Randomized phase II study of weekly paclitaxel with and without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA breast cancer without HER2 overexpression.
Addition of carboplatin to neoadjuvant chemotherapy in HER2-negative breast cancer may improve pathological complete response (pCR) rates. We evaluated the efficacy and safety of carboplatin and weekly paclitaxel (wPTX) followed by cyclophosphamide, epirubicin, and 5-fluorouracil (CEF) as neoadjuvant chemotherapy for HER2-negative breast cancer. Patients with stage II/IIIA HER2-negative breast cancer were randomly assigned to preoperatively receive CP-CEF (four 3-week cycles of carboplatin [area under the curve 5 mg/mL/min, day 1] and wPTX [80 mg/m(2), day 1, 8, 15] followed by four 3-week cycles of CEF [500/100/500 mg/m(2)] or P-CEF (four cycles of wPTX followed by four cycles of CEF). The primary objective was pCR rate. Of 181 eligible patients, 89 were randomly assigned to the CP-CEF and 92 to the P-CEF. Two patients in each arm refused to receive neoadjuvant chemotherapy. Overall 88 patients in the CP-CEF and 91 patients in the P-CEF were assessable for efficacy and safety. The pCR rate in the CP-CEF was significantly higher than that in the P-CEF (31.8 vs. 17.6 %, one-sided P = 0.01). Among patients with triple-negative breast cancer, the pCR rate in the CP-CEF was significantly higher than that in the P-CEF [61.2 (23/37) vs. 26.3 % (10/38), P = 0.003]. Grade 3-4 neutropenia was observed in the CP-CEF more frequently than in the P-CEF (65.9 vs. 38.5 %). Adding carboplatin to neoadjuvant wPTX followed by CEF for HER2-negative breast cancer improved the pCR rate and exacerbated hematotoxicity.


Electrodeposition of Polyporous Sn-Ni Coating in Deep Eutectic Solvents for Removing Organic Dyes.
Materials with a high specific surface area including a porous structure have been widely researched due to the applicability in the adsorption of various organic dyes. However, further application of porous materials is limited by the complicated and expensive preparation process. Herein, a Sn-Ni coating with a polyporous structure is successfully prepared via a simple and high-efficiency electrodeposition approach in deep eutectic solvents (DESs). The prepared Sn-Ni coating exhibits a uniform polyporous structure with a diameter of 15 μm. Furthermore, the coating shows excellent adsorption capacity in the removal of acid grain black organic dyestuff. With the rise of preparation temperature from 85 to 105 °C, the electrochemical active surface area and the ratio of nickel increase, which further enhance dye adsorption capacity.


Nanofibrous topography-driven altered responsiveness to Wnt5a mediates the three-dimensional polarization of odontoblasts.
Cell differentiation with the proper three-dimensional (3-D) structure is critical for cells to carry out their cellular functions in tissues. Odontoblasts derived from neural crest cells are elongated and polarized with the cell process, which is decisive for one directional tubular dentin formation. Here, we report that the fibrous topography of scaffolds directs odontoblast-lineage cells to differentiate to have the 3-D structure of odontoblasts through an altered responsiveness to Wnt family member 5A (Wnt5a). In a pulp-exposure animal model, the scaffolds with the nanofibrous topography supported the regeneration of tubular dentin with odontoblast processes. In cultures of pre-odontoblast cells, the nanofibrous topography heightened the cells on the z-axis. The cells on nanofibrous substrate (FIBER) formed stress fiber cytoskeletons on a conventional tissue culture plate (TCP). Differential activation of Cell division control protein 42 (Cdc42) on FIBER and Ras homolog family member A (RhoA) on TCP led to these differences. The signal from Wnt5a-Cdc42 in the cells on FIBER mediated the phosphorylation of JNK and the polarity growth signaling. Taken together, the nanofibrous topography of the scaffolds led to the 3-D structural differentiation of odontoblasts in vitro and in vivo, implying its application for dentin regeneration. Furthermore, the results on the altered activation of Cdc42 by Wnt5a on FIBER provide evidence that the topography of the scaffolds can cause a distinctive cell responsiveness to their micro-environments.


Structural characterization of a highly-ordered 'molten globule' at low pH.
The characterization of unfolded and partly folded states of proteins is central to understanding protein stability and folding, as well as providing a basis for protein design. The four helix bundle-protein interleukin-4 undergoes an unfolding transition at low pH. Using heteronuclear nuclear magnetic resonance methods we show that following this transition the protein retains a highly ordered hydrophobic core in which most, but not all, of the secondary structure is preserved. Extensive disorder exists, however, in regions of polypeptide chain linking the structural elements which make up this core. We suggest that this 'highly ordered molten globule' could be indicative of the type of structures occurring late in protein folding processes, in contrast to more disordered 'molten globules' which relate to early folding intermediates.


Aptamer-based biosensors for the detection of HIV-1 Tat protein.
Two biosensors have been constructed using an RNA aptamer as biorecognition element. The aptamer, specific for HIV-1 Tat protein, has been immobilised on the gold surface of piezoelectric quartz crystals or surface plasmon resonance (SPR) chips to develop a quartz crystal microbalance (QCM)-based and an SPR-based biosensor, respectively. Both the biosensors were modified with the same immobilisation chemistry based on the binding of a biotinylated aptamer on a layer of streptavidin. The binding between the immobilised aptamer and its specific protein has been evaluated with the two biosensors in terms of sensitivity, reproducibility and selectivity. A protein very similar to Tat, Rev protein, has been used as negative control. The two biosensors both were very reproducible in the immobilisation and the binding steps. The selectivity was high in both cases.


Correlation between heart rate control during exercise and exercise capacity in patients with chronic atrial fibrillation.
Rate control is an acceptable alternative to rhythm control in patients with chronic atrial fibrillation (AF). The aim of this study of AF patients was to understand the correlation between their exercise capacity and both heart rate (HR) and HR variation index during exercise. The exercise capacity of 85 male patients with chronic AF was measured using a cardiopulmonary exercise test (CPX). Within this population, we compared the exercise tolerance of patients with a normal chronotropic response (maximal HR 85%-115% that of the maximal age-predicted HR during CPX) to those whose HR response exceeded this range. Two similar comparisons were made by dividing the subject population according to (1) whether or not their HR variation index (HRVI) during CPX exceeded 10 bpm/min, and (2) whether their HR during the 6-minute walk test exceeded 110 bpm. Patients with an HRVI not over 10 bpm/min showed higher maximal oxygen uptake compared to patients with a higher HRVI (26.7 ± 6.1 vs 22.8 ± 4.8 mL O(2) /kg/min, P = 0.002) and a longer distance walked during CPX (705.6 ± 200.3 vs 520.9 ± 155.5 m, P<0.001). No other significant influence on exercise capacity was seen. Multivariate regression analysis revealed that both the body mass index and the HRVI during CPX were independent predictors of the maximal oxygen uptake. Better HRVI control on CPX was correlated with better exercise capacity in patients with chronic AF.


T-antigen expression in human skin fibroblasts is not regulated by an endogenous interferon response to SV40 infection.
Exogenous interferon may affect SV40 T-antigen expression, depending on the chromosomal complement, time of treatment, and biological factors in human cells. However, no evidence was found for endogenous interferon response to SV40 infection in the regulation of T-antigen expression.


Measurement of 42K concentration in the mucosal portion of the intestine without tissue samples: an approach to the measurement of mucosal blood flow in the dog.
1. The concentration of 42K within the jejunal mucosa was measured by intraluminal miniatrue Geiger-Müller tubes shieleded with platinum foil. 2. Isotope concentration measured by tissue assay of jejunal mucosa gave similar results to that obtained by the Geiger-Müller tubes. 3. Isotope measurement by shielded Geiger-Müller tubes obviates the need for tissue samples and permits repeat measurement in the same animal. This should find physiological application in measuring the mucosal portion of total intestinal blood flow by the indicator fractionation technique.


Chromatic suppression of cone inputs to the luminance flicker mechanism.
Eisner and MacLeod [J. opt. Soc. Am. 71, 705-718 (1981)] showed that intense green and red chromatic adapting fields may suppress respectively the M and L cone input to the luminance mechanism by a factor considerably greater than Weber's law. We obtained evidence for such chromatic suppression by measuring complete detection contours for different ratios of red and green test lights presented in rapid flicker in the center of a uniform field. The detection contours represent thresholds as the quantal modulation of the M and L cones normalized by the quantal catch owing to the field. Luminance flicker mechanisms were identified by sections of the contours where detection was controlled by a linear sum of the M and L cone test signals. The slope of these sections indicated that intense red fields selectively suppressed the L cone input to the luminance mechanism by a factor greater than Weber's law; evidence was much less firm for an analogous suppression of the M cone input by intense green fields. The shape of the detection contours also suggests that intense red fields, which differentially light-adapt the M and L cones, may produce a moderate temporal phase-shift between the M and L cone signals. The shape of the temporal MTF of the M cone and the L cone input to the luminance mechanism may be determined at the cone stage, with the absolute sensitivity (vertical scaling) being partially dependent on selective chromatic suppression of the cone inputs owing to the intense chromatic field. Luminance and red-green chromatic temporal sensitivity functions are presented in terms of the M and L cone quantal modulations. Chromatic sensitivity progressively rises above luminance sensitivity as temporal frequency is gradually lowered below 15 Hz, with the consequence that 'contrast sensitivity' may be much higher for color than for luminance.


Survival after surgical treatment of early gastric cancer: surgical techniques and long-term survival.
Recent results from long-term follow-up of a large number of patients who have undergone gastric resection for early gastric cancer (EGC) have not yet been fully evaluated. A total of 848 patients who had undergone gastric resection for EGC (262 female, 586 male; mean age 58.0 years; range 20-86 years) were studied with respect to surgical technique, long-term survival and prognostic factors on the basis of current TNM classification. Death related to recurrence occurred in only eight patients (0.9%). Hematogenous metastasis to the liver or bone represented the most common pattern of recurrence, developing in six of the eight recurrences (75%). The 5-year and 10-year cancer-related survival rates were 98.6% and 94.8%, respectively. The 5-year and 10-year overall survival rates were 95.2% and 85.0%, respectively. Lymph node metastasis represented an independent prognostic factor when analyzed on the basis of cancer-related survival. The present findings indicate that long-term survival of patients who undergo gastric resection for EGC is extremely good and that lymph node metastasis represents an independent prognostic factor when analyzed according to cancer-related survival. Future developments for the treatment of EGC are expected to improve quality of life for patients after gastric resection.


