Cardiac arrhythmias in patients with surgical repair of Ebstein's anomaly.
Preoperative, perioperative and postoperative arrhythmias in 52 consecutive patients who underwent operation for Ebstein's anomaly were reviewed. There were 25 male and 27 female patients (mean age 18 years, range 11 months to 64 years). Thirty-four patients had one or more documented arrhythmias preoperatively (18 had paroxysmal supraventricular tachycardia, 10 had paroxysmal atrial fibrillation or flutter, 13 had ventricular arrhythmia and 3 had high grade atrioventricular block). Seven patients without documented arrhythmias had a history typical of tachyarrhythmias. During the perioperative and early postoperative periods, 14 patients had atrial tachyarrhythmias and 8 had ventricular tachycardia or ventricular fibrillation. There were seven deaths between day 1 and 27 months after operation. Five of these deaths were sudden (all in male patients, aged 12 to 34 years), and four of the patients had had perioperative ventricular tachycardia or ventricular fibrillation. One patient was taking one antiarrhythmic agent and another patient was taking two at the time of sudden death. Of the 18 patients with paroxysmal supraventricular tachycardia and 9 patients with paroxysmal atrial fibrillation or flutter preoperatively who were followed up for a mean of 40 and 36 months, respectively, 22 and 33% continued to have symptomatic tachycardia. Of the 11 patients (mean age 9 years) without preoperative documentation or symptoms of arrhythmia, follow-up data were obtained (range 1 to 144 months, mean 31) in 9 patients. None died suddenly or developed symptomatic arrhythmia.


Initial Response to Combination Therapies for Tinnitus: Lessons Learned From a Retrospective Analysis.
To investigate the initial reduction of tinnitus effects by combining common therapies applicable in general otology clinics and establishing optimal treatment strategies. Retrospective cohort study. A tertiary university hospital. Patients with nonpulsatile subjective tinnitus who visited the hospital between January and December 2022. Combination therapies consisting of at least one of the directive counseling based on the neurophysiological model, hearing aids, medication, and/or neuromodulation were performed. Tinnitus Handicap Inventory (THI) questionnaire at both their initial visit and 1-month follow-up. A total of 151 patients were enrolled. THI improvement of 20 points or more was observed in 31.8% of participants. One-way analysis of variance revealed that counseling had a significant reduction in THI, whereas neuromodulation, medication, and hearing aids did not. THI improvement was significantly associated with received counseling, severity of initial THI, and mean loudness discomfort level. Hearing aids and neuromodulation were not significant prognostic factors for improvement. Counseling alone is the best treatment for most patients with tinnitus. There will be other patients with tinnitus that, in addition to counseling, would benefit from hearing aids, medications, and/or certain forms of neuromodulation.


Calcitonin resistance: clinical and immunologic studies in subjects with Paget's disease of bone treated with porcine and salmon calcitonins.
15 patients with Paget's bone disease were treated with varying schedules of porcine (3.8-157.5 MRCU/kg per wk) and/or salmon (1.5-210 MRCU/kg per wk) calcitonins over periods ranging from 4 to 24 months. All of the subjects experienced a striking decrease in serum alkaline phosphatase during the first 4 months of treatment. In six patients, however, resistance to these peptides was suggested by a subsequent elevation of alkaline phosphatase activity in spite of continued and augmented hormone administration. These rebounds in alkaline phosphatase levels correlated with the appearance of calcitonin-binding substances and neutralizing material in serum. Incubations of calcitonins-(125)I and sera from these six subjects resulted in the association of radioactivity with material whose behavior on chromatoelectrophoresis (6/6), sucrose density ultracentrifugation and immunoelectrophoresis (one subject) was identical with that of 7S immunoglobulin. Specific, reversible in vitro binding of salmon calcitonins-(125)I was observed in sera obtained from these patients 5 to 12 months after initiation of salmon calcitonin therapy. All six of these subjects' sera acquired the capacity to neutralize salmon calcitonin's hypocalcemic effect in rat bioassay. Neutralization titers correlated with maximal binding capacities, which ranged from 0.042 to 6.6 mg/liter of serum. Competitive displacement of calcitonins-(125)I from the sera of one patient treated with both porcine and salmon calcitonin indicated separate populations of antibodies to these hormones. In spite of return of disease activity comparable to baseline levels, 3/5 resistant subjects treated with salmon calcitonin failed to develop hypocalcemia after injection of 300-1000 MRCU of salmon calcitonin, but two of these patients developed hypocalcemia in response to the porcine hormone. The disappearance of total radioactivity from the circulation after intravenous administration of salmon calcitonin-(125)I was retarded and the amount of serum radioactivity precipitable in 50% (NH(4))(2)SO(4) greater in 3/3 resistant patients compared to control subjects. These observations on the incidence of significant titers of neutralizing antibodies to salmon (40%) and porcine (66%) calcitonins during their chronic (> 4 months) administration to man clearly indicate that an appraisal of this possibility be included in studies involving protracted use of these hormones.


Supererogation and the profession of medicine.
In the light of increasing public mistrust, there is an urgent need to clarify the moral status of the medical profession and of the relationship of the clinician to his/her patients. In addressing this question, I first establish the coherence, within moral philosophy generally, of the concept of supererogation (the doing of more than one's duty). I adopt the notion of an act of "unqualified" supererogation as one that is non-derivatively good, praiseworthy, and freely undertaken for others' benefit at the risk of some cost to the agent. I then argue that committing oneself to the profession of clinical medicine is an act of this kind. This is the case, not because the aim of medicine is to help patients, but because of the open ended commitment of time and the vulnerability to the consequences of failure that the clinician must accept.


Microtubule-organizing centres in mammalian cells in culture.
When microtubules in animal cells are dissociated and then allowed to recover, they re-grow from discrete points in the cytoplasm known as microtubule-organizing centres (MTOC). The microtubules may be dissociated by antimitotic drugs such as colcemid, vinblastine and griseofulvin, or by chilling the cells. Immunofluorescence studies show that the number of MTOC seen does not depend on the concentration of antimitotic drug used or the duration of exposure to the drug; the same results are obtained with vinblastine, griseofulvin and colcemid. However, after cold treatment, the proprotion of cells showing only a single MTOC is greater than that seen with the antimitotic drugs and may exceed 90%. Evidence is presented for the view that procedures involving the use of antimitotic drugs give artificially high values for the number of MTOC per cell.


Ion Mobility Spectrometry of Superheated Macromolecules at Electric Fields up to 500 Td.
Since its inception in 1980s, differential or field asymmetric waveform ion mobility spectrometry (FAIMS) has been implemented at or near ambient gas pressure. We recently developed FAIMS at 15-30 Torr with mass spectrometry and utilized it to analyze amino acids, isomeric peptides, and protein conformers. The separations broadly mirrored those at atmospheric pressure, save for larger proteins that (as predicted) exhibited dipole alignment at ambient but not low pressure. Here we reduce the pressure down to 4.7 Torr, allowing normalized electric fields up to 543 Td-double the maximum in prior FAIMS or IMS studies of polyatomic ions. Despite the collisional heating to ∼1000 °C at the waveform peaks, the proteins of size from ubiquitin to albumin survived intact. The dissociation of macromolecules in FAIMS appears governed by the average ion temperature over the waveform cycle, unlike the isomerization controlled by the peak temperature. The global separation trends in this "superhot" regime extend those at moderately low pressures, with distinct conformers and no alignment as theorized. Although the scaling of the compensation voltage with the field fell below cubic at lower fields, the resolving power increased and the resolution of different proteins or charge states substantially improved.


Aspirin use and p53 expression in colorectal cancer.
p53 protein overexpression indicates loss of tumor suppressor activity and is the most common genetic alteration in colorectal neoplasms. Epidemiologic and experimental studies suggest that regular use of aspirin may reduce colorectal cancer risk. We set out to determine whether p53 overexpression of the colorectum was associated with a patient's history of aspirin use. Self-administered questionnaires, including information on aspirin use, were obtained from 163 patients with nonfamilial colorectal cancer and from 326 healthy controls. Nuclear p53 protein overexpression using anti-p53 CM-1 polyclonal antibody was observed in 44.8% (73/163) of patients' tumors. A nonsignificant inverse association was observed between use of aspirin and colorectal cancer. Compared with that for nonusers, the odds ratio (OR) for individuals who took aspirin at least twice weekly was 0.68 (95% confidence interval [95% CI]: 0.39-1.18). The odds ratio for those individuals who used aspirin for less than 5 years was 0.54 (95% CI: 0.24-1.23), and 0.80 (95% CI: 0.42-1.51) for those who used aspirin for 5 years or more, when compared with nonusers. An inverse association of regular aspirin use (two times per week or more) was found both for cases with p53 overexpression (OR: 0.79; 95% CI: 0.39-1.59), and for cases without p53 overexpression (OR: 0.56; 95% CI: 0.25-1.22). There was little evidence of a difference in the effect of aspirin use on cancer risk between cases with and without p53 overexpression, even after adjustment for potential confounders.


A monoclonal antibody identifies a protective C-protein alpha-antigen epitope in group B streptococci.
Group B streptococci (GBS) are the leading causes of neonatal sepsis and meningitis in the United States, with a high rate of fatality and serious morbidity despite appropriate therapy. The C-protein antigens of GBS appear to be important in immunity to experimental infection, yet these antigens remain incompletely characterized with respect to their number, structure, and function. None of these proteins has yet been purified to homogeneity. We have developed a novel method for extraction of surface proteins from the A909 (Ia/c) strain of GBS by using mutanolysin. Antibodies raised in rabbits against these partially purified proteins conferred passive protection to lethal GBS infection in mice challenged with a GBS strain expressing C proteins with a heterologous capsule type. In addition, mouse monoclonal antibodies were produced and identified by reactivity with the mutanolysin-extracted proteins. One of these monoclonal antibodies (4G8) identifies an epitope on the alpha-antigen of the GBS C proteins (identified by protease susceptibility and mouse protection). On sodium dodecyl sulfate-polyacrylamide gels, this epitope appears as a series of regularly spaced bands ranging in apparent molecular mass from 160,000 to 30,000 Da. The monoclonal antibody 4G8 induces opsonic killing of GBS and protects mice from lethal challenge with GBS. Thus, the 4G8 monoclonal antibody identifies a fully protective epitope on the C-protein alpha-antigen of GBS.


