Ruptured Proximal Anterior Cerebral Artery Aneurysm Treated with Flow Diverter.
To discuss the use of flow modulation in treating ruptured aneurysms of the proximal segment of the anterior cerebral artery (A1 aneurysms). A1 aneurysms are rare, constituting approximately 1% of all intracranial aneurysms. We report a left A1 aneurysm with a wide neck and small sac (3 × 1.8 mm). In order to treat the lesion, a flow diverter (4 × 12?18 mm, FRED, Microvention) was placed from M1 to the proximal end of the paraophthalmic internal carotid artery, without directly covering the neck of the aneurysm. No procedural bleeding occurred. During stent deployment, abciximab was infused. A day after the procedure, double antiplatelet therapy was initiated for 1 month, followed by single antiplatelet therapy for another 3 months. Due to the aneurysm morphology, we opted for a competitive flow diversion, covering the parent artery origin and leaving the A1A neck uncovered. A decreased flow into the aneurysmal parent artery gradually promoted aneurysm sac thrombosis. Both digital subtraction angiography at a 12-month follow-up and computed tomography angiography 24-month follow-up confirmed the regular patency of the stent and resolution of the aneurysm. In addition, the competitive modulation of flow in the ipsilateral anterior cerebral artery results in the narrowing of the vessel. A1 aneurysm endovascular treatment is often challenging. Coiling or assisted coiling is the most frequently employed. Although flow diverter stent (FDS) is a consolidated technique for treating ruptured intracranial blister-like and dissecting aneurysms, its role in treating intracranial saccular ruptured aneurysms has to be elucidated. However, more number of case studies is needed to confirm the efficacy and safety of an FDS in treating ruptured A1 aneurysms.


Open doorway to truth: legacy of the Minnesota tobacco trial.
More than a decade has passed since the conclusion of the Minnesota tobacco trial and the signing of the Master Settlement Agreement (MSA) by 46 US State Attorneys General and the US tobacco industry. The Minnesota settlement exposed the tobacco industry's long history of deceptive marketing, advertising, and research and ultimately forced the industry to change its business practices. The provisions for public document disclosure that were included in the Minnesota settlement and the MSA have resulted in the release of approximately 70 million pages of documents and nearly 20,000 other media materials. No comparable dynamic, voluminous, and contemporaneous document archive exists. Only a few single events in the history of public health have had as dramatic an effect on tobacco control as the public release of the tobacco industry's previously secret internal documents. This review highlights the genesis of the release of these documents, the history of the document depositories created by the Minnesota settlement, the scientific and policy output based on the documents, and the use of the documents in furthering global public health strategies.


Thermal processing reduces PFAS concentrations in blue food - A systematic review and meta-analysis.
Per- and polyfluoroalkyl substances (PFAS) are ubiquitous in the environment and often ingested with food. PFAS exposure in people can have detrimental health consequences. Therefore, reducing PFAS burdens in food items is of great importance to public health. Here, we investigated whether cooking reduces PFAS concentrations in animal-derived food products by synthesizing experimental studies. Further, we examined the moderating effects of the following five variables: cooking time, liquid/animal tissue ratio, cooking temperature, carbon chain length of PFAS and the cooking category (oil-based, water-based & no-liquid cooking). In our systematic review searches, we obtained 512 effect sizes (relative differences in PFAS concentration between raw and cooked samples) from 10 relevant studies. These studies exclusively explored changes in PFAS concentrations in cooked seafood and freshwater fish. Our multilevel-meta-analysis has revealed that, on average, cooking reduced PFAS concentrations by 29%, although heterogeneity among effect sizes was very high (I2 = 94.65%). Our five moderators cumulatively explained 49% of the observed heterogeneity. Specifically, an increase in cooking time and liquid/animal tissue ratio, as well as shorter carbon chain length of PFAS (when cooked with oil) were associated with significant reductions in PFAS concentrations. The effects of different ways of cooking depended on the other moderators, while the effect of cooking temperature itself was not significant. Overall, cooking can reduce PFAS concentrations in blue food (seafood and freshwater fish). However, it is important to note that complete PFAS elimination requires unrealistically long cooking times and large liquid/animal tissue ratios. Currently, literature on the impact of cooking of terrestrial animal produce on PFAS concentrations is lacking, which limits the inference and generalisation of our meta-analysis. However, our work represents the first step towards developing guidelines to reduce PFAS in food via cooking exclusively with common kitchen items and techniques.