A 9-year-old boy with a nonmalignant forehead tumor - a rare case of pediatric Pott's puffy tumor.
Pott's puffy tumor (PPT) is a rare and potentially deadly complication of frontal sinusitis consisting of subperiosteal abscess and osteomyelitis of the frontal bone. We report the case of a 9-year-old boy who presented with fever and soft tissue swelling of the forehead. Magnetic resonance imaging (MRI) depicted an abscess in the subcutaneous tissue frontally and an epidural empyema, while a cranial computed tomography (CT) scan revealed bone erosion as a sign of osteomyelitis. The patient was treated accordingly. This rare condition is essential to keep in mind as it needs a multidisciplinary approach and relevant imaging to start proper treatment and thus decrease the risk of intracranial complications.


Mechanism of glucocorticoid receptor down-regulation by glucocorticoids.
The effect of glucocorticoids on the regulation of glucocorticoid receptor mRNA was studied in two different cell lines, human IM-9 lymphocytes and rat pancreatic acinar AR42J cells. Using a glucocorticoid receptor cDNA probe, glucocorticoid receptor mRNA was examined by Northern blot hybridization and quantitated by slot-blot hybridization. In IM-9 and AR42J cells, dexamethasone decreased steady-state glucocorticoid receptor mRNA levels to approximately 50% of control. This decrease occurred with a one-half time of 3 h for IM-9 cells and 6 h for AR42J cells. Dexamethasone was the most potent steroid tested with a one-half maximal effect occurring at 10 nM and a maximal effect occurring at 100 nM. Glucocorticoid receptor mRNA half-life and gene transcription were then studied to determine the mechanism of decreased mRNA levels. The glucocorticoid mRNA half-life was approximately 120 min in IM-9 cells and 240 min in AR42J cells; these rates were not affected by dexamethasone treatment. In contrast, the rate of glucocorticoid gene transcription as measured by run-on assays in IM-9 cells was decreased to 50 +/- 6% of control by dexamethasone. These results indicate therefore that glucocorticoids regulate glucocorticoid receptor mRNA levels by influencing gene transcription.


Role of water coordination at zinc binding site and its catalytic pathway of dizinc creatininase: insights from quantum cluster approach.
Creatininase is a key enzyme of creatinine-metabolizing pathway in mammals, and has a great potential for diagnostic application. It catalyzes the reversible conversion of creatinine to creatine. Here, we investigated its reaction mechanism with density functional theory in conjunction with the quantum cluster approach. Three reaction pathways in which several possible proton transfers assisted by either His178 or a water ligand to Zn1 (Wat2) or both were considered. DFT calculations reveal, depending on Wat2 coordination mode at Zn1, two competitive ring-opening pathways where His178 playing a central role as a proton shuttle or both His178 and Wat2 serving as a dual catalytic role as a base and an acid, respectively. Three elementary steps were proposed for the reaction: the first involves nucleophilic attack by a bridging hydroxide to the substrate and forms a gem-diolate intermediate, followed by a proton transfer from the gem-diolate to His178 (His178 protonation is a required step for efficient proton transfers). Finally, the second proton transfer from the protonated His178 or Wat2 to the amide of substrate leads to the ring opening. The first proton transfer is the rate-limiting step of the whole reaction, in consistent with previous experimental and computational studies. A detailed understanding of the reaction mechanism of the creatininase enzyme family will also be helpful for developing a biosensor for kidney function.


The endocytic protein GRAF1 is directed to cell-matrix adhesion sites and regulates cell spreading.
The rho GTPase-activating protein GTPase regulator associated with focal adhesion kinase-1 (GRAF1) remodels membranes into tubulovesicular clathrin-independent carriers (CLICs) mediating lipid-anchored receptor endocytosis. However, the cell biological functions of this highly prevalent endocytic pathway are unclear. In this article, we present biochemical and cell biological evidence that GRAF1 interacted with a network of endocytic and adhesion proteins and was found enriched at podosome-like adhesions and src-induced podosomes. We further demonstrate that these sites comprise microdomains of highly ordered lipid enriched in GRAF1 endocytic cargo. GRAF1 activity was upregulated in spreading cells and uptake via CLICs was concentrated at the leading edge of migrating cells. Depletion of GRAF1, which inhibits CLIC generation, resulted in profound defects in cell spreading and migration. We propose that GRAF1 remodels membrane microdomains at adhesion sites into endocytic carriers, facilitating membrane turnover during cell morphological changes.


Evidence that a humoral immune response to autologous cartilage proteoglycan can participate in the induction of cartilage pathology.
We examined antiproteoglycan antibodies as an autoimmune response for induction of synovitis. This hypothesis was studied by monitoring humoral antiproteoglycan antibody following IgG induction of experimental immune synovitis, localization in the articular cartilage of an autologous immune response, and loss of proteoglycan from cartilage following intravenous administration of antiproteoglycan monoclonal antibodies. The data support the hypothesis that autoimmunity to cartilage macromolecules may play a role in the etiopathogenesis of arthritis.


Fluorescent labeling of cysteinyl residues to facilitate electrophoretic isolation of proteins suitable for amino-terminal sequence analysis.
A protein labeling procedure which enables detection of subpicomole quantities of proteins on sodium dodecyl sulfate (SDS)-polyacrylamide gels is described. Proteins are rendered fluorescent by reduction of disulfide bonds with dithiothreitol followed by alkylation with 5-N-[(iodoacetamidoethyl)amino]naphthalene-1-sulfonic acid (5-I-AEDANS) or 5-iodoacetamido-fluorescein. Labeling is performed prior to electrophoresis, thus eliminating the need for staining with dyes and destaining after electrophoresis. As little as 375 fmol (25 ng) of prelabeled bovine serum albumin can be readily visualized after electrophoresis. Bands are still visible after electrophoretic transfer to nitrocellulose. Simultaneous labeling of proteins in complex mixtures is possible using this technique. This includes cysteine containing proteins of disrupted Newcastle disease virus. The magnitudes of the molecular weight increases which occur upon labeling reflect the cysteine contents of proteins. The mode of chemical modification for the prelabeling procedure was chosen because of its compatibility with analytical techniques, such as amino acid analysis, peptide mapping, or sequence analysis, which may be applied to the protein after electroelution from SDS-acrylamide gels. It replaces the need for reduction and carboxymethylation prior to these analytical procedures. Protein-sequence analysis of prelabeled bovine serum albumin, including samples electroeluted from SDS-acrylamide gels, has justified the choice of this method to facilitate isolation of proteins for sequence analysis. Equivalent sequence data were obtained with reduced bovine serum albumin S-alkylated with iodoacetic acid or 5-I-AEDANS.


Involvement of monoamines and proinflammatory cytokines in mediating the anti-stress effects of Panax quinquefolium.
Panax quinquefolium (PQ) is well acclaimed in literature for its effects on central and peripheral nervous system. The present study explores the effects of PQ on stress induced changes of corticosterone level in plasma, monoamines (NA, DA and 5-HT) and interleukin (IL-2 and IL-6) levels in cortex and hippocampus regions of brain and also indicate their possible roles in modulating stress. Mice subjected to chronic unpredictable stress (CUS, for 7 days) showed significant increase in plasma corticosterone level and depletion of noradrenaline (NA), dopamine (DA) and 5-hydroxytryptamine (5-HT) levels in cortex and hippocampal regions along with an increased level of IL-2 and IL-6 in the same areas. Aqueous suspension of PQ was administered daily at a dose of 100 and 200mg/kg p.o. prior to the stress regimen and its effects on selected stress markers in plasma and brain was evaluated. PQ at a dose of 200mg/kg p.o. was found to be effective in normalizing the CUS induced elevation of plasma corticosterone and IL-2, IL-6 levels in brain. Moreover, it was significantly effective in reinstating the CUS induced depletion of NA, DA and 5-HT in hippocampus, while NA and 5-HT in cortex of brain. However, PQ at a dose of 100mg/kg p.o. was found ineffective in regulating any of these CUS induced changes. Present study provides an insight into the possible role of PQ on hyperactive HPA axis in the regulation of immediate stress effectors like corticosterone, cytokines and brain monoamines. In this study, PQ has emerged as a potential therapeutic in the cure of stress related disorders and needs to be evaluated in clinical studies to ascertain its efficacy.


Systemic xanthomatosis associated with hyperchylomicronaemia in a cat.
We report a case of systemic xanthomatosis in a 4-month-old domestic cat. The kitten presented with multiple cutaneous lesions and 'cream tomato soup' coloured blood. Necropsy revealed multiple, whitish, nodular lesions, compatible with xanthomas, on most of the abdominal organs (liver, spleen, kidney, adrenal glands, mesentery and colon). The diagnosis was confirmed by histopathological examination. This is the first report of granulomatous colitis associated with feline xanthomatosis.


First molecular characterization of avian paramyxovirus-1 (Newcastle disease virus) in Botswana.
Avian paramyxovirus-1 (APMV-1), the causative agent of Newcastle disease (ND) in domestic and wild avian species, has recently been reported and characterized in five southern African countries (i.e. Mozambique, Namibia, South Africa, Zambia and Zimbabwe). Since APMV-1s have never been characterized in Botswana, this study was undertaken to determine the genotype circulating in the country. Fourteen samples were collected from ND outbreaks in poultry in 2014, 2018 and 2019 and the complete fusion protein gene was sequenced. Phylogenetic analysis revealed that all of the viruses from Botswana clustered in genotype VII.2 (previously subgenotype VIIh) and that they were more related to viruses from South Africa and Mozambique than the other southern African countries (i.e. Namibia, Zambia and Zimbabwe).


WITHDRAWN: Sharp decline in acute and elective hospital attendances and admissions due to COVID-19 in Malta (Q1 2020) - A population-based study.
This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.


