Effect of emollient therapy on clinical outcomes in preterm neonates in Pakistan: a randomised controlled trial.
Newborn oil massage, a traditional community practice, could potentially benefit thermoregulation and skin barrier function, and prevent serious infections, morbidity and mortality in high-risk preterm infants, but has only been evaluated in limited studies in low income settings. To assess the efficacy of topical coconut oil applications among a cohort of hospital-born preterm infants. A prospective, individually randomised controlled clinical trial. Nursery and neonatal intensive care unit at Aga Khan University Hospital, Pakistan. Of 270 eligible neonates, a consecutive cohort of 258 hospital-born preterm infants (gestational age ≥26 weeks and ≤37 weeks). Twice daily topical application of coconut oil by nurses from birth until discharge and continued thereafter by mothers at home until completion of the 28th day of life. Incidence of hospital-acquired bloodstream infections. Weight gain, skin condition and neonatal mortality. 23% of the enrolled neonates developed clinically suspected sepsis while 14% developed blood culture proven infection. The unadjusted hazard for developing hospital-acquired infection in the control group was 4.7 (95% CI 1.8 to 12.4) compared with the intervention group. After adjusting for gestational age, birth weight, duration of intubation and duration of hospitalisation for possible confounding, the hazard for hospital-acquired infection in the control group was 6.0 (95% CI 2.3 to 16) compared with the intervention group. The rate of hospital-acquired infections in the control and intervention groups was 219.1 and 39.5 per 1000 patient-days, respectively. Mean weight gain was 11.3 g/day higher (95% CI 8.1 to 14.6, p<0.0001) and average skin condition was significantly better in the intervention group when compared with controls. There was no significant impact on duration of hospitalisation or neonatal mortality. No adverse effects such as local irritation or local infection were observed among newborns receiving coconut oil applications. Topical emollient therapy was effective in maintaining skin integrity and reducing the risk of bloodstream infection in preterm infants in a tertiary hospital setting in Pakistan. The effectiveness of this approach in primary care settings needs to be further explored. NCT01396642.


Differentiation of hemodynamic, humoral and metabolic responses to beta 1- and beta 2-adrenergic stimulation in man using atenolol and propranolol.
The respective contributions of beta-adrenoceptor subtypes to the hemodynamic, humoral and metabolic consequences of adrenergic stimulation during graded exercise in man were investigated using nonselective beta-adrenoceptor blockade with propranolol and beta 1-adrenoceptor blockade with atenolol. Doses of these agents that produced comparable suppression of beta 1 response as measured by antagonism of cardioacceleration during exercise were selected. Six healthy, nonsmoking males received these drugs in a placebo-controlled, Latin-square, randomized manner using a double-blind protocol. Both drugs produced comparable reductions of systolic blood pressure and elevation of diastolic blood pressure compared with placebo as exercise load increased. Propranolol produced higher peak epinephrine levels than atenolol or placebo (808 +/- 162, 640 +/- 190 and 584 +/- 153 pg/ml, respectively, p = 0.03), but norepinephrine levels did not show significant differences. Plasma renin activity was similarly suppressed both at rest and during all grades of exercise by both drugs. Lactate levels during moderate exercise were significantly lower after propranolol than after either atenolol or placebo (p = 0.03), but were similar at heavy work loads. Plasma glucose values rose on placebo (from 96.5 +/- 2.1 to 97.7 +/- 2.7 mg/dl) and on atenolol (from 99.7 +/- 2.2 to 102.1 +/- 4.8 mg/dl), but fell on propranolol (from 96.4 +/- 1.9 mg/dl to 87.2 +/- 2.5 mg/dl, p less than 0.01). These results indicate that blockade of vascular smooth muscle beta 2 receptors does not substantially alter hemodynamics during intense short-term exercise. Stimulation of renin release and lipolysis are produced through beta 1-adrenoceptor mechanisms, whereas beta 2 adrenoceptors are important in the provision of carbohydrate as an energy substrate for exercising muscle.


Quality of informed consent: a new measure of understanding among research subjects.
The informed consent of participants is ethically and legally required for most research involving human subjects. However, standardized methods for assessing the adequacy of informed consent to research are lacking. We designed a brief questionnaire, the Quality of Informed Consent (QuIC), to measure subjects' actual (objective) and perceived (subjective) understanding of cancer clinical trials. The QuIC incorporates the basic elements of informed consent specified in federal regulations, assesses the therapeutic misconception (the belief that all aspects of a clinical trial are designed to directly benefit the subject), and employs the language and structure of the new National Cancer Institute template for informed consent documents. We modified the QuIC after receiving feedback from pilot tests with cancer research subjects, as well as validation from two independent expert panels. We then sent the QuIC to 287 adult cancer patients enrolled on phase I, II, or III clinical trials. Two hundred seven subjects (72%) completed the QuIC. To assess test-retest reliability, a random sample of 32 respondents was selected, of whom 17 (53%) completed the questionnaire a second time. The test-retest reliability was good with intraclass correlation coefficients of.66 for tests of objective understanding and.77 for tests of subjective understanding. The current version of the QuIC, which consists of 20 questions for objective understanding and 14 questions for subjective understanding, was tested for time and ease of administration in a sample of nine adult cancer patients. The QuIC required an average of 7.2 minutes to complete. The QuIC is a brief, reliable, and valid questionnaire that holds promise as a standardized way to assess the outcome of the informed consent process in cancer clinical trials.


Kinetic model for biological nitrogen removal using shortcut nitrification-denitrification process in sequencing batch reactor.
A kinetic model for shortcut nitrification-denitrification process with sequencing batch reactor (SBR) was developed. To test this model, the kinetic parameters of the model including maximum specific rates and half-maximum rate concentrations for shortcut nitrification and denitrification were estimated from the results obtained from a laboratory-scale SBR fed with a soybean curd processing wastewater (400-800 mg COD L(-1), 50-65 mg NH(4)(+)-N L(-1)) at 26 degrees C. In the nitrification step, two DO levels (0.5 and 3.5 mg L(-1)) were tested and the predicated nitrification rates under different NH(4)(+)-N concentrations using this model fit well with correlation coefficient R = 0.9902. In the denitrification step, the process of nitrite removal was close to a zero-order reaction if the concentration of electron donor was not so low (COD > 100 mg L(-1)), and concentrations of nitrite and organic matter (as COD) had limited effect on denitrification rate. The model can be used to predict nitrogen removal performance with different influent NH(4)(+)-N and COD concentrations and under various DO concentrations.


Changes in ethnic identity and competence in middle adolescents.
Evidence suggests that the construct of ethnic identity (EI) in adolescents changes over time and is related to factors including social connectedness, social competence, coping, and self-worth. Transitional changes of EI in middle adolescence have not been studied. This analysis, part of a longitudinal study of health behaviors, explored how EI changes from the first year of high school to the last, and it examined relationships among EI, social connectedness, indicators of social competence, coping, and self-worth in 602 youth (49% Hispanic, 59% female). EI was significantly related to social connectedness, social competence, coping, and self-worth as adolescents entered and prepared to exit high school. EI increased significantly over time for both genders and for Hispanics more so than for non-Hispanics. Findings support and extend the conceptual framework and previous research. Socialization with one's ethnic group is associated with developing competence and self-worth. EI development continues throughout high school. Findings extend our understanding of the salience of EI in adolescents in transition throughout high school. Strengthening EI may contribute to adolescents' feelings of self-worth, skills in coping, and competence within an ethnically diverse society. Nurses might plan interventions to strengthen EI throughout adolescence.


Endovascular approach to treating secondary arterioureteral fistula.
Two patients with the rare entity of arterio-ureteral fistula are presented. Both highlight the predisposing factors of radiation, major surgery in the region, history of vascular surgery and presence of double-J-stent. Both patients presented with the clinical sign of intermittent gross hematuria. Both patients were successfully treated by endovascular intervention using graft covered stent.


Colorectal cancer and genetic polymorphism of DNA double-strand break repair gene XRCC4 in Taiwan.
The DNA repair gene X-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) is thought to play a major role in the caretaking of the whole genome via double-strand break repair. However, the association of polymorphic variants of XRCC4 with colorectal cancer susceptibility has never been reported. In this hospital-based case-control study, the association of XRCC4 polymorphisms C-1622T (rs7727691), G-1394T (rs6869366), G-652T (rs2075685), C-571T (rs2075686), intron 3 DIP (rs28360071), S247A (rs3734091) and intron 7 DIP (rs28360317) with colorectal cancer risk in a Taiwanese population was investigated. The genotypes of XRCC4 of 370 patients with colorectal cancer and 370 age- and gender-matched healthy controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. We found significant differences in the genetic and allelic frequencies of the XRCC4 G-1394T between the colorectal cancer and control groups (p=0.0003 and 8.32 x 10(-5), respectively). The distributions of other genetic polymorphisms between cases and the control group were not significantly different. We conclude that the G allele of XRCC4 G-1394T may contribute to colorectal carcinogenesis and may be useful for early detection of colorectal cancer.


A Systematic Review on Opuntia (Cactaceae; Opuntioideae) Flower-Visiting Insects in the World with Emphasis on Mexico: Implications for Biodiversity Conservation.
Opuntia spp. are cacti with high ecological, economic and conservation interest in semiarid environments, particularly in Mexico. We conducted a systematic search of the existing peer-reviewed literature about the state of knowledge of pollination ecology on these plants. We documented the most studied Opuntia species worldwide with an emphasis on Mexico. We found that only 15% of Opuntia species described have been investigated so far, and studies were mainly focused on comprehension of the biology of a single species. Despite the economic and cultural importance of Opuntia, there is a significant lack of knowledge about the flower-visiting insects and their taxonomic identity. We provide a checklist of the insect species associated with Opuntia spp. Through a circular network, we visualize the complex Opuntia flower-visiting insect relationship, and we detected a set of key species constituting the generalist core of the networks constructed. Since pollination is crucial for crop production, a better understanding of ecological interactions would inform management measures to strengthen biodiversity and agriculture sustainability as well as productivity in arid and marginal lands. Further research on pollination ecology is needed to improve the conservation status of the insects associated with Opuntia species.