Chemical and mechanical determinants of apnea during high-frequency ventilation.
The factors responsible for the apnea observed during high-frequency ventilation (HFV) were evaluated in 14 pentobarbital sodium-anesthetized cats. A multiple logistic regression analysis provided an estimate of the probability of apnea during HFV as a function of four respiratory variables: mean airway pressure (Paw), tidal volume (VT), frequency, and arterial PCO2 (PaCO2). When mean Paw was 2 cmH2O, PaCO2, VT, and their interaction contributed significantly to the probability of apnea during HFV. At a low value of PaCO2 (25 Torr), the probability of apnea had a minimum value of 0.19 and gradually increased toward 1.0 as VT increased from 0.5 to 7 ml/kg. At higher levels of PaCO2 (30 and 35 Torr) the probability of apnea was zero in the low range of VT but sharply approached 1.0 above a VT of approximately 2.0 ml/kg. However, when Paw was increased to 6 cmH2O, only PaCO2 was an important determinant of apnea. In this case, the probability of apnea was 0.51 when PaCO2 was 25 Torr but decreased to 0.22 when PaCO2 was raised to 25 Torr. At neither Paw was the probability of apnea dependent on frequency. These results suggest that chemoreceptor inputs, in addition to both static and dynamic lung mechanoreceptor afferents, are responsible for determining the output of the central respiratory centers during HFV.


Bracing in adolescent idiopathic scoliosis, surrogate outcomes, and the number needed to treat.
In this manuscript we will present several evidence-based medicine concepts and tools that can be helpful to the clinician seeking answers to clinical questions. The clinical scenario used to demonstrate these concepts is one of the substantial current controversy in pediatric orthopaedics, that is the efficacy of bracing in adolescent idiopathic scoliosis. We hope to provide some important information about how to search and interpret the current literature on bracing but also to discuss the concepts related to "surrogate outcomes" and the "number needed to treat," which we believe are increasingly important in this era of evidence-based medicine. We performed a structured literature review of scoliosis bracing and also a separate analysis of the number needed to treat (NNT) for preventing surgery in adolescent idiopathic scoliosis. Bracing for idiopathic scoliosis significantly reduces the rate of curve progression more than 6 degrees. However, the applicability of the 6-degree surrogate outcome compared with a more important outcome such as progression to surgery is doubtful. Bracing may decrease the risk of progression to surgery although the confidence intervals are large. The NNT for routine scoliosis bracing is about 9 patients for each surgery prevented. The NNT for patients highly compliant with bracing is about 4. We caution that these NNTs are derived from nonrandomized cohorts, and the true values from quality randomized controlled studies may be substantially different. There is no evidence for any particular brace over another although rigid bracing seems better than SpineCor bracing from 1 small randomized controlled study. Systematic reviews support bracing's ability to prevent curve progression of 6 degrees but not for preventing surgery. Analysis of a patient cohort does support bracing's ability to prevent surgery with NNT of 9 for all patients and 4 for highly compliant patients. Systematic review-therapeutic level 2. Cohort analysis-therapeutic level 2.


How do potential knowledge users evaluate new claims about a contested resource? Problems of power and politics in knowledge exchange and mobilization.
This article examines how potential users of scientific and local/traditional/experiential knowledge evaluate new claims to knowing, using 67 interviews with government employees and non-governmental stakeholders involved in co-managing salmon fisheries in Canada's Fraser River. Research has consistently shown that there are major obstacles to moving new knowledge into policy, management, and public domains. New concepts such as Knowledge Exchange (KE) and Knowledge Mobilization (KMb) are being used to investigate these obstacles, but the processes by which potential users evaluate (sometimes competing) knowledge claims remain poorly understood. We use concepts from the sociology of science and find that potential users evaluate new knowledge claims based on three broad criteria: (1) the perceived merits of the claim, (2) perceptions of the character and motivation of the claimant, and (3) considerations of the social and political context of the claim. However, government employees and stakeholders have different interpretations of these criteria, leading to different knowledge preferences and normative expectations of scientists and other claimants. We draw both theoretical and practical lessons from these findings. With respect to theory, we argue that the sociology of science provides valuable insights into the political dimensions of knowledge and should be explicitly incorporated into KE/KMb research. With respect to practice, our findings underline the need for scientists and other claimants to make conscious decisions about whose expectations they hope to meet in their communications and engagement activities.