Forty-year experience with second malignancies after treatment of childhood cancer: analysis of outcome following the development of the second malignancy.
As the cure rate for childhood malignancies increases, the number of patients at risk for development of second malignancies also increases. Due to the potentially long remaining life span, long-term follow-up is difficult and patients are often at risk after presumptive cures. Some authors believe that cure rates for second malignancies are similar to cure rates for primary malignancies. We reviewed the records of 162 patients seen at our institution who had developed a second malignancy after treatment for childhood cancer. Presentation, age at diagnosis, tumor histology, extent of tumor, treatment (including radiotherapy with dosage when available, and chemotherapy) plus outcome were recorded. Mean age at diagnosis of the primary malignancy was 10.3 years. The most common primary malignancy was Hodgkin's disease (33) followed by soft tissue sarcoma (28), retinoblastoma (20), bone tumor (17), central nervous system (CNS) tumor (13), leukemia (8), Wilms' tumor (7), non-Hodgkin's lymphoma (6), neuroblastoma (5), thyroid neoplasm (5), and others (20). The average interval between diagnosis of the first and second malignancy was 10.8 years. These second tumors carried a high mortality. Only 56 patients have no evidence of disease. Five patients are known to be alive with disease and 92 patients have expired due to their second malignancy. Disease status in 8 patients is unknown. The most common second malignancy was osteosarcoma (35) followed by soft tissue sarcoma (24), breast cancer (15), leukemia (14), thyroid carcinoma (14), CNS tumors (12), melanoma (8), nonmelanomatous skin cancer (8), lymphoma (5), and others (27).(ABSTRACT TRUNCATED AT 250 WORDS)


Emerging stool-based and blood-based non-invasive DNA tests for colorectal cancer screening: the importance of cancer prevention in addition to cancer detection.
Colorectal cancer (CRC) screening can be undertaken utilizing a variety of distinct approaches, which provides both opportunities and confusion. Traditionally, there has often been a trade-off between the degree of invasiveness of a screening test and its ability to prevent cancer, with fecal occult blood testing (FOBT) and optical colonoscopy (OC) at each end of the spectrum. CT colonography (CTC), although currently underutilized for CRC screening, represents an exception since it is only minimally invasive, yet provides accurate evaluation for advanced adenomas. More recently, the FDA approved a multi-target stool DNA test (Cologuard) and a blood-based test (Epi proColon) for average-risk CRC screening. This commentary will provide an overview of these two new non-invasive tests, including the clinical indications, mechanism of action, and diagnostic performance. Relevance to radiology practice, including a comparison with CTC, will also be discussed.


Treatment of patients with unstable angina and non-ST elevation myocardial infarction.
Emergency department (ED) management of patients who present with suspected unstable angina (UA) and non-ST elevation myocardial infarction (NSTEMI) is especially challenging. Therapies that demonstrate benefit in patients who experience proven disease may not be indicated in patients who present with suspected disease. The emergency practitioner must have a clear understanding of the benefit and harm of each therapy, allowing formulation of a simple approach to treatment selection based on disease presentation. This article reviews current literature and discusses the treatment recommendations from the American College of Cardiology (ACC) and American Heart Association (AHA) for patients who experience UA and ST elevation myocardial infarction (STEMI).


Polymeric ionic liquid based on magnetic materials fabricated through layer-by-layer assembly as adsorbents for extraction of pesticides.
In this study, layer-by-layer assembly of polyelectrolyte multilayer films on magnetic silica provided a convenient and controllable way to prepare polymeric ionic liquid-based magnetic adsorbents. The resulting particles were characterized by Fourier transform infrared spectroscopy, X-ray diffraction, transmission electron microscopy, and magnetic measurements. The data showed that the magnetic particles had more homogeneous spherical shapes with higher saturation magnetization when compared to those obtained by free radical polymerization method. This facilitated the convenient collection of magnetic particles, with higher extraction repeatability. The extraction performance of the multilayer polymeric ionic liquid-based adsorbents was evaluated by magnetic solid-phase extraction of four pesticides including quinalphos, fenthion, phoxim, and chlorpropham. The data suggested that the extraction efficiency depended on the number of layers in the film. The parameters affecting the extraction efficiency were optimized, and good linearity ranging from 2 to 250μgL-1 was obtained with correlation coefficients of 0.9994-0.9998. Moreover, the proposed method presented low limit of detection (0.5μgL-1, S/N=3) and limit of quantification (1.5μgL-1, S/N=10), and good repeatability expressed by the relative standard deviation (2.0%-4.6%, n=5). The extraction recoveries of four pesticides were found to range from 58.9% to 85.8%. The reliability of the proposed method was demonstrated by analyzing environmental water samples, and the results revealed satisfactory spiked recovery, relative standard deviation, and selectivity.


Genetics' dreams in the post genomics era.
In this paper I explore the heuristic limits of human genetics, in particular the claim that it is possible to manipulate human germ cells in a pre-ordinate way (Gordon, 1999). I argue that this claim is unrealistic based on genetic reductionism and a wrong concept of genetic diseases.


Acute non-traumatic marrow edema syndrome in the knee: MRI findings at presentation, correlation with spinal DEXA and outcome.
The aim of the study was to present the MRI findings of non-traumatic edema-like lesions presented acutely in the adult knee and to correlate them with the 3-year outcome and the bone mineral density (BMD) in the spine. Ninety-eight patients (40 men, 58 women, mean age 60.1+/-11 years, age range 27-82 years), were followed up clinically as well as with MR imaging, when indicated, for at least 3 years. Patients were classified according to presentation in 3 groups (A: bone marrow edema (BME), B: BME and subchondral fracture, C: BME and articular collapse) and according to outcome in 2 groups (A: reversible BME, B: articular collapse). BMD measurements of the spine were carried out in males over 70 and females over 60 years old using DEXA. The isolated BME pattern was observed in 64.3% (Group A), subchondral fractures without articular collapse in 11.2% (Group B) and articular collapse in 24.5% (Group C). Significant differences were found among the 3 groups at presentation, regarding the age, sex, BMD, affected area and duration of symptoms prior to imaging (p<0.05). Localization of the lesions in the weight-bearing areas of the knee was shown in 100% of C, in 90.9% of B and in 50.8% of A. The duration of symptoms prior to imaging was longer in C (7.6+/-2.8m) than in A (2.5+/-1.7m) and B (4.0+/-3.2m) (p<0.05). Group B progressed to articular collapse in 45.5%, the rest demonstrating a favourable outcome. Group C showed clinical improvement in 75% and persistent symptoms that required knee arthroplasty in 25% of cases. Articular collapse was the final outcome in 29.6% and transient BME in 70.4% of patients. These two groups showed significant differences regarding the age (p approximately 0), sex (p=0.002), low BMD (p=0.004), affected area (p approximately 0), presence of subchondral sparing (p approximately 0), duration of symptoms prior to imaging (p approximately 0), time from onset of symptoms to the final outcome (p approximately 0) and need for arthroplasty (p=0.001). None of the patients with transient BME syndrome eventually progressed to articular collapse. In the context of acute non-traumatic knee BME, the age and sex of the patient, the duration of symptoms before imaging, the pattern of BME, and the BMD appear to correlate with the final outcome.


Application essays and future performance in medical school: are they related?
There is a paucity of research on whether application essays are a valid indicator of medical students' future performance. The goal is to score medical school application essays systematically and examine the correlations between these essay scores and several indicators of student performance during medical school and internship. A journalist created a scoring rubric based on the journalism literature and scored 2 required essays of students admitted to our university in 1 year (N = 145). We picked 7 indicators of medical school and internship performance and correlated these measures with overall essay scores: preclinical medical school grade point average (GPA), clinical medical school GPA, cumulative medical school GPA, U.S. Medical Licensing Exam (USMLE) Step 1 and 2 scores, and scores on a program director's evaluation measuring intern professionalism and expertise. We then examined the Pearson and Spearman correlations between essay scores and the outcomes. Essay scores did not vary widely. American Medical College Application Service essay scores ranged from 3.3 to 4.5 (M = 4.11, SD = 0.15), and Uniformed Services University of the Health Sciences essay scores ranged from 2.9 to 4.5 (M = 4.09, SD = 0.17). None of the medical school or internship performance indicators was significantly correlated with the essay scores. These findings raise questions about the utility of matriculation essays, a resource-intensive admission requirement.


Sudden-onset squint.
Differentiating a sudden-onset concomitant squint from a paralytic squint in an ill child can be difficult, but the distinction is important in view of the neurological implications of the latter. Furthermore, the two types may co-exist, and four such cases are described. The causes of sudden-onset squint are discussed. Methods of examination are described which may help to distinguish a paretic squint, with its neurological implications, from a concomitant deviation with no such systemic associations.


From Colton's guess to Andrews' table to Bunnell's paper to Spencer's card: Misleading the public about nitrous oxide's safety.
Famous for pioneering the oxygenation of nitrous-oxide anesthetics, Chicago surgeon Edmund Andrews trusted the Manhattan-based Colton Dental Association's claim that they had conducted 75,000 nitrous-oxide anesthetics without a single mortality. Those statistics were cited in Andrews' 1870 journal article on anesthetic risks and then, remarkably, advertised on the business cards of dentist James M. Spencer, Jr., of Gouverneur, New York.


Sensitivity of aspiration as a safety test before injection of soft tissue fillers.
Embolism due to accidental intra-arterial injection of a soft tissue filler (STF) can lead to serious complications. Physicians practice aspiration as a safety test before injection to rule out intra-arterial placement of the needle tip. The value of aspiration as a safety test is evaluated in this study, which also considered the rheological properties of different STFs and their needle dimensions. Aspiration with eleven different needle sizes and 24 different STFs was performed using Ringer's lactate (RL) colored with blue skin marking ink and secondly an empty saline bag containing anticoagulated blood, both pressurized to 150 mm Hg to mimic arterial blood pressure. Time between the start of aspiration and liquid in the needle hub was recorded. A total of 340 individual aspiration tests with different STFs and needles were performed, of which 112 yielded true-positive results within 1-s and 128 yielded false-negative results after 10 s. Positive results between one and ten seconds were seen in 101 aspiration tests. True-positive results were seen in 33% of the tests performed with STFs within 1 s of aspiration. Aspiration test results are influenced by needle diameter, needle length, and rheological properties of STFs. Additional safety measures are necessary to further reduce risk of inadvertent intravascular injection of STFs.


Studies on the delayed neuropathic and anticholinesterase potential of quinalphos (diethyl 2-quinoxalyl phosphorothionate) in hens.
Incidence of numerous human poisonings by quinalphos (Ekalux, Bayrusil) in agricultural areas near Belgrade initiated this study on the ability of the compound to inhibit hen brain neuropathy target esterase, acetylcholinesterase and plasma butyrylcholinesterase in vivo. Hens were treated with a single oral dose ranging from 25 to 600 mg kg-1 quinalphos (LD50 = 72 mg kg-1) or 500 mg kg-1 triorthocresyl phosphate (positive control), sacrificed 24-96 h later for enzyme assays and monitored for 25 days for evaluation of walking impairments. High inhibition (> 80%) of both cholinesterases was obtained with 25 and 50 mg kg-1 quinalphos. Doses of 200 and 600 mg kg-1 of the agent inhibited up to 23 and 28% of hen brain neuropathy target esterase activity, respectively. Clinical signs of neuropathy were not seen. Quinalphos was slowly absorbed from the gastrointestinal tract, as indicated by the severity of the cholinergic symptoms and the inhibition of neuropathy target esterase, which reached its maximum 72 and 96 h after poisoning. The results suggest that quinalphos, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.


