Antibacterial Utilization for Febrile Illnesses and Laboratory-Confirmed Bloodstream Infections in Northern Tanzania.
We describe antibacterial use in light of microbiology data and treatment guidelines for common febrile syndromes in Moshi, Tanzania. We compared data from 2 hospital-based prospective cohort studies, cohort 1 (2011-2014) and cohort 2 (2016-2019), that enrolled febrile children and adults. A study team member administered a standardized questionnaire, performed a physical examination, and collected blood cultures. Participants with bloodstream infection (BSI) were categorized as receiving effective or ineffective therapy based upon antimicrobial susceptibility interpretations. Antibacterials prescribed for treatment of pneumonia, urinary tract infection (UTI), or presumed sepsis were compared with World Health Organization and Tanzania Standard Treatment Guidelines. We used descriptive statistics and logistic regression to describe antibacterial use. Among participants, 430 of 1043 (41.2%) and 501 of 1132 (44.3%) reported antibacterial use prior to admission in cohorts 1 and 2, respectively. During admission, 930 of 1043 (89.2%) received antibacterials in cohort 1 and 1060 of 1132 (93.6%) in cohort 2. Inpatient use of ceftriaxone, metronidazole, and ampicillin increased between cohorts (P ≤ .002 for each). BSI was detected in 38 (3.6%) participants in cohort 1 and 47 (4.2%) in cohort 2. Of 85 participants with BSI, 81 (95.3%) had complete data and 52 (64.2%) were prescribed effective antibacterials. Guideline-consistent therapy in cohort 1 and cohort 2 was as follows: pneumonia, 87.4% and 56.8%; UTI, 87.6% and 69.0%; sepsis, 84.4% and 61.2% (P ≤ .001 for each). Receipt of antibacterials for febrile illness was common. While guideline-consistent prescribing increased over time, more than one-third of participants with BSI received ineffective antibacterials.


Laparoscopic Heller Myotomy for Achalasia: Experience from a Single Referral Tertiary Center.
BACKGROUND Achalasia is the most well known esophageal motility disorder. Laparoscopic Heller myotomy (LHM) is the most effective treatment for achalasia. The aim of this study was to review our results on LHM for achalasia. METHODS In this cross-sectional study all patients undergoing LHM between 2015 and 2017 were studied. The myotomy was followed by an anterior or posterior partial fundoplication. All patients were followed up for at least six months. RESULTS We conducted this prospective study on 36 consecutive patients who underwent LHM over 3 years. The mean age of the patients was 36.64 ± 13.47 years. 30 patients (83.3%) underwent Toupet and 6 patients (16.7%) received Dor fundoplication. 11 patients (30.6%) developed reflux after the procedure. According to the Eckardt Symptom Scoring (ESS), the symptoms improved in 74.2% of the patients and remained unchanged in 25.8% of the patients. Analysis of the ESS, indicated a significant change in regurgitation and retrosternal pain, dysphagia, and weight loss after the surgery (p = 0.001, p = 0.002, p = 0.046, and p = 0.001, respectively). CONCLUSION LHM with anterior or posterior partial fundoplication is safe and achieves a good outcome in the treatment of achalasia, especially in patients who have not responded to other methods while no serious complication was reported despite several prior endoscopic interventions.


Relevant Membrane Transport Proteins as Possible Gatekeepers for Effective Pharmacological Ascorbate Treatment in Cancer.
Despite the increasing number of newly diagnosed malignancies worldwide, therapeutic options for some tumor diseases are unfortunately still limited. Interestingly, preclinical but also some clinical data suggest that the administration of pharmacological ascorbate seems to respond well, especially in some aggressively growing tumor entities. The membrane transport and channel proteins are highly relevant for the use of pharmacological ascorbate in cancer therapy and are involved in the transfer of active substances such as ascorbate, hydrogen peroxide, and iron that predominantly must enter malignant cells to induce antiproliferative effects and especially ferroptosis. In this review, the relevant conveying proteins from cellular surfaces are presented as an integral part of the efficacy of pharmacological ascorbate, considering the already known genetic and functional features in tumor tissues. Accordingly, candidates for diagnostic markers and therapeutic targets are mentioned.


Protective behavioral strategies for reducing alcohol involvement: a review of the methodological issues.
Alcohol use among college students remains a major public health concern with many students experiencing negative alcohol-related consequences as a result of their drinking. Protective behavioral strategies (PBS) have been conceptualized as skills used by drinkers to moderate their drinking and/or resulting consequences. The correlational evidence for the relationships among PBS, alcohol use, and related problems has been mixed. Experimental research reveals inconsistent relationships among intervention condition, PBS use, and alcohol outcomes. There is currently insufficient evidence to support the claim that PBS function as a mechanism of behavior change for college drinkers. We propose that the inconsistencies found in the correlational and experimental research are explained in part by psychometric and methodological issues. This review summarizes measurement and methodological issues in studies that have directly assessed the relationship between PBS and alcohol use and/or alcohol-related consequences in college drinking samples. Additionally, we provide some suggestions and future directions to overcome methodological and conceptual limitations and to advance understanding of the role of protective behavioral strategy use in reducing alcohol involvement among college drinkers.


[Semiempirical calculation of the relation of the interaction energy between complementary pairs of nitrogenous bases to nucleic acid conformational parameters].
The calculations of interaction energy between complementary base pairs of nucleic acids in the function of 5 variables determining parameters of double helix (Arnott's parameters) have been carried out by the method of atom-atom potential functions. Four of these parameters are essential in the case of mutual positions of bases corresponding to conformational A-family, and only two parameters (the distance between pairs along helical axis and the angle of rotation around this axis)--in the case of B-family. Positions of the interaction energy minima over each of the essential variables are close to experimentally determined parameters. The interaction energy minima are more pronounced for A-family conformations. The positions of minima in this case are determined by dispersion and short range repulsion energy.


Development and Characteristics of Sodium-selective Transport in Red Beet.
Slices of storage tissue of red beet (Beta vulgaris L.) washed for only 1 day in distilled water readily absorb K(+) but lack a mechanism for rapid Na(+) uptake. A Na(+) transport mechanism develops if the tissue is washed for several days, and the tissue then excludes K(+) during Na(+) uptake.Both the high affinity and low affinity absorption mechanisms show a development of Na(+) transport with washing, and, in contrast to barley roots, cation selectivity in beet is not affected by the presence of calcium ions.K(+) and Na(+) do not appear to compete for binding sites at the surface of the cells, but, as in barley roots, the cations compete in some way for electrically balancing transported ions. Nevertheless, the development of Na(+) transport and the interaction of Na(+) with K(+) occur in the same way whether cation transport is balanced by Cl(-) uptake or by H(+) or HCO(3) (-) transport.


Differential Quantitative Determination of Site-Specific Intact N-Glycopeptides in Serum Haptoglobin between Hepatocellular Carcinoma and Cirrhosis Using LC-EThcD-MS/MS.
Intact N-glycopeptide analysis remains challenging due to the complexity of glycopeptide structures, low abundance of glycopeptides in protein digests, and difficulties in data interpretation/quantitation. Herein, we developed a workflow that involved advanced methodologies, the EThcD-MS/MS fragmentation method and data interpretation software, for differential analysis of the microheterogeneity of site-specific intact N-glycopeptides of serum haptoglobin between early hepatocellular carcinoma (HCC) and liver cirrhosis. Haptoglobin was immunopurified from 20 μL of serum in patients with early HCC, liver cirrhosis, and healthy controls, respectively, followed by trypsin/GluC digestion, glycopeptide enrichment, and LC-EThcD-MS/MS analysis. Identification and differential quantitation of site-specific N-glycopeptides were performed using a combination of Byonic and Byologic software. In total, 93, 87, and 68 site-specific N-glycopeptides were identified in early HCC, liver cirrhosis, and healthy controls, respectively, with high confidence. The increased variety of N-glycopeptides in liver diseases compared to healthy controls was due to increased branching with hyper-fucosylation and sialylation. Differential quantitation analysis showed that 5 site-specific N-glycopeptides on sites N184 and N241 were significantly elevated in early HCC compared to cirrhosis ( p < 0.05) and normal controls ( p ≤ 0.001). The result demonstrates that the workflow provides a strategy for detailed profiles of N-glycopeptides of patient samples as well as for relative quantitation to determine the level changes in site-specific N-glycopeptides between disease states.


Dietary Long-Chain Omega-3 Fatty Acids Are Related to Impulse Control and Anterior Cingulate Function in Adolescents.
Impulse control, an emergent function modulated by the prefrontal cortex (PFC), helps to dampen risky behaviors during adolescence. Influences on PFC maturation during this period may contribute to variations in impulse control. Availability of omega-3 fatty acids, an essential dietary nutrient integral to neuronal structure and function, may be one such influence. This study examined whether intake of energy-adjusted long-chain omega-3 fatty acids [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] was related to variation in impulse control and PFC activity during performance of an inhibitory task in adolescents (n = 87; 51.7% female, mean age 13.3 ± 1.1 years) enrolled in a longitudinal neuroimaging study. Intake of DHA + EPA was assessed using a food frequency questionnaire and adjusted for total energy intake. Inhibitory control was assessed using caregiver rating scale (BRIEF Inhibit subscale) and task performance (false alarm rate) on a Go/No-Go task performed during functional MRI. Reported intake of long-chain omega-3 was positively associated with caregiver ratings of adolescent ability to control impulses (p = 0.017) and there was a trend for an association between intake and task-based impulse control (p = 0.072). Furthermore, a regression of BOLD response within PFC during successful impulse control (Correct No-Go versus Incorrect No-Go) with energy-adjusted DHA + EPA intake revealed that adolescents reporting lower intakes display greater activation in the dorsal anterior cingulate, potentially suggestive of a possible lag in cortical development. The present results suggest that dietary omega-3 fatty acids are related to development of both impulse control and function of the dorsal anterior cingulate gyrus in normative adolescent development. Insufficiency of dietary omega-3 fatty acids during this developmental period may be a factor which hinders development of behavioral control.