Supplementation with vitamin D3 during pregnancy protects against lipopolysaccharide-induced neural tube defects through improving placental folate transportation.
Several reports demonstrated that maternal lipopolysaccharide (LPS) exposure at middle gestational stage caused neural tube defects (NTDs). This study investigated the effects of supplementation with vitamin D3 (VitD3) during pregnancy on LPS-induced NTDs. Pregnant mice except controls were ip injected with LPS (25 μg/kg) daily from gestational day (GD)8 to GD12. In LPS+VitD3 group, pregnant mice were orally administered with VitD3 (25 μg/kg) before LPS injection. As expected, a 5-day LPS injection resulted in 62.5% (10/16) of dams and 20.3% of fetuses with NTDs. Additional experiment showed that a 5-day LPS injection downregulated placental proton-coupled folate transporter (pcft) and reduced folate carrier 1 (rfc1), 2 major folate transporters in placentas. Consistent with downregulation of placental folate transporters, folate transport from maternal circulation into embryos was disturbed in LPS-treated mice. Interestingly, VitD3 not only inhibited placental inflammation but also attenuated LPS-induced downregulation of placental folate transporters. Correspondingly, VitD3 markedly improved folate transport from maternal circulation into the embryos. Importantly, supplementation with VitD3 during pregnancy protected mice from LPS-induced NTDs. Taken together, these results suggest that supplementation with VitD3 during pregnancy prevents LPS-induced NTDs through inhibiting placental inflammation and improving folate transport from maternal circulation into the embryos.


Severe adhesive constrictive pericarditis after coronary artery bypass.
The patient described presented with typical clinical symptoms of constrictive pericarditis nine months after triple saphenous vein bypass. No cause could be found. Cardiac catheterization confirmed the clinical diagnosis. At pericardiectomy a severely thickened pericardium which was intimately adherent to the heart and great vessels made its resection technically impossible.


The relationship between cepstral peak prominence and selected parameters of dysphonia.
Traditional measures of dysphonia vary in their reliability and in their correlations with perceptions of grade. Measurements of cepstral peak prominence (CPP) have been shown to correlate well with perceptions of breathiness. Because it is a measure of periodicity, CPP should also predict roughness. The ability of CPP and other acoustic measures to predict overall dysphonia and the subcategories of breathiness and roughness in pathological voice samples is explored. Preoperative and postoperative speech samples from 19 patients with unilateral recurrent laryngeal nerve paralysis who underwent operative intervention were analyzed by trained listeners and by measures of smoothed CPP (CPPS), noise-to-harmonic ratio (NHR), amplitude perturbation quotient (APQ), relative average perturbation (RAP), and smoothed pitch perturbation quotient (sPPQ). The data were analyzed with bivariate Pearson correlation statistics. Grade of dysphonia and breathiness ratings correlated better with measurements of CPPS than with the other measures. CPPS from samples of connected speech (CPPS-s) best predicted overall dysphonia. None of the measures were useful in predicting roughness.


Mass spectrometric behaviour of carboxylated polyethylene glycols and carboxylated octylphenol ethoxylates.
Mass spectrometric behaviour of mono- and di-carboxylated polyethylene glycols (PEGCs and CPEGCs) and carboxylated octylphenol ethoxylates (OPECs) are discussed. The tendency for ionisation (deprotonation, protonation and cationisation by alkali metal cations) of carboxylated PEGs was compared with that of non-carboxylated correspondents by using both secondary ion mass spectrometry (SIMS) and electrospray ionisation (ESI). The fragmentation of the PEGCs and CPEGCs is discussed and also compared with their neutral correspondents, PEGs. The B/E mass spectra were recorded, using secondary ion mass spectrometry as a method for generation, for deprotonated and protonated molecules and molecules cationised by alkali metal cations. The fragmentation behaviour of PEGs is found to be different from that of CPEGCs, The presence of carboxylic groups may be confirmed not only by the determination of molecular weights of the ethoxylates studied, but also on the basis of the fragment ions formed. The metastable decomposition of the [OPEC-H](-) ions proceed through the cleavage of the bond between the octylphenol moiety and the ethoxylene chain leading to the octylphenoxy anions. It permits determination of the mass of the hydrophobic moiety of the studied carboxylated alkylphenol ethoxylate. ESI mass spectra recorded in the negative ion mode were found to be more suitable for the determination of the average molecular weight of carboxylated ethoxylates than SI mass spectra.


The miR-9-5p/CXCL11 pathway is a key target of hydrogen sulfide-mediated inhibition of neuroinflammation in hypoxic ischemic brain injury.
We previously showed that hydrogen sulfide (H2S) has a neuroprotective effect in the context of hypoxic ischemic brain injury in neonatal mice. However, the precise mechanism underlying the role of H2S in this situation remains unclear. In this study, we used a neonatal mouse model of hypoxic ischemic brain injury and a lipopolysaccharide-stimulated BV2 cell model and found that treatment with L-cysteine, a H2S precursor, attenuated the cerebral infarction and cerebral atrophy induced by hypoxia and ischemia and increased the expression of miR-9-5p and cystathionine β synthase (a major H2S synthetase in the brain) in the prefrontal cortex. We also found that an miR-9-5p inhibitor blocked the expression of cystathionine β synthase in the prefrontal cortex in mice with brain injury caused by hypoxia and ischemia. Furthermore, miR-9-5p overexpression increased cystathionine-β-synthase and H2S expression in the injured prefrontal cortex of mice with hypoxic ischemic brain injury. L-cysteine decreased the expression of CXCL11, an miR-9-5p target gene, in the prefrontal cortex of the mouse model and in lipopolysaccharide-stimulated BV-2 cells and increased the levels of proinflammatory cytokines BNIP3, FSTL1, SOCS2 and SOCS5, while treatment with an miR-9-5p inhibitor reversed these changes. These findings suggest that H2S can reduce neuroinflammation in a neonatal mouse model of hypoxic ischemic brain injury through regulating the miR-9-5p/CXCL11 axis and restoring β-synthase expression, thereby playing a role in reducing neuroinflammation in hypoxic ischemic brain injury.


MtMOT1.2 is responsible for molybdate supply to Medicago truncatula nodules.
Symbiotic nitrogen fixation in legume root nodules requires a steady supply of molybdenum for synthesis of the iron-molybdenum cofactor of nitrogenase. This nutrient has to be provided by the host plant from the soil, crossing several symplastically disconnected compartments through molybdate transporters, including members of the MOT1 family. Medicago truncatula Molybdate Transporter (MtMOT) 1.2 is a Medicago truncatula MOT1 family member located in the endodermal cells in roots and nodules. Immunolocalization of a tagged MtMOT1.2 indicates that it is associated to the plasma membrane and to intracellular membrane systems, where it would be transporting molybdate towards the cytosol, as indicated in yeast transport assays. Loss-of-function mot1.2-1 mutant showed reduced growth compared with wild-type plants when nitrogen fixation was required but not when nitrogen was provided as nitrate. While no effect on molybdenum-dependent nitrate reductase activity was observed, nitrogenase activity was severely affected, explaining the observed difference of growth depending on nitrogen source. This phenotype was the result of molybdate not reaching the nitrogen-fixing nodules, since genetic complementation with a wild-type MtMOT1.2 gene or molybdate-fortification of the nutrient solution, both restored wild-type levels of growth and nitrogenase activity. These results support a model in which MtMOT1.2 would mediate molybdate delivery by the vasculature into the nodules.


Biochemical and molecular studies using human autopsy brain tissue.
The use of human brain tissue obtained at autopsy for neurochemical, pharmacological and physiological analyses is reviewed. RNA and protein samples have been found suitable for expression profiling by techniques that include RT-PCR, cDNA microarrays, western blotting, immunohistochemistry and proteomics. The rapid development of molecular biological techniques has increased the impetus for this work to be applied to studies of brain disease. It has been shown that most nucleic acids and proteins are reasonably stable post-mortem. However, their abundance and integrity can exhibit marked intra- and intercase variability, making comparisons between case-groups difficult. Variability can reveal important functional and biochemical information. The correct interpretation of neurochemical data must take into account such factors as age, gender, ethnicity, medicative history, immediate ante-mortem status, agonal state and post-mortem and post-autopsy intervals. Here we consider issues associated with the sampling of DNA, RNA and proteins using human autopsy brain tissue in relation to various ante- and post-mortem factors. We conclude that valid and practical measures of a variety of parameters may be made in human brain tissue, provided that specific factors are controlled.


[Quantum chemistry analysis of the mechanism of action of proteolytic enzymes. III. Proton transport in serine proteases].
The model system for the proton transfer on the amide atom of the substrate leaving group based on the existence of "charge relay system" in the serine type proteases was analysed by the CNDO/2 method. The unfitness of this model to explain the action mechanism of serine proteases was shown. The model system for proton transfer with the water molecule as the intermediate acceptor of the Ser-195 proton was suggested and analysed by the same method. The acylation activation barrier of this system was shown to localize on the stage of synchronous transfer of the Ser-195 alcoholic proton and the water molecule proton hydrogen bound to the His-57 N epsilon 2-atom on the water molecule oxygen atom and the N epsilon 2-atom, respectively. The protonation of substrate in the case of the model system with the water molecule as the intermediate acceptor of proton was demonstrated to begin before the completion of the tetrahedral intermediate substance and the protonated from of the tetrahedral intermediate was shown to form only. A hypothesis considering the role of this water molecule as the nucleophilic reagent on the deacylation stage is presented.


