spike proteins using dual N-terminal domain–RBD specificities. One bispecific antibody was greater than 100-fold more potent than a cocktail of its parent monoclonals in vitro and prevented clinical disease in a hamster model at a dose of 2.5 mg/kg. Two bispecific antibodies in our panel comparably neutralized the Alpha, Beta, Gamma, and Delta variants and wild-type virus. Furthermore, a bispecific antibody that neutralized the Beta variant protected hamsters against SARS-CoV-2 expressing the E484K mutation. Thus, bispecific antibodies represent a promising next-generation countermeasure against SARS-CoV-2 variants of concern.


Value of prospective tissue typing in kidney transplantation between HL-A identical siblings.
The predictability of leucocyte typing in kidney transplantation was assessed by an analysis of 37 kidney transplants from sibling donors. Recipients who were identical for the HL-A antigens with their donors gave highly predictable results. In comparison with those siblings who were incompatible or compatible but not identical their grafts functioned earlier, they required less immunosuppression, and had never had any rejections. They also appeared to have less postoperative morbidity. These results indicate that less immunosuppression than is current in many transplant centres could well be used with benefit in HL-A identical sibling transplants. This could reduce the risk of infection and possibly minimize the adverse effects of steroids on wound healing in these patients.


Associations of time-dependent changes in phosphorus levels with cardiovascular diseases in patients undergoing hemodialysis: results from the Japan Dialysis Active Vitamin D (J-DAVID) randomized clinical trial.
While the risk of exceeding the standard range of phosphorus levels has been investigated, the impact of the degree of fluctuations has not been investigated. Data were derived from the Japan Dialysis Active Vitamin D trial, a 4-year prospective, randomized study involving 976 patients without secondary hyperparathyroidism undergoing hemodialysis in Japan. Laboratory data were collected every 6 months and the primary outcome was the time to the occurrence of cardiovascular events. The effect of time-dependent changes in phosphorus levels was assessed using a time-varying Cox proportional hazards regression model. The median serum phosphorus levels at baseline and at the final observation were 4.70 mg/dl [interquartile range (IQR) 3.90-5.30] and 5.00 mg/dl (IQR 4.20-5.80), respectively. Over each 6-month period, phosphorus changes ranged from -7.1 to +6.7 mg/dl, with a median value of -0.1 to +0.3 mg/dl. During follow-up, composite cardiovascular events occurred in 103 of 964 patients. Although the P-value for the interaction between serum phosphorus level fluctuations and baseline phosphorus levels was insignificant, the following trends were observed. First, patients with relatively high initial phosphorus levels over a 6-month period showed a trend towards a higher hazard, with greater changes in the phosphorus level over the 6-month period. Second, it was suggested that oral vitamin D receptor activators could contribute to the relationship between fluctuating phosphorus levels and cardiovascular events. Our results suggest the importance of maintaining stable phosphorus levels, not only in the normal range, but also without fluctuations, in the risk of cardiovascular events among patients without secondary hyperparathyroidism undergoing maintenance hemodialysis.


Modulating endoplasmic reticulum stress attenuates mast cell degranulation.
Degranulation of mast cells leads to direct allergic symptoms. The underlying mechanism needs to be explored further. Endoplasmic reticulum (ER) stress is involved in the pathogenesis of allergic conditions. The objective of this study is to gain a better understanding of the mechanism of mast cell degranulation. Bone marrow derived mast cells and mast cells isolated from the airway tissues were prepared. The role of ER stress in mediating the release of mast cells was tested. RNA sequencing (RNAseq) was used to investigate the genetic activities of mast cells. Our observation showed that sensitization increased ER stress in mast cells. X-box-1 binding protein (XBP1) activity was linked to mast cell degranulation. Modulation of ER stress or XBP1 expression regulates the release of the mast cell mediator. XBP1 promoted the mediator release of mast cells by activating spleen tyrosine kinase (Syk). Activation of eukaryotic initiation factor 2a (eIF2a) inhibited XBP1 in mast cells. Semaphorin 3A was effective in preventing experimental allergic rhinitis (AR) due to its ability to suppress the release of mast cell mediators. ER stress is associated with the mast cell degranulation. By inhibiting XBP1, the crucial molecule of ER stress, mast cell degranulation can be suppressed and experimental AR can be mitigated.


The Italian Registry of Therapeutic Apheresis: granulocyte-monocyte apheresis in the treatment of inflammatory bowel disease. A multicentric study.
Leukocytes are thought to play an important role in the pathogenesis of inflammatory bowel diseases; granulocyte-monocyte adsorptive (GMA) apheresis, an extracorporeal technique aimed at removing activated circulating leukocytes from the blood, may represent a safe and effective therapeutic tool in these patients. The Italian Registry of Therapeutic Apheresis performed an observational, multicentric study involving 24 Gastroenterology Units. In this study, laboratory data and clinical outcomes of 230 patients (148 males, mean age 43.5 years) affected with ulcerative colitis (UC, n = 194) or Crohn's disease (CD, n = 36) who underwent one or more cycles of GMA were analyzed. Each cycle consisted of five GMA treatments. The patients were followed up for a mean of 8.7 (min. 3 to max. 12) months. At 3 months, positive outcome was achieved in 77.7% of UC patients (72.0% remission, 5.7% clinical response) and 61.3% of CD patients (54.8% remission, 6.5% clinical response). The cumulative proportion of positive outcome at 12 months was 87.1% for UC patients (83.7% remission, 3.4% clinical response) and 77.4% for CD patients (74.2% remission, 3.2% clinical response). No single clinical or laboratory parameter among those analyzed (age, sex, disease characteristics, history of smoking, medication history, baseline values of clinical activity index (CAI)/Crohn's disease activity index (CDAI), hemoglobin, white blood cells count, and erythrocyte sedimentation rate) was independently associated with clinical outcome. The procedure was well tolerated with no significant adverse effects registered.