CTP:phosphocholine cytidylyltransferase activation by oxidized phosphatidylcholines correlates with a decrease in lipid order: a 2H NMR analysis.
The enzyme CTP:phosphocholine cytidylyltransferase (CT) binds reversibly to membranes and is active only in its membrane-bound form. Membrane lipid composition influences the equilibrium between its soluble and membrane-bound forms. Whereas the enzyme is not activated by phosphatidylcholine (PC) vesicles, it is activated by PC vesicles that have been oxidized with HClO(4) [Drobnies, A. E., et al. (1998) Biochim. Biophys. Acta 1393, 90-98]. Here we explore the mechanism of activation of CT by a PC oxidized with lipoxidase. Multilamellar vesicles (MLVs) containing > or =5 mol % oxidized 1-palmitoyl-2-arachidonoylPC (PAPC) progressively activated the enzyme, which was fully activated by 25 mol % oxidized PC. The effect of oxidized PAPC on lipid order was investigated by (2)H NMR, using MLVs containing PAPC perdeuterated on the palmitoyl chain. Spectral depaking generated order parameter profiles along the sn-1 chain. The average order parameter (S(CD)) in the plateau region at 37 degrees C decreased from 0.18 to 0.15 with increasing percent of oxidized PAPC (0-25%). The change in S(CD) was even greater near the end of the palmitoyl chain. CT activation was inversely related to lipid order. The major component of the lipoxidase-oxidized PAPC was purified and characterized by mass spectrometry and NMR. This component, 1-palmitoyl-2-(11,15-dihydroxy)eicosatrienoylPC (dihydroxyPAPC), incorporated into PAPC MLVs, also stimulated CT activity and reduced the lipid order parameter. Both effects were reversed by egg sphingomyelin. We propose that CT activation by oxidized PAPC is mediated by effects on lipid packing perturbations. This is the first study to report the effects of a purified oxidized PC on the orientational order along the acyl chain and to correlate the lipid disordering of the oxidized PC with the activation of a membrane-associated regulatory enzyme.


Dynamic conductivity of ferroelectric domain walls in BiFeO₃.
Topological walls separating domains of continuous polarization, magnetization, and strain in ferroic materials hold promise of novel electronic properties, that are intrinsically localized on the nanoscale and that can be patterned on demand without change of material volume or elemental composition. We have revealed that ferroelectric domain walls in multiferroic BiFeO(3) are inherently dynamic electronic conductors, closely mimicking memristive behavior and contrary to the usual assumption of rigid conductivity. Applied electric field can cause a localized transition between insulating and conducting domain walls, tune domain wall conductance by over an order of magnitude, and create a quasicontinuous spectrum of metastable conductance states. Our measurements identified that subtle and microscopically reversible distortion of the polarization structure at the domain wall is at the origin of the dynamic conductivity. The latter is therefore likely to be a universal property of topological defects in ferroelectric semiconductors.


Evolution and classification of the CRISPR-Cas systems.
The CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) modules are adaptive immunity systems that are present in many archaea and bacteria. These defence systems are encoded by operons that have an extraordinarily diverse architecture and a high rate of evolution for both the cas genes and the unique spacer content. Here, we provide an updated analysis of the evolutionary relationships between CRISPR-Cas systems and Cas proteins. Three major types of CRISPR-Cas system are delineated, with a further division into several subtypes and a few chimeric variants. Given the complexity of the genomic architectures and the extremely dynamic evolution of the CRISPR-Cas systems, a unified classification of these systems should be based on multiple criteria. Accordingly, we propose a 'polythetic' classification that integrates the phylogenies of the most common cas genes, the sequence and organization of the CRISPR repeats and the architecture of the CRISPR-cas loci.


Risk of multiple myeloma and monoclonal gammopathy of undetermined significance among white and black male United States veterans with prior autoimmune, infectious, inflammatory, and allergic disorders.
In a retrospective cohort of more than 4 million white and black male United States (US) veterans, we explored the role of specific prior autoimmune, infectious, inflammatory, and allergic disorders in the etiology of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Patients were selected from computerized inpatient discharge records at US Veterans Affairs hospitals. The analysis included 4641 patients (3040 white, 1601 black) and 2046 patients (1312 white; 734 black) with a discharge diagnosis of MM and MGUS, respectively. Using Poisson regression, we calculated age-adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the relationship between MM, MGUS, and specific prior medical conditions. Significantly elevated risks of MM were associated with broad categories of autoimmune (RR, 1.15; 95% CI, 1.02-1.28), infectious (RR, 1.29; 95% CI, 1.20-1.38), and inflammatory disorders (RR, 1.18; 95% CI, 1.10-1.27) and specific prior autoimmune (polymyositis/dermatomyositis, systemic sclerosis, autoimmune hemolytic anemia, pernicious anemia, and ankylosing spondylitis), infectious (pneumonia, hepatitis, meningitis, septicemia, herpes zoster, and poliomyelitis), and inflammatory (glomerulonephritis, nephrotic syndrome, and osteoarthritis) disorders. Risks for MGUS were generally of similar magnitude. Our results indicate that various types of immune-mediated conditions might act as triggers for MM/MGUS development.


Recellularization of acellular human small intestine using bone marrow stem cells.
We aimed to produce an acellular human tissue scaffold with a view to test the possibility of recellularization with bone marrow stem cells to produce a tissue-engineered small intestine (TESI). Human small-bowel specimens (n = 5) were obtained from cadaveric organ donors and treated sequentially with 6% dimethyl sulfoxide in hypotonic buffer, 1% Triton X-100, and DNase. Each small intestine (SI) piece (6 cm) was recellularized with EPCAM+ and CD133+ allogeneic bone marrow stem cells. Histological and molecular analysis demonstrated that after decellularization, all cellular components and nuclear material were removed. Our analysis also showed that the decellularized human SI tissue retained its histoarchitecture with intact villi and major structural proteins. Protein films of common extracellular matrix constituents (collagen I, laminin, and fibronectin) were found in abundance. Furthermore, several residual angiogenic factors were found in the decellularized SI. Following recellularization, we found viable mucin-positive goblet cells, CK18+ epithelial cells in villi adjacent to a muscularis mucosa with α-actin+ smooth muscle cells, and a high repopulation of blood vessels with CD31+ endothelial cells. Our results show that in the future, such a TESI would be ideal for clinical purposes, because it can be derived from the recipient's own immunocompatible bone marrow cells, thus avoiding the use of immunosuppression.


Trends of caesarean section rates in Turkey.
The aims of this study was to determine the trends in rates of caesarean sections in Turkey. The data source for this study was the Turkey Demographic and Health Survey (TDHS) 1993-1998-2003-2008-2013 conducted by Hacettepe University, Institute of Population Studies. Cross tables and binary logistic regression were used for analysis. It was found that the caesarean section rate, which was 14.3% in 1993, increased to 51.9% in 2013. The rate increased with maternal age and educational level at childbirth. The Caesarean section rate was higher in women who were under health insurance coverage, first time mothers, childbirth in the private health institutions, those staying in the Western region and urban areas, and having the highest level of wealth. This study aims to contribute to the literature of caesarean sections especially in developing countries, in which caesarean section has become a major healthcare issue. Impact Statement What is already known on this subject: Caesarean section is among the most widely practiced obstetric surgery worldwide. Previous studies have suggested that the rates of caesarean section were affected by the biological, genetic and medical factors. What the results of this study add: Besides the biological, genetic and medical factors, it is believed that social factors (income and social status, education, employment, etc.) play an important role on the caesarean section in developing countries. Although the laws on caesarean sections have been enforced since 2012 in Turkey, this study shows that there has been a significant increase in caesarean section between the 1993 and 2013 periods. The study also reveals that prohibiting caesarean sections, except in cases of medical necessity, is a problematic issue in the health system despite all efforts. What the implications are of these findings for clinical practice and/or further research: This study may be of interest for authorities and researchers in terms of showing the social factors associated with the caesarean section.


Ankle Exoskeleton Assistance Increases Six-Minute Walk Test Performance in Cerebral Palsy.
To determine the effects of providing battery-powered ankle dorsiflexor and plantar flexor exoskeleton assistance on six-minute walk test performance and efficiency in children and young adults with cerebral palsy by comparing distance walked under exoskeleton assisted (Assisted) and no device (Shod) walking conditions, and explore the acclimation rate to maximal walking with ankle exoskeleton assistance. Six-minute walk test performance significantly improved under the final Assisted condition test compared to the Shod condition (42 ± 27 m, p = 0.02), surpassing the minimum clinically important difference range for children and young adults with CP. There was no difference in walking efficiency (-0.06 ± 0.1, p = 0.3). Participants had an average acclimation rate of 19.6 m per session. Powered ankle assistance can significantly improve six-minute walk test performance in individuals with mild-to-moderate gait impairment from CP, supporting the use of this intervention to improve functional mobility and walking capacity in this patient population.


Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.
Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects. To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic. We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes. We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.


Autoantibodies Activating the β2-Adrenergic Receptor Characterize Patients With Primary and Secondary Glaucoma.
Recently, agonistic autoantibodies (agAAb) activating the β2-adrenergic receptor were detected in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients and were linked to intraocular pressure (IOP) (1). The aim of the present study was to quantify β2-agAAb in the sera of glaucoma suspects and patients with primary and secondary glaucoma. Patients with OHT (n = 33), pre-perimetric POAG (pre-POAG; n = 11), POAG (n = 28), and 11 secondary OAG (SOAG) underwent ophthalmological examinations including examinations with Octopus G1 perimetry and morphometry. Twenty-five healthy individuals served as controls. Serum-derived IgG samples were analyzed for β2-agAAb using a functional bioassay. The beat-rate-increase of spontaneously beating cultured neonatal rat cardiomyocytes was monitored with 1.6 beats/15 s as cut-off. None of the sera of normal subjects showed β2-agAAb. In POAG or OHT patients increased beating rates of 4.1 ± 2.2 beats/15 s, and 3.7 ± 2.8 beats/15 s were detected (p > 0.05). Glaucoma patients with (POAG) and without perimetric (pre-POAG) defects did not differ (pre-POAG 4.4 ± 2.6 beats/15 s, POAG 4.1 ± 2.0 beats/15 s, p > 0.05). Patients with SOAG yielded mean beating rates of 4.7 ± 1.7 beats/15 s (p > 0.05). β2-agAAb were seen in 73% of OHT, 82% of pre-POAG, 82% of POAG, and 91% SOAG patients (p < 0.001). Clinical data did not correlate with beating rate (p > 0.05). The robust β2-agAAb seropositivity in patients with OHT, pre-POAG, POAG, and SOAG suggest a primary common role for β2-agAAb starting early in glaucoma pathophysiology and turned out to be a novel marker identifying all patients with increased IOP independent of glaucoma stage and entity.