Mortality patterns in breast versus artificially fed term babies in early infancy: a longitudinal study.
In this study 500 full term breast fed and 500 full term top fed babies were divided into 2 groups of weight > 2.5 kg and < or = 2.5 kg each, and were followed up for the mortality pattern. Eight hundred of these completed the full follow up period of 6 months. Neonatal mortality in term babies in the present study was 40 per thousand and mortality during 1-6 months period was 55 per thousand. Early neonatal mortality in breast fed > 2.5 kg was 0.55% against 7.8% in < or = 2.5 kg breast fed babies. The corresponding figures in artificially fed was 1.17% and 9.37% respectively. Late neonatal mortality in breast fed > 2.5 kg was 0 and in < or = 2.5 kg was 2.14%. These values in artificially fed were 0 and 3.12%, respectively. Mortality in 1-6 months period in breastfed > 2.5 kg was 0.64% and in < or = 2.5 kg was 15.5%; and in artificially fed 1.66% and 23% respectively. Thus LBW babies whether breast fed or artificially fed had higher mortality and artificially fed had overall higher mortality in comparison to breast fed. It is concluded that attention should be directed towards promotion of breast feeding and on prevention of low birth weight for decreasing mortality in early infancy.


Role of OH-stretch/torsion coupling and quantum yield effects in the first OH overtone spectrum of cis-cis HOONO.
A joint theoretical and experimental investigation is undertaken to study the effects of OH-stretch/HOON torsion coupling and of quantum yield on the previously reported first overtone action spectrum of cis-cis HOONO (peroxynitrous acid). The minimum energy path along the HOON dihedral angle is computed at the coupled cluster singles and doubles with perturbative triples level with correlation consistent polarized quadruple zeta basis set, at the structure optimized using the triple zeta basis set (CCSD(T)/cc-pVQZ//CCSD(T)/cc-pVTZ). The two-dimensional ab initio potential energy and dipole moment surfaces for cis-cis HOONO are calculated as functions of the HOON torsion and OH bond length about the minimum energy path at the CCSD(T)/cc-pVTZ and QCISD/AUG-cc-pVTZ (QCISD-quadratic configuration interaction with single and double excitation and AUG-augmented with diffuse functions) level of theory/basis, respectively. The OH-stretch vibration depends strongly on the torsional angle, and the torsional potential possesses a broad shelf at approximately 90 degrees , the cis-perp conformation. The calculated electronic energies and dipoles are fit to simple functional forms and absorption spectra in the region of the OH fundamental and first overtone are calculated from these surfaces. While the experimental and calculated spectra of the OH fundamental band are in good agreement, significant differences in the intensity patterns are observed between the calculated absorption spectrum and the measured action spectrum in the 2nu(OH) region. These differences are attributed to the fact that several of the experimentally accessible states do not have sufficient energy to dissociate to OH+NO(2) and therefore are not detectable in an action spectrum. Scaling of the intensities of transitions to these states, assuming D(0)=82.0 kJ/mol, is shown to produce a spectrum that is in good agreement with the measured action spectrum. Based on this agreement, we assign two of the features in the spectrum to Deltan=0 transitions (where n is the HOON torsion quantum number) that are blue shifted relative to the origin band, while the large peak near 7000 cm(-1) is assigned to a series of Deltan=+1 transitions, with predominant contributions from torsionally excited states with substantial cis-perp character. The direct absorption spectrum of cis-cis HOONO (6300-6850 cm(-1)) is recorded by cavity ringdown spectroscopy in a discharge flow cell. A single band of HOONO is observed at 6370 cm(-1) and is assigned as the origin of the first OH overtone of cis-cis HOONO. These results imply that the origin band is suppressed by over an order of magnitude in the action spectrum, due to a reduced quantum yield. The striking differences between absorption and action spectra are correctly predicted by the calculations.


Murine terminal deoxynucleotidyl transferase: cellular distribution and response to cortisone.
The mouse thymus contains two forms of terminal deoxynucleotidyl transferase (TdT) which are distinguishable by the salt concentration necessary to elute them from a phosphocellulose column, by their distrubtion among the thymocyte subpopulations, and by their sensitivity to cortisone treatment. In the whole thymus the later eluting peak (peak II) is the predominant one with about 3-10% of the total activity appearing in peak I. Both peak I and peak II activities are most sensitively assayed by the polymerization of dGMP onto an oligo(dA) primer. The minor population of thymocytes which is less dense and cortisone-resistant contains a higher specific activity of peak I TdT. The majority of TdT activity is, however, found in the major population of thymocytes which occurs in the center region of a bovine serum albumin gradient and is cortisone-sensitive. A very low level of an activity indistinguishable from peak II TdT activity is also detected in the mouse bone marrow. Other tissues, such as spleen, liver, heart, and brain lack detectable amounts of TdT activity.


Descending projections from the rostral ventromedial medulla (RVM) to trigeminal and spinal dorsal horns are morphologically and neurochemically distinct.
Neurons in the rostral ventromedial medulla (RVM) are thought to modulate nociceptive transmission via projections to spinal and trigeminal dorsal horns. The cellular substrate for this descending modulation has been studied with regard to projections to spinal dorsal horn, but studies of the projections to trigeminal dorsal horn have been less complete. In this study, we combined anterograde tracing from RVM with immunocytochemical detection of the GABAergic synthetic enzyme, GAD67, to determine if the RVM sends inhibitory projections to trigeminal dorsal horn. We also examined the neuronal targets of this projection using immunocytochemical detection of NeuN. Finally, we used electron microscopy to verify cellular targets. We compared projections to both trigeminal and spinal dorsal horns. We found that RVM projections to both trigeminal and spinal dorsal horn were directed to postsynaptic profiles in the dorsal horn, including somata and dendrites, and not to primary afferent terminals. We found that RVM projections to spinal dorsal horn were more likely to contact neuronal somata and were more likely to contain GAD67 than projections from RVM to trigeminal dorsal horn. These findings suggest that RVM neurons send predominantly GABAergic projections to spinal dorsal horn and provide direct input to postsynaptic neurons such as interneurons or ascending projection neurons. The RVM projection to trigeminal dorsal horn is more heavily targeted to dendrites and is only modestly GABAergic in nature. These anatomical features may underlie differences between trigeminal and spinal dorsal horns with regard to the degree of inhibition or facilitation evoked by RVM stimulation.


Using the Five Domains Model to Assess the Adverse Impacts of Husbandry, Veterinary, and Equitation Interventions on Horse Welfare.
The aim of this study was to conduct a series of paper-based exercises in order to assess the negative (adverse) welfare impacts, if any, of common interventions on domestic horses across a broad range of different contexts of equine care and training. An international panel (with professional expertise in psychology, equitation science, veterinary science, education, welfare, equestrian coaching, advocacy, and community engagement; n = 16) met over a four-day period to define and assess these interventions, using an adaptation of the domain-based assessment model. The interventions were considered within 14 contexts: C1 Weaning; C2 Diet; C3 Housing; C4 Foundation training; C5 Ill-health and veterinary interventions (chiefly medical); C6 Ill-health and veterinary interventions (chiefly surgical); C7 Elective procedures; C8 Care procedures; C9 Restraint for management procedures; C10 Road transport; C11 Activity-competition; C12 Activity-work; C13 Activity-breeding females; and C14 Activity-breeding males. Scores on a 1-10 scale for Domain 5 (the mental domain) gathered during the workshop were compared with overall impact scores on a 1-10 scale assigned by the same panellists individually before the workshop. The most severe (median and interquartile range, IQR) impacts within each context were identified during the workshop as: C1 abrupt, individual weaning (10 IQR 1); C2 feeding 100% low-energy concentrate (8 IQR 2.5); C3 indoor tie stalls with no social contact (9 IQR 1.5); C4 both (i) dropping horse with ropes (9 IQR 0.5) and forced flexion (9 IQR 0.5); C5 long-term curative medical treatments (8 IQR 3); C6 major deep intracavity surgery (8.5 IQR 1); C7 castration without veterinary supervision (10 IQR 1); C8 both (i) tongue ties (8 IQR 2.5) and (ii) restrictive nosebands (8 IQR 2.5); C9 ear twitch (8 IQR 1); C10 both (i) individual transport (7.00 IQR 1.5) and group transport with unfamiliar companions (7 IQR 1.5); C11 both (i) jumps racing (8 IQR 2.5) and Western performance (8 IQR 1.5); C12 carriage and haulage work (6 IQR 1.5); C13 wet nurse during transition between foals (7.5 IQR 3.75); and C14 teaser horse (7 IQR 8). Associations between pre-workshop and workshop scores were high, but some rankings changed after workshop participation, particularly relating to breeding practices. Domain 1 had the weakest association with Domain 5. The current article discusses the use of the domain-based model in equine welfare assessment, and offers a series of assumptions within each context that future users of the same approach may make when assessing animal welfare under the categories reported here. It also discusses some limitations in the framework that was used to apply the model.


Homocysteine: predictor of thrombotic disease.
Up to one third of primary cardiovascular and cerebrovascular thrombotic events occur in people who do not have traditional risk factors. This has led the scientific community to look for other potential reasons, i.e., predictors of these events. Numerous clinical trials have demonstrated a definite link between increased levels of homocysteine and the development of cardiovascular, cerebrovascular, and peripheral vascular disease. Hyperhomocysteinemia is caused by a disruption in normal metabolism of homocysteine by lack of nutrition, pharmaceutical agents, and by inherited or acquired disorders associated with this metabolism. Elevated levels of homocysteine promote endothelial cell damage, platelet hyperactivity, and the production of abnormal clotting factors leading to the development of thromboembolic plaques in the coronary, carotid, and peripheral vascular systems. The laboratory assessment of homocysteine has been made easier and more readily available to the clinician by the development of new enzyme immunoassay technology. Preanalytical variables, however, such as collection, processing, and storage are very important considerations for the accurate detection of elevated levels of homocysteine.


Effect of group selection on the evolution of altruistic behavior.
By using a Monte Carlo simulation, we studied the effect of group selection on the altruistic trait that is controlled by a single locus. The altruistic trait is disadvantageous to the bearer but advantageous to the others. Group selection is defined as the differential reproductive rate among demes caused by genotypic difference among demes. We found that the simulation reproduced many results of former studies. Additionally, when the mutation rate and the migration rate are small enough, we observed two new phenomena: (1) When the effect of the group selection is as large as that of the individual selection, the gene frequency is quite unstable. We found two local stable states, the A- and the S-state. When the metapopulation is in the A-state, altruists are nearly fixed. When in the S-state, on the contrary, altruists are almost lost. The metapopulation shifted quickly from one state to another. We call this phenomenon as the S-A transition. (2) When the mutation rate and migration rate are small enough we found an extremely strong mechanism to stop the non-altruists from expanding no matter how strong the individual selection coefficient is. This is caused by a phenomenon, which we call SA splitting, in which most demes are fixed either by altruists or non-altruists; thus, the relatedness of the metapopulation becomes nearly equal to one. We show SA splitting plays an important role in S-A transition. We define a parameter d to see the degree of SA splitting. We found that d is roughly proportional to mutation rate and deme size.


Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein.
Nanophthalmos is a rare disorder of eye development characterized by extreme hyperopia (farsightedness), with refractive error in the range of +8.00 to +25.00 diopters. Because the cornea and lens are normal in size and shape, hyperopia occurs because insufficient growth along the visual axis places these lensing components too close to the retina. Nanophthalmic eyes show considerable thickening of both the choroidal vascular bed and scleral coat, which provide nutritive and structural support for the retina. Thickening of these tissues is a general feature of axial hyperopia, whereas the opposite occurs in myopia. We have mapped recessive nanophthalmos to a unique locus at 11q23.3 and identified four independent mutations in MFRP, a gene that is selectively expressed in the eye and encodes a protein with homology to Tolloid proteases and the Wnt-binding domain of the Frizzled transmembrane receptors. This gene is not critical for retinal function, as patients entirely lacking MFRP can still have good refraction-corrected vision, produce clinically normal electro-retinograms, and show only modest anomalies in the dark adaptation of photoreceptors. MFRP appears primarily devoted to regulating axial length of the eye. It remains to be determined whether natural variation in its activity plays a role in common refractive errors.


Outcome after treatment for sebaceous carcinoma: A multicenter study.
Sebaceous carcinoma (SC) is a rare malignant tumour whereby, comprehensive long-term data are scarce. This study aimed to assess the outcome of patients treated with resection for SC. Patients treated at four tertiary centres were included. Cumulative incidence curves were calculated for recurrences. A total of 100 patients (57 males, 57%) were included with 103 SCs. The median age was 72 (range, 15-95) years with a median follow-up of 52 (interquartile range [IQR], 24-93) months. Most SCs were located (peri)ocular (49.5%). Of all SCs, 17 locally recurred (16.5%) with a median time to recurrence of 19 (IQR, 8-29) months. The cumulative incidence probability for recurrence was statistically higher for (peri)ocular tumours (p = 0.005), and for positive resection margins (p = 0.001). Two patients presented with lymph node metastases and additional seven patients (8.7%) developed lymph node metastases during follow-up with a median time to metastases of 8 (IQR, 0.5-28) months. Three patients had concurrent in-transit metastases and one patient also developed liver and bone metastases during follow-up. SC is a rare, yet locally aggressive tumour. Positive resection margins and (peri)ocular SCs are more frequently associated with local recurrence. SC infrequently presents with locoregional or distant metastases.


Modelling the isotopic evolution of the Earth.
We present a flexible multi-reservoir (primitive lower mantle, depleted upper mantle, upper continental crust, lower continental crust and atmosphere) forward-transport model of the Earth, incorporating the Sm-Nd, Rb-Sr, U-Th-Pb-He and K-Ar isotope-decay systematics. Mathematically, the model consists of a series of differential equations, describing the changing abundance of each nuclide in each reservoir, which are solved repeatedly over the history of the Earth. Fluxes between reservoirs are keyed to heat production and further constrained by estimates of present-day fluxes (e.g. subduction, plume flux) and current sizes of reservoirs. Elemental transport is tied to these fluxes through 'enrichment factors', which allow for fractionation between species. A principal goal of the model is to reproduce the Pb-isotope systematics of the depleted upper mantle, which has not been done in earlier models. At present, the depleted upper mantle has low (238)U/(204)Pb (mu) and (232)Th/(238)U (kappa) ratios, but Pb-isotope ratios reflect high time-integrated values of these ratios. These features are reproduced in the model and are a consequence of preferential subduction of U and of radiogenic Pb from the upper continental crust into the depleted upper mantle. At the same time, the model reproduces the observed Sr-, Nd-, Ar- and He-isotope ratios of the atmosphere, continental crust and mantle. We show that both steady-state and time-variant concentrations of incompatible-element concentrations and ratios in the continental crust and upper mantle are possible. Indeed, in some cases, incompatible-element concentrations and ratios increase with time in the depleted mantle. Hence, assumptions of a progressively depleting or steady-state upper mantle are not justified. A ubiquitous feature of this model, as well as other evolutionary models, is early rapid depletion of the upper mantle in highly incompatible elements; hence, a near-chondritic Th/U ratio in the upper mantle throughout the Archean is unlikely. The model also suggests that the optimal value of the bulk silicate Earth's K/U ratio is close to 10000; lower values suggested recently seem unlikely.


Tubular proteinuria in acute kidney injury: a critical evaluation of current status and future promise.
The diagnosis and prognosis of acute kidney injury (AKI) by current clinical means is inadequate. Biomarkers of kidney injury that are easily measured and unaffected by physiological variables could revolutionize the management of AKI. Our objective was to systematically review the diagnostic and prognostic utility of urine and serum biomarkers of AKI in humans. We searched MEDLINE, PubMed and EMBASE databases (January 2000-August 2009) for biomarker studies that could be classified into the following categories: (a) confirmation of the diagnosis of established AKI, (b) early prediction of AKI, and (c) prognostication of AKI. We identified 54 manuscripts published since 2000 that met our inclusion and exclusion criteria. Urinary interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-beta-D-glucosaminidase (NAG) are potentially useful biomarkers for the diagnosis of established AKI. Urinary NGAL, IL-18, and liver-type fatty acid binding protein, and serum NGAL and cystatin C represent the most promising biomarkers for early prediction of AKI. Urinary cystatin C, alpha1-microglobulin, NAG and retinol-binding protein may be useful to predict severity and outcomes of AKI. In conclusion, we identified several studies of promising biomarkers for the diagnosis, prediction and prognostication of AKI. However, we note several limitations, including small sample sizes, inadequate gold standard, exclusion of patients with chronic kidney disease, incomplete statistical analyses, utilization of research-based assays and a paucity of studies examining prediction for clinical outcomes. Future studies will need to address these limitations in order for further progress to be made.


31P-NMR Metabolomics Revealed Species-Specific Use of Phosphorous in Trees of a French Guiana Rainforest.
Productivity of tropical lowland moist forests is often limited by availability and functional allocation of phosphorus (P) that drives competition among tree species and becomes a key factor in determining forestall community diversity. We used non-target 31P-NMR metabolic profiling to study the foliar P-metabolism of trees of a French Guiana rainforest. The objective was to test the hypotheses that P-use is species-specific, and that species diversity relates to species P-use and concentrations of P-containing compounds, including inorganic phosphates, orthophosphate monoesters and diesters, phosphonates and organic polyphosphates. We found that tree species explained the 59% of variance in 31P-NMR metabolite profiling of leaves. A principal component analysis showed that tree species were separated along PC 1 and PC 2 of detected P-containing compounds, which represented a continuum going from high concentrations of metabolites related to non-active P and P-storage, low total P concentrations and high N:P ratios, to high concentrations of P-containing metabolites related to energy and anabolic metabolism, high total P concentrations and low N:P ratios. These results highlight the species-specific use of P and the existence of species-specific P-use niches that are driven by the distinct species-specific position in a continuum in the P-allocation from P-storage compounds to P-containing molecules related to energy and anabolic metabolism.


Association between physical activity, screen time activities, diet patterns and daytime sleepiness in a sample of Brazilian adolescents.
To examine the association between physical activity, screen time, eating habits and daytime sleepiness among Brazilian adolescents. Adolescents from three high schools (n = 876, 49.8% female, 16.4 ± 1.2 years) participated in this cross-sectional survey. Variables related to lifestyle behaviors (ie, physical activity, screen time, eating habits, sleep duration) were collected through an online questionnaire. Daytime sleepiness was assessed using the Pediatric Daytime Sleepiness Scale (PDSS). Excessive daytime sleepiness was defined as a PDSS score ≥20. The average PDSS score was 18.9 (SD ± 4.8) points and 46.8% of adolescents were classified as having excessive daytime sleepiness. Physical activity was inversely associated with PDSS score (β = -0.29, 95% CI -0.47; -0.11). Consuming processed foods frequently (β = 1.16, 95% CI 0.85; 1.47) and using social media (β = 0.22, 95% CI 0.14; 0.30) were positively associated with PDSS score. Similar findings were observed for the odds of excessive daytime sleepiness. Physical activity was inversely associated (OR = 0.91, 95% CI 0.84; 0.99), while frequent consumption of processed foods (OR = 1.55, 95% CI 1.33; 1.82) and using social media (OR = 1.13, 95% CI 1.02; 1.24) were positively associated with excessive daytime sleepiness. Lower physical activity level, a higher consumption processed foods, and higher social media use were associated with daytime sleepiness in this sample of Brazilian adolescents.


Text mining improves prediction of protein functional sites.
We present an approach that integrates protein structure analysis and text mining for protein functional site prediction, called LEAP-FS (Literature Enhanced Automated Prediction of Functional Sites). The structure analysis was carried out using Dynamics Perturbation Analysis (DPA), which predicts functional sites at control points where interactions greatly perturb protein vibrations. The text mining extracts mentions of residues in the literature, and predicts that residues mentioned are functionally important. We assessed the significance of each of these methods by analyzing their performance in finding known functional sites (specifically, small-molecule binding sites and catalytic sites) in about 100,000 publicly available protein structures. The DPA predictions recapitulated many of the functional site annotations and preferentially recovered binding sites annotated as biologically relevant vs. those annotated as potentially spurious. The text-based predictions were also substantially supported by the functional site annotations: compared to other residues, residues mentioned in text were roughly six times more likely to be found in a functional site. The overlap of predictions with annotations improved when the text-based and structure-based methods agreed. Our analysis also yielded new high-quality predictions of many functional site residues that were not catalogued in the curated data sources we inspected. We conclude that both DPA and text mining independently provide valuable high-throughput protein functional site predictions, and that integrating the two methods using LEAP-FS further improves the quality of these predictions.