The psychotherapist and the adolescent athlete.
Athletic participation is often the focus for the expression of affect in adolescence. Emotions derive from the athletic arena itself, as well as from personal and family life. To help the athlete gain insight and mastery over his or her emotional life, the therapist must understand the role, if any, of the family in the cause of athletic complaints. Appropriate psychologic therapies include individual therapy, family therapy, and a mixture thereof, and they may be oriented toward performance issues, personal issues, or both. In the therapy, it will be helpful to reinforce the opportunity for a psychological "moratorium," a delay on excessive demands of social adaptation. In this way, the adolescent athlete has the opportunity to consider and try alternative solutions to the problem of establishing a satisfactory identity. This process will be facilitated by the therapist's insight into his or her own competitive issues, and efforts to modulate investment in the patient's achieving athletic success. Although athletes as a group are sometimes thought of as unlikely candidates for psychotherapy, adolescent athletes, in particular, often become intensively involved in their therapy for brief periods of time, with good success.


Ruptured traumatic vertebral artery pseudoaneurysm in a child treated with trapping and posterior inferior cerebellar artery reimplantation. Case report and review of the literature.
The authors present the case report of a pediatric patient with a ruptured traumatic pseudoaneurysm of the intracranial vertebral artery (VA) from which the posterior inferior cerebellar artery (PICA) emerged. After considering multiple therapeutic options, the patient was treated surgically by trapping of the aneurysm segment and direct reimplantation of the PICA distal to the rupture site. In addition to presenting this unique case, the authors discuss the treatment of VA pseudoaneurysms and the various techniques for PICA revascularization. A review of the literature on PICA reimplantation is provided as an adjunct in the treatment of complex VA aneurysms.


Short-term changes in tinnitus pitch related to audiometric shape in sudden sensorineural hearing loss.
Sudden sensorineural hearing loss (SSNHL) is frequently accompanied by tinnitus. This study investigated the relationships between new-onset tinnitus and audiometric parameters in SSNHL patients. Sixty-one patients with SSNHL with new-onset tinnitus were enrolled. Changes of tinnitus pitch, and their correlations with the maximum hearing loss frequency (Fmax) and the edge frequency (Fedge) at initial and 1-month follow-up (FU) were analyzed. At 1-month FU, tinnitus disappeared in 16 (26%) patients and they also showed hearing normalization. In 36 patients who still showed tonal tinnitus, the mean tinnitus pitch (2.9 kHz) at initial examination, which was close to Fedge (2.7 kHz), increased to a significantly higher frequency (4.6 kHz) at 1-month examination, which was close to Fmax (5.6 kHz). The tinnitus pitch had a more significant correlation with Fedge (r=0.46) than with Fmax (r=0.33) at initial examination and the tinnitus pitch showed a significant correlation only with Fmax (r=0.52) at 1-month examination. Hearing normalization was crucial for the disappearance of tinnitus at 1-month FU. Patients who still had tonal tinnitus at 1-month FU showed the tinnitus pitch closer to the edge frequency (Fedge) at initial examination, and this tinnitus pitch increased to the maximum hearing loss frequency (Fmax) at 1-month FU. This change in tinnitus pitch may give insight about tinnitus generation.


Dentoskeletal features and growth pattern in Beckwith-Wiedemann spectrum: is surgical tongue reduction always necessary?
The role of tongue reduction surgery (TRS) in preventing excessive mandibular growth and anterior open bite in children with Beckwith-Wiedemann Spectrum (BWSp) is still controversial. This cross-sectional study aimed at comparing craniofacial growth pattern in children affected by BWSp either treated or not treated with early TRS for severe macroglossia. Considering the invasive nature of such surgery, the present study could help in clarifying the need for TRS to reduce or prevent growth disturbances. Orthopantomography and lateral skull x-ray images were taken either from surgically treated or non-surgically treated patients, aged 5 to 8 years, to compare dentoskeletal features and craniofacial growth by cephalometric analysis. Molecular testing results were collected from their medical records. Eighteen BWSp patients were consecutively recruited: 8 underwent TRS at 14.9 ± 2.2 months of age, while 10 did not. Anterior open bite and dental class III were more frequently observed in the surgically treated group, but none showed skeletal class III. No statistically significant differences were observed in growth pattern, but children treated with TRS showed a tendency towards both maxillary and mandibular prognathism with protruding lower lip. Growth pattern seemed to be not related to molecular subtypes. These preliminary data suggest that early TSR does not improve craniofacial growth pattern and dentoskeletal features in BWSp children. Reductive glossectomy may not be justified for preventing or avoiding oro-facial deformities in BWSp; therefore, early monitoring of maxillofacial development of each affected child has a great clinical significance.


Heart Failure in Minority Populations - Impediments to Optimal Treatment in Australian Aborigines.
Chronic heart failure (CHF) among Aboriginal/Indigenous Australians is endemic. There are also grave concerns for outcomes once acquired. This point is compounded by a lack of prospective and objective studies to plan care. To capture the essence of the presented topic it is essential to broadly understand Indigenous health. Key words such as 'worsening', 'gaps', 'need to do more', 'poorly studied', or 'future studies should inform' occur frequently in contrast to CHF research for almost all other groups. This narrative styled opinion piece attempts to discuss future directions for CHF care for Indigenous Australians. We provide a synopsis of the problem, highlight the treatment gaps, and define the impediments that present hurdles in optimising CHF care for Indigenous Australians.


Concise enantioselective construction of a bridged azatricyclic framework via domino semipinacol-Schmidt reaction.
A TiCl(4)-promoted domino semipinacol-Schmidt reaction of oxaspiropentane-azide provides an easy access to bridged azatricyclic ring systems, which possess the azaquaternary center, present in the immunosupressant FR901483 and platelet aggregation inhibitor daphlongeranine B.


Atmospheric carbonyls in a heavy ozone pollution episode at a metropolis in Southwest China: Characteristics, health risk assessment, sources analysis.
Ambient carbonyls were continuously observed in the field during a heavy ozone pollution episode in Chengdu, China from August 4 to August 19, 2019, and the pollution characteristics, atmospheric photochemical reactivity, human health risk, and sources of carbonyls were analyzed. Fifteen carbonyls were quantified with average total mixing ratios of 20.38 ppbv Formaldehyde (9.86 ppbv), acetone (4.41 ppbv), and acetaldehyde (3.57 ppbv) were the three most abundant carbonyls. During the heavy ozone pollution episode, the concentration of carbonyls was found to be higher on pollution days than on the clean days, and relatively higher in the daytime, especially at noon on the pollution days. This was influenced by the intensity of photochemical reactions and precipitation. The "weekend effect" with the concentration of carbonyls was higher on the weekends than on the weekdays was pointed out. Formaldehyde, acetaldehyde and hexaldehyde were the dominant oxidative species during the observation. The carcinogenic and non-carcinogenic risk values of formaldehyde and acetaldehyde were higher on pollution days than on clean days, and these values were higher compared with those of other cities in China and abroad. Long-term exposure to these compounds should therefore be avoided. Diagnostic ratios and correlation analysis together with backward trajectory analysis showed that primary emission and secondary formation accounted 66%-76% and 24%-34% of carbonyls in Chengdu, respectively, with primary emission being the main sources of carbonyls, and carbonyls from the surrounding cities and emission from natural sources also had a significant contribution to the carbonyls in Chengdu.


Biodegradable polycaprolactone scaffold with controlled porosity obtained by modified particle-leaching technique.
Scaffold with controlled porosity constitute a cornerstone in tissue engineering, as a physical support for cell adhesion and growth. In this work, scaffolds of polycaprolactone were synthesized by a modified particle leaching method in order to control porosity and pore interconnectivity; the aim is to observe their influence on the mechanical properties and, in the future, on cell adhesion and proliferation rates. Low molecular weight PEMA beads with an average size of 200 microm were sintered with various compression rates in order to obtain the templates (negatives of the scaffolds). Then the melt polycaprolactone was injected into the porous template under nitrogen pressure in a custom made device. After cooling and solidifying of the melt polymer, the porogen was removed by selective dissolution in ethanol. The porosity and morphology of the scaffold were studied as well as the mechanical properties. Porosities from 60% to 85% were reached; it was found that pore interconnectivity logically increases with increasing porosity, and that mechanical strength decreases with increasing porosity. Because of their interesting properties and interconnected structure, these scaffolds are expected to find useful applications as a cartilage or bone repair material.


Determination of active, non-zymogen acrosin, proacrosin and total acrosin in different andrological patients.
A spectrophotometric assay is described which, due to improved extraction conditions, allows quantitative determination of enzymatically active, non-zymogen acrosin, proacrosin and total acrosin activity from human sperm acrosomes. Acrosomal proteinase activity is assessed by acid extraction of the sperm pellet and the suspension medium before and after snap-freezing, followed by zymogen autoactivation. Release of acrosin from the acrosome can be used as a sensitive biochemical marker to characterize acrosomal membrane stability, severe disturbance of which may be the cause of impaired male fertility. Acrosin activities in different populations of semen specimens are reported and compared to data available in the literature. Different degrees of acrosomal membrane alterations are observed in men with oligozoospermia, tetratozoospermia and polyzoospermia. Particularly in oligozoospermia, a significant increase of active, non-zymogen acrosin points to severe acrosomal membrane alterations and, in addition, to a premature activation of proacrosin, which may impair fertilization in certain individuals. Finally, acrosin activity is shown to be significantly influenced by the time of sexual abstinence. It is concluded that determination of acrosin may be a useful indicator of the fertility potential in men.