Xeroderma pigmentosum complementation group A protein is driven to nucleotide excision repair sites by the electrostatic potential of distorted DNA.
The presumed DNA-binding cleft of xeroderma pigmentosum group A (XPA) protein, a key regulatory subunit of the eukaryotic nucleotide excision repair complex, displays a distinctive array of 6 positively charged amino acid side chains. Here, the molecular function of these closely spaced electropositive residues has been tested by systematic site-directed mutagenesis. After the introduction of single amino acid substitutions, the mutants were probed for protein-DNA interactions in electrophoretic mobility shift and photochemical crosslinking assays. This analysis led to the identification of a critical hot-spot for DNA substrate recognition composed of two neighboring lysines at codons 141 and 179 of the human XPA sequence. The replacement of other basic side chains in the DNA interaction domain conferred more moderate defects of substrate binding. When the function of XPA was tested as a fusion product with either mCherry or green-fluorescent protein, a glutamate substitution of one of the positively charged residues at positions 141 and 179 was sufficient to decrease DNA repair activity in human fibroblasts. Thus, the removal of a single cationic side chain abolished DNA-binding activity and significant excision repair defects could be induced by single charge inversions on the XPA surface, indicating that this molecular sensor participates in substrate recognition by monitoring the electrostatic potential of distorted DNA repair sites.


HER-2 expression and cell proliferation: prognostic markers in patients with node-negative breast cancer.
We analyzed the clinical relevance of HER-2 expression, widely investigated in breast cancer but with contradictory results, in the largest case series of node-negative breast cancer patients investigated to date. The pure prognostic value of HER-2 expression was investigated in 529 patients treated with locoregional therapy alone until early relapse. Proliferative activity was evaluated as [3H]thymidine labeling index and HER-2 expression by immunohistochemistry. All biologic determinations were conducted within the context of an intra- and interlaboratory National Quality Control Program. HER-2 expression was not related to relapse-free survival in the overall series but was a significant discriminant of prognosis in the subgroup of patients with rapidly proliferating tumors. Six-year rate of relapse was 40% for patients with highly (> or =30%) positive tumors and 26% for those with weakly HER-2-expressing tumors (P =.039). HER-2 expression in association with proliferative activity identifies a subgroup of node-negative breast cancer patients with the worst prognosis, who are candidates for specific intensive adjuvant therapy.


Absolute photoacoustic thermometry in deep tissue.
Photoacoustic thermography is a promising tool for temperature measurement in deep tissue. Here we propose an absolute temperature measurement method based on the dual temperature dependences of the Grüneisen parameter and the speed of sound in tissue. By taking ratiometric measurements at two adjacent temperatures, we can eliminate the factors that are temperature irrelevant but difficult to correct for in deep tissue. To validate our method, absolute temperatures of blood-filled tubes embedded ~9 mm deep in chicken tissue were measured in a biologically relevant range from 28°C to 46°C. The temperature measurement accuracy was ~0.6°C. The results suggest that our method can be potentially used for absolute temperature monitoring in deep tissue during thermotherapy.


The signs of a passed ureteral stone.
Ten patients with typical renal colic fortuitously passed a urinary calculus, which was retrieved during or shortly after excretory urography. Characteristic alterations in the urogram included: (a) no delay in passage of contrast medium down the entire length of the ureter, (b) decreased radiodensity of contrast on the affected as compared to that of the normal side, (c) dilatation of the ureter on the affected side and (d) a hazy appearance of the ureter with poor definition of its borders. Post-obstructive diuresis explains these changes. This constellation of findings, with accompanying absence of an opaque calculus on the plain film, correctly diagnoses a recently passed stone. The sign complex indicates that obstruction has been relieved, even when the calculus remains in situ.


Acute Effects of Local Ischemic Hypoxia and Systemic Hypoxemia on Neuromuscular and Cognitive Function.
Rivera, Paola M., Chris E. Proppe, Esther Beltran, and Ethan C. Hill. Acute effects of local ischemic hypoxia and systemic hypoxemia on neuromuscular and cognitive function. High Alt Med Biol. 23:18-25, 2022. Background: The application of blood flow restriction (BFR) induces local ischemic hypoxia within the muscle(s) distal to the restriction device. Systemic hypoxemia via oxygen or barometric pressure manipulation achieves whole-body hypoxia and thus may be a more potent exercise adjunct than BFR. Therefore, the purpose of this study was to examine the acute effects of local ischemic hypoxia versus systemic hypoxemia on maximal voluntary isometric contraction (MVIC) torque, electromyographic amplitude (EMG AMP), EMG mean power frequency (MPF), and cognition. Materials and Methods: Twelve recreationally trained women (mean age ± standard deviation = 21 ± 1.6 years) performed 75 submaximal (1 × 30, 3 × 15) unilateral leg extension muscle actions under normoxia, local ischemic hypoxia, and systemic hypoxemia. Before and immediately after the 75 repetitions, MVIC muscle actions were performed, and surface EMG was simultaneously assessed from the vastus lateralis. Cognitive function was assessed immediately after each exercise using the Automated Neuropsychological Assessment Metrics (ANAM). Separate repeated-measures analyses of variance (ANOVAs) were performed to examine changes in MVIC, reaction time, EMG AMP, and EMG MPF responses during the MVIC muscle actions. Results: There were no significant (p = 0.21-0.953) Condition × Time interactions for MVIC, EMG AMP, or EMG MPF but a significant (p < 0.001-0.005) main effect for the Time collapsed across Condition for MVIC torque (pretest 238.8 ± 19.5, posttest 212.7 ± 20.1 Nm) and EMG MPF (88.5% ± 1.4% of pretest). There were no significant (p = 0.503) differences in reaction time among Conditions. Conclusions: The findings of the present study suggest that all three conditions elicited comparable acute changes in performance as assessed by MVIC torque that were associated with no changes in muscle activation but decrease in action potential conduction velocity. Therefore, the application of local ischemic hypoxia or systemic hypoxemia during low-load resistance exercise can be used to elicit similar acute physiological responses and not adversely affect cognitive function relative to nonhypoxic conditions.


Frequency of differential placental transfer to twins of maternal antiretroviral medications.
Placental passage of drugs in twins is poorly understood, and is unknown regarding antiretrovirals (ARVs). In the event of large differences in the exposure of 2 twins to the same maternal therapy, this could have a clinical impact in terms of prevention of perinatal HIV transmission or adverse effects. To describe the frequency of differential transplacental passage of antiretrovirals between twins. The study was performed retrospectively, on data from women included in a multicenter perinatal HIV cohort study. All twin pairs for which the mother received antiretroviral therapy and for which drug concentrations in both of the umbilical cords after cord clamping at delivery were studied. We considered that a difference in concentrations of more than 50 % between twins was a substantial difference (ratios below 0.67 or above 1.50). We analyzed 29 twin pairs, 27 dichorionic and 2 monochorionic diamniotic. Cord blood concentrations differed between the 2 twins by more than 50 % for at least one ARV in 9 twin pairs, 8 dichorionic and 1 monochorionic. Discordant concentrations were observed in one or more cases for several nucleoside reverse transcriptase inhibitors (tenofovir, emtricitabine, lamivudine, zidovudine) and protease inhibitors (atazanavir, lopinavir, saquinavir et ritonavir); within individual twin pairs placental transfer was discordant for one or more ARVs, but identical for others. Concentrations differed in nearly one third of twin pairs. This may be due to interindividual genetic variability of placental transporters between dizygotic twins as well as physiological differences between twins.


T cells from patients with Hodgkin's disease have a defective T-cell receptor zeta chain expression that is reversible by T-cell stimulation with CD3 and CD28.
To investigate the mechanisms underlying the deficiency of T lymphocytes from patients with Hodgkin's disease, we investigated the expression of the T-cell receptor (TCR) zeta chain in patients with Hodgkin's disease. By flow cytometry using an anti-zeta chain monoclonal antibody, peripheral blood T lymphocytes from patients with untreated Hodgkin's disease were shown to express decreased levels of the TCR zeta chain. After stimulation by combined CD3 and CD28 cross-linking, T cells from Hodgkin's disease patients upregulated zeta chain protein expression to normal values within 48 hours and achieved a cytolytic potential and levels of interleukin (IL)-2 secretion that were not different from T cells obtained from healthy controls. These results show that downregulation of the TCR zeta chain in Hodgkin's T lymphocytes is a reversible event. Costimulation of CD3 and CD28 is a novel approach for overcoming the T-cell deficiency in Hodgkin's disease and might be exploited clinically. As upregulation of the zeta chain can also be achieved using bispecific monoclonal antibodies (BI-MoAbs) with specificity for tumor antigens and CD3 and CD28, respectively, an immunotherapy with CD3/CD30 and CD28/CD30 Bi-MoAbs may overcome and should therefore, not be jeopardized by the inherent T-cell deficiency in patients with Hodgkin's disease.