In vivo tracking of stem cell by nanotechnologies: future prospects for mouse to human translation.
Advances in stem cell research have provided important understanding of the cell biology and offered great promise for developing new strategies for tissue regeneration. Dynamic determination of stem cell migration and distribution in real time is essential for optimizing treatments in preclinical models and designing clinical protocols. Recent developments in the use of nanotechnologies have contributed to advance of the high-resolution in vivo imaging methods, including the positron emission tomography, the single-photon emission computed tomography, the magnetic resonance imaging, and microcomputed tomography. This review examines the use of nanotechnologies for stem cell tracking, the many contrast agents, and detectors that have been proposed and suggest future directions for mouse to human translation of these techniques, for both therapeutic and diagnostic purposes.


Improved reversible jump algorithms for Bayesian species delimitation.
Several computational methods have recently been proposed for delimiting species using multilocus sequence data. Among them, the Bayesian method of Yang and Rannala uses the multispecies coalescent model in the likelihood framework to calculate the posterior probabilities for the different species-delimitation models. It has a sound statistical basis and is found to have nice statistical properties in simulation studies, such as low error rates of undersplitting and oversplitting. However, the method suffers from poor mixing of the reversible-jump Markov chain Monte Carlo (rjMCMC) algorithms. Here, we describe several modifications to the algorithms. We propose a flexible prior that allows the user to specify the probability that each node on the guide tree represents a true speciation event. We also introduce modifications to the rjMCMC algorithms that remove the constraint on the new species divergence time when splitting and alter the gene trees to remove incompatibilities. The new algorithms are found to improve mixing of the Markov chain for both simulated and empirical data sets.


Clinical significance of serum S100B levels in neurointensive care.
S100B is viewed as the most promising biomarker for brain damage. It has been proposed that this marker is useful in a Neurointensive Care Unit (NICU) as a monitoring parameter. This study aims to examine the clinical usefulness of daily serum S100B measurements in this setting. Prospective consecutive inclusion of patients. A total of 79 patients with confirmed or suspected head injury or cerebrovascular insults (CVIs) (based upon patient history, computed tomography (CT) and/or magnetic resonance imaging (MRI) and neurological examination including coma scoring) who required neurointensive care were included in the study. Sampling for S100B was performed at admission and daily until patients were discharged from the NICU. S100B measurements were statistically compared to occurrence of secondary complications and outcome according to Glasgow Outcome Scale (GOS), with focus on clinical prediction. 17 of 79 patients (22%) had secondary neurological complications. Mean S100B levels were found to be an independent parameter associated with these complications (P=0.03). Mean S100B levels were higher in patients with complications compared to those without on both the complication day (P=0.033) and the day after (P=0.015), but not the day prior to the complication (P=0.62). S100B did not predict secondary neurological complication. Neither mean (P=0.182) nor peak (P=0.370) S100B levels were associated with or predicted outcome according to dichotomised GOS. Daily S100B measurements are associated with secondary complications but not to outcome. However, daily S100B levels do not predict secondary complications, which limit the usefulness of this brain biomarker in this setting.


Mechanism of putative neo-antigen formation from N-propionyl-4-S-cysteaminylphenol, a tyrosinase substrate, in melanoma models.
Metastatic melanoma is resistant to conventional therapies. N-propionyl-4-S-cysteaminylphenol (NPrCAP), an N-protected sulfur-amine analog of tyrosine, is a good substrate for tyrosinase and is selectively incorporated into melanoma cells, causing cytotoxicity in vitro and in vivo. We have recently shown that intratumoral injections of NPrCAP suppress not only the growth of primary B16F1 melanoma tumors but also of secondary, re-challenged tumors. The participation of CD8(+) T cells has been suggested for the NPrCAP-mediated anti-B16 melanoma immunity. In this study, the molecular mechanism of the NPrCAP cytotoxicity and immunogenicity was examined. The phenol NPrCAP was shown to be activated by mushroom tyrosinase to the ortho-quinone N-propionyl-4-S-cysteaminyl-1,2-benzoquinone (NPrCAQ), and the structure was confirmed by reducing it to the corresponding catechol. NPrCAQ reacted rapidly with biologically relevant sulfhydryl compounds such as cysteine, glutathione and bovine serum albumin. The NPrCAQ-thiol adduct formation was proven with a model thiol N-acetylcysteine by spectroscopic methods. The production and release of NPrCAQ-protein adducts was verified in B16F1 melanoma cells in vitro and in B16F1 melanoma-bearing mice in vivo through the detection of 5-S-cysteaminyl-3-S-cysteinylcatechol after acid hydrolysis of the protein fraction. These results suggest that the phenol NPrCAP, acting as a prohapten, can be activated in melanoma cells by tyrosinase to the quinone-hapten NPrCAQ, which binds to melanosomal proteins through their cysteine residues to form possible neo-antigens, thus triggering the immunological response. NPrCAP thus represents a potential new approach to immunotherapy against metastatic melanoma.


Voltammetry of ion transfer across the electrochemically polarized micro liquid-liquid interface between water and a room-temperature ionic liquid, tetrahexylammonium bis(trifluoromethylsulfonyl)imide, using a glass capillary micropipette.
Ion transfer across the polarized interface between a room-temperature ionic liquid (RTIL) or room-temperature molten salt, tetrahexylammonium bis(trifluoromethylsulfonyl)imide (THAC(1)C(1)N), and water has been studied voltammetrically using a micro liquid-liquid interface formed at the orifice of a glass capillary micropipette. A small current of nanoampere level circumvents the problem of the iR drop in the viscous ionic liquid phase. Voltammograms for the transfer of moderately hydrophilic ions, such as BF(4)(-) and ClO(4)(-), from the aqueous phase in the capillary to the bulk of THAC(1)C(1)N in which the capillary is submerged, show steady-state characteristics in that the current does not depend on the scan rate up to a few hundred millivolt per second, and the plateau in the limiting current region is proportional to the bulk concentration of analyte ions. Owing to the steady-state current, which is presumably ascribed to a noncylindrical geometry of the capillary tip, the relative magnitude of the hydrophobicity, or the affnity to the RTIL, of a series of ions can be determined from the half-wave potentials of voltammograms.


Quantitative and qualitative hydrologic balance for a suburban watershed with a separate sewer system (Nantes, France).
A qualitative and quantitative budget at the outlet of the storm-water runoff system of a small suburban watershed is presented together with some data regarding waste-water. 445,000 m3 (34% of the rain-water volume) were drained by the storm-water runoff system and 40,879 m3 by the waste-water system from September 2002 to March 2004. Storm-water runoff is generally not heavily polluted with regard to trace metals but concentrations occasionally exceed the standards for surface water of good quality. On the contrary, pesticides (diuron and glyphosate) have very high concentrations especially in spring and autumn when their use is maximum. As the St Joseph storm-water runoff is finally discharged into the Erdre River, measures to reduce the use of these pollutants should be considered.


[The ColIb-CA53 plasmid suppresses umuC- and umuD-mutations in Escherichia coli K-12].
The presence of the ColIa-CA53 plasmid in umuC and umuD mutant Escherichia coli K-12 cells restores their mutability under UV irradiation to a level that even exceeds that of the isogenic umuC+umuD+ strains, as well as increases their resistance to the lethal effects of UV irradiation. The ColIb-P9 plasmid which suppresses the umuC mutant phenotype, as we have shown earlier, acts in the same manner with respect to the umuD mutant cells. The results of the study demonstrate that both plasmids encode products that are functionally similar to those of the chromosomal genes umuC and umuD. The plasmids ColIa-CA53, ColIb-P9 and pKM101 are shown to have practically the same effect upon the mutagenesis and survival of the umuC, umuD mutant cells.


Oral colonization by Candida spp. in liver transplant patients: Molecular identification and antifungal susceptibilityOral colonization by Candida spp. in liver transplant.
Candida species are commensal to normal oral microbiota; however, they can cause infections if immune functions are reduced. The aim of this study was to investigate oral colonization, identify species, and test the susceptibility profile to antifungals. A descriptive study included 97 liver transplant patients who attended the transplant center of a referral hospital in southern Brazil. Two oral swab collections were performed, with a 6-month gap between collections. The samples were identified by sequencing the internal transcribed spacer ITS region of the ribosomal DNA. The sensitivity test was performed with fluconazole, amphotericin B, and micafungin using a broth microdilution method recommended by Clinical and Laboratory Standards Institute document M27-A4. Eighty-two patients were investigated and 15 were excluded for presenting clinical infection. The identification of yeasts showed colonization in 66% and 61.9% in collections A and B, respectively. Candida albicans was the most prevalent species in both collections (n = 29/50 and n = 27/49, respectively). In 31 (62%) patients, the yeast species remained the same for 6 months, and in 19 (38%) the colonizing species was substituted. Thirty-two isolates from collection A were sensitive (S) to Fluconazole, 13 sensitive dose-dependent (SDD), and five resistant (R). In collection B, 32 were S, 12 SDD, and 5 R. For amphotericin B and micafungin, all isolates were sensitive. With knowledge of the species and identification of strains resistant to fluconazole, useful information can be alerts about the emergence of antifungal resistance strains. Study of great importance because it is the first investigation that identifies Candida in the oral cavity of liver transplant patients, allowing an understanding of epidemiology and contributing to the knowledge about strains resistant to fluconazole.


Occupational variation in incidence of oropharyngeal cancer in the Nordic countries.
Evaluate the occupational variation in incidence of oropharyngeal cancer (OPC). We calculated standardized incidence ratios (SIRs) of OPC in occupational categories in the Nordic countries relative to the entire national populations. The data covered 6155 OPC cases. Among men high risk of OPC was observed, among else, in waiters (SIR 6.28, 95% CI 4.68-8.26), beverage workers (SIR 3.00, 95% CI 1.72-4.88), and artistic workers (SIR 2.97, 95% CI 2.31-3.76). Among women high risk of OPC was observed in waiters (SIR 2.02, 95% CI 1.41-2.81) and packers (SIR 1.73, 95% CI 1.07-2.64). The lowest SIRs were observed in female gardeners (SIR 0.27, 95% CI 0.12-0.51) and male farmers (SIR 0.30, 95% CI 0.25-0.35). The 20-fold variation in incidence of OPC between occupations needs further investigation in studies with detailed information on occupational and non-occupational risk factors.