Experience-dependent central vision deficits: Neurobiology and visual acuity.
Abnormal visual experience during childhood often leads to amblyopia, with strong links to binocular dysfunction that can include poor acuity in both eyes, especially in central vision. In animal models of amblyopia, the non-deprived eye is often considered normal and what limits binocular acuity. This leaves open the question whether monocular deprivation (MD) induces binocular dysfunction similar to what is found in amblyopia. In previous studies of MD cats, we found a loss of excitatory receptors restricted to the central visual field representation in visual cortex (V1), including both eyes' columns. This led us to ask two questions about the effects of MD: how quickly are receptors lost in V1? and is there an impact on binocular acuity? We found that just a few hours of MD caused a rapid loss of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor proteins across all of V1. But after a few days of MD, there was recovery in the visual periphery, leaving a loss of AMPA receptors only in the central region of V1. We reared animals with early MD followed by a long period of binocular vision and found binocular acuity deficits that were greatest in the central visual field. Our results suggest that the greater binocular acuity deficits in the central visual field are driven in part by the long-term loss of AMPA receptors in the central region of V1.


Lateral Para-Olecranon Approach for the Treatment of Distal Humeral Fracture.
To assess the outcomes of the lateral para-olecranon triceps-splitting approach for the treatment of distal humeral fracture. Ten patients (3 males, 7 females) with a mean age of 59 years were retrospectively reviewed. There were 2 A2, 3 C1, and 5 C2 fractures according to the AO/ASIF classification. Types B3 and C3 fractures were excluded from this study because the olecranon osteotomy approach was indicated to visualize the anterior fragment. The triceps was split at the midline, and the anconeus muscle was incised from the proximal ulna. The lateral half of the triceps along with anconeus was retracted laterally as a single unit. The distal part of the humerus could be visualized from medial and lateral windows by retracting the medial half of the triceps. The articular fragment was anatomically reduced and fixed temporarily with a Kirschner wire, and the reconstructed distal articular block was then fixed to the humeral shaft with double locking plates. After surgery, average elbow flexion was 127° (range, 110°-145°), and extension was -10° (range, -20°-0°) at the average follow-up time of 12.4 months (range, 8‒20 months). Seven patients had normal muscle strength against full resistance (manual muscle testing grade 5), and the other 3 patients had slightly reduced muscle strength (grade 4). No articular stepoffs of more than 1 mm were seen on postoperative radiographs. There were no cases of triceps insufficiency and nonunion. The average (± SD) Mayo Elbow Score was 93.5 ± 5.8 points at the final follow-up. The lateral para-olecranon approach is useful for the management of selected fractures of the distal humerus, preserving extension strength and providing satisfactory clinical outcomes, with no risk of olecranon osteotomy-related complications. Therapeutic V.


Hartree-Fock complete basis set limit properties for transition metal diatomics.
Numerical Hartree-Fock (HF) energies accurate to at least 1 microhartree are reported for 27 diatomic transition-metal-containing species. The convergence of HF energies toward this numerical limit upon increasing the basis set size has been investigated, where standard nonrelativistic all-electron correlation consistent basis sets and augmented basis sets, developed by Balabanov and Peterson [J. Chem. Phys. 123, 064107 (2005)], were employed. Several schemes which enable the complete basis set (CBS) limit to be determined have been investigated, and the resulting energies have been compared to the numerical Hartree-Fock energies. When comparing basis set extrapolation schemes, those in the form of exponential functions perform well for our test set, with mean absolute deviations from numerical HF energies of 234 and 153 microE(h), when the CBS limit has been determined using a two-point fit as proposed by Halkier et al. [Chem. Phys. Lett. 302, 437 (1999)] on calculations of triple- and quadruple-zeta basis set qualities and calculations of quadruple- and quintuple-zeta basis set qualities, respectively. Overall, extrapolation schemes in the form of a power series are not recommended for the extrapolation of transition metal HF energies. The impact of basis set superposition error has also been examined.


Effect of particle packing and density on shock response in ordered arrays of Ni + Al nanoparticles.
We investigate the shock response of Ni + Al reactive nanoparticle systems through molecular dynamics simulations. The powder configurations with varying arrangements and densities are constructed by stacking equal-sized Ni and Al particles based on five typical crystal structures, i.e., zinc-blende, NaCl, CsCl, AuCu and the close-packed. The effects of configuration and shock strength on mechanochemical and diffusion processes in the shock-induced chemical reactions are characterized. A reaction kinetic model is developed to describe these behaviors, assess the extent of mechanochemical effect, and explain the occurrence of ultra-fast reaction. Significant dependence of shock wave velocity, plastic deformation, temperature response, chemistry and microstructure change on particle packing and density is observed under shock loading at the same piston velocity, but we see a relatively weak dependency on the stacking mode with the same density. Our results indicate the important role of particle coordination number and density in shock response of energetic powder materials.


The Association of 3-D Volume and 2-D Area of Post-swallow Pharyngeal Residue on CT Imaging.
Pharyngeal residue, the material that remains in the pharynx after swallowing, is an important marker of impairments in swallowing and prandial aspiration risk. The goals of this study were to determine whether the 2D area of post-swallow residue accurately represents its 3D volume, and if the laterality of residue would affect this association. Thirteen patients with dysphagia due to brainstem stroke completed dynamic 320-detector row computed tomography while swallowing a trial of 10 ml honey-thick barium. 3D volumes of pharyngeal residue were compared to 2D lateral and anterior-posterior areas, and a laterality index for residue location was computed. Although the anteroposterior area of residue was larger than the lateral area, the two measures were positively correlated with one another and with residue volume. On separate bivariate regression analyses, residue volume was accurately predicted by both lateral (R2 = 0.91) and anteroposterior (R2 = 0.88) residue areas, with limited incidence of high residuals. Half of the sample demonstrated a majority of pharyngeal residue lateralized to one side of the pharynx, with no effect of laterality on the association between areas and volume. In conclusion, the area of post-swallow pharyngeal residue was associated with volume, with limitations in specific cases. Direct measurement of pharyngeal residue volume and swallowing physiology with 3D-CT can be used to validate results from standard 2D instrumentation.


Persistence of within-species lineages: a neglected control of speciation rates.
We present a framework distinguishing three principal controls of speciation rate: rate of splitting, level of persistence, and length of speciation duration. We contend that discussions on diversification become clearer in the light of this framework, because speciation rate variation could be attributed to any of these controls. In particular, we claim that the role of persistence of within-species lineages in controlling speciation rates has been greatly underappreciated. More emphasis on the persistence control would change expectations of the role of several biological traits and environmental factors, because they may drive speciation rate in one direction through the persistence control and in the opposite direction through the other two controls. Traits and environments have been little studied regarding their influence on speciation rate through the persistence control, with climatic fluctuations being a relatively well-studied exception. Considering the recent advances in genomic and phylogenetic analysis, we think that the time is ripe for applying the framework in empirical research. Variation among clades and areas (and thus among traits and environments) in the importance of the three rate controls could be addressed for example by dating splitting events, detecting within-species lineages, and scanning genomes for evidence of divergent selection.