Does a culture of happiness increase rumination over failure?
Promoting happiness within society is good for health, but could the overpromotion of happiness have a downside? Across 2 studies, we investigate 2 emotion norms associated with an emphasis on happiness-the importance of (a) seeking positive emotion, and (b) avoiding negative emotion-and whether these norms have implications for how people respond to, and seek to regulate, their negative emotional experiences. In Study 1, we used an experimental design to show that emphasizing the importance of happiness increased rumination in response to failure. In Study 2, we drew on cross-sectional evidence to investigate the other side of this equation, finding that emphasizing the importance of not experiencing negative emotional states (e.g., depression and anxiety) was also associated with increased rumination, and that this had downstream consequences for well-being. Together, the findings suggest that the overpromotion of happiness, and, in turn, the felt social pressure not to experience negative emotional states, has implications for maladaptive responses to negative emotional experiences. (PsycINFO Database Record


Myocardial Edema, Myocyte Injury, and Disease Severity in Fabry Disease.
Background Cardiovascular magnetic resonance can demonstrate myocardial processes in Fabry disease (FD), such as low native T1 (sphingolipid storage) and late gadolinium enhancement (LGE, scar). Recently, high T2 (edema) has been observed in the basal inferolateral wall along with troponin elevation. We hypothesized that edema and myocyte injury would be chronically associated and have electrical, mechanical, and disease associations in FD. Methods A prospective international multicenter study was conducted on 186 consecutive FD patients (45.2±1.1 years, 58% females). Additionally, 28 patients with hypertrophic cardiomyopathy, 30 with chronic myocardial infarction and 59 healthy volunteers were included. All study participants underwent comprehensive cardiovascular magnetic resonance with T1 and T2 mapping, cines, and LGE imaging. Results LGE in the basal inferolateral wall in FD had T2 elevation (FD 58.2±5.0 ms versus hypertrophic cardiomyopathy 55.6±4.3 ms, chronic myocardial infarction 53.7±3.4 ms and healthy volunteers 48.9±2.5 ms, P<0.001), but when LGE was present there was also global T2 elevation (53.1±2.9 versus 50.6±2.2 ms, P<0.001). Thirty-eight percent of FD patients had high troponin. The strongest predictor of increased troponin was high basal inferolateral wall T2 (odds ratio, 18.2 [95% CI, 3.7-90.9], P<0.0001). Both T2 and troponin elevations were chronic over 1 year. High basal inferolateral wall T2 was associated with baseline global longitudinal strain impairment (P=0.005) and electrocardiographic abnormalities (long PR, complete bundle branch block, left ventricular hypertrophy voltage criteria, long QTc, and T-wave inversion, all P<0.05) and predicted clinical worsening after 1 year (Fabry stabilization index >20%, P=0.034). Conclusions LGE in Fabry has chronic local T2 elevation that is strongly associated with chronic troponin elevation. In addition, there is slight global T2 elevation. Both are associated with ECG and mechanical changes and clinical worsening over 1 year.


Occlusive disease of the vessels of the aortic arch-diagnosis and management.
Physicians should be alert to the possibility of occlusion of one or more of the branches of the aortic arch in any patient having neurologic symptoms or complaint of claudication in the upper extremities. The finding of a pulse deficit in the neck or arm and a blood pressure difference of more than 30 mm of mercury between the two arms is pathognomic of this disease. The presence of the occlusive process can be confirmed and its extent determined by angiography.Vascular reconstruction can be expected to restore normal hemodynamics with gratifying relief of symptoms in the majority of cases.


Single-photon emission tomography of a computerised model of pulmonary embolism.
Planar pulmonary scintigraphy is currently the standard investigation for the diagnosis of pulmonary embolism. There are a number of problems with the technique, particularly in patients with an intermediate scan report under the PIOPED criteria. The technique is also under threat from the increasing use of spiral CT angiography. A putative improvement may be gained by use of tomography. The incremental value of tomography over planar studies was therefore evaluated in a virtual model of pulmonary scintigraphy. A model of the segmental anatomy of the lungs was developed from computed tomography, cadaveric human lungs and available anatomical texts. Counts were generated within the phantom by Monte Carlo simulation of photon emission. Eighteen single segmental lesions were interspersed with 47 subsegmental defects and displayed on an Icon reporting station. These were presented in the transaxial, sagittal and coronal planes to four experienced reporters to obtain assessment of defect size. Planar studies of the same defects were displayed to the same observers in the standard eight views with a normal study for comparison. With planar studies, the accuracy of estimation of defect size was 51% compared with 97% using tomographic studies. Defects in the medial basal segment of the right lower lobe were not identified in planar studies but were easily seen by all observers in the tomographic study. It is concluded that there is marked improvement in the accuracy of determination of defect size for tomographic studies over the planar equivalents. This is especially important in the lung bases, the most common reported site of pulmonary emboli. Tomography permits visualisation of defects in the medial basal segment of the right lung, which are not seen in planar studies.


Incidence and predictors of secondary fibromyalgia in an early arthritis cohort.
Secondary fibromyalgia (FM) is common among patients with inflammatory arthritis, but little is known about its incidence and the factors leading to its development. The authors examined the incidence of secondary FM in an early inflammatory arthritis cohort, and assessed the association between pain, inflammation, psychosocial variables and the clinical diagnosis of FM. Data from 1487 patients in the Canadian Early Arthritis Cohort, a prospective, observational Canadian cohort of early inflammatory arthritis patients were analysed. Diagnoses of FM were determined by rheumatologists. Incidence rates were calculated, and Cox regression models were used to determine HRs for FM risk. The cumulative incidence rate was 6.77 (95% CI 5.19 to 8.64) per 100 person-years during the first 12 months after inflammatory arthritis diagnosis, and decreased to 3.58 (95% CI 1.86 to 6.17) per 100 person-years 12-24 months after arthritis diagnosis. Pain severity (HR 2.01, 95% CI 1.17 to 3.46) and poor mental health (HR 1.99, 95% CI 1.09 to 3.62) predicted FM risk. Citrullinated peptide positivity (HR 0.48, 95% CI 0.26 to 0.88) was associated with decreased FM risk. Serum inflammatory markers and swollen joint count were not significantly associated with FM risk. The incidence of FM was from 3.58 to 6.77 cases per 100 person-years, and was highest during the first 12 months after diagnosis of inflammatory arthritis. Although inflammation was not associated with the clinical diagnosis of FM, pain severity and poor mental health were associated with the clinical diagnosis of FM. Seropositivity was inversely associated with the clinical diagnosis of FM.


[Herpetic brain stem encephalitis: report of an autopsied case with immunohistochemical and electron microscopy studies].
A post-mortem examined case of herpetic brainstem encephalitis is presented. Clinically, the patient had cephalalgia followed by ataxia, drowsiness and multiple palsies of some cranial nerves, developing into death in eight days. The pathologic examination of the brain showed necrotizing encephalitis in multiple foci limited to the brainstem, more distinctly in the pons and medulla oblongata. The technique of immunoperoxidase revealed rare glial cells with intranuclear immunoreactivity for herpes antigen. Rare viral particles with the morphological characteristics of the herpesvirus were identified in the nuclei of neurons in 10% formol fixed material. This is the second reported case of herpetic brainstem encephalitis confirmed by post-mortem examination. The pathway used by the virus to reach the central nervous system and its posterior dissemination to the oral cavity, the orbitofrontal region and the temporal lobes as well as to the brainstem, after a period of latency and reactivation, are discussed.


Mechanistic studies of Ser/Thr dehydration catalyzed by a member of the LanL lanthionine synthetase family.
Members of the LanL family of lanthionine synthetases consist of three catalytic domains, an N-terminal pSer/pThr lyase domain, a central Ser/Thr kinase domain, and a C-terminal lanthionine cyclase domain. The N-terminal lyase domain has sequence homology with members of the OspF family of effector proteins. In this study, the residues in the lyase domain of VenL that are conserved in the active site of OspF proteins were mutated to evaluate their importance for catalysis. In addition, residues that are fully conserved in the LanL family but not in the OspF family were mutated. Activity assays with these mutant proteins are consistent with a model in which Lys80 in VenL deprotonates the α-proton of pSer/pThr residues to initiate the elimination reaction. Lys51 is proposed to activate this proton by coordination to the carbonyl of the pSer/pThr, and His53 is believed to protonate the phosphate leaving group. These functions are very similar to the corresponding homologous residues in OspF proteins. On the other hand, recognition of the phosphate group of pSer/pThr appears to be achieved differently in VenL than in the OspF proteins. Arg156 and Lys103 are thought to interact with the phosphate group on the basis of a structural homology model.


Superior mesenteric artery (Wilkie's) syndrome: report of three cases and review of the literature.
Of the three cases of superior mesenteric artery (Wilkie's) syndrome presented, one was associated with anorexia nervosa; this association has not been reported before. Two patients were treated surgically with a duodenojejunostomy, and one was treated medically. Vascular compression of the duodenum is a controversial subject. The syndrome probably is more common than generally recognized and is underdiagnosed due to its exclusion from the differential diagnosis of small-bowel obstruction. Its recognition is important because early diagnosis of a partial obstruction may allow for medical rather than surgical intervention, as exemplified by our third case.


Associated ilium and femur from Koobi Fora, Kenya, and postcranial diversity in early Homo.
During the evolution of hominins, it is generally accepted that there was a shift in postcranial morphology between Australopithecus and the genus Homo. Given the scarcity of associated remains of early Homo, however, relatively little is known about early Homo postcranial morphology. There are hints of postcranial diversity among species, but our knowledge of the nature and extent of potential differences is limited. Here we present a new associated partial ilium and femur from Koobi Fora, Kenya, dating to 1.9 Ma (millions of years ago) that is clearly attributable to the genus Homo but documents a pattern of morphology not seen in eastern African early Homo erectus. The ilium and proximal femur share distinctive anatomy found only in Homo. However, the geometry of the femoral midshaft and contour of the pelvic inlet do not resemble that of any specimens attributed to H. erectus from eastern Africa. This new fossil confirms the presence of at least two postcranial morphotypes within early Homo, and documents diversity in postcranial morphology among early Homo species that may reflect underlying body form and/or adaptive differences.