Human relaxins (RLNH1, RLNH2), their receptor (RXFP1) and fetoplacental growth.
Relaxin, a systemic and placental hormone, has potential roles in fetoplacental growth. Human placenta expresses two RLN genes, RLNH1 and RLNH2 Maternal obesity is common and is associated with abnormal fetal growth. Our aims were to relate systemic and cord blood RLNH2, placental RLNs and their receptor (RXFP1) with fetoplacental growth in context of maternal body mass index, and associations with insulin-like growth factor 2 (IGF2) and vascular endothelial growth factor A (VEGFA) in the same placentas. Systemic, cord blood and placental samples were collected prior to term labor, divided by prepregnancy body mass index: underweight/normal (N = 25) and overweight/obese (N = 44). Blood RLNH2 was measured by ELISA; placental RLNH2, RLNH1, RXFP1, IGF2 and VEGFA were measured by quantitative immunohistochemistry and mRNAs were measured by quantitative reverse transcription PCR. Birthweight increased with systemic RLNH2 only in underweight/normal women (P = 0.036). Syncytiotrophoblast RLNH2 was increased in overweight/obese patients (P = 0.017) and was associated with placental weight in all subjects (P = 0.038). RLNH1 had no associations with birthweight or placental weight, but was associated with increased trophoblast and endothelial IGF2 and VEGFA, due to female fetal sex. Thus, while systemic RLNH2 may be involved in birthweight regulation in underweight/normal women, placental RLNH2 in all subjects may be involved in placental weight. A strong association of trophoblast IGF2 with birthweight and placental weight in overweight/obese women suggests its importance. However, an association of only RLNH1 with placental IGF2 and VEGFA was dependent upon female fetal sex. These results suggest that both systemic and placental RLNs may be associated with fetoplacental growth.


Optimizing fiducial visibility on periodically acquired megavoltage and kilovoltage image pairs during prostate volumetric modulated arc therapy.
Robust detection of implanted fiducials is essential for monitoring intrafractional motion during hypofractionated treatment. The authors developed a plan optimization strategy to ensure clear visibility of implanted fiducials and facilitate 3D localization during volumetric modulated arc therapy (VMAT). Periodic kilovoltage (kV) images were acquired at 20° gantry intervals and paired with simultaneously acquired 4.4° short arc megavoltage digital tomosynthesis (MV-DTS) to localize three fiducials during VMAT delivery for hypofractionated prostate cancer treatment. Beginning with the original optimized plan, control point segments where fiducials were consistently blocked by multileaf collimator (MLC) within each 4.4° MV-DTS interval were first identified. For each segment, MLC apertures were edited to expose the fiducial that led to the least increase in the cost function. Subsequently, MLC apertures of all control points not involved with fiducial visualization were reoptimized to compensate for plan quality losses and match the original dose-volume histogram. MV dose for each MV-DTS was also kept above 0.4 MU to ensure acceptable image quality. Different imaging (gantry) intervals and visibility margins around fiducials were also evaluated. Fiducials were consistently blocked by the MLC for, on average, 36% of the imaging control points for five hypofractionated prostate VMAT plans but properly exposed after reoptimization. Reoptimization resulted in negligible dosimetric differences compared with original plans and outperformed simple aperture editing: on average, PTV D98 recovered from 87% to 94% of prescription, and PTV dose homogeneity improved from 9% to 7%. Without violating plan objectives and compromising delivery efficiency, the highest imaging frequency and largest margin that can be achieved are a 10° gantry interval, and 15 mm, respectively. VMAT plans can be made to accommodate MV-kV imaging of fiducials. Fiducial visualization rate and workflow efficiency are significantly improved with an automatic modification and reoptimization approach.


Overview of diabetes mellitus and exercise.
Diabetes mellitus is a common chronic disorder the primary therapeutic principles of which have long been based on the combination of physical activity with appropriate diet. Although exercise in insulin-dependent diabetes mellitus (IDDM) may be associated with metabolic deterioration in the case of lack of adequate provision of insulin and carbohydrate in balanced amounts, the beneficial effects of exercise in diabetes are numerous. Exercise facilitates the utilization of glucose as the main source of energy for contracting muscles and decreases peripheral insulin resistance. Limited epidemiological studies have demonstrated that lack of physical activity may be involved in the epidemic outburst of non-insulin-dependent diabetes mellitus (NIDDM) in some unusual populations. Long-term studies are still needed to show that lifelong physical training and exercise reduce morbidity and mortality in diabetes.


[Clinical effectiveness and pharmacokinetics of gliflozin from the point of view of individual genetic characteristics: A review].
A review of publications devoted to the analysis of genetic polymorphisms and features of the functioning of genes that affect the pharmacokinetics and pharmacodynamics of sodium-glucose cotransporter-2 inhibitors (SGLT2i) is presented. Objective of the study was to reveal information about genes whose polymorphism may affect the effectiveness of SGLT2i. The review was carried out in accordance with the PRISMA 2020 recommendations, the search for publications was carried out in the PubMed databases (including Medline), Web of Science, as well as Russian scientific electronic libraries eLIBRARY.RU from 1993 to 2022. Polymorphisms in the structure of several genes (SLC5A2, UGT1A9, ABCB1, PNPLA3) have been described that may affect the treatment of type 2 diabetes mellitus complicated by diseases such as chronic heart failure, chronic kidney disease, or non-alcoholic fatty liver disease. The information found on the genetic features of the development of the effects of SGLT2i is limited to a description of the differences in their pharmacokinetics. The relevance of currently available pharmacogenetic studies is largely constrained by small sample sizes.


Thermal conductivity of Ho2Ti2O7 along the [111] direction.
Thermal transport measurements have been made on the spin-ice material Ho(2)Ti(2)O(7) in an applied magnetic field with both the heat current and the field parallel to the [111] direction for temperatures from 50 mK to 1.2 K. A large magnetic field >6 T is applied to suppress the magnetic contribution to the thermal conductivity in order to extract the lattice conductivity. The low field thermal conductivity thus reveals a magnetic field dependent contribution to the conductivity which both transfers heat and scatters phonons. We interpret these magnetic excitations as monopolelike excitations and describe their behavior via existing Debye-Hückel theory.


Quantum afterburner: improving the efficiency of an ideal heat engine.
By using a laser and maser in tandem, it is possible to obtain laser action in the hot exhaust gases of a heat engine. Such a "quantum afterburner" involves the internal quantum states of the working molecules as well as the techniques of cavity quantum electrodynamics and is therefore in the domain of quantum thermodynamics. It is shown that Otto cycle engine performance can be improved beyond that of the "ideal" Otto heat engine. Furthermore, the present work demonstrates a new kind of lasing without initial inversion.


Parameter on Periodontitis Associated With Systemic Conditions.
The American Academy of Periodontology has developed the following parameter on periodontitis associated with systemic conditions. Patients affected by periodontal disease with concomitant systemic factors should be informed about the significance of the systemic condition(s) to the periodontal disease process. Patients should also be informed of the periodontal disease process, therapeutic alternatives, potential complications, expected results, and their responsibilities in treatment. Consequences of no periodontal treatment should be explained. Failure to treat periodontitis appropriately can result in progressive loss of periodontal supporting tissues, an adverse change in prognosis, tooth loss, and compromise of the dentition. Given this information, patients should then be able to make informed decisions regarding their periodontal therapy. J Periodontol 2000;71:876-879.


[Human monocyte-derived multinucleated giant cells].
Multinucleated giant cells (MGC) are characteristic cells in granulomatous disorders such as sarcoidosis and leprosy. There are two types of MGC; foreign body-type and Langhans-type cells. The exact mechanisms of the formation and the functional significance of MGC are not determined, although their morphological features are well understood. MGC are also formed in vitro from peripheral blood mononuclear cells by stimulation with cytokines and lectins. Particularly IFN-gamma is considered to play a pivotal role in monocyte fusion. IL-3, IL-4, IL-13, and GM-CSF are other reported cytokines involved in MGC formation. In addition to such inflammatory mediators, a factor derived from the pathogens of granulomatous disorders may be necessary for MGC formation. Muramyl dipeptide, a peptidoglycan portion of bacterial cell walls, is one of the candidates and can preferentially induce Langhans-type cells in in vitro MGC formation system. Although the exact mechanisms of in vitro MGC formation remains unknown, cell surface molecules such as P2X7 receptor, integrins, CD98, and macrophage fusion protein are considered to be involved in fusion process. Monocytes of sarcoidosis patients expressed higher levels of P2X7 and had a higher ability to induce MGC than those of healthy controls. Effective agents for sarcoidosis such as tranilast, alloprinol, and captopril inhibited in vitro MGC formation, suggesting their therapeutic effects through the direct effects on monocytes. Thus, an in vitro MGC formation model would be a useful tool to understand the relevance of MGC in granulomatous disorders.


The immunosuppressive drug azathioprine inhibits biosynthesis of the bacterial signal molecule cyclic-di-GMP by interfering with intracellular nucleotide pool availability.
In Gram-negative bacteria, production of the signal molecule c-di-GMP by diguanylate cyclases (DGCs) is a key trigger for biofilm formation, which, in turn, is often required for the development of chronic bacterial infections. Thus, DGCs represent interesting targets for new chemotherapeutic drugs with anti-biofilm activity. We searched for inhibitors of the WspR protein, a Pseudomonas aeruginosa DGC involved in biofilm formation and production of virulence factors, using a set of microbiological assays developed in an Escherichia coli strain expressing the wspR gene. We found that azathioprine, an immunosuppressive drug used in the treatment of Crohn's disease, was able to inhibit WspR-dependent c-di-GMP biosynthesis in bacterial cells. However, in vitro enzymatic assays ruled out direct inhibition of WspR DGC activity either by azathioprine or by its metabolic derivative 2-amino-6-mercapto-purine riboside. Azathioprine is an inhibitor of 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase, an enzyme involved in purine biosynthesis, which suggests that inhibition of c-di-GMP biosynthesis by azathioprine may be due to perturbation of intracellular nucleotide pools. Consistent with this hypothesis, WspR activity is abolished in an E. coli purH mutant strain, unable to produce AICAR transformylase. Despite its effect on WspR, azathioprine failed to prevent biofilm formation by P. aeruginosa; however, it affected production of extracellular structures in E. coli clinical isolates, suggesting efficient inhibition of c-di-GMP biosynthesis in this bacterium. Our results indicate that azathioprine can prevent biofilm formation in E. coli through inhibition of c-di-GMP biosynthesis and suggest that such inhibition might contribute to its anti-inflammatory activity in Crohn's disease.