Relative contribution of additive, dominance, and imprinting effects to phenotypic variation in body size and growth between divergent selection lines of mice.
Epigenetic effects attributed to genomic imprinting are increasingly recognized as an important source of variation in quantitative traits. However, little is known about their relative contribution to phenotypic variation compared to those of additive and dominance effects, and almost nothing about their role in phenotypic evolution. Here we address these questions by investigating the relative contribution of additive, dominance, and imprinting effects of quantitative trait loci (QTL) to variation in "early" and "late" body weight in an intercross of mice selected for divergent adult body weight. We identified 18 loci on 13 chromosomes; additive effects accounted for most of the phenotypic variation throughout development, and imprinting effects were always small. Genetic effects on early weight showed more dominance, less additive, and, surprisingly, less imprinting variation than that of late weight. The predominance of additivity of QTL effects on body weight follows the expectation that additive effects account for the evolutionary divergence between selection lines. We hypothesize that the appearance of more imprinting effects on late body weight may be a consequence of divergent selection on adult body weight, which may have indirectly selected for alleles showing partial imprinting effects due to their associated additive effects, highlighting a potential role of genomic imprinting in the response to selection.


Effect of Acute Administration of loganin on Spatial Memory in Diabetic Male Rats.
Diabetes is associated with memory and learning disorder. The purpose of this study is to determine the effect of acute oral administration of loganin on memory in diabetic male rats. 42 male Wistar rats (250-300 g) were divided into six groups: Control, Diabetic (1 week), Diabetic (12 weeks), Loganin, Diabetic (1 week) + Loganin, Diabetic (12 weeks) + Loganin. Diabetes was induced by IP injection of Streptozotocin (60 mg/kg). Loganin (40 mg/kg, po) was administrated 1 hour before test. Then, spatial memory was compared between groups with Morris Water Maze tests. Administration of loganin during acquisition, significantly (p<0.05) decreased both escape latency and traveled distance to find hidden platform in 1 and 12 weeks diabetic rats. In evaluation of recall phase of memory, loganin significantly (p<0.05) increased time and distance spent in the target quadrant in 1 and 12 weeks diabetic rats. Acute administration of loganin could improve spatial memory in diabetic rats.


Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction.
Individuals at high risk of developing seropositive rheumatoid arthritis (RA) can be identified for translational research and disease prevention studies through the presence of highly informative and predictive patterns of RA-related autoantibodies, especially anti-citrullinated protein antibodies (ACPAs), in the serum. In serologically positive individuals without arthritis, designated ACPA positive at risk, the presence of mucosal inflammatory processes associated with the presence of local ACPA production has been demonstrated. In other at-risk populations, local RA-related autoantibody production is present even in the absence of serum autoantibodies. Additionally, a proportion of at-risk individuals exhibit local mucosal ACPA production in the lung, as well as radiographic small-airway disease, sputum hypercellularity and increased neutrophil extracellular trap formation. Other mucosal sites in at-risk individuals also exhibit autoantibody production, inflammation and/or evidence of dysbiosis. As the proportion of individuals who exhibit such localized inflammation-associated ACPA production is substantially higher than the likelihood of an individual developing future RA, this finding raises the hypothesis that mucosal ACPAs have biologically relevant protective roles. Identifying the mechanisms that drive both the generation and loss of externally focused mucosal ACPA production and promote systemic autoantibody expression and ultimately arthritis development should provide insights into new therapeutic approaches to prevent RA.


Synthesis and evaluation of melphalan-containing N,N-dialkylenkephalin analogues as irreversible antagonists of the delta opioid receptor.
N,N-Dialkylated leucine enkephalin analogues containing melphalan (Mel) in place of Phe4 were synthesized as potentially irreversible antagonists of the delta opioid receptor. These compounds, along with the corresponding Phe4 peptides, were tested for both agonist and antagonist activity in the GPI and MVD smooth muscle preparations. All but two of the eight compounds showed antagonist activity at 1 microM against [D-Ala2,D-Leu5]enkephalin (DADLE) in the MVD when tested under reversible conditions; in all cases the Mel4 peptide had lower activity against DADLE than did the corresponding Phe4 peptide. At higher concentrations (10 microM) the two active Mel4 analogues, (benzyl)2Tyr-Gly-Gly-Mel-Leu (2a) and (allyl)2Tyr-Aib-Aib-Mel-Leu (3a), both showed weak irreversible antagonism at the delta receptor. Compound 2a was a selective irreversible delta opioid antagonist while 3a was an irreversible antagonist at both the mu and delta opioid receptors.


Long non‑coding RNA PCAT1 sponges miR‑134‑3p to regulate PITX2 expression in breast cancer.
Breast cancer (BC) is the most prevalent cancer among women. Long non‑coding (lnc)RNAs and microRNAs (miRs) both regulate the expression of key genes in tumorigenesis. The present study aimed to explore the molecular mechanism of the prostate cancer‑associated transcript 1 (PCAT1)/miR‑134‑3p/pituitary homeobox 2 (PITX2) in BC. Reverse transcription‑quantitative PCR was performed to examine the expression of miR‑134‑3p. Cell proliferation, viability, cell cycle, apoptosis and migration were analyzed using Cell Counting Kit‑8, colony formation, flow cytometry, wound healing and Transwell assays. Protein expression levels were determined by western blotting. The present study demonstrated that PCAT1 was significantly highly expressed in BC cells. Knockdown of PCAT1 significantly inhibited cell proliferation, migration and invasion, but promoted apoptosis in human BC cell lines. The results of the dual‑luciferase assay showed that PCAT1 targeted miR‑134‑3p, and PITX2 was a potential target of miR‑134‑3p. Western blotting results demonstrated that PCAT1 knockdown significantly reduced the protein expression levels of anti‑apoptotic protein Bcl‑2, and significantly upregulated the protein expression levels of proapoptotic proteins, Bax, cleaved caspase‑3 and cleaved caspase‑9. Furthermore, the effect of a miR‑134‑3p inhibitor on BC progression was rescued by the knockdown of PITX2 in cells transfected with short hairpin RNA‑lncRNA PCAT1. To conclude, the results of the present study indicated that the PCAT1/miR‑134‑3p/PITX2 axis could be a promising therapeutic target in BC treatment.