Intraoperative pathologically-calibrated diagnosis of lymph nodes involved by breast cancer cells based on electrical impedance spectroscopy; a prospective diagnostic human model study.
Nodal status evaluation is a crucial step in determining prognostic factors and managing treatment strategies for breast cancer patients. Preoperative (CNB), intraoperative (SLNB), and even postoperative techniques (Formalin-Fixed Paraffin-Embedded sectioning, FFPE) have definite limitations of precision or sometimes are time-consuming for the result declaration. The primary purpose of this prospective study is to provide a precise complementary system for distinguishing lymph nodes (LNs) involved by cancerous cells in breast cancer patients intraoperatively. The proposed system, Electrical Lymph Scoring(ELS), is designed based on the dielectric properties of the under-test LNs. The system has a needle-shaped 2-electrode probe entered into SLNs or ALNs dissected from patients through standard surgical guidelines. Impedance magnitude in f = 1 kH (Z1kHz) and Impedance Phase Slope in frequency ranges of 100 kHz-500 kHz (IPS) were then extracted from the impedance spectroscopy data in a cohort study of 77 breast cancer patients(totally 282 dissected LNs) who had been undergone surgery before (n = 55) or after (n = 22) chemical therapies (non-neoadjuvant or neoadjuvant chemotherapy). A new admittance parameter(Yn') also proposed for LN detection in neoadjuvant chemotherapy patients. Considering the permanent pathology result as the gold standard checked by two independent expert pathologists, a significant correlation was observed between the presence of cancerous cells in LNs and individual ranges of the ELS electrical responses. Compared with normal LNs containing fatty ambient and immune cells, LNs involved by cancerous clusters would reduce the Z1kHz and increase the IPS. These changes correlate with fat metabolism by cancer cells due to their Fatty Acid Oxidation (FAO) in LN, which results in different dielectric properties between high and low-fat content of normal and cancerous LNs, respectively. By finding the best correlation between our defined impedimetric parameters and pathological states of tested LNs, a real-time intraoperative detection approach was developed for highly-sensitive (92%, P<0.001) diagnosis of involved sentinel or axillary LNs. The impact of real-time intraoperative scoring of SLNs would make a pre-estimation about the necessity of excising further LNs to help the surgeon for less invasive surgery, especially in the absence of frozen-section equipment.


Role of the CLOCK protein in the mammalian circadian mechanism.
The mouse Clock gene encodes a bHLH-PAS protein that regulates circadian rhythms and is related to transcription factors that act as heterodimers. Potential partners of CLOCK were isolated in a two-hybrid screen, and one, BMAL1, was coexpressed with CLOCK and PER1 at known circadian clock sites in brain and retina. CLOCK-BMAL1 heterodimers activated transcription from E-box elements, a type of transcription factor-binding site, found adjacent to the mouse per1 gene and from an identical E-box known to be important for per gene expression in Drosophila. Mutant CLOCK from the dominant-negative Clock allele and BMAL1 formed heterodimers that bound DNA but failed to activate transcription. Thus, CLOCK-BMAL1 heterodimers appear to drive the positive component of per transcriptional oscillations, which are thought to underlie circadian rhythmicity.


Association of the Est1 protein with telomerase activity in yeast.
The est1 mutant was previously identified because it is defective in telomere maintenance and displays a senescent phenotype. To see if Est1 might be a component of yeast telomerase, we examined immunoprecipitated Est1. The yeast telomerase RNA Tlc1 specifically coprecipitated with Est1. Furthermore, the Est1 immunoprecipitates contained a telomerase-like activity. As expected for yeast telomerase, the activity elongated telomeric primers, it required dGTP and dTTP but not dATP or dCTP, and it was sensitive to RNase A. Further evidence suggesting that the activity was telomerase was obtained from experiments using a TLC1-1 mutant strain, which has a mutant telomerase template containing dG residues. The activity immunoprecipitated from TLC1-1 mutant strains incorporated 32P-labeled dCTP, while activity from TLC1 strains did not. Use of different telomeric primer substrates revealed two distinguishable telomerase-like activities: one was dependent on TLC1, and one was not. The TLC1-independent activity may be due to a second yeast telomerase RNA, or it may be some other kind of activity.


Tonic Endocannabinoid Levels Modulate Retinal Signaling.
The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.


COMPUTER PROGRAMS: onesamp: a program to estimate effective population size using approximate Bayesian computation.
The estimation of effective population size from one sample of genotypes has been problematic because most estimators have been proven imprecise or biased. We developed a web-based program, onesamp that uses approximate Bayesian computation to estimate effective population size from a sample of microsatellite genotypes. onesamp requires an input file of sampled individuals' microsatellite genotypes along with information about several sampling and biological parameters. onesamp provides an estimate of effective population size, along with 95% credible limits. We illustrate the use of onesamp with an example data set from a re-introduced population of ibex Capra ibex.


Direct magnetic separation of immune cells from whole blood using bacterial magnetic particles displaying protein G.
Direct separation of target cells from mixed population, such as peripheral blood, umbilical cord blood, and bone marrow, is an essential technique for various therapeutic or diagnosis applications. In this study, novel particles were fabricated, and direct magnetic separation of immune cells from whole blood using such particles was performed. The magnetotactic bacterium Magnetospirillum magneticum AMB-1 synthesizes intracellular bacterial magnetic particles (BacMPs), and protein G was expressed on the surface of the BacMPs by gene fusion techniques with anchor proteins isolated from BacMP membrane. The BacMPs displaying protein G (protein G-BacMPs) had high binding capabilities to a wide range of antibody types, and various versions of protein G-BacMPs binding with different anti-CD monoclonal antibodies were constructed. Consequently, direct magnetic separation of immune cells from whole blood using protein G-BacMPs binding with anti-CD monoclonal antibodies was demonstrated. B lymphocytes (CD19+ cells) or T lymphocytes (CD3+ cells), which represent less than 0.05% in whole blood cells, were successfully separated at a purity level of more than 96%. This level was superior to that from previous reports using other magnetic separation approaches. The results of this study demonstrate the utility of protein G-BacMP and this particle may become a powerful tool for various therapeutic or diagnosis applications.


Class-switched memory B cells remodel BCRs within secondary germinal centers.
Effective vaccines induce high-affinity memory B cells and durable antibody responses through accelerated mechanisms of natural selection. Secondary changes in antibody repertoires after vaccine boosts suggest progressive rediversification of B cell receptors (BCRs), but the underlying mechanisms remain unresolved. Here, the integrated specificity and function of individual memory B cell progeny revealed ongoing evolution of polyclonal antibody specificities through germinal center (GC)-specific transcriptional activity. At the clonal and subclonal levels, single-cell expression of the genes encoding the costimulatory molecule CD83 and the DNA polymerase Polη segregated the secondary GC transcriptional program into four stages that regulated divergent mechanisms of memory BCR evolution. Our studies demonstrate that vaccine boosts reactivate a cyclic program of GC function in class-switched memory B cells to remodel existing antibody specificities and enhance durable immunological protection.


Quantitation of proteinuria by the use of protein-to-creatinine ratios in single urine samples.
Measurements of protein-to-creatinine ratios in single-voided urine samples were compared with 24-hour urinary protein excretions for quantitation of proteinuria in inpatients and outpatients. Patients included those representing a broad spectrum of renal diseases, a wide range of proteinuria, and various degrees of reduction in glomerular filtration rate. Protein-to-creatinine ratios in single-voided urine samples correlated well with measurements of 24-hour urinary protein. This simple single-voided test is reliable and useful in the screening, assessment, and follow-up of proteinuria and avoids the problems associated with 24-hour urine collection.


Chloroplasts as expression platforms for plant-produced vaccines.
Production of recombinant subunit vaccines from genes incorporated in the plastid genome is advantageous because of the attainable expression level due to high transgene copy number and the absence of gene silencing; biocontainment as a consequence of maternal inheritance of plastids and no transgene presence in the pollen; and expression of multiple transgenes in prokaryotic-like operons. We discuss the core technology of plastid transformation in Chlamydomonas reinhardtii, a unicellular alga, and Nicotiana tabacum (tobacco), a flowering plant species, and demonstrate the utility of the technology for the production of recombinant vaccine antigens.


Electrical power generation characteristics of PZT piezoelectric ceramics.
The electrical power generation characteristics of Mn-doped PZT ceramics responding to slow mechanical stress as well as to impact stress have been investigated. Although both the slow and impact stresses induce a reversible electrical response, the generation properties are distinctly different. Slow stress releases two output current peaks with opposite directions, responding to the increasing and decreasing part of the stress, respectively. However, impact stress produces a nearly one-directional signal. The output charge and energy by slow stress are found to be two orders of magnitude higher than that produced by impact stress. This work shows that the energy conversion efficiency of piezoelectric ceramics strongly depends on the method of stress application.


Sex effects in mouse prion disease incubation time.
Prion disease incubation time in mice is determined by many factors including PrP expression level, Prnp alleles, genetic background, prion strain and route of inoculation. Sex differences have been described in age of onset for vCJD and in disease duration for both vCJD and sporadic CJD and have also been shown in experimental models. The sex effects reported for mouse incubation times are often contradictory and detail only one strain of mice or prions, resulting in broad generalisations and a confusing picture. To clarify the effect of sex on prion disease incubation time in mice we have compared male and female transmission data from twelve different inbred lines of mice inoculated with at least two prion strains, representing both mouse-adapted scrapie and BSE. Our data show that sex can have a highly significant difference on incubation time. However, this is limited to particular mouse and prion strain combinations. No sex differences were seen in endogenous PrP(C) levels nor in the neuropathological markers of prion disease: PrP(Sc) distribution, spongiosis, neuronal loss and gliosis. These data suggest that when comparing incubation times between experimental groups, such as testing the effects of modifier genes or therapeutics, single sex groups should be used.


Responsiveness to epinephrine in adult spontaneously hypertensive rat tail artery: preferential mediation by postjunctional alpha 2-adrenoceptors.
We studied the role played by postjunctional adrenoceptors in the vasoconstrictor responses of perfused tail arteries of young prehypertensive (4-6 weeks old) and adult (14-16 weeks) spontaneously hypertensive rats (SHR) with norepinephrine (NE), phenylephrine and epinephrine. Age-matched Wistar normotensive rats (WNR) were also used. In tail artery of young SHR, as well as in age-matched WNR and adult WNR, responsiveness to the vasoconstrictor agents did not differ. Determination of KB values of prazosin using phenylephrine and epinephrine as agonists and analysis of Schild plots indicate that responsiveness to the vasoconstrictor agents in young SHR tail artery is mediated by alpha 1-adrenoceptors. Tail arteries of adult SHR were more responsive to epinephrine than were tail arteries of age-matched WNR. In tail arteries of adult SHR, the KB value of prazosin against epinephrine remains undetermined since the slope of the Schild plot statistically differs from 1.0 (0.32). These results strongly suggest that in perfused tail arteries of adult SHR, responses to epinephrine are also mediated by alpha 2-adrenoceptors. We postulate an important but unknown role for the interaction between epinephrine and postjunctional alpha 2-adrenoceptors in the development and maintenance of genetically-induced hypertension.