Applicability of an enzymatic quantitation of methylmalonic, propionic, and acetic acids in normal and megaloblastic states.
A rapid sensitive spectrophotometric assay for the measurement of methylmalonic and propionic acids in urine is described. The assay is based upon the quantitation of propionic acid using acetyl coenzyme A synthetase isolated from baker's yeast. This enzyme is highly specific for acetate and propionate, and acetate interference is eliminated by conversion to citrate. Methylmalonic acid was assayed by converting it to propionate by heat decarboxylation and then measuring the propionate increment over the endogenous amount in the noncarboxylated sample. Studies of urine obtained from normal subjects (by isolation, partial purification, and then assay by the isotope dilution technique) demonstrated urinary excretion of less than 1 mg of propionic acid and 1-5 mg of methylmalonic acid per day. In 22 consecutive patients with documented vitamin B12 deficiency, methylmalonic acid excretion in excess of 30 mg/24 hr was found. In four other patients, with only neurologic involvement methylmalonic aciduria aided in identifying B12 deficiency as an etiologic factor. Methylmalonic acid excretion was measured by direct assay of an aliquot of urine, requiring neither a valine load nor special extraction procedures. Propionic aciduria was variably increased in B12 deficiency and did not correlate either with the severity of the deficit or degree of methylmalonic aciduria. The assay was performed on urine, but it is potentially applicable to tissue extracts. In addition, this assay method can be utilized for the quantification of urine acetate levels as well.


Knowledge and perceived competence with sexual and gender minority healthcare topics among medical students and medical school faculty.
Despite changes in social attitudes in the United States over the last decade, sexual and gender minority (SGM) individuals continue to face significant health disparities, driven partly by disproportionately higher rates of self-reported discrimination and harassment when seeking healthcare. Historically, physicians have received little to no required training on how to provide sensitive, competent care to SGM patients, and continue to demonstrate poor competency with SGM topics despite calls for increased education and published guidelines to promote competency. The present study aimed to investigate competency with SGM topics among both faculty and medical students at one institution. The authors distributed an anonymous online survey (2020-2021) to medical students and student-facing faculty at one allopathic medical school in the United States. The objective of the study was to evaluate knowledge, clinical skills, and self-reported competence with SGM topics. Of survey respondents, 223 medical students and 111 faculty were included in final analysis. On average, medical students were significantly more likely to answer General Knowledge questions correctly (97.2%) compared to faculty (89.9%). There were no significant differences in responses to Clinical Knowledge questions between medical students and faculty. however medical students were significantly more likely to report competence with eliciting a thorough sexual history, and faculty were significantly more likely to report receiving adequate clinical training and supervision to work with lesbian, gay, and bisexual patients. Medical students demonstrated significantly higher general knowledge about SGM topics compared to faculty. Medical students and faculty demonstrated similarly low average clinical knowledge, with percent correct 65.6% for students and 62.7% for faculty. Despite significant differences in general knowledge and low clinical knowledge, medical students and faculty self-reported similar levels of competence with these topics. This indicates insufficient curricular preparation to achieve the AAMC competencies necessary to care for SGM patients.


CHARACTERIZING THE EPIDEMIOLOGY OF HISTORIC AND NOVEL PATHOGENS IN BLANDING'S TURTLES (EMYDOIDEA BLANDINGII).
Pathogens such as herpesviruses, Mycoplasma spp., and frog virus 3-like ranavirus have contributed to morbidity and mortality in many species of free-living and zoo-maintained chelonians. However, their prevalence is understudied in Blanding's turtles (Emydoidea blandingii) across North America. To assess the presence of these pathogens, Blanding's turtles were sampled in Lake County, Illinois, in 2017 (N = 213) and 2018 (N = 160). DNA from cloacal-oral swabs was assayed for four ranaviruses, three Mycoplasma spp., two Salmonella spp., Emydoidea herpesvirus 1 (EBHV1), and tortoise intranuclear coccidiosis (TINC) using a multiplex quantitative polymerase chain reaction (qPCR). Pathogens were most frequently detected in adult turtles (n = 25) and rarely in subadults (n = 2) or juveniles (n = 1). EBHV1 was detected in 22 individuals with no clinical signs of illness, most (n = 20) occurring in the month of May (P < 0.0001). EBHV1 cases at one study site significantly clustered within the same 0.64-km area from 17 to 22 May 2017 (P < 0.0001) and 14 to 15 May 2018 (P = 0.0006). Individuals were rarely positive for Salmonella typhimurium (n = 6). A novel Mycoplasma sp. sharing high homology with other emydid Mycoplasma spp. was detected in one turtle with nasal discharge. Neither TINC nor any ranaviruses were detected. Continued monitoring of this population and habitat may facilitate identification of risk factors for pathogen occurrence and clarify the impact of infectious diseases on Blanding's turtle conservation outcomes.


Patients with peritoneal mesothelioma lack epidermal growth factor receptor tyrosine kinase mutations that would make them sensitive to tyrosine kinase inhibitors.
The epidermal growth factor receptor (EGFR) is a promising target for cancer therapy. The presence of certain somatic mutations in the tyrosine kinase (TK) domain of the EGFR gene is associated with clinical response to TK inhibitors (TKI) in patients with lung adenocarcinoma. In this study we evaluated the status of somatic mutations in the entire TK domain of the EGFR gene by direct sequencing using early passage peritoneal mesothelioma cells, established cell lines as well as 33 peritoneal mesothelioma tumor samples. No novel mutations were found in the cell lines. Sequence analysis of the EGFR TK domain revealed the presence of a silent polymorphism (c.2607G → A, Q787Q) at exon 20 of both peritoneal mesothelioma cell lines as well as tumor specimens. The frequency of genotypes AA and GA was 42.8 and 57.2% in the cell lines and 33.3 and 57.6% in tumor specimens, respectively. The TKI erlotinib showed an IC50 in the range of 10-50 µM in five out of the seven cell lines with a GA genotype while all five cell lines with the AA genotype had an IC50 >50 µM. Of the 33 peritoneal mesothelioma tumor samples analyzed none had an EGFR TKI sensitizing mutation and only one specimen showed an earlier reported somatic mutation at codon 850 in exon 21 of the EGFR gene. Our data show that patients with peritoneal mesothelioma do not harbor somatic mutations in the EGFR TK domain that would make them sensitive to EGFR TKI.


Decrease in excitatory neurons, astrocytes and proliferating progenitors in the cerebral cortex of mice lacking exon 3 from the Fgf2 gene.
The Fgf2 gene is expressed in the brain neuroepithelium during embryonic development and in astroglial cells throughout life. Previous knockout studies suggested that FGF2 plays a role in the proliferation of neural progenitors in the embryonic cerebral cortex. These studies exclusively used knockout alleles lacking the Fgf2 exon 1. However, the description of putative alternative exons located downstream from the canonical exon 1 raised the possibility that alternatively spliced transcripts may compensate for the lack of the canonical exon 1 in the Fgf2 -/- mice. We generated and characterized a new line of Fgf2 knockout mice lacking the expression of exon 3, which is conserved in all Fgf2 transcripts and contains essential heparin and receptor binding interfaces. The expression of Fgf2 exon 3 was prevented by inserting a transcriptional STOP cassette in the Fgf2 genomic locus. These mice demonstrate a phenotype in the adult neocortex characterized by decreased density and number of cortical excitatory neurons and astrocytes, which is virtually identical to that of the Fgf2 -/- mice lacking exon 1. In addition, we also show that the Fgf2 exon 3 knockout mice have decreased proliferation of precursors in the adult cerebral cortex, which had not been previously investigated in the other mutant lines. The results demonstrate that the phenotype of two completely different Fgf2 KO mouse lines, lacking exon 1 or exon 3, is remarkably similar. The combined results from these KO models clearly indicate that FGF2 plays a role in cortical cell genesis during embryonic development as well as in adulthood. Thus, FGF2 may be required for the maintenance of the pool of adult cortical progenitor cells.


Comparison of Analytical Values in Diffusion Kurtosis Imaging among Different MRI Units.
Diffusion kurtosis imaging (DKI) is a method of analyzing restricted diffusion. Mean kurtosis (MK) is obtained from DKI. It is not known how different MRI scanners and coil systems will change MK when the same imaging parameters are used. The purpose of this study is to identify tendencies in MK when using various MRI scanners and coil systems. A total of 27 healthy volunteers were enrolled in this study. DKI was performed on the brain for each volunteer on five MRI scanner/coil system combinations using the same scan parameters. MK of 10 anatomical areas of the brain were compared, and the signal-noise ratios (SNRs) of b-2000 s/mm2 images were measured in identical areas. There were no significant differences among MKs from multi transmit (MT) MRI systems, but MK was significantly lower on the single transmit MRI system because of pepper artifact caused by low SNR. In conclusion, we found no significant differences in MK among MT systems, and MK was significantly lower without MT.


No Time to Waste: Real-World Repurposing of Generic Drugs as a Multifaceted Strategy Against COVID-19.
Real-world drug repurposing-the immediate "off-label" prescribing of drugs to address urgent clinical needs-is an indispensable strategy gaining rapid traction in the current COVID-19 crisis. Although off-label prescribing (ie, for a nonapproved indication) is legal in most countries, it tends to shift the burden of liability and cost to physicians and patients, respectively. Nevertheless, in urgent public health crises, it is often the only realistic source of a meaningful potential solution. To be considered for real-world repurposing, drug candidates should ideally have a track record of safety, affordability, and wide accessibility. Although thousands of such drugs are already available, the absence of a central repository of off-label uses presents a barrier to the immediate identification and selection of the safest, potentially useful interventions. Using the current COVID-19 pandemic as an example, we provide a glimpse at the extensive literature that supports the rationale behind six generic drugs, in four classes, all of which are affordable, supported by decades of safety data, and pleiotropically target the underlying pathophysiology that makes COVID-19 so dangerous. Having previously fast-tracked this paper to publication in summary form, we now expand on why cimetidine/famotidine (histamine type-2 receptor antagonists), dipyridamole (antiplatelet agent), fenofibrate/bezafibrate (cholesterol/triglyceride-lowering agents), and sildenafil (phosphodiesterase-5 inhibitor) are worth considering for patients with COVID-19 based on their antiviral, anti-inflammatory, renoprotective, cardioprotective, and anticoagulation properties. These examples also reveal the unlimited opportunity to future-proof public health by proactively mining, synthesizing, and cataloging the off-label treatment opportunities of thousands of safe, well-established, and affordable generic drugs.


AN ADJUSTABLE RESISTANCE WITH LINEAR RESPONSE TO AIR FLOW FOR RESPIRATION EXPERIMENTS.
A. simple easily adjustable linear response resistance apparatus is described. The resistance unit contains a glass filter cloth, the effective area of which is adjusted by a mercury column. The resistance of the unit can be adjusted from 0.1 to 1.0 millimeters of water per liter of air flow per minute. The resistance can be easily increased or decreased during the progress of an experiment. The mercury hazard during inspiration was evaluated and not found significant for experiments of one hour.