Implementation of an Automated Dispensing Cabinet System and Its Impact on Drug Administration: Longitudinal Study.
A technology that has been widely implemented in hospitals in the United States is the automated dispensing cabinet (ADC), which has been shown to reduce nurse drug administration errors and the time nurses spend administering drugs. This study aimed to determine the impact of an ADC system on medication administration by nurses as well as safety before and after ADC implementation. We conducted a 24-month-long longitudinal study at the National Taiwan University Hospital in Taipei, Taiwan. Clinical observations and questionnaires were used to evaluate the time differences in drug preparation, delivery, and returns in the inpatient ward by nurses before and after using the ADC. Drug errors recorded in the Medical Incident Events system were assessed the year before and after ADC implementation. The drug preparation time of the wards increased significantly (all P<.005). On average, 2 minutes of preparation time is needed for each patient. Only 1 unit showed an increase in the drug return time, but this was not significant. There were 9 (45%) adverse events during the drug administration phase, and 11 (55%) events occurred during the drug-dispensing phase. Although a decrease in the mean number of events reported was observed during the ADC implementation period, this difference was not significant. As for the questionnaire that were administered to the nurses, the overall mean score was 3.90; the highest score was for the item "I now spend less time waiting for medications that come from the pharmacy than before the ADC was implemented" (score=4.24). The item with the lowest score was "I have to wait in line to get my patient medications" (score=3.32). The nurses were generally satisfied with ADC use over the 9 months following complete implementation and integration of the system. It was acknowledged that the ADC offers benefits in terms of pharmaceutical stock management; however, this comes at the cost of increased nursing time. In general, the nurses remained supportive of the benefits for their patients, despite consequences to their workflows. Their acceptance of the ADC system in this study demonstrates this.


Prognostic Value of the Staging System for Eyelid Tumors in the 7th Edition of the American Joint Committee on Cancer Staging Manual.
To determine the prognostic value of the staging criteria for eyelid tumors in the 7th edition of the American Joint Committee on Cancer (AJCC) staging manual and to determine, for each type of eyelid tumor, which AJCC T categories are associated with increased risk of nodal metastasis and thus potential usefulness of sentinel lymph node biopsy. Systematic review and analysis of articles found by searching PubMed and Google Scholar using the search terms "AJCC," "eyelid," "carcinoma," and "melanoma." Rates of local recurrence, regional nodal metastasis, and distant metastasis were approximately 7% to 10%, 1% to 9%, and 0% to 0.8%, respectively, for eyelid squamous cell carcinoma; 5% to 6%, 8% to 23%, and 2% and 14%, respectively, for eyelid sebaceous carcinoma; 10%, 10% to 22%, and 19% to 22%, respectively, for eyelid Merkel cell carcinoma (when staged according to the criteria for eyelid carcinoma as opposed to Merkel cell carcinoma), 14%, 5%, and 0%, respectively, for eyelid sweat gland carcinoma; and 2%, 9%, and 6%, respectively, for eyelid melanoma. Overall, the risks of local recurrence and regional nodal and distant metastasis appeared to increase with increasing AJCC T category, although not statistically significant in all studies. Clinical T2b or greater T category was significantly associated with increased risk of nodal metastasis for eyelid squamous cell carcinomas, sebaceous carcinomas, Merkel cell carcinomas (staged with eyelid carcinoma criteria), sweat gland carcinomas, and melanomas. Clinical T3 or greater T category was significantly associated with distant metastasis for eyelid carcinomas and melanomas. For eyelid carcinomas and eyelid melanomas, AJCC 7th edition T category correlates with the risks of nodal and distant metastasis, with T2b and larger tumors associated with highest risk of nodal metastasis. Patients with T2b or larger tumors may be candidates for sentinel lymph node biopsy or close nodal surveillance.


Nonspecific Interstitial pneumonia (NSIP)/ Overlap or Distinct Entity: A case report from the National Research Institute of Tuberculosis and Lung Disease (NRITLD).
In many cases of ILD (interstitial lung disease), overlap diagnosis is considered. Here, a few cases with diagnosis of a variety of ILDs, where eventual open lung biopsy has been performed are selected. Reference will be made to reliable sources to show that NSIP can still be a variant of UIP (Usual interstitial pneumonia) with better treatment response and prognosis. In case 1, there is a difference between the HRCT(High Resolution Computed Tomography) result (NSIP pattern without fibrosis) and pathologic result (which includes fibrosing NSIP more closely related to UIP).Case 2 shows obvious discord between HRCT result (UIP pattern) and pathologic result (NSIP pattern). In case 3, there is again a discrepancy between HRCT report (very mild architectural distortion suggestive for ILD like NSIP) and pathology report (destructed lung tissue with interstitial fibrosis suggestive of HP (Hypersesitivity Pneumonitis) and not NSIP. In this paper, we demonstrate that although NSIP can be a distinct diagnosis in most cases, but in rare cases the distinction between the other kinds of ILD especially UIP and NSIP in spite of full workup including tissue assessment can be very difficult.


Barriers and Facilitators perceived by the health team for the implementation of pre and post ductal saturometry as a method of detection of congenital heart diseases in newborns, prior to discharge.
To describe the main barriers and facilitators perceived by the health care workers for the implementation of Pre- and Post-Ductal Oxygen Saturation (SPPD) as a detection method of Con genital Heart Disease in newborns, prior to hospital discharge. From a cons tructivist research paradigm, a case study was carried out in three public hospitals in the Metropoli tan Region, Chile, two of them are high-complexity hospitals. The first one, the NEW Hospital, has recently started its activity, and the second one, the OLD Hospital, has been operating for many years. The third one, the RURAL Hospital, is a low-complexity institution, located near Santiago. Data were collected through individual semi-structured interviews and focus groups to Nursing Technicians (TENS), Midwives and Physicians. The interviews were recorded and transcribed. Thematic content analysis is performed using the NVivo11 qualitative software. The investigation was approved by the Ethics Committee recognized by the hospitals involved. In the NEW Hospital, where the SPPD was implemented more than a year ago, barriers are detected at execution level, especially in oximeter inputs and on weekends. In the OLD Hospital and the RURAL Hospital, in which the SPPD was not implemented, the main perceived barriers are concentrated in insufficient knowledge about their usefulness, economic aspects, work overload, and organizational aspects. In the NEW Hospital, the main facilitators for the application of SPPD were its simplicity, economy, and the fact that it is an important contribution to the safety of newborns discharged. The disposition regar ding the practice of PPDS as a screening, varies in the 3 hospitals explored. To achieve this goal it is recommended to overcome organizational, management and economic barriers. Although there is a need to train the personnel in charge of screening, there is good disposition given the importance for the health of the RN. The flow of referral after screening for positive SPPD is quite clear.


Carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophy families, using dinucleotide repeat polymorphisms.
To improve carrier detection and prenatal diagnosis for Duchenne and Becker muscular dystrophy families, we determined allele frequencies and measures of variation for four (dC-dA)n.(dG-dT)n loci identified within a deletion-prone region of the human dystrophin gene. The loci are highly polymorphic, with predicted heterozygosities of 71.6%-93.3%. Direct DNA sequence analysis of the (dC-dA)n.(dG-dT)n locus in intron 49 revealed an additional length polymorphism which varies by single-basepair increments, is adjacent to the dinucleotide repeat block, and enhances the polymorphic content of this marker. The four (dC-dA)n.(dG-dT)n loci are each easily amplified by PCR in two diplex reactions. The variability of allele lengths at these loci makes them ideal for carrier detection and prenatal diagnosis, often providing diagnostic information when RFLP analysis is uninformative. These markers have aided in identification of deletion mutations, exclusion of maternal cell contamination of chorionic villus samples, confirmation of paternity, and mapping of gene recombinations. The allele identification of these loci can be performed either with a radiolabel or with an automated, nonradioactive, fluorescent gel detection system.


The burgeoning role of global health diplomacy to alleviate suffering of cancer patients in low- and middle-income countries.
The science of global health diplomacy (GHD) consists of cross-disciplinary, multistakeholder credentials comprised of national security, public health, international affairs, management, law, economics and trade policy. GHD is well placed to bring about better and improved multilateral stakeholder leverage and outcomes in the prevention and control of cancer. It is important to create an evidence base that provides clear and specific guidance for health practitioners in low- and middle-income countries (LMICs) through involvement of all stakeholders. GHD can assist LMICs to negotiate across multilateral stakeholders to integrate prevention, treatment and palliative care of cancer into their commercial and trade policies.


Prevalence of human papillomavirus infection & cervical abnormalities in HIV-positive women in eastern India.
India has the third highest burden of HIV and highest number of cervical cancer in the world. A cross-sectional study was performed to determine the prevalence and types of human papillomavirus (HPV) infection, and the factors associated with HPV infection and abnormal cervical cytology in HIV-positive women attending the Antiretroviral Therapy (ART) Centre in a tertiary care hospital in eastern India. We screened 216 HIV- positive women with Papanicolau smear cytology and HPV testing. HPV DNA was detected by using consensus primers followed by sequencing. Of the 216 HIV-positive women screened, 58 (26.85%) were HPV-positive; 56 (25.9%) were of high-risk (HR) HPV type. The most prevalent HPV type was HPV-16 (7.9%); non 16 and 18 HPV types were present in 17.6 per cent patients. Age ≤ 35 yr [(OR), 2.56 (1.26-5.19)], illiteracy [OR, 2.30 (1.19-4.46)], rural residence [OR, 3.99 (1.27-12.56)] and CD4 ≤ 350/µl [OR, 2.46 (1.26-4.83)] were associated with increased risk of acquisition of HPV. One hundred thirty nine (74.33%) patients had normal/ negative for intraepithelial lesions (NILM) cytology, three (1.60%) had atypical squamous cells of undetermined significance (ASCUS), 32 (17.11%) had low-grade squamous intraepithelial lesions (LSIL), 10 (5.35%) had high-grade squamous intraepithelial lesions (HSIL) and three (1.60%) had carcinoma cervix. WHO clinical Stage III and IV [OR, 2.83 (1.07-7.49)] and CD4 ≤ 350/µl [OR, 2.84 (1.30-6.20)] were risk factors for abnormal cytology. Our study showed 26.85 per cent HPV positivity in HIV infected women in this region, with HPV-16 as the commonest genotype. Abnormal cervical cytology was seen in about 25 per cent women. Regular Pap smear screening as recommended by the National AIDS Control Organization will help in early detection of cervical abnormalities in HIV- positive women.


Recombinant expression and purification of the botulinum neurotoxin type A translocation domain.
Botulinum neurotoxin type A in its fully activated form exists as a dichain protein consisting of a 50-kDa light chain and a 100-kDa heavy chain linked by a disulfide bond (B. R. DasGupta and H. Sugiyama, Biochem. Biophys. Res. Commun. 48, 108-112, 1972). The protein can be further subdivided into three functional domains: a catalytic domain corresponding to the light chain, a translocation domain associated with the N-terminal half of the heavy chain, and a binding domain as the C-terminal half. To facilitate further structural and functional studies on the mechanism of toxin translocation, we report here the recombinant Escherichia coli expression and purification of the isolated translocation domain with a yield of 1 mg pure protein per 1 g cell paste. Circular dichroism, enzyme-linked immunosorbent assays, and preliminary crystallization experiments verify proper protein folding. This reagent should serve as a key tool in elucidating the mechanism of translocation and in determining how the catalytic domain, a large 50-kDa metalloprotease, is delivered to the cytosol.