Thermodynamic characterization of the biocompatible ionic liquid effects on protein model compounds and their functional groups.
The stability of proteins under co-solvent conditions is dependant on the nature of the co-solvent; the co-solvent can alter a protein's properties and structural effects through bimolecular interactions between its functional groups and co-solvent particles. Ionic liquids (ILs) represent a rather diverse class of co-solvents that are combinations of different ions, which are liquids at or close to room temperature. To quantify the bimolecular interactions of protein functional groups with biocompatible ILs, we report the systematic and quantitative apparent transfer free energies (ΔG'(tr)) of a homologous series of cyclic dipeptides (CDs) from water to aqueous solutions of ILs through solubility measurements, as a function of IL concentration at 25 °C under atmospheric pressure. The materials investigated in the present work included the CDs of cyclo(Gly-Gly), cyclo(Ala-Gly), cyclo(Ala-Ala), cyclo(Leu-Ala), and cyclo(Val-Val). The ILs used such as diethylammonium acetate ([Et(2)NH][CH(3)COO], DEAA), triethylammonium acetate ([Et(3)NH][CH(3)COO], TEAA), diethylammonium dihydogen phosphate ([Et(3)NH][H(2)PO(4)], DEAP), triethylammonium dihydogen phosphate ([Et(3)NH][H(2)PO(4)], TEAP), diethylammonium sulfate ([Et(3)NH][HSO(4)], DEAS) and triethylammonium sulfate ([Et(3)NH][HSO(4)], TEAS). We observed positive values of ΔG'(tr) for CDs from water to ILs, indicating that interactions between ILs and CDs are unfavourable, which leads to stabilization of the native structure of CDs. The experimental results were further used for estimating the transfer free energies (Δg'(tr)) of the peptide bond (-CONH-), the peptide backbone unit (-CH(2)C=ONH-), and various functional groups from water to IL solutions. Our results explicitly elucidate that a series of all ammonium ILs act as stabilizers for tested model compounds through the exclusion of ILs from CDs surface.


[Female sexual functioning: the role of psychopathology].
In the study of the relationship between sexuality and psychopathology, female sexual functioning appears to be relatively poorly explored. In addition, most studies have been conducted on clinical samples, so that the question of whether non-clinically relevant psychopathological symptoms may have a negative impact on women's sexual response still remains unanswered. The aim of this study was to analyze the influence of psychopathology on specific phases of sexual functioning (desire, arousal, lubrication, orgasm, satisfaction) and pain in a sample of young women without psychiatric case history. Two questionnaires were administered to a sample of female students in Psychology of the University of Florence (n=75): the Symptom Checklist (SCL-90) to evaluate psychic distress and the Female Sexual Function Index (FSFI) for data collection on sexual functioning. 44 questionnaires were valid. The dimensions of SCL-90 explain a relatively high percentage of variance of the global severity index of sexuality (R²=0.49); significant predictors were: somatization (Beta=-0.75), depression (Beta=-0.89), anxiety (Beta=-0.79), and hostility (Beta=-0.48). The same variables were significant predictors, though at a lesser extent, for all the single dimensions of sexuality, with the exception of pain, on which only hostility had a significant correlation (Beta=-0.55). Although the small size and the peculiar characteristics of the sample do not allow to extrapolate the results, the findings of this study show that psychopathological dimensions can affect female sexual functioning at subclinical level in the absence of the confounding effect of drug therapy.


Ridle for sparse regression with mandatory covariates with application to the genetic assessment of histologic grades of breast cancer.
Many questions in statistical genomics can be formulated in terms of variable selection of candidate biological factors for modeling a trait or quantity of interest. Often, in these applications, additional covariates describing clinical, demographical or experimental effects must be included a priori as mandatory covariates while allowing the selection of a large number of candidate or optional variables. As genomic studies routinely require mandatory covariates, it is of interest to propose principled methods of variable selection that can incorporate mandatory covariates. In this article, we propose the ridge-lasso hybrid estimator (ridle), a new penalized regression method that simultaneously estimates coefficients of mandatory covariates while allowing selection for others. The ridle provides a principled approach to mitigate effects of multicollinearity among the mandatory covariates and possible dependency between mandatory and optional variables. We provide detailed empirical and theoretical studies to evaluate our method. In addition, we develop an efficient algorithm for the ridle. Software, based on efficient Fortran code with R-language wrappers, is publicly and freely available at https://sites.google.com/site/zhongyindaye/software . The ridle is useful when mandatory predictors are known to be significant due to prior knowledge or must be kept for additional analysis. Both theoretical and comprehensive simulation studies have shown that the ridle to be advantageous when mandatory covariates are correlated with the irrelevant optional predictors or are highly correlated among themselves. A microarray gene expression analysis of the histologic grades of breast cancer has identified 24 genes, in which 2 genes are selected only by the ridle among current methods and found to be associated with tumor grade. In this article, we proposed the ridle as a principled sparse regression method for the selection of optional variables while incorporating mandatory ones. Results suggest that the ridle is advantageous when mandatory covariates are correlated with the irrelevant optional predictors or are highly correlated among themselves.


Expression of histocompatibility antigens H-2K, -D, and -L is reduced in adenovirus-12-transformed mouse cells and is restored by interferon gamma.
Primary mouse cells transformed by adenovirus type 12 (Ad12) expressed negligible amounts of class I antigens H-2K, -D, and -L on the cell surface and were capable of forming tumors in syngeneic animals, whereas cells transformed by Ad5 continued to express class I antigens and were nontumorigenic. Cells from a tumor, generated by injection of Ad12-transformed mouse cells into a syngeneic mouse, also expressed low levels of H-2 antigens, indicating that this phenotype is maintained in vivo. In all Ad12-transformed cells, synthesis of the H-2 heavy chain was not detected whereas the beta 2-microglobulin light chain was synthesized. Furthermore, the level of cytoplasmic H-2 mRNA in the Ad12 lines was greatly reduced. Reduction of H-2 expression is instructed solely by the transforming region of the viral genome, since this repression occurred in cells transformed by a DNA fragment containing only Ad12 E1A and E1B genes. Addition of recombinant murine interferon gamma strongly stimulated expression of class I antigens in the Ad12 transformants as well as in cells from the Ad12 tumor. This result indicates that Ad12 does not preferentially transform cells that are deficient for class I genes and that Ad12 does not mutate the class I genes in cells it transforms. The correlation between tumorigenicity and loss of H-2 expression in Ad12-transformed cells is discussed.


Noninvasive evaluation of the effectiveness of endovascular AAA exclusion.
To evaluate the relationship between aneurysm sac pressure and endograft wall motion in vitro and in vivo and to compare this to sac volume changes after endovascular aneurysm repair. In a flow model of an aneurysm with a stent-graft in situ, sac pressure was incrementally increased by adding volume to an otherwise excluded sac; sac pressure waves were registered. Clinically, 43 patients who had unsupported endografts were monitored for stent-graft wall motion using electrocardiographically-guided M-mode ultrasonography. At 3 predetermined points in the cardiac cycle, 2 independent observers measured the maximal endograft diameter. Graft wall motion was then compared to changes in aneurysm thrombus volume (shrinking, static, growth) based on serial spiral computed tomographic angiography measurements. In the in vitro model, as the sac was incrementally pressurized, the initially static pressure waveform changed to a more dynamic waveform identical to that of the systemic pressure. Additionally, graft wall motion was noted visually when the pressure exceeded 40 mm; it became increasingly vigorous at higher pressures. The 0.13-cm wall motion in the growth group (n=5) was significantly larger than the 0.04 cm in the static group (n=19; p=0.012) and the 0.03 cm in the shrinking group (n=19; p=0.002). No significant difference was found between the static and the shrinking groups (p=0.209). Increases in sac pressure are reflected as increased wall motion in unsupported endografts. Clinically, increased endograft wall motion can be demonstrated by M-mode ultrasound; in growing aneurysms, the significant change in wall motion may suggest increased sac pressures as the etiology of the aneurysm growth.


Anterior corpectomy versus posterior laminoplasty for multilevel cervical myelopathy: a systematic review and meta-analysis.
Surgical strategy for multilevel cervical myelopathy resulting from cervical spondylotic myelopathy (CSM) or ossification of posterior longitudinal ligament (OPLL) still remains controversial. There are still questions about the relative benefit and safety of direct decompression by anterior corpectomy (CORP) versus indirect decompression by posterior laminoplasty (LAMP). To perform a systematic review and meta-analysis evaluating the results of anterior CORP compared with posterior LAMP for patients with multilevel cervical myelopathy. Systematic review and meta-analysis of cohort studies comparing anterior CORP with posterior LAMP for the treatment of multilevel cervical myelopathy due to CSM or OPLL from 1990 to December 2012. An extensive search of literature was performed in Pubmed, Embase, and the Cochrane library. The quality of the studies was assessed according to GRADE. The following outcome measures were extracted: pre- and postoperative Japanese orthopedic association (JOA) score, neurological recovery rate (RR), surgical complications, reoperation rate, operation time and blood loss. Two reviewers independently assessed each study for quality and extracted data. Subgroup analysis was conducted according to the mean number of surgical segments. A total of 12 studies were included in this review, all of which were prospective or retrospective cohort studies with relatively low quality. The results indicated that the mean JOA score system for cervical myelopathy and the neurological RR in the CORP group were superior to those in the LAMP group when the mean surgical segments were <3, but were similar between the two groups in the case of the mean surgical segments equal to 3 or more. There was no statistical difference in the surgical complication rate between the two groups when the mean surgical segments <3, but were significantly higher incidences of surgical complications and complication-related reoperation in the CORP group compared with the LAMP group in the case of the mean surgical segments equal to 3 or more. Besides, the operation time in the CORP group was longer than that in the LAMP group, and the average blood loss was significantly more in the CORP group compared with the LAMP group. Based on the results above, anterior CORP and fusion is recommended for the treatment of multilevel cervical myelopathy when the involved surgical segments were <3. Given the higher rates of surgical complications and complication-related reoperation and the higher surgical trauma associated with multilevel CORP, however, it is suggested that posterior LAMP may be the preferred method of treatment for multilevel cervical myelopathy when the involved surgical segments were equal to 3 or more. In addition, taking the limitations of this study into consideration, it was still not appropriate to draw a strong conclusion claiming superiority for CORP or LAMP. A well-designed, prospective, randomized controlled trial is necessary to provide objective data on the clinical results of both procedures.