Structural basis for human NADPH-cytochrome P450 oxidoreductase deficiency.
NADPH-cytochrome P450 oxidoreductase (CYPOR) is essential for electron donation to microsomal cytochrome P450-mediated monooxygenation in such diverse physiological processes as drug metabolism (approximately 85-90% of therapeutic drugs), steroid biosynthesis, and bioactive metabolite production (vitamin D and retinoic acid metabolites). Expressed by a single gene, CYPOR's role with these multiple redox partners renders it a model for understanding protein-protein interactions at the structural level. Polymorphisms in human CYPOR have been shown to lead to defects in bone development and steroidogenesis, resulting in sexual dimorphisms, the severity of which differs significantly depending on the degree of CYPOR impairment. The atomic structure of human CYPOR is presented, with structures of two naturally occurring missense mutations, V492E and R457H. The overall structures of these CYPOR variants are similar to wild type. However, in both variants, local disruption of H bonding and salt bridging, involving the FAD pyrophosphate moiety, leads to weaker FAD binding, unstable protein, and loss of catalytic activity, which can be rescued by cofactor addition. The modes of polypeptide unfolding in these two variants differ significantly, as revealed by limited trypsin digestion: V492E is less stable but unfolds locally and gradually, whereas R457H is more stable but unfolds globally. FAD addition to either variant prevents trypsin digestion, supporting the role of the cofactor in conferring stability to CYPOR structure. Thus, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy in utero, if predicted prenatally, or rescued postnatally in less severe cases.


Urban African American women's explanations of recurrent chlamydia infections.
To explore reasons for the high chlamydia recurrence rate among African American (AA) urban women. In this phenomenological qualitative study, young AA urban women with recurrent chlamydia were interviewed using open-ended questions guided by the conceptual framework of the health belief model (HBM). The study was set in three urban health clinics in Michigan. Ten African American adolescents, age 15 to 19, participated. In face-to-face recorded interviews, participants shared their personal experiences and viewpoints on what led to their recurrent chlamydia infections. The data were transcribed and analyzed through hand coding and NVivo 8 a qualitative software package. Overall, participants demonstrated significant knowledge deficits about the seriousness of chlamydia compared to other sexually transmitted infections (STIs). After reinfection, their perceived susceptibility changed: condom use was seen as beneficial and perceived barriers to condom use diminished as participants gained a new sense of empowerment. Chlamydia infection among African American urban adolescents is nearly 3 times that of the general population. Lack of education is still a barrier to STI prevention. Participants reported a desire to receive counseling and support from the health care staff. A STI care model that includes education, counseling, and regular screening of high-risk adolescents should be considered. Further research, using the HBM or similar theoretical models, are needed to gauge the success of any planned or implemented intervention.


Source localization approach for functional DOT using MUSIC and FDR control.
In this paper, we formulate diffuse optical tomography (DOT) problems as a source localization problem and propose a MUltiple SIgnal Classification (MUSIC) algorithm for functional brain imaging application. By providing MUSIC spectra for major chromophores such as oxy-hemoglobin (HbO) and deoxy-hemoglobin (HbR), we are able to investigate the spatial distribution of brain activities. Moreover, the false discovery rate (FDR) algorithm can be applied to control the family-wise error in the MUSIC spectra. The minimum distance between the center of mass in DOT and the Montreal Neurological Institute (MNI) coordinates of target regions in experiments was between approximately 6 and 18 mm, and the displacement of the center of mass in DOT and fMRI ranged between 12 and 28 mm, which demonstrate the legitimacy of the DOT-based imaging. The proposed brain mapping method revealed its potential as an alternative algorithm to monitor the brain activation.