Differences in photoreceptor processing speed for chromatic and achromatic vision in the bumblebee, Bombus terrestris.
Fast detection of visual change can be mediated by visual processes that ignore chromatic aspects of the visual signal, relying on inputs from a single photoreceptor class (or pooled input from similar classes). There is an established link between photoreceptor processing speed (in achromatic vision) and visual ecology. Highly maneuverable flies, for example, have the fastest know photoreceptors, relying on metabolically expensive membrane conductances to boost performance. Less active species forgo this investment and their photoreceptors are correspondingly slower. However, within a species, additional classes of photoreceptors are required to extract chromatic information, and the question therefore arises as to whether there might be within-species differences in processing speed between photoreceptors involved in chromatic processing compared with those feeding into fast achromatic visual systems. We used intracellular recording to compare light-adapted impulse responses in three spectral classes of photoreceptor in the bumblebee. Green-sensitive photoreceptors, which are known to provide achromatic contrast for motion detection, generated the fastest impulse responses (half-width, Deltat = 7.9 +/- 1.1 ms). Blue- and UV-sensitive photoreceptors (which are involved in color vision) were significantly slower (9.8 +/- 1.2 and 12.3 +/- 1.8 ms, respectively). The faster responses of green photoreceptors are in keeping with their role in fast achromatic vision. However, blue and UV photoreceptors are still relatively fast in comparison with many other insect species, as well as vertebrate cones, suggesting a significant investment in photoreceptor processing for color vision in bees. We discuss this finding in relation to bees' requirement for accurate learning of flower color, especially in conditions of variable luminance contrast.


An analytic model of two-level compressive buckling with applications in the assembly of free-standing 3D mesostructures.
Recently developed methods for mechanically-guided assembly exploit stress release in prestretched elastomeric substrates to guide the controlled formation of complex three-dimensional (3D) mesostructures in advanced functional materials and integrated electronic devices. The techniques of interfacial photopolymerization allow for realization of such 3D mesostructures in free-standing forms, separated from their elastomeric substrate, via formation of an integrated base layer. Theoretical models for the complex modes of deformation associated with this scheme are essential in the optimal design of the process parameters. Here, we present an analytic finite-deformation model of an isolated double-ribbon structure to describe the buckling process and morphology change of the assembled mesostructures upon removal of the substrate. As validated by finite element analyses (FEA), this analytic model can accurately predict the profiles of the double-ribbon structure with a range of different design parameters. We further illustrate the extension of this model to the analyses of 3D mesostructures with different geometries. Inspired by analytic results for flexible base structures, combined experimental results and numerical simulations demonstrate that mechanical interactions between the two different layers can be leveraged to achieve hierarchical assembly of 3D mesostructures. These findings could be useful in further advances in designs of free-standing 3D mesostructures based on mechanically-guided assembly.


Plastics and carcinogenesis: The example of vinyl chloride.
The manufacture, use and disposal of various plastics can pose numerous health risks, including the risk of cancer. A model example of carcinogenic risk from plastics is provided by polyvinyl chloride, since it is composed of the known human carcinogen vinyl chloride (VC). In recent years, much has been learned about the molecular biological pathways of VC carcinogenesis. This has led to molecular epidemiologic studies of VC carcinogenesis in exposed human populations which have identified useful biomarkers of exposure, effect and susceptibility for VC. These studies have in turn provided the basis for new molecular approaches for the prevention and treatment of VC cancers. This model could have much wider applicability for many other carcinogenic exposures and many other human cancers.


Spatiotemporal patterns and dispersal of stink bugs (Heteroptera: Pentatomidae) in peanut-cotton farmscapes.
In the southeast United States, a field of peanuts, Arachis hypogaea L., is often closely associated with a field of cotton, Gossypium hirsutum L. The objective of this 4-yr on-farm study was to examine and compare the spatiotemporal patterns and dispersal of the southern green stink bug, Nezara viridula L., and the brown stink bug, Euschistus servus (Say), in six of these peanut-cotton farmscapes. GS(+) Version 9 was used to generate interpolated estimates of stink bug density by inverse distance weighting. Interpolated stink bug population raster maps were constructed using ArcMap Version 9.2. This technique was used to show any change in distribution of stink bugs in the farmscape over time. SADIE (spatial analysis by distance indices) methodology was used to examine spatial aggregation of individual stink bug species and spatial association of the two stink bug species in the individual crops. Altogether, the spatiotemporal analyses for the farmscapes showed that some N. viridula and E. servus nymphs and adults that develop in peanuts disperse into cotton. When these stink bugs disperse from peanuts into cotton, they aggregate in cotton at the interface, or common boundary, of the two crops while feeding on cotton bolls. Therefore, there is a pronounced edge effect observed in the distribution of stink bugs as they colonize the new crop, cotton. The driving force for the spatiotemporal distribution and dispersal of both stink bug species in peanut-cotton farmscapes seems to be availability of food in time and space mitigated by landscape structure. Thus, an understanding of farmscape ecology of stink bugs and their natural enemies is necessary to strategically place, in time and space, biologically based management strategies that control stink bug populations while conserving natural enemies and the environment and reducing off-farm inputs.


Higher-order structure of bovine mitochondrial tRNA(Phe) lacking the 'conserved' GG and T psi CG sequences as inferred by enzymatic and chemical probing.
Bovine mitochondrial (mt) phenylalanine tRNA (tRNA(Phe)), which lacks the 'conserved' GG and T psi YCG sequences, was efficiently purified by the selective hybridization method using a solid phase DNA probe. The entire nucleotide sequence of the tRNA, including modified nucleotides, was determined and its higher-order structure was investigated using RNaseT2 and chemical reagents as structural probes. The D and T loop regions as well as the anticodon loop region were accessible to RNaseT2, and the N-3 positions of cytidines present in the D and T loops were easily modified under the native conditions in the presence of 10mM Mg2+. On the other hand, the nucleotides present in the extra loop were protected from the chemical modification under the native conditions. From the results of these probing analyses and a comparison of the sequences of mitochondrial tRNA(Phe) genes from various organisms, it was inferred that bovine mt tRNA(Phe) lacks the D loop/T loop tertiary interactions, but does have the canonical extra loop/D stem interactions, which seem to be the main factor for bovine mt tRNA(Phe) to preserve its L-shaped higher-order structure.


Effects of chain length on Rouse modes and non-Gaussianity in linear and ring polymer melts.
The dynamics of ring polymer melts are studied via molecular dynamics simulations of the Kremer-Grest bead-spring model. Rouse mode analysis is performed in comparison with linear polymers by changing the chain length. Rouse-like behavior is observed in ring polymers by quantifying the chain length dependence of the Rouse relaxation time, whereas a crossover from Rouse to reptation behavior is observed in linear polymers. Furthermore, the non-Gaussian parameters of the monomer bead displacement and chain center-of-mass displacement are analyzed. It is found that the non-Gaussianity of ring polymers is remarkably suppressed with slight growth for the center-of-mass dynamics at long chain length, which is in contrast to the growth in linear polymers for both the monomer bead and center-of-mass dynamics.


Bimetallic and postsynthetically alloyed PtCu nanostructures with tunable reactivity for the methanol oxidation reaction.
Designing effective catalysts by controlling morphology and structure is key to improving the energy efficiency of fuel cells. A good understanding of the effects of specific structures on electrocatalytic activity, selectivity, and stability is needed. Here, we propose a facile method to synthesize PtCu bimetallic nanostructures with controllable compositions by using Cu nanowires as a template and ascorbic acid as a reductant. A further annealing process provided the alloy PtCu with tunable crystal structures. The combination of distinct structures with tunable compositions in the form of PtCu nanowires provides plenty of information for better understanding the reaction mechanism during catalysis. HClO4 cyclic voltammetry (CV) tests confirmed that various phase transformations occurred in bimetallic and alloy samples, affecting morphology and unit cell structures. Under a bifunctional synergistic effect and the influence of the insertion of a second metal, the two series of structures show superior performance toward methanol electrooxidation. Typically, the post-product alloy A-Pt14Cu86 with a cubic structure (a = 3.702 Å) has better methanol oxidation reaction (MOR) catalysis performance. Density functional theory (DFT) calculations were performed to determine an optimal pathway using the Gibbs free energy and to verify the dependence of the electrocatalytic performance on the lattice structure via overpotential changes. Bimetallic PtCu has high CO tolerance, maintaining high stability. This work provides an approach for the systematic design of novel catalysts and the exploration of electrocatalytic mechanisms for fuel cells and other related applications.


Transfusion-associated Chagas' disease in Texas: report of a case.
A 59-year-old woman with metastatic colon cancer, immunosuppressed secondary to chemotherapy and prolonged granulocytopenia, developed acute Chagas' disease that was fatal. During her illness, she received transfusions with large numbers of blood components. Although we were unable to identify an infected donor, we believe her infection was acquired from transfusion of a contaminated blood component. Recently, three similar cases were reported in North America. An influx of immigrants from areas in which Chagas' disease is endemic may account for the increased number of cases of transfusion-associated Chagas' disease in this country.


Epigenetic QTL mapping in Brassica napus.
There is increasing evidence that epigenetic marks such as DNA methylation contribute to phenotypic variation by regulating gene transcription, developmental plasticity, and interactions with the environment. However, relatively little is known about the relationship between the stability and distribution of DNA methylation within chromosomes and the ability to detect trait loci. Plant genomes have a distinct range of target sites and more extensive DNA methylation than animals. We analyzed the stability and distribution of epialleles within the complex genome of the oilseed crop plant Brassica napus. For methylation sensitive AFLP (MSAP) and retrotransposon (RT) epimarkers, we found a high degree of stability, with 90% of mapped markers retaining their allelic pattern in contrasting environments and developmental stages. Moreover, for two distinct parental lines 97% of epialleles were transmitted through five meioses and segregated in a mapping population. For the first time we have established the genetic position for 17 of the 19 centromeres within this amphidiploid species. Epiloci and genetic loci were distributed within distinct clusters, indicating differential detection of recombination events. This enabled us to identify additional significant QTL associated with seven important agronomic traits in the centromeric regions of five linkage groups.


Radiolographic exhibits in gross anatomy.
The discipline radiology is well suited to teach anatomy to first-year medial students. A series of exhibits of radiographic anatomy in the dissection laboratory, in conjuction with small group teaching sessions, serves this purpose well. Such displays are readily constructed from materials available in most radiology departments and are easily reproduced.