The C-Terminal Domain of Salmonid Alphavirus Nonstructural Protein 2 (nsP2) Is Essential and Sufficient To Block RIG-I Pathway Induction and Interferon-Mediated Antiviral Response.
Salmonid alphavirus (SAV) is an atypical alphavirus that has a considerable impact on salmon and trout farms. Unlike other alphaviruses, such as the chikungunya virus, SAV is transmitted without an arthropod vector, and it does not cause cell shutoff during infection. The mechanisms by which SAV escapes the host immune system remain unknown. By studying the role of SAV proteins on the RIG-I signaling cascade, the first line of defense of the immune system during infection, we demonstrated that nonstructural protein 2 (nsP2) effectively blocks the induction of type I interferon (IFN). This inhibition, independent of the protease activity carried by nsP2, occurs downstream of IRF3, which is the transcription factor allowing the activation of the IFN promoter and its expression. The inhibitory effect of nsP2 on the RIG-I pathway depends on the localization of nsP2 in the host cell nucleus, which is linked to two nuclear localization sequences (NLS) located in its C-terminal part. The C-terminal domain of nsP2 by itself is sufficient and necessary to block IFN induction. Mutation of the NLS of nsP2 is deleterious to the virus. Finally, nsP2 does not interact with IRF3, indicating that its action is possible through a targeted interaction within discrete areas of chromatin, as suggested by its punctate distribution observed in the nucleus. These results therefore demonstrate a major role for nsP2 in the control by SAV of the host cell's innate immune response. IMPORTANCE The global consumption of fish continues to rise, and the future demand cannot be met by capture fisheries alone due to limited stocks of wild fish. Aquaculture is currently the world's fastest-growing food production sector, with an annual growth rate of 6 to 8%. Recurrent outbreaks of SAV result in significant economic losses with serious environmental consequences for wild stocks. While the clinical and pathological signs of SAV infection are fairly well known, the molecular mechanisms involved are poorly described. In the present study, we focus on the nonstructural protein nsP2 and characterize a specific domain containing nuclear localization sequences that are critical for the inhibition of the host innate immune response mediated by the RIG-I pathway.


[Pilot study: Wrist digital sphygmomanometers as an alternative for noninvasive blood pressure measurement in pediatric population].
In current clinical practice, the mercury sphygmomanometer (MS) is being replaced by alternatives as aneroid sphygmomanometer and semiautomatic and automatic-type digital sphygmomanometers (DS). However, a validated DS in adults may not be appropriate for use in the pediatric population, particularly for wrist-type devices. A pilot study was conducted to determine if wrist DS can replace the MS for clinical use in children population. Measuring blood pressure for pediatric patients with wrist diameter greater 13.5 cm was made. The correlation between wrist DS and mercurial device was evaluated and compared by Bland-Altman. The flexible-bracelet wrist DS (CH-656C) showed discrepancies in the mean ± standard deviation differences from 2.6 ± 5.5 to 5.8 ± 6.2 mmHg compared to the mercury device, while the rigid-wrist DS (CH-607) showed variations from 3.9 ± 5.2 to 11.4 ± 7.6 mmHg compared to the MS. For some cases, the agreement was not presented because the results are above the criteria of the American Association for Advancement Medical Instrumentation. This study revealed that the discrepancy of the results is so high for both digital devices, which makes it impossible suggest that any of them can replace the MS. Therefore, it is recommended that hospitals should ensure validation in the pediatric population before the wrist DS is used, particularly when it is utilized for diagnosis in children under 11 years.


Prenatal exposure to integerrimine N-oxide impaired the maternal care and the physical and behavioral development of offspring rats.
Plants that contain pyrrolizidine alkaloids (PAs) have been reported as contaminants of pastures and food, as well as being used in herbal medicine. PAs are responsible for poisoning events in livestock and human beings. The aim of this present study was to evaluate effects of prenatal exposure to integerrimine N-oxide, the main PA found in the butanolic residue (BR) of Senecio brasiliensis, on both physical and behavioral parameters of Wistar rat offspring. The toxicity and maternal behavior were also evaluated. For this, pregnant Wistar rats received integerrimine N-oxide from the BR of Senecio brasiliensis, by gavage, on gestational days 6-20 (during organogenesis and fetal development period) at doses of 3, 6 and 9 mg/kg. During treatment, maternal body weight gain, and food and water intake were evaluated. After parturition, maternal behavior and aggressive maternal behavior were analyzed. In addition, physical development and behavioral assessments were observed in both male and female pups. Results showed that prenatal exposure to integerrimine N-oxide of S. brasiliensis induced maternal toxicity, impairment in maternal behavior and aggressive maternal behavior, mainly in the highest dose group. Between sexes comparison of pups showed loss of body weight, delayed physical development such as pinna detachment, hair growth, eruption of incisor teeth, eye and vaginal openings. These pups also showed a delay of palmar grasp, surface righting reflex, negative geotaxis and auditory startle reflexes. Thus, prenatal exposure to integerrimine N-oxide induces maternal toxicity, impairment of maternal care and delayed in physical and behavioral development of the offspring.


Non-specific antiviral activity of bovine leukocytes against infectious bovine rhinotracheitis virus in vitro.
Leukocytes collected from bovine blood inhibit the multiplication of virus in IBR infected MDBK cells. This inhibition is non-specific and can be observed in the absence of serum. Number of infected cells, number of leukocytes per infected cell and time of placing of leukocytes onto infected cells are some of the important factors in this protection. We observed variations between animals, but for each animal the activity of leukocytes was constant for several months. Contact between leukocytes and the susceptible cell is a vital factor in this protection. We could not detect any soluble mediator in the supernatant fluid. The different types of cells which constitute the population of leukocytes are less efficient than the original heterogenous population (80% lymphocytes and 20% neutrophils and monocytes).


Ultrafast X-ray probing of water structure below the homogeneous ice nucleation temperature.
Water has a number of anomalous physical properties, and some of these become drastically enhanced on supercooling below the freezing point. Particular interest has focused on thermodynamic response functions that can be described using a normal component and an anomalous component that seems to diverge at about 228 kelvin (refs 1-3). This has prompted debate about conflicting theories that aim to explain many of the anomalous thermodynamic properties of water. One popular theory attributes the divergence to a phase transition between two forms of liquid water occurring in the 'no man's land' that lies below the homogeneous ice nucleation temperature (TH) at approximately 232 kelvin and above about 160 kelvin, and where rapid ice crystallization has prevented any measurements of the bulk liquid phase. In fact, the reliable determination of the structure of liquid water typically requires temperatures above about 250 kelvin. Water crystallization has been inhibited by using nanoconfinement, nanodroplets and association with biomolecules to give liquid samples at temperatures below TH, but such measurements rely on nanoscopic volumes of water where the interaction with the confining surfaces makes the relevance to bulk water unclear. Here we demonstrate that femtosecond X-ray laser pulses can be used to probe the structure of liquid water in micrometre-sized droplets that have been evaporatively cooled below TH. We find experimental evidence for the existence of metastable bulk liquid water down to temperatures of 227(-1)(+2) kelvin in the previously largely unexplored no man's land. We observe a continuous and accelerating increase in structural ordering on supercooling to approximately 229 kelvin, where the number of droplets containing ice crystals increases rapidly. But a few droplets remain liquid for about a millisecond even at this temperature. The hope now is that these observations and our detailed structural data will help identify those theories that best describe and explain the behaviour of water.