Successful Pediatric Penile Replantation Following Amputation During Ritual Circumcision: A Case Report and Literature Review.
BACKGROUND Circumcision is commonly performed in males, especially in Jewish and Muslim cultures, and is considered a safe surgical procedure with a low complication rate. Major complications, such as partial and total penile amputation, can occur, but those are rare complications. However, high replantation success rates have been reported and reviewed. CASE REPORT We describe the case of an 8-year-old boy who experienced total penile amputation during ritual circumcision performed by a layperson outside the hospital setting. Microsurgical penile replantation was performed after an ischemic period of 16 hours 43 minutes, with successful outcomes and without any major complications. In our technique, we repaired both dorsal and deep cavernosal vessels. At 1-year postoperative period, the results of two-point discrimination test were 4 mm, 7 mm, and 7 mm on the dorsal part, ventral part, and glans, respectively. After a follow-up period of 4 years, there were no late complications such as penile deformity, urethral fistula, urethral stenosis, absence of penile sensation, or erectile dysfunction. The results of two-point discrimination test were 3 mm, 5 mm, and 5 mm on the dorsal part, ventral part, and glans, respectively. The patient also experienced good penile sensation, morning erection, satisfaction with the cosmetic outcome, and a peak urine flow rate of 21 mL/s with a consistently strong void stream and a low postvoid residual urine volume of 20 mL. CONCLUSIONS Our experience suggests that a short ischemic time, prompt surgical correction, microscopic technique of replantation, and intensive postoperative care can result in good functional outcomes.


Paediatric Drug Development and Formulation Design-a European Perspective.
The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed drug use are associated with a greater risk for harm than on-label drug use, a range of global initiatives have been developed to realize "better" medicines for children. This review describes the challenges and achievements of the European Union to realize this goal, with a focus on paediatric drug development and formulation design. In 2007, a European Paediatric Regulation was installed enforcing companies to consider children in the early development of drugs with a new drug substance, for a new indication or with a new route of administration. The Regulation, e.g. requires companies to develop a paediatric investigation plan discussing the proposed clinical trials in children of different ages and the formulations for future marketing. Since 2013, the pharmaceutical design of any newly marketed paediatric drug should comply with the "Guideline on the Pharmaceutical Development of Medicines for Paediatric Use." Companies should, e.g. justify the route of administration, dosage form, formulation characteristics, safety of excipients, dosing frequency, container closure system, administration device, patient acceptability and user information. In this review, the guideline's key aspects are discussed with a focus on novel formulations such as mini-tablets and orodispersible films, excipients with a potential risk for harm such as azo dyes and adequate user instructions.


Prior experience conditionally inhibits the expression of new learning in Drosophila.
Prior experience of a stimulus can inhibit subsequent acquisition or expression of a learned association of that stimulus. However, the neuronal manifestations of this learning effect, named latent inhibition (LI), are poorly understood. Here, we show that prior odor exposure can produce context-dependent LI of later appetitive olfactory memory performance in Drosophila. Odor pre-exposure forms a short-lived aversive memory whose lone expression lacks context-dependence. Acquisition of odor pre-exposure memory requires aversively reinforcing dopaminergic neurons that innervate two mushroom body compartments-one group of which exhibits increasing activity with successive odor experience. Odor-specific responses of the corresponding mushroom body output neurons are suppressed, and their output is necessary for expression of both pre-exposure memory and LI of appetitive memory. Therefore, odor pre-exposure attaches negative valence to the odor itself, and LI of appetitive memory results from a temporary and context-dependent retrieval deficit imposed by competition with the parallel short-lived aversive memory.


Behavioural health interventions in the Johns Hopkins Community Health Partnership: integrated care as a component of health systems transformation.
Health systems in the USA have received a mandate to improve quality while reining in costs. Several opportunities have been created to stimulate this transformation. This paper describes the design, early implementation and lessons learned for the behavioural components of the John Hopkins Community Health Partnership (J-CHiP) programme. J-CHiP is designed to improve health outcomes and reduce the total healthcare costs of a group of high healthcare use patients who are insured by the government-funded health insurance programmes, Medicaid and Medicare. These patients have a disproportionately high prevalence of depression, other psychiatric conditions, and unhealthy behaviours that could be addressed with behavioural interventions. The J-CHiP behavioural intervention is based on integrated care models, which include embedding mental health professionals into primary sites. A four-session behaviour-based protocol was developed to motivate self-efficacy through illness management skills. In addition to staff embedded in primary care, the programme design includes expedited access to specialist psychiatric services as well as a community outreach component that addresses stigma. The progress and challenges involved with developing this programme over a relatively short period of time are discussed.