Stress-specific composition, assembly and kinetics of stress granules in Saccharomyces cerevisiae.
Eukaryotic cells respond to cellular stresses by the inhibition of translation and the accumulation of mRNAs in cytoplasmic RNA-protein (ribonucleoprotein) granules termed stress granules and P-bodies. An unresolved issue is how different stresses affect formation of messenger RNP (mRNP) granules. In the present study, we examine how sodium azide (NaN(3)), which inhibits mitochondrial respiration, affects formation of mRNP granules as compared with glucose deprivation in budding yeast. We observed that NaN(3) treatment inhibits translation and triggers formation of P-bodies and stress granules. The composition of stress granules induced by NaN(3) differs from that of glucose-deprived cells by containing eukaryotic initiation factor (eIF)3, eIF4A/B, eIF5B and eIF1A proteins, and by lacking the heterogeneous nuclear RNP (hnRNP) protein Hrp1. Moreover, in contrast with glucose-deprived stress granules, NaN(3)-triggered stress granules show different assembly rules, form faster and independently from P-bodies and dock or merge with P-bodies over time. Strikingly, addition of NaN(3) and glucose deprivation in combination, regardless of the order, always results in stress granules of a glucose deprivation nature, suggesting that both granules share an mRNP remodeling pathway. These results indicate that stress granule assembly, kinetics and composition in yeast can vary in a stress-specific manner, which we suggest reflects different rate-limiting steps in a common mRNP remodeling pathway.


Facial Reconstruction of a Mucormycosis Survivor by Free Rectus Abdominis Muscle Flap, Tissue Expansion, and Ocular Prosthesis.
Invasive sinonasal mucormycosis is a rare fungal infection that usually occurs in immunocompromised or diabetic patients, and it is often fatal. The authors present a case of a woman patient suffering from systemic lupus erythematosus and diabetes mellitus treated with prednisone, presenting with a rapidly progressive rhino-orbital-cerebral mucormycosis. She was successfully treated with combined intravenous antifungal therapy and radical debridement followed by complex defect reconstruction with a free vertical rectus abdominis myocutaneous flap, tissue expander, and ophthalmic prosthesis.


'Not at target': prevalence and consequences of inadequate disease control in systemic lupus erythematosus-a multinational observational cohort study.
The unmet need in systemic lupus erythematosus (SLE) with the current standard of care is widely recognised, but few studies have quantified this. The recent definition of treat-to-target endpoints and other thresholds of uncontrolled disease activity provide an opportunity to formally define unmet need in SLE. In this study, we enumerated the prevalence of these states and examined their association with adverse outcomes. Data were collected prospectively in a 13-country longitudinal SLE cohort between 2013 and 2019. Unmet need was defined as never attaining lupus low disease activity state (LLDAS), a time-adjusted mean SLEDAI-2K (AMS) > 4, or ever experiencing high disease activity status (HDAS; SLEDAI-2K ≥10). Health-related quality of life (HRQoL) was assessed using SF36 (v2) and damage accrual using the SLICC-ACR SLE Damage Index (SDI). A total of 3384 SLE patients were followed over 30,313 visits (median [IQR] follow-up 2.4 [0.4, 4.3] years). Eight hundred thirteen patients (24%) never achieved LLDAS. Median AMS was 3.0 [1.4, 4.9]; 34% of patients had AMS > 4. Twenty-five per cent of patients had episodes of HDAS. Each of LLDAS-never, AMS>4, and HDAS-ever was strongly associated with damage accrual, higher glucocorticoid use, and worse HRQoL. Mortality was significantly increased in LLDAS-never (adjusted HR [95% CI] = 4.98 [2.07, 12.0], p<0.001) and HDAS-ever (adjusted hazard ratio (HR) [95% CI] = 5.45 [2.75, 10.8], p<0.001) patients. Failure to achieve LLDAS, high average disease activity, and episodes of HDAS were prevalent in SLE and were significantly associated with poor outcomes including organ damage, glucocorticoid exposure, poor quality of life, and mortality.


Policy recommendations and cost implications for a more sustainable framework for European human biomonitoring surveys.
The potential of Human Biomonitoring (HBM) in exposure characterisation and risk assessment is well established in the scientific HBM community and regulatory arena by many publications. The European Environment and Health Strategy as well as the Environment and Health Action Plan 2004-2010 of the European Commission recognised the value of HBM and the relevance and importance of coordination of HBM programmes in Europe. Based on existing and planned HBM projects and programmes of work and capabilities in Europe the Seventh Framework Programme (FP 7) funded COPHES (COnsortium to Perform Human Biomonitoring on a European Scale) to advance and improve comparability of HBM data across Europe. The pilot study protocol was tested in 17 European countries in the DEMOCOPHES feasibility study (DEMOnstration of a study to COordinate and Perform Human biomonitoring on a European Scale) cofunded (50%) under the LIFE+ programme of the European Commission. The potential of HBM in supporting and evaluating policy making (including e.g. REACH) and in awareness raising on environmental health, should significantly advance the process towards a fully operational, continuous, sustainable and scientifically based EU HBM programme. From a number of stakeholder activities during the past 10 years and the national engagement, a framework for sustainable HBM structure in Europe is recommended involving national institutions within environment, health and food as well as European institutions such as ECHA, EEA, and EFSA. An economic frame with shared cost implications for national and European institutions is suggested benefitting from the capacity building set up by COPHES/DEMOCOPHES.


[Blood ionized calcium fraction in various serum albumin levels surveyed in non-dialysis patients].
Blood ionized calcium (iCa) fraction is affected by the serum albumin(Alb) level, even though this effect might not be appropriately estimated by the formulae proposed previously. To clarify a reasonable regimen for predicting iCa from serum total Ca (tCa), we investigated the relationship of blood iCa, tCa, and serum Alb levels through 124 samples from 116 non-dialysis patients requiring iCa measurement at the Nephrology Section of Toride Kyodo General Hospital. The patients comprised 61 males and 55 females with the mean age of 66.9 +/- 1.4 years, including 9 cases of hypercalcemia, 110 of normocalcemia, and 5 of hypocalcemia based on their iCa levels. Their background diseases were 25 cases of chronic glomerulonephritis, 17 of nephrotic syndrome, 40 of diabetes mellitus, 4 of collagen diseases, and 30 of others. Their mean serum Cr was 2.44 +/- 0.21 mg/dl, and 77 patients showed elevated Cr levels. Four adjustment formulae: one derived from Payne's, two from the proposal of K/DOQI Clinical Practice Guidelines, and a theoretical one based on the previous in vitro experiments, were compared with the non-adjusted value (tCa itself) with respect to their suitability for estimating iCa. The correlation coefficient of tCa with iCa was higher than the values adjusted by the above four formulae. The difference of iCa from tCa divided by eight, which concisely predicted iCa based on the assumption that half the serum Ca is bound to protein, was less than 1/8th of the other adjusted Ca levels. Hence none of the adjusted Ca by the above formulae was superior to nonadjusted tCa from the point of estimating the iCa level. Moreover, the sensitivity for predicting hypocalcemia was the highest in tCa, even though its specificity was lower than the other adjusted values. In conclusion, no adjustment formula is required to predict ionized Ca from tCa, and to screen hypo- or hypercalcemia.


A BDNF sensitive mechanism is involved in the fear memory resulting from the interaction between stress and the retrieval of an established trace.
The present study investigates the fear memory resulting from the interaction of a stressful experience and the retrieval of an established fear memory trace. Such a combination enhanced both fear expression and fear retention in adult Wistar rats. Likewise, midazolam intra-basolateral amygdala (BLA) infusion prior to stress attenuated the enhancement of fear memory thus suggesting the involvement of a stress-induced reduction of the GABAergic transmission in BLA in the stress-induced enhancing effect. It has been suggested that, unlike the immediate-early gene Zif268 which is related to the reconsolidation process, the expression of hippocampal brain-derived neurotrophic factor (BDNF) is highly correlated with consolidation. We therefore evaluate the relative contribution of these two neurobiological processes to the fear memory resulting from the above-mentioned interaction. Intra-dorsal hippocampus (DH) infusions of either the antisense Zif268 or the inhibitor of the protein degradation (Clasto-Lactacystin β-Lactone), suggested to be involved in the retrieval-dependent destabilization process, did not affect the resulting contextual memory. In contrast, the knockdown of hippocampal BDNF mitigated the stress-induced facilitating influence on fear retention. In addition, the retrieval experience elevated BDNF level in DH at 60 min after recall exclusively in stressed animals. These findings suggest the involvement of a hippocampal BDNF sensitive mechanism in the stress-promoting influence on the fear memory following retrieval.


Acrofacial dysostosis syndrome type Rodriguez: prenatal diagnosis and autopsy findings.
A new lethal form of acrofacial dysostosis (AFD) syndrome was delineated by Rodriguez et al. [Rodriguez et al. (1990); Am J Med Genet 35:484-489]. We report on a male fetus with mandibulofacial dysostosis, including phocomelia-like upper limb deficiencies and lower limb anomalies which are characteristic of AFD Rodriguez type. The diagnosis was made on prenatal sonogram at 20 and at 24.1 weeks gestation. The severity of the upper limb defects, the involvement of lower limbs, and the absence of eyelid coloboma and polythelia excluded the possibility of other conditions associated with acrofacial dysostosis (AFD) including Nager acrofacial dysostosis syndrome (NADS) and postaxial acrofacial dysostosis syndrome (POADS). This case further delineates the AFD syndrome type Rodriguez.


Tertiary hyperparathyroidism in kidney transplant recipients: characteristics of patients selected for different treatment strategies.
Several treatment options exist for kidney transplant patients with tertiary hyperparathyroidism. However, the decision to endorse observation (OBS), medical therapy, or parathyroidectomy (PTX) remains controversial. We performed a retrospective cohort study of kidney transplant patients with tertiary hyperparathyroidism at a single institution over a 7-year period. Patients were classified by treatment mode: OBS, medical therapy with cinacalcet (CIN), or PTX. Descriptive statistics were performed. Serum calcium levels and change in serum creatinine level were compared using analysis of variance with comparisons between individual groups using the Student's t test with a Bonferroni correction. Time to treatment was compared between CIN and PTX groups using the Student's t test. Complication rates were compared using the Fisher exact test. We identified 83 patients: 52 were treated by OBS; 13 were treated with CIN, and 18 underwent PTX. Six weeks after treatment, PTX resulted in lower serum calcium level (9.28 mg/dL) compared with CIN (10.20 mg/dL) (P<0.01). There was no difference in the change in serum creatinine level 1 year after treatment initiation (P=0.98). Time to treatment was shorter (1.7 vs. 3.3 years, P<0.01), and the highest pretreatment calcium level was higher (12.2 vs. 11.7 mg/dL, P<0.01) in patients treated with PTX compared with CIN. Complication rates differed by treatment group (P<0.01). A quarter of OBS patients showed persistent hypercalcemic symptoms, compared with only 7.7% in the CIN group and 0% in the PTX group (P<0.01). PTX led to a greater reduction in serum calcium level and lower chance of persistent hypercalcemic symptoms, without any appreciable harm to the kidney allograft.