Accuracy of digitally fabricated trial dentures.
Information about the accuracy of digital computer-aided design and computer-aided manufacturing (CAD-CAM) complete dentures is scarce. The purpose of this in vitro study was to assess the reproducibility of the occlusion of wax dentures fabricated with digital steps and the contraction behavior of wax trial dentures processed with combined conventional-digital steps. These were compared with those fabricated completely conventionally in terms of storage duration. Five sets of maxillary and mandibular wax trial dentures were milled from a gingiva-colored wax blank (Ceramill D-Wax, Amann Girrbach AG) using the Ceramill Motion 2 System (Amann Girrbach), scanned, and matched by best-fit triangulation for each of the 5 denture pairs. Processing deformation was measured and the maximum deviations calculated. A 3-dimensional color-coded mapping of the differences between each pair of dentures was generated. Five sets of maxillary and mandibular wax trial dentures were processed with digital steps, and 5 sets of maxillary and mandibular wax trial dentures were fabricated in the conventional way with the help of a silicone index from a CAM-fabricated wax trial denture to standardize the wax amount. All dentures were scanned immediately after waxing and after 1 week of storage. After surface matching, the deformation was measured, and the milled wax bases were compared with those conventionally fabricated. Data were interpreted using descriptive statistics. The occlusion of wax trial dentures fabricated with digital steps was not reproducible. The deviations in the maxillary dentures were mostly marginal, with exceptions for single teeth/tooth groups in denture No. 2 (occlusal areas of teeth in second quadrant, second molars) and No. 4 (central incisor and canine in second quadrant inclined to palatal side, and first premolar in first quadrant and first molar in second quadrant displayed greater deviations). Among the mandibular dentures, denture Nos. 4 and 5 the central incisor (fourth quadrant) inclined to the labial side. Additionally, in denture No. 5 the lateral incisor (fourth quadrant) inclined to the lingual side. In digitally fabricated dentures, the manual placing of the teeth into the denture base sockets can lead to deviations from the planned arrangement. The deviations were greater in the area of the denture bases in the conventionally fabricated dentures compared with those processed with combined conventional-digital steps. The milled wax bases showed better contraction behavior than the conventionally fabricated wax bases.


Kinetics of cutinase catalyzed transesterification in AOT reversed micelles: modeling of a batch stirred tank reactor.
A transesterification process is analyzed in its multiple kinetic components that include the determination of the kinetic constants for both substrates, butyl acetate (BAc) and hexanol (H), involved in the alcoholysis reaction and for the products formed (hexyl acetate (HAc) and butanol (B)), participating into the reverse reaction. The order of magnitude of these constants is discussed in relation with the AOT/isooctane reverse micellar system under study. The values of the equilibrium conversion (X(e)) and constant (K(eq)) were also determined. Diffusional limitations were detected for H concentrations lower than 450 mM and the correspondent effectiveness factors were calculated. Above 450 mM H the reaction is kinetically controlled. The operation of a batch stirred tank reactor (BSTR) was modeled considering the integrated rate equation for reversible kinetics.


Flow velocities in the external carotid artery following carotid revascularization.
To study the changes in peak systolic velocities of the ipsilateral external carotid artery (ECA) following carotid revascularization. All patients randomized to carotid artery stenting (CAS) or carotid endarterectomy (CEA) in the International Carotid Stenting Study (ICSS; ISRCTN25337470) in our center were included. Peak systolic velocities (PSV) were assessed with duplex ultrasound (DUS) at baseline, at 30 days, and at 12 and 24 months after treatment. Our primary outcome measure was the change in blood flow velocities in the ECA (ΔPSVECA). Secondary outcome measure was the prevalence of post interventional ECA occlusion. Of 270 patients enrolled in ICSS at our center, 224 patients (mean age, 68.8 years; 154 males) were included in the present study (116 CAS, 108 CEA). Baseline PSV in the ipsilateral ECA was similar between the groups. Following CAS, PSV gradually increased during follow-up, whereas PSV remained relatively stable after CEA; mean difference of PSV between CAS and CEA: 23 cm/s (95% CI, -5 to 52), 58 cm/s (95% CI, 27-89), and 69 cm/s (95% CI, 31-107) at 30 days, 12 months, and 24 months. One new ECA occlusion occurred after CAS and two after CEA. Blood flow velocities in the ipsilateral ECA increase significantly after CAS but not after CEA. However, this does not lead to a higher rate of ECA occlusion in the first 2 years after revascularization. We conclude that CAS is not inferior to CEA in preserving the ECA as a possible potential collateral pathway for cerebral blood supply within 2 years following revascularization.


Grip strength is an important predictor for nutritional risk and early postoperative ambulation in gastrointestinal tumors undergoing laparoscopic surgery: a prospective multicenter clinical study.
Using grip strength as a predictor of nutritional risk and early ambulation for gastrointestinal tumor surgery and determining its critical value have not been reported. This study was designed to explore the influencing factors of early postoperative ambulation ability for patients with gastrointestinal tumors who underwent laparoscopic surgery. Four-hundred twenty-seven patients with gastrointestinal tumors who underwent laparoscopic surgery at three tertiary A hospitals in Beijing were prospectively enrolled. Subsequently, logistic regression analysis was conducted to determine the independent predictors of early postoperative ambulation. Logistic regression analyses for the different gender were also performed. In addition, the effectiveness of preoperative grip strength measurement in nutritional risk assessment was analyzed by using nutritional risk score 2002 (NRS 2002) as a control. The included cases were comprised of 283 male and 144 female patients, with an age of 59.35 ± 11.70 years. Gender, preoperative grip strength, operative time, and number of indwelling tubes were independent predictors of early postoperative ambulation. In the male group, lower preoperative grip strength and more indwelling tubes were independent risk factors for early postoperative ambulation. In the female group, lower preoperative grip strength and extended operating time were independent risk factors. Moreover, preoperative grip strength (male < 32 kg, female < 21 kg) can be used as a risk predictor for both preoperative nutritional risk and early postoperative ambulation. As a simple and objective measure of muscle strength, grip strength measurement is expected to be an effective predictor for both early postoperative ambulation ability and nutritional status of patients.


Structure and function in native and pathological erythrocytes: a quantitative view from the nanoscale.
The red blood cells (RBCs) are among the most simple and less expensive cells to purify; for this reason and for their physiological relevance, they have been extensively studied with a variety of techniques. The picture that results is that these cells have several peculiarities including extreme mechanical performances, relatively simple architecture, biological relevance and predictable behavior that make them a perfect laboratory of testing for novel techniques, methodologies and ideas. These include the re-evaluation of old concepts, such as the relationship between structure and function (which is one of the guideline of this report) but considered at the cellular level. The studies reported on this paper, indeed, exploit the full potential of an high resolution quantitative microscopy such as the atomic force microscopy (AFM) to investigate different aspect of the erythrocytes' life, death and interaction with the environment. Indeed, the erythrocytes have a special relationship with the environment that is able to deeply influence their morphology as consequence of alteration of their biochemical or biophysical status. In this context the conditions under which the erythrocytes can be considered as biochemically programmable systems have been investigated by analyzing different environmentally induced alteration of the cell's morphology and comparing the results with naturally occurring pathological morphologies. This class of studies takes great advantage by the additional consideration of the nanomechanical properties of the cells. These latter are particularly important for the cell functionality and are shown to be of practical usefulness to discriminate and partition environmental effects charging different cellular structure (e.g. membrane or membrane-skeleton). Moreover, the development of novel morphological parameter can be important to push the level of investigation on the RBCs' status towards the molecular level. In particular, we describe the introduction and use of the plasma membrane roughness as a morphometric parameter of simple derivation from the AFM images and that results sensitive to the structural integrity of the cells' membrane-skeleton. This offer a remarkable opportunity to investigate the relationship between structure and function in normal and pathological cells by using a morphometric parameter that probes the cell surface at the nanoscale level. At last, a complex but physio-pathologically important phenomenon such as the erythrocytes aging was considered. To properly analyze the many variation that the cells experience during the whole aging path we used all the parameters that the AFM can provides: quantitative imaging, analysis of the membrane roughness and local measure of the nanomechanical properties analyzed together with biochemical parameter such as the ATP content. The picture that emerged is that the aging path is triggered by the ATP intracellular concentration that influence the membrane-skeleton structure and the support exerted on the plasma membrane. The consequences of the membrane-skeleton involvement can be monitored by AFM and showed the occurrence of peculiar morphologies and morphological defects that appear in the very place where the membrane-skeleton contact with the membrane became loose. As a whole, the collected data enable to describe the entire phenomenon as a sequence of morphological intermediates following one another along the aging path.


ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson-Gilford progeria syndrome.
Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson-Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.


Comparison of efficacy and safety of intracoronary nicardipine and adenosine for fractional flow reserve assessment of coronary stenosis.
Administration of intracoronary (IC) adenosine allows an easily feasible, inexpensive, and more rapid alternative method for fractional flow reserve (FFR). It is common practice in many centers worldwide. Nicardipine is a strong coronary vasodilator but its efficacy and safety for assessing FFR is not established. The purpose of present study was to compare the efficacy and safety of IC nicardipine and adenosine for assessing FFR. One hundred and fifty-nine patients with a total of 193 vessels undergoing clinically indicated FFR assessment of intermediate coronary stenoses were included. For the initial assessment of FFR, hyperemia was induced by an IC adenosine. After a washout period of 3 min, FFR was reassessed using 200 μg of IC nicardipine. Hyperemic efficacy among two different stimuli was compared. The mean FFR with IC adenosine was 0.83 ± 0.09 and that with an IC nicardipine was 0.84 ± 0.09. The median FFR with an IC adenosine was 0.83 (0.78-0.91) and that with an IC nicardipine was 0.85 (0.79-0.91) (p-value 0.246). Both FFR values showed an excellent correlation (R2 = 0.982, p < 0.001). Nicardipine produced fewer changes in heart rate, less chest pain and less flushing than adenosine. Transient atrioventricular block occurred in 29 patients with IC adenosine and none with IC nicardipine. IC bolus injection of nicardipine could be introduced as a safe and practical alternative method of inducing hyperemia during FFR measurements. Compared to IC adenosine, IC nicardipine has a similar hyperemic efficacy and excellent side-effect profile.


Kinetic analysis of a split cell population following reinoculation of an Ehrlich ascites tumor.
When Ehrlich ascites cells from old tumors are inoculated into fresh hosts, their cell cycle parameters show several unusual features when studied by means of four independent techniques. These experiments measure: Labeling Index (LI); Mitotic Index (MI); Percent Labeled Mitosis (PLM); Percent of population mitotic and initially G0, (Mu/P). The minimum modifications of the standard cell-cycle model that allow simultaneous simulation of the four sets of data were then determined. These modifications are: (1) sudden shortening of transit time for the S state immediately following reinoculation; (2) a more gradual change in the transit time for M; (3) an orderly reentry of G0 cells into the beginning of the cycle; (4) a shorter first cycle for the reentering G0 cells along with a smaller coefficient of variation for the first cycle of the G0 cells. These changes allow a simultaneous simulation of the four experiments with a single parameter set. This was not achievable without the modifications. Hence, resolution of a cell population into two components allows one to account for additional kinetic features.