Desmoglein 3 anchors telogen hair in the follicle.
Little is known about the function of desmosomes in the normal structure and function of hair. Therefore, it was surprising that mice without desmoglein 3 (the autoantigen in pemphigus vulgaris) not only developed mucous membrane and skin lesions like pemphigus patients, but also developed hair loss. Analysis of this phenotype indicated that hair was normal through the first growth phase ('follicular neogenesis'). Around day 20, however, when the hair follicles entered the resting phase of the hair growth cycle (telogen), mice with a targeted disruption of the desmoglein 3 gene (DSG3-/-) lost hair in a wave-like pattern from the head to the tail. Hair then regrew and was lost again in the same pattern with the next synchronous hair cycle. In adults, hair was lost in patches. Gentle hair pulls with adhesive tape showed that anagen (growing) hairs were firmly anchored in DSG3-/- mice, but telogen hairs came out in clumps compared to that of DSG3+/- and +/+ littermates in which telogen hairs were firmly anchored. Histology of bald skin areas in DSG3-/- mice showed cystic telogen hair follicles without hair shafts. Histology of hair follicles in early telogen, just before clinical hair loss occurred, showed loss of cell adhesion (acantholysis) between the cells surrounding the telogen club and the basal layer of the outer root sheath epithelium. Electron microscopy revealed 'half-desmosomes' at the plasma membranes of acantholytic cells. Similar acantholytic histology and ultrastructural findings have been previously reported in skin and mucous membrane lesions of DSG3-/- mice and pemphigus vulgaris patients. Immunoperoxidase staining with an antibody raised against mouse desmoglein 3 showed intense staining on the cell surface of keratinocytes surrounding the telogen hair club in normal mice. Similar staining was seen in human telogen hair with an anti-human desmoglein 3 antibody. Finally, a scalp biopsy from a pemphigus vulgaris patient showed empty telogen hair follicles. These data demonstrate that desmoglein 3 is not only critical for cell adhesion in the deep stratified squamous epithelium, but also for anchoring the telogen hair to the outer root sheath of the follicle and underscore the importance of desmosomes in maintaining the normal structure and function of hair.


On the catalytic mechanism of human ATP citrate lyase.
ATP citrate lyase (ACL) catalyzes an ATP-dependent biosynthetic reaction which produces acetyl-coenzyme A and oxaloacetate from citrate and coenzyme A (CoA). Studies were performed with recombinant human ACL to ascertain the nature of the catalytic phosphorylation that initiates the ACL reaction and the identity of the active site residues involved. Inactivation of ACL by treatment with diethylpyrocarbonate suggested the catalytic role of an active site histidine (i.e., His760), which was proposed to form a phosphohistidine species during catalysis. The pH-dependence of the pre-steady-state phosphorylation of ACL with [γ-(33)P]-ATP revealed an ionizable group with a pK(a) value of ~7.5, which must be unprotonated for the catalytic phosphorylation of ACL to occur. Mutagenesis of His760 to an alanine results in inactivation of the biosynthetic reaction of ACL, in good agreement with the involvement of a catalytic histidine. The nature of the formation of the phospho-ACL was further investigated by positional isotope exchange using [γ-(18)O(4)]-ATP. The β,γ-bridge to nonbridge positional isotope exchange rate of [γ-(18)O(4)]-ATP achieved its maximal rate of 14 s(-1) in the absence of citrate and CoA. This rate decreased to 5 s(-1) when citrate was added, and was found to be 10 s(-1) when both citrate and CoA were present. The rapid positional isotope exchange rates indicated the presence of one or more catalytically relevant, highly reversible phosphorylated intermediates. Steady-state measurements in the absence of citrate and CoA showed that MgADP was produced by both wild type and H760A forms of ACL, with rates at three magnitudes lower than that of k(cat) for the full biosynthetic reaction. The ATPase activity of ACL, along with the small yet significant positional isotope exchange rate observed in H760A mutant ACL (~150 fold less than wild type), collectively suggested the presence of a second, albeit unproductive, phosphoryl transfer in ACL. Mathematical analysis and computational simulation suggested that the desorption of MgADP at a rate of ~7 s(-1) was the rate-limiting step in the biosynthesis of AcCoA and oxaloacetate.