A Bayesian hierarchical nonlinear mixture model in the presence of artifactual outliers in a population pharmacokinetic study.
The purpose of this study is to develop a statistical methodology to handle a large proportion of artifactual outliers in a population pharmacokinetic (PK) modeling. The motivating PK data were obtained from a population PK study to examine associations between PK parameters such as clearance of dexmedetomidine (DEX) and cytochrome P450 2A6 phenotypes. The blood samples were sparsely sampled from patients in intensive care units (ICUs) while different doses of DEX were continuously infused. Conventional population PK analysis of these data revealed several challenges and intricacies. Especially, there was strong evidence that some plasma drug concentrations were artifactually high and likely contaminated with the infused drug due to blood sampling processes that are sometimes unavoidable in an ICU setting. If not addressed, or if arbitrarily excluded, these outlying values could lead to biased estimates of PK parameters and miss important relationships between PK parameters and covariates due to increased variability. We propose a novel population PK model, a Bayesian hierarchical nonlinear mixture model, to accommodate the artifactual outliers using a finite mixture as the residual error model. Our results showed that the proposed model handles the outliers well. We also conducted simulation studies with a varying proportion of the outliers. These simulation results showed that the proposed model can accommodate the outliers well so that the estimated PK parameters are less biased.


Sudden Recanalization: A Game-Changing Factor in Endovascular Treatment of Large Vessel Occlusion Strokes.
Background and Purpose- First pass (FP) recanalization has been shown to be a predictor of favorable outcome in endovascular treatment of stroke. The reasons why FP recanalization leads to better outcome as compared with multiple passes (MP) are unknown. We aim to investigate the recanalization pattern and its relationship with outcome. Methods- Six hundred nine consecutive patients underwent endovascular treatment. Recanalization was defined as modified Thrombolysis in Cerebral Infarction score 2B-3. Favorable outcome was defined as modified Rankin Scale score of 0 to 2 at 90 days. Sudden recanalization (SR) was considered when modified Thrombolysis in Cerebral Infarction score varied from 0-1 to 2B-3 in a single pass. Progressive recanalization (PR) was considered if modified Thrombolysis in Cerebral Infarction score 2A was achieved at an interim pass before achieving recanalization. Patients were also categorized as recanalizers at FP, MP, or nonrecanalizers. Results- Five hundred nine (83.9%) patients achieved recanalization. SR was achieved in 378 (62.1%) patients; 280 (46%) were FP-SR, and 98 (16.1%) were MP-SR. MP-PR was achieved in 131 (21.5%) patients. Rates of favorable outcome were similar between patients with FP-SR (57.5%) and MP-SR (57.1%; odds ratio [OR], 0.9 [CI, 0.53-1.54]; P=0.7) but lower in MP-PR (29.8%; OR, 3.33 [CI, 1.71-5.63]; P<0.01). Patients with MP-PR had better outcome than nonrecanalizer (17%; OR, 2.93 [CI, 1.42-6.15]; P<0.01). In univariate analysis, both FP recanalization (OR, 1.91 [CI, 1.31-2.72]; P<0.01) and SR (OR, 3.19 [CI, 2.12-4.95]; P<0.01) were associated with favorable outcome. However multivariate analysis adjusting for FP recanalization showed that the only procedural predictor of favorable outcome was SR (OR, 3.12 [CI, 1.91-5.16]; P<0.01). Higher number of passes were associated with worse outcome in patients with recanalization (OR, 0.75 [CI, 0.66-0.85]; P<0.01) but not in those with SR (OR, 0.94 [CI, 0.59-1.61]; P=0.937). Conclusions- SR strongly predicts favorable outcome in patients undergoing endovascular treatment, even after previous unsuccessful attempts. PR may reflect clot fragmentation and embolization due to more friable composition, leading to worse outcomes. Prospective studies with independent assessment of recanalization pattern should validate these results.


[The dynamics of the indices of reactivity of the body in patients with chronic bronchitis and bronchiectasis in the course of treatment].
Complex determination of lymphocyte functional activity and the condition of the organism's immunological values in patients with chronic bronchitis and bronchiectasis helps in obtaining additional objective information which makes it possible to appraise the severity of the course of the disease, correct the treatment and determine its efficacy in different stages of the disease, come to a decision in regard to operative intervention, and form a judgement on the fullness of recovery. These tests acquire additional diagnostic value in patients with mild clinical manifestations of the disease as well as in the absence of its laboratory signs. A direct dependence between the severity of the disease and the above named values was revealed.


Effects of aromatic compounds on the production of bacterial nanocellulose by Gluconacetobacter xylinus.
Bacterial cellulose (BC) is a polymeric nanostructured fibrillar network produced by certain microorganisms, principally Gluconacetobacter xylinus. BC has a great potential of application in many fields. Lignocellulosic biomass has been investigated as a cost-effective feedstock for BC production through pretreatment and hydrolysis. It is well known that detoxification of lignocellulosic hydrolysates may be required to achieve efficient production of BC. Recent results suggest that phenolic compounds contribute to the inhibition of G. xylinus. However, very little is known about the effect on G. xylinus of specific lignocellulose-derived inhibitors. In this study, the inhibitory effects of four phenolic model compounds (coniferyl aldehyde, ferulic acid, vanillin and 4-hydroxybenzoic acid) on the growth of G. xylinus, the pH of the culture medium, and the production of BC were investigated in detail. The stability of the phenolics in the bacterial cultures was investigated and the main bioconversion products were identified and quantified. Coniferyl aldehyde was the most potent inhibitor, followed by vanillin, ferulic acid, and 4-hydroxybenzoic acid. There was no BC produced even with coniferyl aldehyde concentrations as low as 2 mM. Vanillin displayed a negative effect on the bacteria and when the vanillin concentration was raised to 2.5 mM the volumetric yield of BC decreased to ~40% of that obtained in control medium without inhibitors. The phenolic acids, ferulic acid and 4-hydroxybenzoic acid, showed almost no toxic effects when less than 2.5 mM. The bacterial cultures oxidized coniferyl aldehyde to ferulic acid with a yield of up to 81%. Vanillin was reduced to vanillyl alcohol with a yield of up to 80%. This is the first investigation of the effect of specific phenolics on the production of BC by G. xylinus, and is also the first demonstration of the ability of G. xylinus to convert phenolic compounds. This study gives a better understanding of how phenolic compounds and G. xylinus cultures are affected by each other. Investigations in this area are useful for elucidating the mechanism behind inhibition of G. xylinus in lignocellulosic hydrolysates and for understanding how production of BC using lignocellulosic feedstocks can be performed in an efficient way.