Auditory performance in bald eagles and red-tailed hawks: a comparative study of hearing in diurnal raptors.
Collision with wind turbines is a conservation concern for eagles with population abundance implications. The development of acoustic alerting technologies to deter eagles from entering hazardous air spaces is a potentially significant mitigation strategy to diminish associated morbidity and mortality risks. As a prelude to the engineering of deterrence technologies, auditory function was assessed in bald eagles (Haliaeetus leucocephalus), as well as in red-tailed hawks (Buteo jamaicensis). Auditory brainstem responses (ABRs) to a comprehensive battery of clicks and tone bursts varying in level and frequency were acquired to evaluate response thresholds, as well as suprathreshold response characteristics of wave I of the ABR, which represents the compound potential of the VIII cranial nerve. Sensitivity curves exhibited an asymmetric convex shape similar to those of other avian species, response latencies decreased exponentially with increasing stimulus level and response amplitudes grew with level in an orderly manner. Both species were responsive to a frequency band at least four octaves wide, with a most sensitive frequency of 2 kHz, and a high-frequency limit of approximately 5.7 kHz in bald eagles and 8 kHz in red-tailed hawks. Findings reported here provide a framework within which acoustic alerting signals might be developed.


Polycitone A, a novel and potent general inhibitor of retroviral reverse transcriptases and cellular DNA polymerases.
Polycitone A, an aromatic alkaloid isolated from the ascidian Polycitor sp. exhibits potent inhibitory capacity of both RNA- and DNA-directed DNA polymerases. The drug inhibits retroviral reverse transcriptase (RT) [i.e. of human immunodeficiency virus type 1 (HIV), murine leukaemia virus (MLV) and mouse mammary tumour virus (MMTV)] as efficiently as cellular DNA polymerases (i.e. of both DNA polymerases alpha and beta and Escherichia coli DNA polymerase I). The mode and mechanism of inhibition of the DNA-polymerase activity associated with HIV-1 RT by polycitone A have been studied. The results suggest that the inhibitory capacity of the DNA polymerase activity is independent of the template-primer used. The RNase H function, on the other hand, is hardly affected by this inhibitor. Polycitone A has been shown to interfere with DNA primer extension as well as with the formation of the RT-DNA complex. Steady-state kinetic studies demonstrate that this inhibitor can be considered as an allosteric inhibitor of HIV-1 RT. The target site on the enzyme may be also spatially related to the substrate binding site, since this inhibitor behaves competitively with respect to dTTP with poly(rA).oligo(dT) as template primer. Chemical transformations of the five phenol groups of polycitone A by methoxy groups have a determinant effect on the inhibitory potency. Thus, the pentamethoxy derivative which is devoid of all hydroxy moieties, loses significantly, by 40-fold, the ability to inhibit the DNA polymerase function. Furthermore, this analogue lacks the ability to inhibit DNA primer extension as well as the formation of the RT-DNA complex. Indeed, inhibition of the first step in DNA polymerization, the formation of the RT-DNA complex, and hence, of the overall process, could serve as a model for a universal inhibitor of the superfamily of DNA polymerases.


Reversible protein phosphorylation modulates nucleotide excision repair of damaged DNA by human cell extracts.
Nucleotide excision repair of DNA in mammalian cells uses more than 20 polypeptides to remove DNA lesions caused by UV light and other mutagens. To investigate whether reversible protein phosphorylation can significantly modulate this repair mechanism we studied the effect of specific inhibitors of Ser/Thr protein phosphatases. The ability of HeLa cell extracts to carry out nucleotide excision repair in vitro was highly sensitive to three toxins (okadaic acid, microcystin-LR and tautomycin), which block PP1- and PP2A-type phosphatases. Repair was more sensitive to okadaic acid than to tautomycin, suggesting the involvement of a PP2A-type enzyme, and was insensitive to inhibitor-2, which exclusively inhibits PP1-type enzymes. In a repair synthesis assay the toxins gave 70% inhibition of activity. Full activity could be restored to toxin-inhibited extracts by addition of purified PP2A, but not PP1. The p34 subunit of replication protein A was hyperphosphorylated in cell extracts in the presence of phosphatase inhibitors, but we found no evidence that this affected repair. In a coupled incision/synthesis repair assay okadaic acid decreased the production of incision intermediates in the repair reaction. The formation of 25-30mer oligonucleotides by dual incision during repair was also inhibited by okadaic acid and inhibition could be reversed with PP2A. Thus Ser/Thr- specific protein phosphorylation plays an important role in the modulation of nucleotide excision repair in vitro.


RNA complementary to alfalfa mosaic virus RNA 4 is not translated in vitro.
cDNA of the subgenomic messenger RNA (RNA 4) of alfalfa mosaic virus was ligated in both orientations into plasmids containing the bacteriophage SP 6 promoter. Upon transcription in vitro these plasmids yielded synthetic full-length complementary RNA and messenger-sense RNA. The complementary RNA contained an open reading frame of 417 nucleotides; the messenger-sense RNA encodes the virus coat protein. No translation products from the complementary RNA were detected in a wheat germ translation system, a reticulocyte lysate translation system, or Xenopus oocytes, whereas the messenger sense RNA was very active in these translation systems.


An ultralong-acting tenofovir ProTide nanoformulation achieves monthslong HBV suppression.
Treatment of chronic hepatitis B virus (HBV) requires lifelong daily therapy. However, suboptimal adherence to the existing daily therapy has led to the need for ultralong-acting antivirals. A lipophilic and hydrophobic ProTide was made by replacing the alanyl isopropyl ester present in tenofovir alafenamide (TAF) with a docosyl phenyl alanyl ester, now referred to as M1TFV. NM1TFV and nanoformulated TAF (NTAF) nanocrystals were formulated by high-pressure homogenization. A single intramuscular injection of NM1TFV, but not NTAF, delivered at a dose of TFV equivalents (168 milligrams per kilogram) demonstrated monthslong antiviral activities in both HBV-transgenic and human hepatocyte transplanted TK-NOG mice. The suppression of HBV DNA in blood was maintained for 3 months. Laboratory experiments on HBV-transfected HepG2.2.15 cells affirmed the animal results and the critical role of docosanol in the sustained NM1TFV antiviral responses. These results provide clear "proof of concept" toward an emerging therapeutic paradigm for the treatment and prevention of HBV infection.


[Clinical profile and non-recreational methamphetamine abuse (shabu) among stroke patients in the Philippine population].
Chronic non-recreational use of methamphetamine (shabu) is increasing among the Filipino population in Barcelona. The Asian population presents a different stroke pattern, with a higher incidence of haemorrhage, and different vascular risk factors and health behaviours. The objective of this study is to describe the stroke profile and incidence of methamphetamine use in patients of Filipino origin admitted to our centre. Demographic data, vascular risk factors, clinical data and prognosis were recorded. Methamphetamine exposure was analysed in plasma samples collected on admission, which were then analysed by liquid chromatography-mass spectrometry. Of a total of 6,418 stroke patients, 73 (1.1%) were identified as being of Filipino origin. The mean age was 54.4 ± 12.1 years, 54% were male and the stroke was ischaemic in 64.4% of cases. Arterial hypertension was the main risk factor. Ten (13.7%) patients tested positive for methamphetamine and amphetamine. These results confirm recent substance use prior to the stroke, mostly in men (80%). In patients who were consumers, 60% had a haemorrhagic stroke, with a poor functional prognosis at three months in 55.6% of patients. In our setting, patients of Filipino ethnicity admitted for stroke related to the consumption of shabu belonged a younger age bracket, with a lower prevalence of vascular risk factors and a predominance of the haemorrhagic subtype. Methamphetamine testing in Filipino stroke patients is recommended due to the high prevalence of methamphetamine use in our country.


Meta-analysis of the impact of the principal venoactive drugs agents on malleolar venous edema.
The aim of this study was to compare the reduction of venous ankle edema in randomized controlled trials of the main venoactive drugs versus a placebo or versus another venoactive drug and thereby to confirm or invalidate the existing recommendations on the pharmacological treatment of venous edema. Publications of randomized controlled trials of venoactive drugs versus either a placebo or another venoactive drug on the reduction of ankle circumferences (AC) were searched through Medline and selected according to the Jadad and the Cucherat evaluation grids. Ten publications dated between 1975 and 2009 including a total of 1010 patients were identified for the meta-analysis. Included were the following venoactive drugs: micronised purified flavonoid fraction (MPFF), hydroxyethylrutoside, ruscus extracts and diosmin. The mean reduction in AC was -0.80 ± 0.53 cm with MPFF , -0.58 ± 0.47 cm with ruscus extract, -0.58 ± 0.31 cm with hydroxyethylrutoside, -0.20 ± 0.5 cm with single diosmin, and -0.11 ± 0.42 cm with placebo. The reduction in AC was significantly superior to that of placebo whatever the drug concerned (P<0.0001). The comparison between MPFF, ruscus extract and hydroxyethylrutoside on the reduction of ankle edema was in favour of MPFF. This was significant (P<0.0001), while the efficacy of the latter two venoactive agents was comparable. This meta-analysis confirms the validity of the grade A assigned to MPFF in the management of symptoms and edema in recent international guidelines.


Rho-kinase regulates extracellular matrix-mediated osteogenic differentiation of periodontal ligament cells.
The periodontal ligament (PDL) cells contain heterogeneous mesenchymal cell populations, which have the ability to differentiate into cells that produce adjacent mineralized tissues and abundant extracellular matrix (ECM). ECM is essential not only for the homeostasis of the periodontal tissue, but also for controlling the differentiation of the PDL cells. The process of differentiation involves mechanotransduction, which links the ECM to the cytoskeleton. The present study investigated the roles of Rho-associated coiled-coil containing protein kinase (ROCK) signaling, a crucial regulator of the cytoskeleton, during ECM-mediated osteogenic differentiation of PDL cells in vitro. The PDL cells were isolated from human periodontal ligaments of extracted teeth and cultured in osteogenic medium with or without Y-27632, a pharmacological inhibitor of ROCK. ECM-coated plates were used for ECM-mediated differentiation. The osteogenic phenotype was evaluated at different time points by real-time RT-PCR for the gene encoding alkaline phosphatase (ALP) and an ALP activity assay. The effects of ROCK on cytoskeletal changes and ECM synthesis were examined by immunofluorescence analysis. Y-27632 significantly inhibited ALP at the mRNA and protein activity levels in the late stage of differentiation; concomitantly, the actin filament content and the extracellular levels of collagen-I and fibronectin were markedly decreased by Y-27632. Exogenous collagen-I and fibronectin temporally increased ALP activity, with fibronectin showing a more pronounced effect. Importantly, ECM-mediated differentiation was almost completely inhibited by Y-27632. These findings indicated that ECM-mediated differentiation is dependent on ROCK signaling, and ROCK signaling contributes to the establishment of the ECM microenvironment for PDL cell differentiation.