First-principles calculation of the bulk photovoltaic effect in bismuth ferrite.
We compute the bulk photovoltaic effect (BPVE) in BiFeO(3) using first-principles shift current theory, finding good agreement with experimental results. Furthermore, we reconcile apparently contradictory observations: by examining the contributions of all photovoltaic response tensor components and accounting for the geometry and ferroelectric domain structure of the experimental system, we explain the apparent lack of BPVE response in striped polydomain samples that is at odds with the significant response observed in monodomain samples. We reveal that the domain-wall-driven response in striped polydomain samples is partially mitigated by the BPVE, suggesting that enhanced efficiency could be obtained in materials with cooperative rather than antagonistic interaction between the two mechanisms.


Analysis of fomepizole safety based on a 16-year post-marketing experience in France.
Introduction: Fomepizole has been recommended as first-line antidote to treat ethylene glycol and methanol poisoning. Despite more than 30 years of utilization, the safety of fomepizole when used clinically has not been well documented. Based on the long-standing clinical experience with fomepizole in France, we investigated its safety profile in patients treated for suspected toxic alcohol poisoning.Methods: We designed a 16-year post-marketing study to evaluate the indications for fomepizole prescriptions and to investigate its safety. Data were retrospectively collected using a standardized questionnaire sent each month by post to each French hospital that ordered fomepizole during the month before. The response rate to our survey was 59%.Results: Five hundred and thirty-six patients [188 females/348 males; age, 46 years [34-55] (median [25th-75th percentiles])] were treated with fomepizole [cumulative dose, 18.6 mg/kg [15.5-26.3] (1,268 mg [900-2,100])]. Ethylene glycol/methanol poisoning was confirmed in 275 patients (51%) while a nontoxic exposure was diagnosed in 147 patients (27%). Toxic alcohol poisoning was misdiagnosed in the remaining 114 patients (21%), before the assessment of an alternative poisoning or non-poisoning diagnosis. Fifty adverse reactions were attributed to fomepizole in 36 patients (7%) including general reactions (N = 22), local reactions (N = 22) and laboratory test impairments (N = 6). All were considered mild and transient. None required stopping fomepizole. The most frequent adverse effects were injection site pain/burning (N = 13), nausea/vomiting (N = 8), vessel puncture site inflammation (N = 7), drowsiness/confusion (N = 5) and serum aminotransferase elevation (N = 3). None of the fatalities (N = 37, 7%) or persistent symptoms on discharge (N = 9; 2%) was related to fomepizole.Conclusion: Our longitudinal cohort study supports the safety of fomepizole administered to treat presumed EG and methanol poisoning.


[Changes in smoking habits among medical students in Bergen 2004-2006].
Smoking and snuff habits among medical students are of interest because they may reflect the attitude to smoking and snuff among future doctors, but few longitudinal studies have been performed. A standard questionnaire, developed by Statistics Norway, was handed out to all medical students at the University of Bergen during plenum lectures in the spring 2004 and 2006. The questionnaires were marked by personal codes to enable follow-up of smoking and snuff habits for each individual student during the study period. New questionnaires were sent by post to all students who did not respond after the initial handout. 799 medical students (89 %) responded in the spring 2004 and 789 students (84 %) in the spring 2006. The study revealed that 3 % of the students smoked regularly in 2004 and 1 % in 2006 and that 20 % were occasional smokers in 2004 and 18 in 2006. 15 % of the students were snuff users in 2004 and this had increased to 24 % in 2006. A decrease was observed in both daily and occasional smokers among medical students in Bergen during the two-year study period. However, the frequency of snuff users increased. The frequency of regular smokers is low, but the number of occasional smokers is higher than in the general population of the same age.


[Hepatic function and significance of the increase in serum concentrations of IgA in alcoholic cirrhosis].
Elevated serum gammaglobulin concentrations are frequently observed in patients with liver cirrhosis. Predominant elevation of the IgA is generally considered as suggestive of an alcoholic aetiology. The aim of this study was to define the factors that determine the serum concentration of IgA in alcoholic cirrhosis. Twenty-seven patients with alcoholic cirrhosis were studied. Serum concentrations of IgG, IgA and IgM were measured by immunonephelometry. Hepatocellular function was assessed by the Child-Turcotte score, the prothrombin time and the intrinsic clearance of indocyanine green. The importance of intra-hepatic shunts was estimated according to the intact hepatocyte theory, and the degree of hepatic necrosis by serum levels of transaminases. It was noted that: 1) the IgA concentration correlated significantly with the Child-Turcotte score and with the decrease of the prothrombin time, intrinsic clearance and the functional fraction of hepatic blood flow; 2) there was no such correlation between the serum concentration of IgA and the total hepatic blood flow or transaminase levels; 3) there was no correlation between serum concentration of IgG or IgM and the factors studied. These results suggest that in alcoholic cirrhosis, increase in serum IgA, reflects the degree of impairment of hepatic function and intrahepatic shunting.


Endothelial differentiation of amniotic fluid-derived stem cells: synergism of biochemical and shear force stimuli.
Human amniotic fluid-derived stem (AFS) cells possess several advantages over embryonic and adult stem cells, as evidenced by expression of both types of stem cell markers and ability to differentiate into cells of all three germ layers. Herein, we examine endothelial differentiation of AFS cells in response to growth factors, shear force, and hypoxia. We isolated human AFS cells from amniotic fluid samples (1-4 cc/specimen) obtained from patients undergoing amniocentesis at 15-18 weeks of gestation (n = 10). Isolates maintained in nondifferentiating medium expressed the stem cell markers CD13, CD29, CD44, CD90, CD105, OCT-4, and SSEA-4 through passage 8. After 3 weeks of culture in endothelial growth media-2 (EGM-2), the stem cells exhibited an endothelial-like morphology, formed cord-like structures when plated on Matrigel, and uptook acetylated LDL/lectin. Additionally, mRNA and protein levels of CD31 and von Willebrand factor (vWF) significantly increased in response to culture in EGM-2, with further up-regulation when stimulated by physiological levels (12 dyne/cm(2)) of shear force. Culture in hypoxic conditions (5% O(2)) resulted in significant expression of vascular endothelial growth factor (VEGF) and placental growth factor (PGF) mRNA. This study suggests that AFS cells, isolated from minute amounts of amniotic fluid, acquire endothelial cell characteristics when stimulated by growth factors and shear force, and produce angiogenic factors (VEGF, PGF, and hepatocyte growth factor [HGF]) in response to hypoxia. Thus, amniotic fluid represents a rich source of mesenchymal stem cells potentially suitable for use in cardiovascular regenerative medicine.


Genome- and CD4+ T-cell methylome-wide association study of circulating trimethylamine-N-oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN).
Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n=626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4+ T-cells. We tested for association of methylation loci with circulating TMAO (n=847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4+ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans.


Endostar, a novel recombinant human endostatin, exerts antiangiogenic effect via blocking VEGF-induced tyrosine phosphorylation of KDR/Flk-1 of endothelial cells.
Endostar, a novel recombinant human endostatin expressed and purified in Escherichia coli with an additional nine-amino acid sequence and forming another his-tag structure, was approved by the SFDA in 2005 for the treatment of non-small-cell lung cancer. But its mechanism of action has not been illustrated before. In this study, we examined the antiangiogenic activities of endostar in vitro and in vivo. The results showed that endostar suppressed the VEGF-stimulated proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro. Endostar blocked microvessel sprouting from rat aortic rings in vitro. Moreover, it could inhibit the formation of new capillaries from pre-existing vessels in the chicken chorioallantoic membrane (CAM) assay and affect the growth of vessels in tumor. We further found the antiangiogenic effects of endostar were correlated with the VEGF-triggered signaling. Endostar suppressed the VEGF-induced tyrosine phosphorylation of KDR/Flk-1(VEGFR-2) as well as the overall VEGFR-2 expression and the activation of ERK, p38 MAPK, and AKT in HUVECs. Collectively, these data indicated the relationship between endostar and VEGF signal pathways and provided a molecular basis for the antiangiogenic effects of endostar.


Optimizing experimental parameters for tracking of diffusing particles.
We describe how a single-particle tracking experiment should be designed in order for its recorded trajectories to contain the most information about a tracked particle's diffusion coefficient. The precision of estimators for the diffusion coefficient is affected by motion blur, limited photon statistics, and the length of recorded time series. We demonstrate for a particle undergoing free diffusion that precision is negligibly affected by motion blur in typical experiments, while optimizing photon counts and the number of recorded frames is the key to precision. Building on these results, we describe for a wide range of experimental scenarios how to choose experimental parameters in order to optimize the precision. Generally, one should choose quantity over quality: experiments should be designed to maximize the number of frames recorded in a time series, even if this means lower information content in individual frames.


Libet's Legacy: A Primer to the Neuroscience of Volition.
The neuroscience of volition is an emerging subfield of the brain sciences, with hundreds of papers on the role of consciousness in action formation published each year. This makes the state-of-the-art in the discipline poorly accessible to newcomers and difficult to follow even for experts in the field. Here we provide a comprehensive summary of research in this field since its inception that will be useful to both groups. We also discuss important ideas that have received little coverage in the literature so far. We systematically reviewed a set of 2220 publications, with detailed consideration of almost 500 of the most relevant papers. We provide a thorough introduction to the seminal work of Benjamin Libet from the 1960s to 1980s. We also discuss common criticisms of Libet's method, including temporal introspection, the interpretation of the assumed physiological correlates of volition, and various conceptual issues. We conclude with recent advances and potential future directions in the field, highlighting modern methodological approaches to volition, as well as important recent findings.


Advanced breast cancer - additive hormonal therapy.
Increased response rates with nonhormonal combination chemotherapy have led many oncologists to deprecate the use of hormonal therapy in the management of advanced breast cancer. The estrogen and progesterone receptor assay, on the one hand, has restimulated the enthusiasm for hormonal therapy when positive, but conversely when negative suggests that their use is precluded from further consideration. The author's thoughts on the continuing employment of additive hormonal therapy for almost all patients, either singly or in combination with other hormonal and nonhormonal drugs, with minimal restrictions imposed by hormonal assays or sites of disease will be presented. A short review of estrogen, androgens, progestins, Teslac, and corticosteroids will be offered. The ease of administration of hormones and the increase in recurrent disease survival in responders compared with nonhormonal therapy strongly indicate that additive hormonal therapy still has a major role in the management of the advanced breast cancer patient.