Evaluation of jar lid design characteristics by older women with hand use limitations.
The study evaluated several lid design characteristics (diameter, height, top shape, side shape, and surface texture) by means of controlled laboratory testing with older women with hand function limitations. A subjective evaluation process was applied to examine main effects and interactions of lid design characteristics on usability, determined by participants' perceptions of effort and discomfort. Results showed that lid height was the most important design characteristic associated with usability. For 42 mm diameter lids, designs perceived as best were ones with taller height, hexagonal top shape, and convex side shape. For 28 mm diameter lids, the best designs were ones with taller height and hexagonal top shape. Additionally, when the smaller lid's side shape was flat, a serrate surface texture provided some advantages, particularly for subjects with more severe hand dysfunction. This information could be used by package designers to improve jar lid usability for a growing sector of consumers.


Effect of horticultural activities on quality of life, perceived stress, and working memory of community-dwelling older adults.
This study sampled 86 community-dwelling older adults to investigate the effect of horticultural activities on their quality of life, perceived stress, and working memory. The results demonstrated that after 8 weeks of horticultural activities, the effect sizes (Cohen's d) of their quality of life, perceived stress, and working memory were 0.92, -1.32, and 0.62, respectively. Among the four domains of quality of life, the social relationships domain improved the most. For perceived stress, the score of the experimental group decreased from 1.70 (0.48) to 1.29 (0.58). For working memory, the score increased from 3.43 (1.13) to 4.14 (1.27), whereas the score of the control group did not change substantially. Statistical analysis conducted using a generalized estimating equation revealed a significant interaction effect between group and time (P < 0.001). This study provides a reference for improving the quality of life, perceived stress, and working memory in older people.


Effects of zolpidem, codeine phosphate and placebo on respiration. A double-blind, crossover study in volunteers.
The effects of zolpidem, codeine phosphate and placebo on respiration were evaluated in a double-blind, randomised, crossover study involving 12 healthy men. Single oral doses of zolpidem 10 or 20 mg, codeine phosphate 60 mg or placebo were administered in the morning. Each treatment was separated by a washout period of at least 72 h. Ventilatory responses to carbon dioxide and mouth occlusion pressure, measured 1 h before and at 1 and 3 h after doses, were not significantly affected by either zolpidem dose; however, codeine phosphate produced a small but significant respiratory suppressant effect at 3 h. Mean inspiratory flow was noninvasively assessed using respiratory inductive plethysmography 1 h predose and at 1 to 5 h postdose. No significant change in mean inspiratory flow was noted after zolpidem 10 mg. Two hours after administration of zolpidem 20 mg, mean inspiratory flow was significantly lower than after placebo, possibly related to some individuals falling asleep during data collection. All volunteers reported adverse events; the most common were slurred speech (in 1 after 10 mg and in 5 after 20 mg of zolpidem), dizziness (in 4 after both 10 mg and 20 mg of zolpidem) and diplopia/blurred vision (in 4 after 20 mg of zolpidem). Zolpidem appears to be well tolerated, with no respiratory suppression up to doses of 10 mg and minimal suppression of mean inspiratory drive at doses of 20 mg.


Quantitative 1H-NMR analysis of amniotic fluid.
Ten amniotic fluid samples (36-38 weeks gestation) are analysed by NMR spectroscopy. Of the species identified in the spectra, valine (mean 198 microM: SEM 57 microM), lactate (9.73 mM; 2.05 mM), alanine (689 microM: 115 microM), acetate (6.87 mM: 1.54 mM), citrate (363 microM: 59 microM), glucose (4.54 mM: 1.28 mM) indoxyl-sulphate (n = 4,270 microM), histidine (n = 6, 125 microM: 31 microM) and formate (n = 4, 92 microM) are quantified using standard addition. The factors governing the detection limits and lowest quantifiable amounts are discussed as are the extension of the work into in vivo magnetic resonance spectroscopy (MRS) in the clinic.


Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia.
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Care delivery for HHT patients is impeded by the need for laborious, repeated phenotyping and gaps in knowledge regarding the relationships between causal DNA variants in ENG, ACVRL1, SMAD4 and GDF2, and clinical manifestations. To address this, we analyzed DNA samples from 183 previously uncharacterized, unrelated HHT and suspected HHT cases using the ThromboGenomics high-throughput sequencing platform. We identified 127 rare variants across 168 heterozygous genotypes. Applying modified American College of Medical Genetics and Genomics Guidelines, 106 variants were classified as pathogenic/likely pathogenic and 21 as nonpathogenic (variant of uncertain significance/benign). Unlike the protein products of ACVRL1 and SMAD4, the extracellular ENG amino acids are not strongly conserved. Our inferences of the functional consequences of causal variants in ENG were therefore informed by the crystal structure of endoglin. We then compared the accuracy of predictions of the causal gene blinded to the genetic data using 2 approaches: subjective clinical predictions and statistical predictions based on 8 Human Phenotype Ontology terms. Both approaches had some predictive power, but they were insufficiently accurate to be used clinically, without genetic testing. The distributions of red cell indices differed by causal gene but not sufficiently for clinical use in isolation from genetic data. We conclude that parallel sequencing of the 4 known HHT genes, multidisciplinary team review of variant calls in the context of detailed clinical information, and statistical and structural modeling improve the prognostication and treatment of HHT.


Inequity of maternal-child health services in ASEAN member states from 1993 to 2021.
Inequity in maternal-child health services is a challenge to global health as it hinders the achievement of Sustainable Development Goals (SDGs) and Universal Health Coverage. Though the Association of Southeast Asian Nations (ASEAN) has made remarkable achievements in maternal-child health, there remain gaps in reaching global goals. This study aimed to compare and investigate the inequity in maternal-child health (MCH) services in ASEAN member states to help guide policy decisions to improve equitable health services in the SDG era and beyond. Using the WHO Health Inequality Monitor, we identified inequity summary measures for five MCH services in ASEAN member states from 1993 to 2021: antenatal care, births attended by skilled health personnel, diphtheria, tetanus and pertussis (DTP3) immunization, measles immunization, and polio immunization. We divided the analysis dimension of inequity into urban-rural inequity, economic status inequity, and sub-regional inequity. Trends of absolute and relative inequity in every dimension of MCH services in ASEAN member states were examined with the principal component analysis (PCA). The mean coverages of MCH services are 98.80% (Thailand), 86.72% (Cambodia), 84.54% (Viet Nam), 78.52 (Indonesia), 76.94% (Timor-Leste), 72.40% (Lao PDR), 68.10% (Philippines) and 48.52% (Myanmar) in 2021. Thailand have the lowest MCH services absolute inequity indexes of -1.945, followed by Vietnam (-1.449). Lao PDR and Myanmar have relatively higher MCH services absolute inequity indexes of 0.852 and 0.054 respectively. The service in Cambodia, Indonesia, and the Philippines is pro-specific regions (with subnational region absolute inequity indexes of -0.02, 0.01, and 1.01 respectively). The service in Myanmar is pro-rich (with economic status absolute inequity index of 0.43). The service in Lao PDR and Timor-Leste is pro-urban areas, pro-rich, and pro-specific regions. The inequity of MCH services in ASEAN persists but is in a declining trend. Thailand and Vietnam have performed well in ensuring MCH services equity, while Laos and Myanmar are still facing serious inequity dilemmas. The progress of MCH service equity in Myanmar, Cambodia, the Philippines, and Indonesia is uneven. It is acceptable to learn from the successful experiences of Thailand and Vietnam to improve the equities in other ASEAN countries. Policies should be developed according to the specific types of MCH inequity in member states to improve equity levels.


Myocardial energy provision is preserved by increased utilization of glucose and ketone bodies in CD36 knockout mice.
CD36 is an important transporter of long-chain fatty acids (LCFAs) in the myocardium. As we have reported previously, CD36-deficient patients demonstrate a marked reduction in myocardial uptake of (123)I-15-(p-iodophenyl)-(R, S)-methyl pentadecanoic acid (BMIPP), which is an analog of LCFAs, while myocardial (18)F-fluorodeoxy-glucose (FDG) uptake is increased. However, it has not been clarified whether energy provision is preserved in patients with CD36 deficiency. The aims of the current study were to investigate the myocardial uptake of glucose and alterations in myocardial metabolites in wild-type (WT) and CD36 knockout (KO) mice. High-resolution positron emission tomography (PET) demonstrated markedly enhanced glucose uptake in KO mouse hearts compared with those of WT mice in real-time. The myocardial protein expression of glucose transporter protein 1 (GLUT1) was significantly enhanced in KO mice compared to WT mice, whereas that of GLUT4 was not altered. While the myocardial expression of genes involved in fatty acid metabolism did not increase in KO mice, that of genes related to glucose utilization compensatorily increased in KO mice. The metabolomic analysis of cardiac tissues revealed that the myocardial concentrations of ATP and phosphocreatine were maintained, even in KO mice. The concentration of 3-hydroxybutyric acid and mRNA expression of hydroxybutyrate dehydrogenase in the heart were significantly higher in KO than in WT mice. These data suggest that high-energy phosphate might be preserved by the increased utilization of glucose and ketone bodies in CD36KO mouse hearts under conditions of deficient LCFA uptake.


Phase II Trial of a Novel Paclitaxel Schedule As Single-Agent, First-Line Therapy for HER-2/neu-Negative Metastatic Breast Cancer: A Community-Based Study.
To determine the response rate (RR), progression-free survival (PFS), and toxicity in patients with HER-2/neu-negative metastatic breast cancer treated with first-line paclitaxel in a de-escalating dosing schedule. Between August 1999 and December 2000, 73 patients were enrolled. Paclitaxel was administered on day 1 (175 mg/m(2)) and on days 8 and 15 (80 mg/m(2) each) in each 4-week cycle (1 week of rest). Doses were de-escalated with the aim of reducing toxicity. An Eastern Cooperative Oncology Group performance status of 0, 1, or 2 was found in 55%, 41%, and 4% of patients, respectively. Median age was 59 years (range, 38 to 84 years), and 86% of patients had received prior surgery; 60%, adjuvant chemotherapy; and 59%, radiation therapy. Based on an intention-to-treat analysis (N = 73), there were five patients with a complete response (6.8%), 16 with a partial response (21.9%), 17 with stable disease (23.3%), and 23 with progressive disease (31.5%) for an RR of 28.7%. Twelve patients (16.4%) were not assessable for response due to toxicity (seven patients, mainly neuropathy), withdrawal of consent (two patients), early death (two patients), or noncompliance (one patient). Median PFS was 6.5 months (range, < 1 to 36.1 months), median survival was 22.8 months (range, < 1 to 36.1 months), and median duration of response was 8.8 months (range, 3.0 to 31.8 months). Patients (n = 72) were evaluated for toxicity. Grade 3 to 4 treatment-related toxicities occurring in more than 5% of patients included neutropenia (22.2%), neuropathy (18.1%), fatigue (6.9%), and leukopenia (5.6%). In a unique de-escalating schedule, this study of single-agent paclitaxel produced a response rate similar to other single-agent paclitaxel schedules, in first-line therapy for metastatic breast cancer, published in the literature. However, this schedule is not recommended for the therapy of metastatic breast cancer because of the higher rate of toxicity.