Refractive outcomes of lens-sparing vitrectomy for retinopathy of prematurity.
To evaluate the refractive outcomes of 3-port lens-sparing vitrectomy (LSV) for subtotal retinal detachments owing to retinopathy of prematurity. The study included 9 infants who had undergone complete ablative laser treatment for threshold retinopathy of prematurity in both eyes, subsequently developed stage 4A retinal detachment in 1 eye for which they underwent LSV, and maintained complete retinal attachment bilaterally. Eyes that underwent LSV were compared with fellow eyes. Cycloplegic refraction was performed, and corneal curvature, axial length, lens thickness, lens position, and anterior chamber depth were measured. Significantly less myopia was present in eyes that had undergone LSV compared with control eyes (mean spherical equivalent, -6.78 vs -10.33 diopter [D]; P < .001). The reduced myopia in LSV eyes was predominantly owing to increased anterior chamber depth (mean, 3.81 vs 2.96 mm; P < .001) and a more posterior position of the lens (mean, 5.58 vs 4.63 mm; P < .001). There was a minor contribution from reduced corneal power in LSV eyes (mean, 43.90 vs 44.20 D; P = .02). There was no significant difference in axial length, lens thickness, or lens power between LSV and control eyes. Infant eyes undergoing 3-port LSV for stage 4A retinopathy of prematurity develop less myopia than fellow eyes treated with ablative laser alone. The difference is owing to posterior displacement of the lens, with a smaller contribution from reduced corneal power. The reduction in myopia may explain the excellent functional outcomes following 3-port LSV for stage 4A retinopathy of prematurity.


Treatment of "en coup de sabre" deformity with adipose-derived regenerative cell-enriched fat graft.
Linear scleroderma "en coup de sabre" is characterized by atrophy and furrowing of the skin of the front parietal region above the level of the eyebrow. In most cases, it occurs as a single paramedian line that may be associated with hypoplasia of underlying structures and hemiatrophy of the face. The affected region is a depression that may be associated with hypoplasia of the underlying soft tissues and bone that results in facial hemiatrophy. If the lesion is narrow, it can be resected and directly sutured; in the case of a wide lesion, many different reconstructive techniques, directed at augmentation of deficient soft tissue volume, have been proposed such as autologous tissue grafts, biomaterials, pedicled flaps, and free flaps. Adipose-derived regenerative cells (ADRCs) can be easily processed from lipoaspirated fat and can provide a significant quantity of multipotent cells for a variety of therapeutic regenerative medicine therapies. There is an increasing interest in a possible therapeutic role of ADRCs from processed lipoaspirate for many applications, including their use as soft-tissue fillers. We introduce the application of a successful ADRC therapy for a linear scleroderma en coup de sabre deformity.


Racial and ethnic disparities in pediatric appendicitis rupture rate.
To determine if there are racial/ethnic differences in the rates of appendiceal rupture among the children of two large states. Because rupture is primarily due to delayed diagnosis, differences would suggest disparities in timely access to quality emergency care. This was an observational, cross-sectional analysis of full-year samples of acute appendicitis cases from California and New York children 4 to 18 years old. Racial/ethnic groups were compared for risk of appendiceal rupture adjusted for biological factors both before and after adjustment for the following socioeconomic, hospital, and admission characteristics: income, insurance, hospital type, and admission source. Results were interpreted in light of census data on the proportion of immigrants in each racial/ethnic group. Compared with white children with acute appendicitis, Hispanic and Asian children have higher odds of rupture in California, whereas Asian and black/African American children have higher odds in New York. These differences roughly parallel the within-state proportion of immigrant children in these groups. Adjustments for family, socioeconomic, and hospital characteristics attenuate but do not eliminate disparities. The authors found evidence of significant racial/ethnic disparities in rate of appendiceal rupture, an important and preventable outcome, in two large but dissimilar states. Immigrant groups may be most at risk for delayed emergency care. Future research should focus on immigration and acculturation as risk factors for appendicitis rupture in children.


Four observations about "Six Domains of Research Ethics".
Stimulated by Kenneth Pimple's "Six Domains of Research Ethic", this paper examines four aspects of the responsible conduct of research and scientists' social responsibilities. I argue that scholars and decision-makers concerned with the responsible conduct of research should take notice of the rapidly growing body of scholarship on the social organization of science and the behavior of scientists, integrating that work with ethical principles. Of particular concern are the increasing heterogeneity and interdisciplinary of research, the ambivalences in the practice of peer review, the social tensions of research life, and the heightened concern for social and economic returns from federal research investments. In all, the paper echoes and develops Pimple's call for integrative thinking about the responsible conduct of research.


Real-world practices of hormone monitoring during ovarian stimulation in assisted reproductive technology: a global online survey.
The aim of this study is to understand the global practice of routine hormonal monitoring (HM) during ovarian stimulation (OS) in the context of assisted reproductive technique (ART) treatment. An open-access questionnaire was available to 3,845 members of IVF-Worldwide.com from September 8 to October 13, 2021. The survey comprised 25 multiple-choice questions on when and how ultrasound (US) and hormone tests were conducted during ovarian stimulation OS. For most questions, respondents were required to select a single option. Some questions allowed the selection of multiple options. In all, 528 (13.7%) members from 88 countries responded to the questionnaire. Most respondents (98.9%) reported using US to monitor OS cycles. HM was used by 79.5% of respondents during any of the cycle monitoring visits and was most commonly performed on the day of, or a day prior to final oocyte maturation. Overall, 87% of respondents claimed adjusting the dose of gonadotropin during OS, with 61.7% adjusting the dose based on hormonal levels. Oestradiol (E2) was the most frequently monitored hormone during all visits and was used by 74% of respondents for the prediction of ovarian hyperstimulation syndrome (OHSS). On or a day prior to ovulation triggering (OT), the number of respondents who measured progesterone increased from 34.3% in the second/third visit to 67.7%. Approximately one-third of respondents measured luteinizing hormone during all visits. Globally, most ART specialists (~80%) use HM, along with US, for monitoring OS, especially for the prevention of OHSS.