Pharmacokinetics of T-2 toxin and its metabolite HT-2 toxin, after intravenous administration in dogs.
The pharmacokinetics of T-2 toxin and HT-2 toxin were investigated comparatively in five dogs, after iv administration of the toxins (0.4 mg/kg). T-2 toxin was very rapidly and almost completely biotransformed to HT-2 toxin (fm = 83.6 +/- 3.9%). The following mean pharmacokinetic parameters were determined in this study for T-2 toxin and HT-2 toxin, respectively: half-life 5.3 +/- 2.1 and 19.6 +/- 4.7 min, clearance 0.107 +/- 0.056 and 0.167 +/- 0.074 liters/min/kg, and volume of distribution 0.86 +/- 0.63 and 4.47 +/- 1.38 liters/kg. The high clearance values suggest that the metabolism of T-2 toxin and HT-2 toxin is carried out in blood and/or through diffusion by nonspecific carboxyesterases. The results of this study suggest the possibility of a sustenance of T-2 toxin metabolism by its binding to blood cells.


An evaluation of the effects of a dynamic lycra orthosis on arm function in a late stage patient with acquired brain injury.
The aim of this study was to assess the effect of a dynamic lycra orthosis in the management of upper limb paresis in a late stage stroke patient. A single case experiment, adopting a 3-phase ABA withdrawal design (without follow-up), approximately 6-weeks per phase, intervention being delivered in the middle/B phase. Assessment of arm function was carried out on a weekly basis for the 18-weeks, using a battery of upper limb tests. The subject was prescribed a tailor-made lycra orthosis which was worn daily during the middle phase of the trial. Orthosis wear appeared to result in improvements in active range of movement, self-rated function and one component of a writing test, with some suggestion of a carryover effect when treatment was withdrawn. No intervention-related changes were seen in a dressing test. Ambiguous results were seen in a further writing test and a peg board manipulation assessment. Irrespective of intervention, the subject made positive changes in scores in the majority of assessments used, throughout the 18-week period. The findings suggest that a lycra orthosis may have some beneficial effects on upper limb function late after brain injury. Results were however equivocal, suggesting (a) that effect mechanisms may be quite complex and (b) that future evaluations may require careful construction.


Presence of ethanol-sensitive glycine receptors in medium spiny neurons in the mouse nucleus accumbens.
The nucleus accumbens (nAc) is involved in addiction-related behaviour caused by several drugs of abuse, including alcohol. Glycine receptors (GlyRs) are potentiated by ethanol and they have been implicated in the regulation of accumbal dopamine levels. We investigated the presence of GlyR subunits in nAc and their modulation by ethanol in medium spiny neurons (MSNs) of the mouse nAc. We found that the GlyR α1 subunit is preferentially expressed in nAc and is potentiated by ethanol. Our study shows that GlyR α1 in nAc is a new target for development of novel pharmacological tools for behavioural intervention in drug abuse. Alcohol abuse causes major social, economic and health-related problems worldwide. Alcohol, like other drugs of abuse, increases levels of dopamine in the nucleus accumbens (nAc), facilitating behavioural reinforcement and substance abuse. Previous studies suggested that glycine receptors (GlyRs) are involved in the regulation of accumbal dopamine levels. Here, we investigated the presence of GlyRs in accumbal dopamine receptor medium spiny neurons (MSNs) of C57BL/6J mice, analysing mRNA expression levels and immunoreactivity of GlyR subunits, as well as ethanol sensitivity. We found that GlyR α1 subunits are expressed at higher levels than α2, α3 and β in the mouse nAc and were located preferentially in dopamine receptor 1 (DRD1)-positive MSNs. Interestingly, the glycine-evoked currents in dissociated DRD1-positive MSNs were potentiated by ethanol. Also, the potentiation of the GlyR-mediated tonic current by ethanol suggests that they modulate the excitability of DRD1-positive MSNs in nAc. This study should contribute to understanding the role of GlyR α1 in the reward system and might help to develop novel pharmacological therapies to treat alcoholism and other addiction-related and compulsive behaviours.


Risk factors for nontuberculous mycobacterial pulmonary disease (NTM-PD) in Croatia.
The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting. We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records. Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003). The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.


Is there any relation between coronary atherosclerosis and tympanosclerosis?
Atherosclerosis is a chronic inflammatory disease of medium and large-sized arteries. Tympanosclerosis is the hyalinization and calcification of the connective tissue in the middle ear, including the tympanic membrane. The etiology and pathogenesis of tympanosclerosis are still controversial. There are some reports about the possible relationship between development of tympanosclerosis and atherosclerosis. Therefore, we aimed a cross-sectional study to investigate relationship between tympanosclerosis and atherosclerosis in patients referred for coronary angiography. The study population consisted of 203 consecutive patients (145 men, mean age 59+/-11 years) who underwent coronary angiography. Otoscopic examination was performed in all patients. All angiographies were examined to calculate coronary artery vessel stenosis and extent scores. Mann-Whitney U test was used to compare the angiographic scores with existence of tympanosclerosis. Among the 203 patients, 35 (17%) patients had angiographically normal coronary arteries without any atheroma plaque and 168 (83%) had coronary atherosclerosis. In the otoscopic examination, tympanosclerosis was found in 14 patients (6.9%). No significant differences in distribution of clinical atherosclerotic risk factors (age, gender, body mass index, hypertension, diabetes mellitus, cigarette smoking and cholesterol levels) were found between groups with and without tympanosclerosis. Tympanosclerosis was found in 4 patients with normal coronary arteries (11.4%). In the group of coronary atherosclerosis, 10 patients have tympanosclerosis (5.9%). In addition, there was no statistically significant association of coronary artery vessel, stenosis or extent scores of atherosclerosis with tympanosclerosis (p>0.05). We could not find any association between tympanosclerosis and angiographic extent and severity of atherosclerosis, contrary to other studies. More studies are needed to understand etiological mechanisms and association between them.


[Short evaluation of the QBC-Vet Autoread System].
The QBC-Vet Autoread-System (QBC = Quantitative Buffy Coat) is an advanced version of the OBC-Vet Haematology-System, to which an automatic reader and a printer have been added. In addition to the determination of haematocrit, haemoglobin, MCHC, white blood cell, granulocyte, lympho-/monocyte and platelet counts, measurement of eosinophils and neutrophils in dogs, and the estimation of reticulocytes and nucleated red blood cells in both dogs and cats are possible. The aim of this study was to evaluate the QBC-Vet Autoread-System with respect to its suitability in veterinary practice. Samples collected from 213 mostly ill animals were analysed and the results compared with conventionally measured values. The system was found to be easy both in handling and interpretation of results. Accuracy was found to be good for the majority of the parameters (correlation coefficients: haematocrit r > 0.96, WBC r > 0.89). The printed buffy coat profile was found to be very useful to verify accuracy of results immediately and to prevent misinterpretations. Although this is a preliminary study with a small number of samples, the QBC-Vet Autoread-System was found to be a true improvement over the older system and will be very useful in veterinary practices.


In vivo MR tractography of thigh muscles using diffusion imaging: initial results.
The aims of this preliminary study were (1) to demonstrate the feasibility of providing in vivo 3D architecture of human thigh muscles using tractography on a 1.5T magnet, and (2) to assess the value of tractography images to obtain averaged microstructural parameters, i.e., the fractional anisotropy (FA) and the mean apparent diffusion coefficient (ADC), over the whole thigh. Five healthy volunteers were included in this study. Their right thighs were imaged using diffusion tensor imaging and gradient-echo T2* sequences. Muscular tractography was performed on each muscle. MR tractography provided a good approach of the muscle shape and of the orientation of the muscle fibers. There was no aberration in the color-encoding scheme nor in the luminosity assigned to each fiber. In contrast, tendons were not drawn in any of the muscles studied. FA values ranged from 0.27 to 0.38. Mean ADC values ranged from 0.76 to 0.96 x 10(-3) mm2/s. Our study demonstrated the feasibility of providing in vivo 3D architecture of human thigh muscles using tractography on a 1.5T magnet, and of determining muscular microstructural parameters (FA and ADC). Musculoskeletal radiologists should be aware of these new developments that may provide complementary information on muscles to the usual sequences.


Quercetin may repair the impaired oxidant-antioxidant balance in 1, 2, 3, 4-tetrachlorodibenzo-p-dioxin induced cardiac injury in male rats.
The purpose of this study was to evaluate the prophylactic effects of quercetin (QUE) against oxidative damages and histological changes induced by 1, 2, 3, 4-tetrachlorodibenzo-p-dioxin (TCDD) in rat heart. For this purpose, 20 adult male Wistar rats were divided into four groups as fellow control group, TCDD group (10µg/kg BW/day by gavage daily for 60 consecutive days), QUE group (30 mg/kg BW/day) and TCDD + QUEgroup. The oxidative biomarkers of heart tissue and the levels of cTnI and lipid profile in serum were measured. Our results showed that the cTnI serum level and the heart lipid peroxidation significantly increased and the heart level of antioxidant profile significantly decreased in the TCDD group compared to control and QUEgroups. While pretreatment with QUEcould significantly improved these factors in serum and heart tissue in animals that consumed TCDD. It can be concluded that QUEat doses of 30 mg/kg/day could alleviate heart oxidative damage and histological changes induced by TCDD.