Kinetic analysis of DNA double-strand break repair pathways in Arabidopsis.
Double-strand breaks in genomic DNA (DSB) are potentially lethal lesions which separate parts of chromosome arms from their centromeres. Repair of DSB by recombination can generate mutations and further chromosomal rearrangements, making the regulation of recombination and the choice of recombination pathways of the highest importance. Although knowledge of recombination mechanisms has considerably advanced, the complex interrelationships and regulation of pathways are far from being fully understood. We analyse the different pathways of DSB repair acting in G2/M phase nuclei of irradiated plants, through quantitation of the kinetics of appearance and loss of γ-H2AX foci in Arabidopsis mutants. These analyses show the roles for the four major recombination pathways in post-S-phase DSB repair and that non-homologous recombination pathways constitute the major response. The data suggest a hierarchical organisation of DSB repair in these cells: C-NHEJ acts prior to B-NHEJ which can also inhibit MMEJ. Surprisingly the quadruple ku80 xrcc1 xrcc2 xpf mutant can repair DSB, although with severely altered kinetics. This repair leads to massive genetic instability with more than 50% of mitoses showing anaphase bridges following irradiation. This study thus clarifies the relationships between the different pathways of DSB repair in the living plant and points to the existence of novel DSB repair processes.


Aircraft and road traffic noise and children's cognition and health: a cross-national study.
Exposure to environmental stressors can impair children's health and their cognitive development. The effects of air pollution, lead, and chemicals have been studied, but there has been less emphasis on the effects of noise. Our aim, therefore, was to assess the effect of exposure to aircraft and road traffic noise on cognitive performance and health in children. We did a cross-national, cross-sectional study in which we assessed 2844 of 3207 children aged 9-10 years who were attending 89 schools of 77 approached in the Netherlands, 27 in Spain, and 30 in the UK located in local authority areas around three major airports. We selected children by extent of exposure to external aircraft and road traffic noise at school as predicted from noise contour maps, modelling, and on-site measurements, and matched schools within countries for socioeconomic status. We measured cognitive and health outcomes with standardised tests and questionnaires administered in the classroom. We also used a questionnaire to obtain information from parents about socioeconomic status, their education, and ethnic origin. We identified linear exposure-effect associations between exposure to chronic aircraft noise and impairment of reading comprehension (p=0.0097) and recognition memory (p=0.0141), and a non-linear association with annoyance (p<0.0001) maintained after adjustment for mother's education, socioeconomic status, longstanding illness, and extent of classroom insulation against noise. Exposure to road traffic noise was linearly associated with increases in episodic memory (conceptual recall: p=0.0066; information recall: p=0.0489), but also with annoyance (p=0.0047). Neither aircraft noise nor traffic noise affected sustained attention, self-reported health, or overall mental health. Our findings indicate that a chronic environmental stressor-aircraft noise-could impair cognitive development in children, specifically reading comprehension. Schools exposed to high levels of aircraft noise are not healthy educational environments.


Early intervention for human immunodeficiency virus in Baltimore Sexually Transmitted Diseases Clinics. Impact on gonorrhea incidence in patients infected with HIV.
High incidences of sexually transmitted diseases (STD) after posttest counseling have been documented in patients diagnosed with human immunodeficiency virus (HIV) in Baltimore STD clinics. In July 1991, the authors instituted an HIV early intervention program providing long-term medical care and social work services. This study compares the incidence of gonorrhea after post-HIV+ test counseling in patients diagnosed with HIV before and after the institution of the early intervention program. Medical records of a cohort composed of all patients newly diagnosed with HIV and those who underwent posttest counseling for HIV in 1991 to 1993 in two Baltimore STD clinics were reviewed. Patients were offered early intervention medical and social work services. Gonorrhea incidence in this cohort was compared to a historical cohort diagnosed and counseled for post-HIV+ testing in 1988 to 1989 who were not offered early intervention services. The mean follow-up time was 418 days (range, 26 to 703 days). After post-HIV+ test counseling, gonorrhea developed in 39 of 468 (8.3%) men in the 1989 cohort and 13 of 400 (3.3%) men in the 1991 to 1993 cohort. Controlling for variable length of follow-up, the 1991 to 1993 cohort had a relative risk of 0.442 for the development of gonorrhea during the study period (95% confidence interval, 0.225 to 0.790; P = 0.006). Incident gonorrhea after post-HIV+ test counseling also was associated with a prevalent gonorrhea condition at the time of HIV diagnosis (RR = 3.02; 95% CI, 1.75 to 5.23; P = 0.0001) and failure to return for post-HIV+ test counseling as scheduled (RR = 2.27; 95% CI, 1.17-4.43; P = 0.013). After adjustment for gonorrhea at the time of HIV diagnosis and failure to return for scheduled posttest counseling, the difference in gonorrhea incidence between men in the two cohorts remained statistically significant (RR = 0.494; 95% CI, 0.260 to 0.941; P = 0.032). In comparison, overall gonorrhea rates in Baltimore changed little between 1988 and 1993. No significant difference was found in gonorrhea incidence in women, which may have been the result of active gonorrhea screening during the 1991 to 1993 period, which was not performed in 1988 to 1989. Providing clinical care to persons with HIV may facilitate the reduction of high-risk behaviors that lead to incident STDs and further HIV transmission.


The occurrence and distribution of polycyclic aromatic hydrocarbons, bisphenol A and organophosphate flame retardants in indoor dust and soils from public open spaces: Implications for human exposure.
Global concern exists regarding human exposure to organic pollutants derived from public open spaces and indoor dust. This study has evaluated the occurrence of 18 polycyclic aromatic hydrocarbons (PAHs), 11 organophosphorus flame retardants (OPFRs) and bisphenol A (BPA). To achieve this, a new simple, efficient and fast multi-residue analytical method based on a fully automated pressurised liquid extraction (PLE) and subsequent quantification by gas chromatography coupled to electron ionization-mass spectrometry (GC-EI-MS) in selected ion monitoring (SIM) mode was developed. The developed method was applied to indoor dust (12 sampling households) and soil derived from two public open spaces (POSs). Among all compounds studied, PAHs were the most ubiquitous contaminants detected in POS soils and indoor dust although some OPFRs and BPA were detected in lower concentrations. An assessment of the incremental lifetime cancer risk (ILCR) was done and indicated a high potential cancer risk from the POS sites and some of the indoor dust sampled sites. However, key variables, such as the actual exposure duration, frequency of contact and indoor cleaning protocols will significantly reduce the potential risk. Finally, the ingestion of soils and indoor dust contaminated with OPFRs and BPA was investigated and noted in almost all cases to be below the USEPA reference doses.


Inhibitory effects of Bombusae concretio Salicea on neuronal secretion of Alzheimer's beta-amyloid peptides, a neurodegenerative peptide.
Alzheimer's disease (AD) is characterized by the age-related deposition of beta-amyloid (A beta) 40/42 peptide aggregates in vulnerable brain regions. Multiple levels of evidence implicate a central role for A beta in the pathophysiology of AD. A beta is generated by the regulated cleavage of a = 700 amino acid A beta precursor protein (betaAPP). Full-length betaAPP can undergo proteolytic cleavage either within the A beta domain to generate secreted sbetaAPP alpha or at the N-terminal and C-terminal domain(s) of A beta to generate amyloidogenic A beta peptides. Several epidemiological studies have reported that estrogen replacement therapy protects against the development of AD in postmenopausal women. The aim of this study was to elucidate the antioxidant neuroprotective mechanism of Bombusae concretio Salicea (BC). BC was effective protectants against oxidative glutamate toxicity in the murine neuroblastoma cells (N2a) and human neuroblastoma cells (SK-N-MC). BC exhibited similar protective properties against oxidative glutamate toxicity and H2O2 toxicity. BC exhibited an antioxidant activity at approximately 20 microg/ml. BC of 5 microg/ml was ineffective in preventing the oxidative modification of LDL. The half-maximal effective concentration for BC was 16 microg/ml. These results suggested that BC supplementation in elderly men may be protective in the treatment of Alzheimer's disease (AD). We report here that treatment with BC increases the secretion of the nonamyloidogenic APP fragment, sbetaAPP alpha and decreases the secretion of A beta peptides from N2a cells and rat primary cerebrocortical neurons. These results raise the possibility that BC supplementation in elderly men may be protective in the treatment of AD.


Three principles of mental functioning in psychoanalytic theory and practice.
In this essay I have reformulated the relationship of the pleasure principle, reality principle, and Nirvana principle. I have linked this conception of the three principles of mental functioning to the idea of the paranoid-schizoid position. And I have attempted to demonstrate the utility of these various notions for illuminating the analyst's sleepiness during analytic sessions.


The effect of monochromatic infrared energy on transcutaneous oxygen measurements and protective sensation: results of a controlled, double-blind, randomized clinical study.
Monochromatic infrared energy has been reported to restore protective sensation by increasing circulation. A controlled, double-blind, quasi-experimental, randomized clinical study was conducted to 1) examine the effects of monochromatic infrared energy treatments on tissue perfusion, 2) determine the effects of a published monochromatic infrared energy neuropathy protocol on sensation on the feet of patients with diabetes and a loss of protective sensation; 3) examine monochromatic infrared energy's effect on pain; and 4) examine the relationship between transcutaneous oxygen levels and loss of protective sensation. The study was conducted at a wound and hyperbaric treatment center in Norwalk, Conn; 18 adults (12 men, six women; mean age 65 +/-13 years, range 39 to 86 years) with diabetes and loss of protective sensation were recruited using convenience sampling methods. All patients served as their own control. Pre- and post treatment tests assessed sensation, pain, and transcutaneous oxygen measurements on two sites per foot. Participants underwent a series of 30-minute monochromatic infrared energy treatments (one foot active treatment, one foot sham). Monochromatic infrared energy was delivered at the manufacturer pre-set level of energy of 1.5 J/cm(2)/min at a wavelength of 890 nm; sham units delivered no energy. Scores were analyzed using paired t-tests and Pearson's correlation coefficient. No significant differences were observed between active and sham treatments for transcutaneous oxygen values, pain, or sensation. Both active and sham monochromatic infrared energy-treated feet had significantly improved sensation when compared to pretest baseline scores (P <0.05). No statistical relationship was found between transcutaneous oxygen and sensation. This small study did not demonstrate any effects of monochromatic infrared energy treatment on transcutaneous oxygen measurements, pain, or sensation in adults with diabetes and loss of protective sensation.