Production and characterisation of monoclonal antibodies specific for bovine interleukin-4.
Genetic immunisation is a simple method for producing polyclonal antibodies in mice. By this method, we produced antibodies against bovine interleukin-4 (BoIL-4). After a final injection with a recombinant BoIL-4 protein, nine stable hybridoma cell lines were established which secreted monoclonal antibodies (MAbs) against this cytokine. Specific binding of each of the MAbs to recombinant BoIL-4 produced by Escherichia coli, baculovirus, and Trypanosoma brucei was demonstrated in an indirect ELISA and/or in Western blotting. These MAbs recognise the same antigenic region localised in the first 47 amino acids of the mature protein. None of them was able to neutralise the biological activity of the BoIL-4 under the conditions tested but one allowed the detection of BoIL-4 by flow cytometry.


Some factors controlling cell polarity in chick retinal pigment epithelial cells in clonal culture.
In clonal culture differentiated chick retinal pigmented epithelial (RPE) cells form a monolayer which shows little or no cellular division. The cells usually rest on a basal and reticular lamina and are polarized with their apical surface towards the medium. The apical surface is characterized by apical protrusions, an extensive apical web of microfilaments and junctional complexes which join the apical-lateral borders. A PA/S positive material with a felt-like appearance from the serum component of the medium coats the surfaces of the tissue culture plates. A similar material is found on any membrane filter which has been exposed to medium containing serum. When such a filter brought in contact with the upper surfaces of the RPE cells, the apical surface characteristics are lost, the cells often accumulate Alcian Blue positive material between the cells and the filter and secrete a reticular and a basal lamina, i.e. they establish a second basal surface. Once this has occurred, the cells appear to either detach from the plate and reverse their polarity, or undergo division forming two cell layers. In the latter case new apical surfaces are created between the cell layers but the cells appear to join to form circular structures rather than sheets. These results suggest that contact with this felt-like material initiates formation of a basal surface. They further suggest that where the apical surface has been converted to a basal one the cell attempts to restore the apical surface either by separating from the plate and reversing its polarity or by creating circular structures and developing new apices oriented toward the center of the circle.


Molecular mechanisms of cellular transformation by HTLV-1 Tax.
The HTLV Tax protein is crucial for viral replication and for initiating malignant transformation leading to the development of adult T-cell leukemia. Tax has been shown to be oncogenic, since it transforms and immortalizes rodent fibroblasts and human T-lymphocytes. Through CREB, NF-kappaB and SRF pathways Tax transactivates cellular promoters including those of cytokines (IL-13, IL-15), cytokine receptors (IL-2Ralpha) and costimulatory surface receptors (OX40/OX40L) leading to upregulated protein expression and activated signaling cascades (e.g. Jak/STAT, PI3Kinase, JNK). Tax also stimulates cell growth by direct binding to cyclin-dependent kinase holenzymes and/or inactivating tumor suppressors (e.g. p53, DLG). Moreover, Tax silences cellular checkpoints, which guard against DNA structural damage and chromosomal missegregation, thereby favoring the manifestation of a mutator phenotype in cells.


Neuroinflammation in Primary Cultures of the Rat Spinal Dorsal Horn Is Attenuated in the Presence of Adipose Tissue-Derived Medicinal Signalling Cells (AdMSCs) in a Co-cultivation Model.
Neuroinflammation within the superficial dorsal horn (SDH) of the spinal cord induces inflammatory pain with symptoms of hyperalgesia and allodynia. Glial activation and production of inflammatory mediators (e.g. cytokines) is associated with modulation of nociceptive signalling. In this context, medicinal signalling cells, e.g. obtained from adipose tissue (AdMSCs), gained attention due to their capacity to modulate the inflammatory response in several diseases, e.g. spinal cord injury. We applied the recently established mixed neuroglial primary cell culture of the rat SDH to investigate effects of AdMSCs on the inflammatory response of SDH cells. Following establishment of a co-cultivation system, we performed specific bioassays for tumour necrosis factor alpha (TNFα) and interleukin (IL)-6, RT-qPCR and immunocytochemistry to detect changes in cytokine production and glial activation upon inflammatory stimulation with lipopolysaccharide (LPS). LPS-induced expression and release of pro-inflammatory cytokines (TNFα, IL-6) by SDH cells was significantly attenuated in the presence of AdMSCs. Further evidence for anti-inflammatory capacities of AdMSCs derived from a blunted LPS-induced TNFα/IL-10 expression ratio and suppressed nuclear translocation of the inflammatory transcription factor nuclear factor kappa B (NFκB) in SDH microglial cells. Expression of IL-10, transforming growth factor beta (TGF-β) and TNFα-stimulated gene-6 (TSG-6) was detected in AdMSCs, which are putative candidates for anti-inflammatory capacities of these cells. We present a novel co-cultivation system of AdMSCs with neuroglial primary cultures of the SDH to investigate immunomodulatory effects of AdMSCs at a cellular level.


Perceived Barriers to Treatment in Persons Treated for Functional Gastrointestinal Disease with Constipation.
Despite expanding treatment options, patients with functional gastrointestinal disorders (FGID) frequently express concerns about problems with access to care. We hypothesized that health insurance coverage contributes to the perceived problems with care delivery. Using the Medical Expenditure Panel Survey, we examined a cohort of participants defined by the diagnosis code for FGID plus the recorded prescription for laxative therapy. Demographic data, healthcare utilization and cost, insurance coverage, comorbid conditions, and information about provider characteristics were extracted for the years 2005-2015. Age- and sex-matched controls were identified for each year included. Barriers to care were based on responses to questions about inability to receive timely care or medication. Logistic regression was used to identify independent predictors of perceived barriers. The cohort was female predominant (67.8%; mean age: 58.8 ± 0.33 years) with 15.4% reporting problems with access to care. Limited insurance coverage was most commonly cited by respondents. Consistent with this result, uninsured persons were significantly more likely to report barriers to care, while the type of insurance for those covered did not independently predict access problems. In addition, comorbidity burden and provider-specific factors, such as available contact options or insufficient explanations, correlated with perceived barriers to care delivery. While the study design cannot establish causal links, persons with FGID commonly report access problems, which correlate with lack of health insurance and comorbidities. Providers can influence this perception by offering more flexible office hours and incorporating patient expectations related to treatment explanations and shared decision-making.


The implications of dysglycaemia on aerobic exercise and ventilatory function in cystic fibrosis.
The development of cystic fibrosis (CF)-related diabetes (CFRD) in paediatric groups is associated with a reduced aerobic fitness. However, this has yet to be investigated in adults with more severe lung disease. Cardiopulmonary exercise and glycaemic control tests were retrospectively analysed in 46 adults with CF (age: 26.9 y [range: 16.3-66.5 y]; forced expiratory volume in 1s: 65.3% [range: 26.8-105.7%]; 26 males), diagnosed with CFRD (n = 19), impaired glucose tolerance (IGT; n = 8) or normal glucose tolerance (NGT; n = 19). Maximal oxygen uptake (V˙O2max) was reduced in adults with IGT and CFRD compared to their age- and gender-matched counterparts with NGT (p < 0.05); however, there was no difference when lung function was included as a covariate (all p > 0.05). V˙O2max was greater in adults who experienced post-reactive hypoglycaemia vs. NGT without hypoglycaemia (p < 0.05). The frequency of ventilatory limitation (84%, 63% and 37%, respectively; p < 0.05) but not ventilation-perfusion mismatch (42%, 38% and 16%, respectively; p > 0.05), was greater with CFRD and IGT vs. NGT. There was also no difference in arterial oxygen saturation changes between groups (p > 0.05). Gender and body mass index were significant predictors of V˙O2max (adjusted R2 = 0.37, p < 0.01), but glycaemic control did not explain additional variance (p > 0.05). Adults with CF-related dysglycaemia had a reduced V˙O2max compared to age- and gender-matched counterparts, due to a greater degree of CF lung disease in these populations.


Transplantation of purified CD34+ cells in the treatment of critical limb ischemia.
This study investigated the feasibility, safety, and efficacy of the intramuscular injection of CD34+ cells isolated from peripheral blood mononuclear cells (PB-MNCs) mobilized by granulocyte colony-stimulating factor (G-CSF) for the management of patients with critical limb ischemia (CLI) who were considered unlikely to have successful long-term revascularization with open bypass or endovascular methods. Cell therapy represents a new treatment modality for this subgroup of patients with CLI. To date, bone marrow or PB-MNCs have usually been used for transplantation. The current pilot study investigated whether the transplantation of purified CD34+ cells only would be competent in ischemia relief and limb salvage. From May 2009 to July 2011, 25 patients (mean age, 44 ± 12 years) were enrolled, and 25 lower extremities and three upper extremities were treated. After subcutaneous administration of G-CSF for 5 days at a dose of 5 to 10 μg/kg, apheresis and immunomagnetic separation were performed to acquire the isolated CD34+ cells, which were then intramuscularly injected into the ischemic sites. The patients were divided into three groups: low-dose, 10(5)/kg; medium-dose, 5 × 10(5)/kg; and high-dose, 10(6)/kg. The overall outcomes among all patients and the comparison among the groups were evaluated. During the follow-up of 6 to 33 months, the overall outcomes showed that the Wong-Baker FACES pain rating scale score (WFPRSS) decreased from 7 ± 2 to 3 ± 3 (P < .001) and 1 ± 2 (P < .001) at 1 and 2 months, respectively; at 3 and 6 months, respectively, the peak pain-free walking time increased from 4 ± 3 to 13 ± 7 (P < .001) and 18 ± 6 minutes (P < .001), the ankle-brachial index increased from 0.46 ± 0.21 to 0.60 ± 0.17 (P = .003) and 0.67 ± 0.15 (P = .001), and the transcutaneous partial oxygen pressure increased from 27 ± 10 to 41 ± 11 (P < .001) and 55 ± 12 mm Hg (P < .001). Ulcers were healed in 10 of the 14 patients; four patients required above-knee or below-knee amputation ≤ 3 months. The Kaplan-Meier estimate of the rate of freedom from major amputation at 6 months was 84% (95% confidence interval, 63%-94%). The comparison among the three groups (low-dose, 5; medium-dose, 11; high-dose, 9) revealed no significant difference, except that the WFPRSS improvement at 1 month from baseline in the high-dose group (6.3 ± 1.7) was significantly superior to that in the low-dose (3.2 ± 3.3; P = .0487) and medium-dose (3.7 ± 2.8; P = .0352) groups. Transplantation of CD34+ cells isolated from G-CSF-mobilized PB-MNCs appears to be feasible and safe, showing encouraging outcomes in the treatment of CLI patients who appear to have compromised options for long-term revascularization.