A Data Set and Deep Learning Algorithm for the Detection of Masses and Architectural Distortions in Digital Breast Tomosynthesis Images.
Breast cancer screening is among the most common radiological tasks, with more than 39 million examinations performed each year. While it has been among the most studied medical imaging applications of artificial intelligence, the development and evaluation of algorithms are hindered by the lack of well-annotated, large-scale publicly available data sets. To curate, annotate, and make publicly available a large-scale data set of digital breast tomosynthesis (DBT) images to facilitate the development and evaluation of artificial intelligence algorithms for breast cancer screening; to develop a baseline deep learning model for breast cancer detection; and to test this model using the data set to serve as a baseline for future research. In this diagnostic study, 16 802 DBT examinations with at least 1 reconstruction view available, performed between August 26, 2014, and January 29, 2018, were obtained from Duke Health System and analyzed. From the initial cohort, examinations were divided into 4 groups and split into training and test sets for the development and evaluation of a deep learning model. Images with foreign objects or spot compression views were excluded. Data analysis was conducted from January 2018 to October 2020. Screening DBT. The detection algorithm was evaluated with breast-based free-response receiver operating characteristic curve and sensitivity at 2 false positives per volume. The curated data set contained 22 032 reconstructed DBT volumes that belonged to 5610 studies from 5060 patients with a mean (SD) age of 55 (11) years and 5059 (100.0%) women. This included 4 groups of studies: (1) 5129 (91.4%) normal studies; (2) 280 (5.0%) actionable studies, for which where additional imaging was needed but no biopsy was performed; (3) 112 (2.0%) benign biopsied studies; and (4) 89 studies (1.6%) with cancer. Our data set included masses and architectural distortions that were annotated by 2 experienced radiologists. Our deep learning model reached breast-based sensitivity of 65% (39 of 60; 95% CI, 56%-74%) at 2 false positives per DBT volume on a test set of 460 examinations from 418 patients. The large, diverse, and curated data set presented in this study could facilitate the development and evaluation of artificial intelligence algorithms for breast cancer screening by providing data for training as well as a common set of cases for model validation. The performance of the model developed in this study showed that the task remains challenging; its performance could serve as a baseline for future model development.


Engineering stable carbonic anhydrases for CO2 capture: a critical review.
Targeted inhibition of misregulated protein-protein interactions (PPIs) has been a promising area of investigation in drug discovery and development for human diseases. However, many constraints remain, including shallow binding surfaces and dynamic conformation changes upon interaction. A particularly challenging aspect is the undesirable off-target effects caused by inherent structural similarity among the protein families. To tackle this problem, phage display has been used to engineer PPIs for high-specificity binders with improved binding affinity and greatly reduced undesirable interactions with closely related proteins. Although general steps of phage display are standardized, library design is highly variable depending on experimental contexts. Here in this review, we examined recent advances in the structure-based combinatorial library design and the advantages and limitations of different approaches. The strategies described here can be explored for other protein-protein interactions and aid in designing new libraries or improving on previous libraries.


Exploring presentations of sustainability by US synthetic biology companies.
The field of synthetic biology is increasingly being positioned as a key driver of a more sustainable, bio-based economy, and has seen rapid industry growth over the past 15 years. In this paper we undertake an exploratory investigation of the relationship between sustainability and synthetic biology, identifying and analyzing sustainability-related language on the public websites of 24, US-based synthetic biology companies. We observe that sustainability is a visible part of the self-presentation of the nascent synthetic biology industry, explicitly mentioned by 18 of the 24 companies. The dominant framing of sustainability on these company websites emphasizes environmental gains and "free-market" approaches to sustainability, with little explicit mention of social dimensions of sustainability such as access, justice or intergenerational equity. Furthermore, the model of sustainability presented focuses on incremental transition towards environmental sustainability through direct substitution of products and processes using bioengineered alternatives (n = 16 companies), with no change in societal consumption or policy frameworks required in order to see sustainability gains. One-third of the companies analyzed (n = 8) mention "nature" on their websites, variously framing it as a resource to be managed or as a source of inspiration; whether the latter signals a potentially more complex relationship with nature than advanced free-market models of sustainability remains to be seen. As the synthetic biology industry begins to grow in size and visibility, we suggest this is an opportune time for the community to engage in explicit deliberation about its approach to sustainability.


Plasticity matches phenotype to local conditions despite genetic homogeneity across 13 snake populations.
In a widespread species, a matching of phenotypic traits to local environmental optima is generally attributed to site-specific adaptation. However, the same matching can occur via adaptive plasticity, without requiring genetic differences among populations. Adult sea kraits (Laticauda saintgironsi) are highly philopatric to small islands, but the entire population within the Neo-Caledonian Lagoon is genetically homogeneous because females migrate to the mainland to lay their eggs at communal sites; recruits disperse before settling, mixing up alleles. Consequently, any matching between local environments (e.g. prey sizes) and snake phenotypes (e.g. body sizes and relative jaw sizes (RJSs)) must be achieved via phenotypic plasticity rather than spatial heterogeneity in gene frequencies. We sampled 13 snake colonies spread along an approximately 200 km northwest-southeast gradient (n > 4500 individuals) to measure two morphological features that affect maximum ingestible prey size in gape-limited predators: body size and RJS. As proxies of habitat quality (HQ), we used protection status, fishing pressure and lagoon characteristics (lagoon width and distance of islands to the barrier reef). In both sexes, spatial variation in body sizes and RJSs was linked to HQ; albeit in different ways, consistent with sex-based divergences in foraging ecology. Strong spatial divergence in morphology among snake colonies, despite genetic homogeneity, supports the idea that phenotypic plasticity can facilitate speciation by creating multiple phenotypically distinct subpopulations shaped by their environment.


A Comparative Study of Effect of 0.25% Levobupivacaine with Dexmedetomidine versus 0.25% Levobupivacaine in Ultrasound-Guided Supraclavicular Brachial Plexus Block.
Dexmedetomidine, an α2-agonist, has been studied widely as an adjuvant to local anesthetics in regional anesthesia techniques to enhance the quality and duration of analgesia (DOA). It was hypothesized that addition of dexmedetomidine 0.5 ug.kg‒1 to levobupivacaine would prolong the DOA. We aimed to evaluate the efficacy of dexmedetomidine as an adjuvant to levobupivacaine in supraclavicular brachial plexus block with respect to onset and duration of sensory and motor blockade, and duration of analgesia. This was a prospective randomized double-blind study carried out at a tertiary hospital attached to medical college. Sixty American Society of Anesthesiologists PS Class I and II patients aged between 18 and 60 years of either sex, undergoing elective upper-limb surgery lasting more than 30 min, were included in the study. They were randomly divided into two groups of thirty each to receive ultrasound-guided supraclavicular brachial plexus block. Group L was given nerve block with 20 mL of 0.25% levobupivacaine and 1 mL saline, and Group D received 20 mL of 0.25% levobupivacaine with 0.5 ug.kg‒1 of dexmedetomidine (diluted to volume of 1 mL). Onset time and duration of sensory and motor blockade, time to first rescue analgesia, and hemodynamic parameters were recorded. Chi-square test for qualitative variables and Student's unpaired "t" test for continuous variables were used for statistical analysis. The onset of sensory and motor blockade was 6.51 ± 0.77 min and 10.71 ± 0.34 min in Group D and 9.9 ± 0.45 and 15.93 ± 1.92 min in Group L, respectively (P < 0.005). DOA was 9.53 ± 0.29 h in Group D and 3.89 ± 0.30 h in Group L (P < 0.001). The duration of sensory and motor block was 9.14 ± 0.19 h and 8.55 ± 0.31 h in Group D and 6.15 ± 3.02 and 5.61 ± 2.98 h in Group L, respectively (P < 0.005). No adverse effects were observed in either of the groups. Addition of 0.5 ug.kg‒1 of dexmedetomidine to 20 mL 0.25% levobupivacaine in ultrasound guided (USG)-guided supraclavicular brachial plexus block shortens the onset time of sensory and motor blockade and prolongs duration of sensory and motor block and DOA.


Ca2+ release from sarcoplasmic reticulum of skinned fast- and slow-twitch muscle fibers.
We have performed a comparative study of Ca2+ release from the sarcoplasmic reticulum (SR) of chemically skinned fibers from rabbit fast- and slow-twitch skeletal muscle. Ca2+ fluxes have been indirectly monitored by following either tension development or the inhibition of net Ca2+-loading rate by a light-scattering method. Several drugs (Ca2+-release modulators) have been used to either trigger or block Ca2+ release. Our results indicate that caffeine, doxorubicin, and ryanodine activate Ca2+ release, whereas ruthenium red blocks Ca2+ release from both fast- and slow-twitch skinned fibers. Caffeine has greater affinity for slow SR, whereas doxorubicin, ruthenium red, and ryanodine have greater affinity for fast SR. Our results indicate that Ca2+-release mechanisms in fast and slow SR are homologous but not identical and that differences in twitch-contraction time might be also related to the inherent properties of the Ca2+-release mechanism.


Different Targets of Monoclonal Antibodies in Neuromyelitis Optica Spectrum Disorders: A Meta-Analysis Evidenced From Randomized Controlled Trials.
Background: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune inflammatory disorder of the central nervous system, often leads to vision loss or paralysis. This meta-analysis focused on the assessment of the monoclonal antibody therapy in NMOSD and compared different targets of monoclonal antibodies with each other in terms of efficacy and safety outcomes. Method: We searched through the databases of MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov for randomized controlled trials (RCTs) evaluating monoclonal antibody therapy in NMOSD up to April 2020. Results: We identified seven randomized controlled trials (RCTs), including 775 patients (monoclonal antibody group, n = 485 and placebo group, n = 290). Monoclonal antibody therapy decreased relapse risk (RR 0.33, 95% CI 0.21-0.52, P < 0.00001), annualized relapse rate (ARR) (mean -0.28, 95% CI -0.35-0.20, P < 0.00001), expanded disability status scale score (EDSS) (mean -0.19, 95% CI -0.32-0.07, P = 0.002) and serious adverse events (RR 0.78, 95% CI 0.61-1.00, P = 0.05). However, we did not observe any significant difference in terms of adverse events or mortality. Further, the subgroup analysis demonstrated that the anti-complement protein C5 monoclonal antibody (eculizumab) might have a lower relapse risk (RR 0.07, 95% CI 0.02-0.23, P < 0.0001) in the AQP4 seropositive patients, and anti-interleukin-6 receptor monoclonal antibodies (satralizumab and tocilizumab) showed decreased EDSS score (mean -0.17, 95% CI -0.31-0.02, P = 0.02) more effectively than other monoclonal antibodies. Conclusions: Monoclonal antibodies were effective and safe in NMOSD. Different targets of monoclonal antibodies might have their own advantages.