Expression of adrenomedullin and its receptor in normal and malignant human skin: a potential pluripotent role in the integument.
Adrenomedullin (AM) is a multifunctional peptide involved in a variety of physiological functions, including growth regulation and antimicrobial activity. We have determined by immunohistochemistry and in situ hybridization that AM and its receptor are present in all the epithelial cells of the normal skin, including keratinocytes of the epidermis and hair follicles, as well as cells of the glands and secretory ducts. We also have detected AM in the sweat, by RIA. In addition, AM and its receptor were found in skin tumors of different histologies. The presence of AM and its receptor in normal and neoplastic skin was confirmed by RT-PCR and Western blot analysis performed on cell extracts from human skin cell lines. Radiolabeled AM bound to specific sites in cultured cells with a Kd of 9 nM. This binding was blocked by the addition of cold AM but not by related peptides such as AM 22-52, pro-AM 20 N-terminal peptide, calcitonin gene-related peptide, calcitonin gene-related peptide 8-37, or amylin. Finally, exposure to synthetic AM resulted in an increase of thymidine intake by skin cells. These results implicate AM as a potential player in skin defense against infectious microorganisms and as a possible autocrine growth factor in normal skin physiology and tumor development.


Impact of Urinalysis on Medical Decision-making and Length of Stay.
Introduction The emergency department (ED) is under pressure to meet length of stay (LOS) metrics for care in the ED. An aspect that we propose affects LOS is the order for urine sample collection and subsequent urinalysis (UA) as both are time consuming steps. This project's primary goals are to determine if ordering a UA increases LOS and how often UA contributes to clinical decision-making and/or disposition decisions in the ED. Secondary objectives were to identify factors that contribute to the ordering of a UA and to decipher if LOS was more impacted in patients who were discharged vs. admitted to the hospital. Methods Retrospective chart review was conducted of patients who presented to our ED in April 2016 during 12 consecutive days. Data were abstracted onto a data collection sheet with the abstractor blinded to study hypotheses. Variables included whether a UA was ordered, times of UA order and result, who ordered the UA (mid-level provider [MLP] vs. physician), whether the UA was cancelled, whether the UA result influenced clinical decision-making (based on the medical decision-making section of the physician chart) or disposition decision, LOS, age, and gender. Descriptive statistics and multivariable regression analysis were used to analyze relationships between the variables collected and their influence on LOS. Results The overall median LOS was 157 minutes, with an interquartile range (IQR) of 81 to 246 minutes. For discharged patients, it was 142 minutes, with an IQR of 46 to 236 minutes. For admitted patients, it was 177 minutes, with an IQR of 118 to 260 minutes. Amongst admitted patients, multivariable regression analysis demonstrated that the following factor was associated with increased LOS: being seen first by the provider-in-triage (PIT) then physician in main ED (p < 0.0001). Amongst discharged patients, multivariable regression analysis demonstrated that the following factors were associated with increased LOS: being seen first by the PIT then physician in main ED (p = 0.0296), being seen by MLP only (p < 0.0001), having a UA ordered (p = 0.0005), being seen on weekend (p = 0.0166), and being an older patient (p = 0.0475). The UA was cancelled in 9% of our patients, and in 60% of cases, these UAs were ordered by the PIT. Patient disposition decision was made prior to UA resulting in 60 cases (25%). The UA was used in clinical decision-making in 118 cases (66%). The following predictor factors were associated via univariate analysis with using a UA for decision-making: being female (p = 0.0050, 95% CI: 0.0068-0.378), being an older patient (p < 0.0001, 95% CI: -0.010 to -0.004), being first seen by the PIT and then a physician (p = 0.0486, 95% CI: 0.0048-0.1555), and discharged patients (p < 0.0001, 95% CI: -0.6749 to -0.4487). Conclusion Our results suggest that having a UA ordered increased ED LOS, especially in patients who are ultimately discharged. In our ED, routine UAs are ordered more often by MLPs than physicians. A routine UA may not impact clinical decision-making up to 33% of the time, nor alter disposition decision one out of four times. Given that 9% have the test eventually cancelled, one should reconsider the utility in ordering routine UAs in ED patients, as they increase LOS and place an additional burden on the patient and the ED personnel.


Prognostic Factors in Differentiated Thyroid Cancer Revisited.
More than 90% of all thyroid cancers are differentiated thyroid carcinomas (DTC) with a 10 year survival rate greater than 90%. The commonly used risk stratification systems for DTC include: European Organization for Research and Treatment of Cancer (EORTC), AGES (Age, histologic Grade, Extent of tumor, Size), AMES (Metastasis) and MACIS (Completeness of resection, local Invasion). Other systems are also utilized. Several new factors that may be involved in DTC risk stratification have emerged in recent studies, with other "traditional" factors being challenged. To present recent updates in the literature on new potential prognostic factors for DTC. We conducted a literature review and analysis of publications regarding DTC prognostic factors or risk stratification published in the last 10 years. Several new factors with potential prognostic implications for DTC were noted, including family history, lymph node involvement parameters, positive PET-CT findings, multifocal disease, thyroglobulin level and several molecular markers including BRAF. Increasing age is associated with poorer outcome in DTC; however, recent studies suggest that the cutoff point of 45 years may be contested. Furthermore, several studies have shown contradictory results regarding male gender as a negative prognostic factor, thus questioning its prognostic significance. A number of new factors with potential prognostic implications for DTC have emerged and should be addressed. However, their role and possible inclusion in new staging systems has yet to be determined.


A phase 1 study of PAmAb, a fully human monoclonal antibody against Bacillus anthracis protective antigen, in healthy volunteers.
Inhibition of the binding of Bacillus anthracis protective antigen (PA) to its cellular receptor can abrogate the downstream toxin-mediated deleterious effects of the anthrax toxin. A fully human monoclonal antibody against B. anthracis PA, PAmAb, was previously shown to provide a survival advantage in rabbit and monkey models of inhalational anthrax. A randomized, single-blind, placebo-controlled, dose-escalation study with 105 healthy volunteers was conducted to evaluate the safety, pharmacokinetics, and biological activity of PAmAb. Subjects received PAmAb or placebo as a single intramuscular injection (11 subjects/cohort) or intravenous infusion (10 subjects/cohort). Three intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg) were studied. Two separate intramuscular injection sites (gluteus maximus and vastus lateralis) were evaluated in the cohorts (hereafter, the "IM-GM" and "IM-VL" cohorts, respectively). PAmAb was well tolerated, with no dose-limiting adverse events. All adverse events were transient and mild to moderate in incidence and/or severity. The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the IM-GM and IM-VL cohorts. The mean terminal elimination half-life ranged from 15 to 19 days. The bioavailability of PAmAb is approximately 50% for IM-GM injection and 71%-85% for IM-VL injection. The biological activity of PAmAb in serum, assessed using a cyclic adenosine monophosphate assay, correlated with serum concentrations. PAmAb is safe, well tolerated, and bioavailable after a single intramuscular or intravenous dose, which supports further clinical development of PAmAb as a novel therapeutic agent for inhalational anthrax.


Neddylation-dependent LSD1 destabilization inhibits the stemness and chemoresistance of gastric cancer.
Histone lysine-specific demethylase 1 (LSD1) expression has been evaluated in multiple tumors, including gastric cancer (GC). However, the mechanisms underlying LSD1 dysregulation in GC remain largely unclear. In this study, neural precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) was identified to be conjugated to LSD1 at K63 by ubiquitin-conjugating enzyme E2 M (UBE2M), and this neddylated LSD1 could promote LSD1 ubiquitination and degradation, leading to a decrease of GC cell stemness and chemoresistance. Herein, our findings revealed a novel mechanism of LSD1 neddylation and its contribution to decreasing GC cell stemness and chemoresistance. Taken together, our findings may whistle about the future application of neddylation inhibitors.


Acclimation of photosystem II to high temperature in two Wedelia species from different geographical origins: implications for biological invasions upon global warming.
More intense, more frequent, and longer heat waves are expected in the future due to global warming, which could have dramatic ecological impacts. However, few studies have involved invasive species. The aims of this study were to examine the effect of extreme heating (40/35 degrees C for 30 d) on the growth and photosynthesis of an alien invasive species Wedelia trilobata and its indigenous congener (Wedelia chinensis) in South China, and to determine the development of this invasive species and its potential adaptive mechanism. In comparison with W. chinensis, W. trilobata suffered less inhibition of the relative growth rate (RGR) and biomass production due to high temperature, which was consistent with the changes of photosystem II (PSII) activity and net photosynthetic rate (P(n)). High temperature caused a partial inhibition of PSII, but the adverse effect was more severe in W. chinensis. Measurement of the minimum fluorescence (F(o)) versus temperature curves showed that W. trilobata had a higher inflexion temperature of F(o) (T(i)), indicating greater thermostability of the photosynthetic apparatus. Moreover, comparisons of absorbed light energy partitioning revealed that W. trilobata increased xanthophyll-dependent thermal dissipation (Phi(NPQ)) under high temperature, while retaining the higher fraction of absorbed light allocated to photochemistry (Phi(PSII)) relative to W. chinensis. The results suggest that the invasive W. trilobata has a high thermostability of its photosynthetic apparatus and an effective regulating mechanism in energy partitioning of PSII complexes to minimize potential damage and to retain greater capability for carbon assimilation. These factors confer greater heat stress tolerance compared with the native species. Therefore, the invasive W. trilobata may become more aggressive with the increasingly extreme heat climates.