Novel protective effect of diosmin against cisplatin-induced prostate and seminal vesicle damage: Role of oxidative stress and apoptosis.
Multiple organ toxicity has been associated with cisplatin (CIS) treatment, limiting its clinical use. The human prostate and seminal vesicles are accessory sex organs with androgen-dependent morphogenesis, growth, and secretion. The present study aimed to investigate, for the first time, the toxic effect of CIS on normal prostate and seminal vesicles in the presence and absence of diosmin (DS). The animals were randomized into 4 groups as follows: control (received vehicle), CIS group (7.5 mg/kg, i.p. on 5th and 12th day), DS group (100 mg/kg, p.o. for 15 days), and DS+CIS group. Histopathological and biochemical analyses were conducted to elucidate the goal of this study. CIS administration significantly induced prostate and seminal vesicle toxicity as evidenced by alteration of serum testosterone, LH, FSH, PSA, steroidogenic HSD17B6 as well as seminal analysis markers. Remarkably, marked histopathological changes in thin and ultrathin structures were observed. Besides, CIS significantly boosted oxidative stress as evidenced by the up-regulation of MDA and down-regulation of TAC. CIS significantly induced tissue apoptosis concomitant with suppression of cellular proliferation and stem cell expression as indicated by up-regulation of activated caspase-3 and Bax expression along with down-regulation of Bcl-2, Ki67, and CD44 expression. Interestingly, DS fixed all disturbances in the prostate and seminal vesicles induced by CIS. Together, CIS could cause prostate and seminal vesicle toxicity by affecting hormonal, steroidogenic, oxidative stress, apoptosis, and proliferation processes, and this effect was reversed by DS administration.


Overstated carbon emission reductions from voluntary REDD+ projects in the Brazilian Amazon.
Reducing emissions from deforestation and forest degradation (REDD+) has gained international attention over the past decade, as manifested in both United Nations policy discussions and hundreds of voluntary projects launched to earn carbon-offset credits. There are ongoing discussions about whether and how projects should be integrated into national climate change mitigation efforts under the Paris Agreement. One consideration is whether these projects have generated additional impacts over and above national policies and other measures. To help inform these discussions, we compare the crediting baselines established ex-ante by voluntary REDD+ projects in the Brazilian Amazon to counterfactuals constructed ex-post based on the quasi-experimental synthetic control method. We find that the crediting baselines assume consistently higher deforestation than counterfactual forest loss in synthetic control sites. This gap is partially due to decreased deforestation in the Brazilian Amazon during the early implementation phase of the REDD+ projects considered here. This suggests that forest carbon finance must strike a balance between controlling conservation investment risk and ensuring the environmental integrity of carbon emission offsets. Relatedly, our results point to the need to better align project- and national-level carbon accounting.


Extract of Tagetes erecta L., a medicinal plant rich in lutein, promotes gastric healing and reduces ulcer recurrence in rodents.
Tagetes erecta L. (Asteraceae), popularly known as Aztec Marigold, is used in South America to treat several ailments. Despite reports that T. erecta flowers are used in folk medicine to treat gastrointestinal diseases, there is no study regarding its gastric healing effects. The effect of dry extract of T. erecta L. (DETe) in gastric healing and gastric ulcer recurrence was evaluated, contributing to the validation of the antiulcer potential of this medicinal plant. Rats were treated orally with vehicle (1 ml/kg), omeprazole (20 mg/kg), or DETe (3, 30 or 300 mg/kg) for 7 days, twice a day. The lesion area was evaluated, and the levels of reduced glutathione (GSH) and lipoperoxides (LOOH) and the activity of the superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), and myeloperoxidase (MPO) were measured. The ulcer recurrence was evaluated in mice and induced by interleukin (IL)-1β (1 μg/kg, i.p). The recurred area, gastric wall thickness, GSH and cytokines levels, MPO and N-acetylglucosaminidase (NAG) activities were measured. DETe accelerated the healing of gastric ulcers only at 300 mg/kg, reducing the ulcerated area by 66%. In parallel, DETe reduced LOOH levels, SOD, CAT and MPO activities, while increasing GST activity and mucin amount. In the recurrence model, DETe reduced the lesion area by 94%, and in parallel decreased the gastric wall thickness and TNF levels, while increasing IL-10 amount. Corroborating the popular use of T. erecta, DETe favors the antioxidant system and reduce gastric inflammation, accelerating the gastric healing process and reducing the ulcer recurrence.


Chitin and L(+)-lactic acid production from crab (Callinectes bellicosus) wastes by fermentation of Lactobacillus sp. B2 using sugar cane molasses as carbon source.
Crab wastes are employed for simultaneous production of chitin and L(+)-lactic acid by submerged fermentation of Lactobacillus sp. B2 using sugar cane molasses as carbon source. Response surface methodology was applied to design the culture media considering demineralization. Fermentations in stirred tank reactor (2L) using selected conditions produced 88% demineralization and 56% deproteinization with 34% yield of chitin and 19.5 gL(-1) of lactic acid (77% yield). The chitin purified from fermentation displayed 95% degree of acetylation and 0.81 and 1 ± 0.125% of residual ash and protein contents, respectively.


Wave similarity mapping shows the spatiotemporal distribution of fibrillatory wave complexity in the human right atrium during paroxysmal and chronic atrial fibrillation.
The complexity of waveforms during atrial fibrillation may reflect critical activation patterns for the arrhythmia perpetuation. In this study, we introduce a novel concept of map, based on the analysis of the wave morphology, which gives a direct evidence in the human right atrium on the spatiotemporal distribution of fibrillatory wave complexity in paroxysmal (PAF) and chronic (CAF) atrial fibrillation. Electrograms were recorded from a 64-electrode catheter in the right atrium of 15 patients during PAF (n = 8) and CAF (n = 7). Wave similarity maps were constructed by calculating the degree of morphological similarity of activation waves (S) at each atrial site and by following its temporal evolution. During PAF the spatiotemporal distribution of the waveforms was highly consistent across the subjects and was determined by the anatomic location. Wave similarity maps showed the existence of an extended area with low similarity index, which covered the low posteroseptal atrium (S = 0.28 +/- 0.09) and the septal region (S = 0.22 +/- 0.04), and the presence of a large tongue with high similarity index, which penetrated the lateral wall (S = 0.55 +/- 0.08) starting from the high anterolateral atrium (S = 0.54 +/- 0.06). A completely different spatiotemporal pattern was seen during CAF. No distinct regions with different similarity indexes were recognized, but a uniformly distributed low similarity index (S = 0.27 +/- 0.07) was found. The spatial pattern was highly stable in time with fluctuations of S < 0.04. Quantification of the spatiotemporal distribution of fibrillatory wave complexity is feasible in humans by wave similarity mapping. Anatomic anchoring of waveforms during PAF and pattern destruction during CAF was determined.


Low-frequency electromagnetic field effects on functional groups in human skin keratinocytes cells revealed by IR-SNOM.
Human HaCaT cells, exposed for 24 h to a 1 mT (rms) 50 Hz sinusoidal magnetic field in a temperature-regulated solenoid, suffer detectable changes in their biochemical properties and shapes. By using infrared wavelength-selective scanning near-field optical microscopy, we observed changes in the distribution of the inner chemical functional groups and in the cell morphology with a resolution of 80-100 nm.


Distribution of proteoglycans and hyaluronic acid in transverse sections of bovine thoracic aorta.
The distribution of hyaluronic acid and proteoglycans in bovine thoracic aorta was studied by Alcian Blue staining of frozen tissue sections under controlled electrolyte conditions with and without prior enzymic digestion. Some sections were digested with chondroitinase ABC, testicular hyaluronidase or bacterial collagenase and subsequent staining permitted conclusions to be drawn about the distribution of specific glycosaminoglycans within the tissue. The total glycosaminoglycan content was maximal in the intima and decreased across the arterial wall to the outermost adventitial layer. The content of proteoglycan containing chondroitin sulphate and/or dermatan sulphate chains paralleled this distribution. However, other glycosaminoglycans also contributed significantly to staining, although there was no evidence for any appreciable concentration of heparin or highly sulphated heparan sulphate. Several experiments indicated that proteoglycan containing chondroitin sulphate and/or dermatan sulphate was associated with elastic laminae which were often seen stained along their periphery. Hyaluronic acid was present at significant concentrations in all locations of the aorta and there was evidence for a similar distribution of heparan sulphate which was possible also present at a high concentration in the endothelium. Staining of sections after treatment with 4 M guanidinium chloride confirmed that this extractant removed most of the proteoglycan from the tissue section.


The nervous supply to the nasal cavity of the Bactrian camel (Camelus bactrianus).
The Bactrian camel is an important domestic animal in some of the desert and semi-desert areas of the world. However, there is no detailed report about the nervous supply to the nasal cavity of the Bactrian camel. In the present study, seven heads of adult Bactrian camels were collected and the nerve distribution in the nasal cavity was dissected grossly. The results demonstrated that the nerves supplying to the nasal cavity included the olfactory nerve, the ethmoidal nerve from the ophthalmic nerve, and the caudal nerve from the maxillary nerve. The general patterns of nervous distribution in the nasal cavity of the Bactrian camel corresponded with those of other domestic animals. However, the terminal nerve was not observed by this gross anatomical method in the Bactrian camel.