A biochemical guide to yeast adhesins: glycoproteins for social and antisocial occasions.
Fungi are nonmotile eukaryotes that rely on their adhesins for selective interaction with the environment and with other fungal cells. Glycosylphosphatidylinositol (GPI)-cross-linked adhesins have essential roles in mating, colony morphology, host-pathogen interactions, and biofilm formation. We review the structure and binding properties of cell wall-bound adhesins of ascomycetous yeasts and relate them to their effects on cellular interactions, with particular emphasis on the agglutinins and flocculins of Saccharomyces and the Als proteins of Candida. These glycoproteins share common structural motifs tailored to surface activity and biological function. After being secreted to the outer face of the plasma membrane, they are covalently anchored in the wall through modified GPI anchors, with their binding domains elevated beyond the wall surface on highly glycosylated extended stalks. N-terminal globular domains bind peptide or sugar ligands, with between millimolar and nanomolar affinities. These affinities and the high density of adhesins and ligands at the cell surface determine microscopic and macroscopic characteristics of cell-cell associations. Central domains often include Thr-rich tandemly repeated sequences that are highly glycosylated. These domains potentiate cell-to-cell binding, but the molecular mechanism of such an association is not yet clear. These repeats also mediate recombination between repeats and between genes. The high levels of recombination and epigenetic regulation are sources of variation which enable the population to continually exploit new niches and resources.


Comparison of curative and palliative radiotherapy efficacy in unresectable advanced non-small cell lung cancer patients with or without metastasis.
To evaluate the efficacy of curative and palliative radiotherapy in inoperable advanced non-small cell lung cancer (NSCLC) patients with a performance status (PS) equal or greater than 2, and to compare the therapy effect on survival with or without metastatic disease. From January 1998 through December 2004, 797 patients with inoperable stage III and IV NSCLC were treated with radiotherapy alone because of older age, cardiovascular disease, insufficient respiratory reserve or general frailty. Radical radiotherapy, consisting of approximately 60 Gy, given in 30 fractions was performed in 363 (45.5 %) of these patients. The other 434 patients (54.5%) were treated with palliative dose radiotherapy. Conventional follow-up of the patients was conducted at Izmir Oncology Center. All results were evaluated statistically. Seven hundred and sixty-three patients (95.7%) were male. The mean age was 61.02 years (+/- 9.678), ranging from 30-88 years. The prominent histology was squamous cell carcinoma (70.7%). Sixty-five patients (8.2%) have been staged IIIA, 419 (52.6%) IIIB, and 313 (39.3%) IV. The median follow up of patients was 274.19 days. One-year survival rate was 37%, and 2-year survival rate was 11% in the radical radiotherapy group, while these rates were 20% and 5% in the others. Although radical thoracic radiotherapy for metastatic NSCLC has not been adopted universally, this study shows that curative radiotherapy for the primary tumor provides additional survival benefit in patients with metastatic disease compared with palliative radiotherapy. This result raises the question of whether treatment with radical radiotherapy alone might be the most beneficial and cost-effective treatment of advanced stage NSCLC.


Anti-M Alloimmunization: Management and Outcome at a Single Institution.
Objective The objective of this study was to review the management strategies and outcomes in gravidas with anti-M alloimmunization over 15 years. Study Design Data collected from 195 pregnant patients with anti-M antibodies from July 2000 through June 2016 were reviewed retrospectively. We analyzed indirect antiglobulin test titer results, paternal or fetal/neonatal M antigen status, antepartum course, and perinatal outcomes. Results Anti-M antibodies were found in 146 women and 195pregnancies. Among those with positive indirect antiglobulin tests, 193 pregnancies had titers at or below 1:4. Only one patient with an initial low titer experienced a more than twofold increase to a titer 1:64. Two women underwent an amniocentesis and cordocentesis. Ninety-five (73.6%) of the 129 infants tested were positive for the M antigen. Nine infants required phototherapy. There were no cases of hemolytic disease of the fetus or newborn, mild or severe. Conclusion The incidence of severe hemolytic disease of the newborn due to anti-M is extremely low. We found no cases in our review of 195 pregnancies, despite several cases of severe hemolytic disease of the newborn reported in the literature. We have created an algorithm for the management of anti-M antibodies in pregnancy based on our data and extensive literature review.


Monitoring the stimulated release of dopamine with in vivo voltammetry. II: Clearance of released dopamine from extracellular fluid.
Microvoltammetric electrodes implanted in the caudate nucleus of the anesthetized rat have been used to monitor dopamine released following electrical stimulation of the medial forebrain bundle. These electrodes are fabricated from unmodified carbon fibers and have been used with normal pulse voltammetry. Dopamine appears in the vicinity of the electrode when the stimulation is initiated, and disappears almost immediately when the stimulation is terminated. The data suggest that the effective diffusion distance is less than 100 micron. Postmortem analysis using liquid chromatography with electrochemical detection shows that dopamine released in this manner is metabolized to 3,4-dihydroxyphenylacetic acid (DOPAC); however, neither substance is observed electrochemically in the extracellular fluid within seconds after the stimulation. In addition, inhibitors of neuronal uptake of dopamine, amphetamine (1.8 or 15 mg X kg-1) or benztropine (25 mg X kg-1), or of dopamine metabolism, pargyline (150 mg X kg-1) or tropolone (100 mg X kg-1), do not significantly affect the rate at which dopamine disappears from extracellular fluid, although they can affect the amount released. These results suggest that dopamine cannot freely diffuse in the extracellular fluid because an extraneuronal uptake mechanism exists that clears dopamine from extracellular fluid into an extraneuronal pool where metabolism to 3,4-dihydroxyphenylacetic acid occurs. Dopamine can be observed during electrical stimulation of the ascending fibers because neuronal and extraneuronal uptake systems are unable to remove dopamine on these short time scales.


Effects of vitamin A and insulin on the antioxidative state of diabetic rat heart: a comparison study with combination treatment.
Because elevated oxidative stress may exacerbate cardiovascular complications of diabetes mellitus, the current study aimed to investigate the effects of treatment with either vitamin A, an antioxidant, or with insulin on lipid peroxidation products and antioxidant enzyme activities of diabetic rat heart. Also to evaluate whether a combination of vitamin A and insulin exerts more beneficial effects than treatment with each agent alone. Rats were made diabetic with a single injection of streptozotocin (STZ, 55 mg kg(-1) i.p.). Two days after STZ-injection, one group of diabetic rats was treated with vitamin A (retinol acetate, 30 mg kg(-1) day(-1) i.o.) for 12 weeks. A second group of diabetic rats was untreated for 6 weeks and then treated for another 6 weeks with insulin (8-10 IU rat(-1) day(-1) s.c.). Both therapies were applied to another group of diabetic rats for assessment of combined therapy with vitamin A plus insulin. Hearts from 12-week untreated diabetic animals showed about a four-fold increase in the level of thiobarbituric acid reactive substances (TBARS), indicative of increased lipid peroxidation. This was accompanied by approximately 100% increase in both catalase and glutathione peroxidase (GSHPx) enzyme activities. Therapy with insulin alone caused a small but significant improvement in plasma TBARS as well as GSHPx activities, but no significant change in plasma catalase in diabetic animals. Diabetes-induced disturbance in TBARS was almost completely prevented by vitamin A therapy. Although, a similar degree of activities for GSHPx was determined in diabetic animals treated with each agent alone, combination therapy was found to be more effective than single therapies in the recovery of GSHPx of diabetic heart. In contrast to insulin single therapy, vitamin A alone significantly prevented an increase in catalase activity of diabetic heart, and a combination of these agents did not supply any further benefit. Superoxide dismutase (SOD) activity was not found significantly different among the experimental groups. STZ-diabetes also resulted in less plasma retinol and retinol-binding protein (RBP), which was significantly improved by insulin single therapy while vitamin A used alone, failed to increase plasma retinol and RBP levels of diabetic animals. Our findings suggest that single therapy with insulin is unable to preclude oxidative reactions in diabetic heart to the same extent as obtained by vitamin A therapy alone, in spite of allowing recovery of normal growth rate and improved vitamin A metabolism in diabetic rats. A combination of insulin with vitamin A may provide more benefits than use of either agent alone in the treatment of general characteristics of diabetes and the maintenance of antioxidant defence of diabetic heart and thus in the reduction of peroxidative stress-induced cardiac injury.


Sustainability of the Collaborative Chronic Care Model in Outpatient Mental Health Teams Three Years Post-Implementation: A Qualitative Analysis.
Our goal was to investigate the sustainability of care practices that are consistent with the collaborative chronic care model (CCM) in nine outpatient mental health teams located within US Department of Veterans Affairs (VA) medical centers, three to four years after the completion of CCM implementation. We conducted qualitative interviews (N = 30) with outpatient mental health staff from each of the nine teams. We based our directed content analysis on the six elements of the CCM. We found variable sustainability of CCM-based care processes across sites. Some care processes, such as delivery of evidence-based psychotherapies (EBPs) and use of measurement-based care (MBC) to guide clinic decision-making, were robustly maintained or even expanded within participating teams. In contrast, other care processes-which had in some cases been developed with considerable effort-had not been sustained. For example, care manager roles were diminished in scope or eliminated completely in response to workload pressures, frontline care needs, or the COVID-19 pandemic. Similarly, processes for engaging Veterans more fully in decision-making had generally been scaled back. Leadership support in the form of adequate team staffing and time to conduct team meetings were seen as crucial for sustaining CCM-consistent care. Given the potential impact of leadership turnover on sustainability in mental health, future efforts to implement CCM-based mental health care should strive to involve multiple leaders in implementation and sustainment efforts, lest one key departure undo years of implementation work. Our results also suggest that implementing CCM processes may best be conceptualized as a partnership across multiple levels of medical center leadership.