A New Root-knot Nematode, Meloidogyne Moensi n. Sp. (Nematoda: Meloidogynidae), Parasitizing Robusta Coffee from Western Highlands, Vietnam.
A new root-knot nematode, parasitizing Robusta coffee in Dak Lak Province, Western Highlands of Vietnam, is described as Meloidogyne moensi n. sp. Morphological and molecular analyses demonstrated that this species differs clearly from other previously described root-knot nematodes. Morphologically, the new species is characterized by a swollen body of females with a small posterior protuberance that elongated from ovoid to saccate; perineal patterns with smooth striae, continuous and low dorsal arch; lateral lines marked as a faint space or linear depression at junction of the dorsal and ventral striate; distinct phasmids; perivulval region free of striae; visible and wide tail terminus surrounding by concentric circles of striae; medial lips of females in dumbbell-shaped and slightly raised above lateral lips; female stylet is normally straight with posteriorly sloping stylet knobs; lip region of second stage juvenile (J2) is not annulated; medial lips and labial disc of J2 formed dumbbell shape; lateral lips are large and triangular; tail of J2 is conoid with rounded unstriated tail tip; distinct phasmids and hyaline; dilated rectum. Meloidogyne moensi n. sp. is most similar to M. africana, M. ottersoni by prominent posterior protuberance. Results of molecular analysis of rDNA sequences including the D2-D3 expansion regions of 28S rDNA, COI, and partial COII/16S rRNA of mitochondrial DNA support for the new species status.


Cumulative exposure to high-strain and active jobs as predictors of cognitive function: the Whitehall II study.
A high-strain job (a combination of high job demands and low job control) is expected to increase the risk of health problems, whereas an active job (high demands and high control) can be hypothesised to be associated with a greater capacity to learn. We tested associations between high-strain and active jobs and cognitive function in middle-aged men and women. Data on 4146 British civil servants (2989 men and 1157 women) aged 35-55 years at baseline came from the Whitehall II study. Cumulative exposure to both high-strain and active jobs was assessed at phases 1 (1985-1988), 2 (1989-1990) and 3 (1991-1993). Cognitive performance was assessed at phases 5 (1997-1999) and 7 (2003-2004) using the following tests: verbal memory, inductive reasoning (Alice Heim), verbal meaning (Mill Hill), phonemic and semantic fluency. Analyses were adjusted for age, sex and employment grade. Longer exposure to high job strain and shorter exposure to active jobs were associated with lower scores in most of the cognitive performance tests. However, these associations disappeared on adjustment for employment grade. Phonemic fluency was an exception to this pattern. Associations between exposure to an active job and phonemic fluency at both follow-up phases were robust to adjustment for employment grade. However, there was no association between exposure to active jobs and change in phonemic fluency score between the follow-up phases after adjustment for employment grade. In these data, associations between cumulative exposure to high-strain or active jobs and cognition are largely explained by socioeconomic position.


Face to Face : The Perception of Automotive Designs.
Over evolutionary time, humans have developed a selective sensitivity to features in the human face that convey information on sex, age, emotions, and intentions. This ability might not only be applied to our conspecifics nowadays, but also to other living objects (i.e., animals) and even to artificial structures, such as cars. To investigate this possibility, we asked people to report the characteristics, emotions, personality traits, and attitudes they attribute to car fronts, and we used geometric morphometrics (GM) and multivariate statistical methods to determine and visualize the corresponding shape information. Automotive features and proportions are found to covary with trait perception in a manner similar to that found with human faces. Emerging analogies are discussed. This study should have implications for both our understanding of our prehistoric psyche and its interrelation with the modern world.


The Plasticity of the Carbohydrate Recognition Domain Dictates the Exquisite Mechanism of Binding of Human Macrophage Galactose-Type Lectin.
The human macrophage galactose-type lectin (MGL), expressed on macrophages and dendritic cells (DCs), modulates distinct immune cell responses by recognizing N-acetylgalactosamine (GalNAc) containing structures present on pathogens, self-glycoproteins, and tumor cells. Herein, NMR spectroscopy and molecular dynamics (MD) simulations were used to investigate the structural preferences of MGL against different GalNAc-containing structures derived from the blood group A antigen, the Forssman antigen, and the GM2 glycolipid. NMR spectroscopic analysis of the MGL carbohydrate recognition domain (MGL-CRD, C181-H316) in the absence and presence of methyl α-GalNAc (α-MeGalNAc), a simple monosaccharide, shows that the MGL-CRD is highly dynamic and its structure is strongly altered upon ligand binding. This plasticity of the MGL-CRD structure explains the ability of MGL to accommodate different GalNAc-containing molecules. However, key differences are observed in the recognition process depending on whether the GalNAc is part of the blood group A antigen, the Forssman antigen, or GM2-derived structures. These results are in accordance with molecular dynamics simulations that suggest the existence of a distinct MGL binding mechanism depending on the context of GalNAc moiety presentation. These results afford new perspectives for the rational design of GalNAc modifications that fine tune MGL immune responses in distinct biological contexts, especially in malignancy.


Leucine turnover and oxidation in trained rats during exercise.
The effects of training on leucine turnover and oxidation were studied during rest and exercise in young, postabsorptive female rats. Relationships were primarily studied by the continuous infusion method, using [1-14C]leucine. Arterial blood was assayed for leucine specific activity and expired air was monitored for O2 consumption, CO2 production, and the specific activity of 14CO2. The rate of leucine turnover in trained rats was 70% greater than the rate of leucine turnover in untrained rats and was not affected by exercise. By virtue of a higher turnover, the rate of leucine oxidation was 40% greater in trained rats during both rest and exercise. Moreover, leucine oxidation was proportional to the metabolic rate and represented 30% of the leucine turnover at rest and 40-60% of the leucine turnover during exercise. In the same animals leucine turnover was secondarily assessed by measuring the fraction of the [1-14C]leucine dose contained in the hemoglobin pool 4 wk after infusion (occupancy tracer method). Occupancy values for leucine turnover were not different from those determined by the continuous infusion method. The results show that whole body leucine turnover is increased by training and that leucine oxidation is increased by both training and exercise.


Hamp Type-1 Promotes Antimicrobial Defense via Direct Microbial Killing and Regulating Iron Metabolism in Grass Carp (Ctenopharyngodon idella).
Hepcidin is an antimicrobial peptide and regulator of iron homeostasis which has two isoforms in most fishes and some mammals. Previous studies have reported that the two hepcidin isoforms have different roles. Hamp type-1 plays a regulatory role in iron metabolism and hamp type-2 mostly performs an antimicrobial role. In this study, we found that Ctenopharyngodon idella (C. idella) have only one hepcidin isoform (hamp type-1), which showed both broad-spectrum antibacterial and iron regulatory functions. C. idella hepcidin mature peptide (hepcidin-25) and truncated peptide (hepcidin-20) exhibited bactericidal activities against both Gram-positive and Gram-negative bacteria in a dose-dependent manner in part through membrane rupture and binding to bacterial genomic DNA. The data from challenge tests demonstrated that the administration of hepcidin-25 significantly reduced mortality rates of C. idella by A. hydrophila infection, probably due to direct bactericidal activities of the peptide and a reduction of iron content in the fish serum. In addition, a comparison between hepcidin-20 and -25 suggests that the N terminal 5 amino acids play a critical role in reducing iron content in fish serum. Our findings revealed an important role of hamp type-1 in maintaining iron homeostasis and fighting against bacterial infections, suggesting the hepcidin has implications for the prevention and control of bacterial infection in aquaculture.


Phenotyping chronic pelvic pain based on latent class modeling of physical examination.
Introduction. Defining clinical phenotypes based on physical examination is required for clarifying heterogeneous disorders such as chronic pelvic pain (CPP). The objective of this study was to determine the number of classes within 4 examinable regions and then establish threshold and optimal exam criteria for the classes discovered. Methods. A total of 476 patients meeting the criteria for CPP were examined using pain pressure threshold (PPT) algometry and standardized numeric scale (NRS) pain ratings at 30 distinct sites over 4 pelvic regions. Exploratory factor analysis, latent profile analysis, and ROC curves were then used to identify classes, optimal examination points, and threshold scores. Results. Latent profile analysis produced two classes for each region: high and low pain groups. The optimal examination sites (and high pain minimum thresholds) were for the abdominal wall region: the pair at the midabdomen (PPT threshold depression of > 2); vulvar vestibule region: 10:00 position (NRS > 2); pelvic floor region: puborectalis (combined NRS > 6); vaginal apex region: uterosacral ligaments (combined NRS > 8). Conclusion. Physical examination scores of patients with CPP are best categorized into two classes: high pain and low pain. Standardization of the physical examination in CPP provides both researchers and general gynecologists with a validated technique.


Oral granisetron for the prevention of acute late onset nausea and vomiting in patients treated with moderately emetogenic chemotherapy.
To demonstrate the efficacy of oral granisetron 1 mg twice daily for the prevention of late onset nausea and vomiting after moderately emetogenic chemotherapy that includes cyclophosphamide, carboplatin, or doxorubicin. Prior to chemotherapy, patients were stratified by gender and randomized to receive oral granisetron (1 mg tablet twice daily) or prochlorperazine (10 mg sustained release capsule twice daily). Study agents were administered 1 h prior to and 12 h after chemotherapy. Antiemetics were administered for seven consecutive days. Efficacy variables were assessed 48 and 72 h after administration of chemotherapy, and included no emesis, no nausea, no moderate or severe nausea, and no antiemetic rescue. Safety analysis included all patients who received medication. A total of 230 patients were included in the intent-to-treat analysis; 119 patients received granisetron and 111 patients received prochlorperazine. Females, and all patients combined, who received granisetron had significantly higher no-emesis rates at 48 h (p =.010 and p =.016, respectively) than patients who received prochlorperazine. No-nausea rates at 48 h were numerically higher for all patients combined and females who received granisetron rather than prochlorperazine. Response rates for no nausea or mild nausea were also numerically higher in females treated with granisetron, compared to prochlorperazine, at 48 h. Significantly more patients (p <.001) and females (p <.001) in the granisetron group than in the prochlorperazine group did not require rescue antiemetics at 48 h. At 72 h, efficacy results were comparable for granisetron and prochlorperazine. Oral granisetron is well tolerated and more effective than prochlorperazine in preventing nausea and vomiting for up to 48 h following treatment with moderately emetogenic chemotherapy.