Volume and shape of masticatory muscles in patients with hemifacial microsomia.
To test the following hypotheses in hemifacial microsomia (HFM): (1) the volumes of the masseter, lateral and medial pterygoid, and temporal muscles are reduced on the affected versus unaffected side; (2) significant differences exist between the degrees of right-left disproportion in these four masticatory muscles; (3) circumferential shapes of the masticatory muscles are more irregular on the affected versus unaffected side; and (4) the degree of masticatory muscle right-left disproportion can be judged by the degree of ear, mandibular, or dental anomalies. Ten preadolescent patients with HFM were studied using facial photographs, dental casts, cephalometric and panoramic radiographs, and helical computed tomography scanning and three-dimensional reconstruction technique. Volumes of masseter, lateral and medial pterygoid, and temporal muscles on both sides were measured. Muscle volume disproportion was expressed as the affected/unaffected ratio. Muscle circumferential irregularity was expressed as the ratio between the total circumferential length and corresponding cross-sectional area. Masticatory muscle volumes were significantly smaller on the affected versus unaffected side. No significant differences were observed between the degrees of disproportion of the four masticatory muscles examined. Circumferential shapes of masticatory muscles were significantly more irregular on the affected versus unaffected side. There were no significant relationships of the degree of ear, mandibular, or dental anomalies in relation to masticatory muscle disproportion. In HFM the masseter, lateral and medial pterygoid, and temporal muscles all have a significantly smaller volume on the affected versus unaffected side, and specific muscles were not severely affected in the present subjects. Furthermore, all four muscles showed a significantly more irregular shape on the affected versus unaffected side. Finally, the severity of masticatory muscle disproportion can probably not be judged by the degree of ear, mandibular, and dental anomalies in preadolescent patients with HFM.


Increased risk of childhood type 1 diabetes in children born after 1985.
The incidence rate of childhood type 1 diabetes is thought to be increasing; however, Danish studies have not confirmed this. Using a national diabetes register initiated in 1996 and two previous regional incidence studies, we studied the age-specific incidence of type 1 diabetes over 30 years. Here, we describe the incidence rates of type 1 diabetes in Danish children from 1996 to 2000 and evaluate trends in age-specific incidence rates from 1970 to 2000. A nationwide registration of all newly diagnosed cases of type 1 diabetes among children under the age of 15 years was established in Denmark in 1996. Incidence rates of type 1 diabetes in Denmark were obtained from this register. Age-specific incidence rates were compared with data collected from 1970 to 1976 and from 1980 to 1984, both population-based studies using existing national routine registration of hospitalizations within the survey areas. Population data were obtained from Statistics Denmark. During the study period, 1,421 Danish children developed type 1 diabetes before the age of 15 years. The incidence rates by age-groups were: 12.7, 19.4, and 26.3 for the 0-4, 5-9, and 10-14 years age-groups, respectively, and 19.5 for the 0-14 years age-group per 100,000 in the period 1996-2000. An age-period-cohort analysis showed a modest drift effect (yearly increase) of 1.2% (0.7-1.8) from 1970 to 2000, and a significant birth cohort effect with an increased risk for children born after 1985 was observed. The incidence rate of type 1 diabetes is rising in children living in Denmark. The steep increase in the youngest age-group was explained by the increased risk for cohorts born at the beginning of the 1980s.


Automated CT-based segmentation and quantification of total intracranial volume.
To develop an algorithm to segment and obtain an estimate of total intracranial volume (tICV) from computed tomography (CT) images. Thirty-six CT examinations from 18 patients were included. Ten patients were examined twice the same day and eight patients twice six months apart (these patients also underwent MRI). The algorithm combines morphological operations, intensity thresholding and mixture modelling. The method was validated against manual delineation and its robustness assessed from repeated imaging examinations. Using automated MRI software, the comparability with MRI was investigated. Volumes were compared based on average relative volume differences and their magnitudes; agreement was shown by a Bland-Altman analysis graph. We observed good agreement between our algorithm and manual delineation of a trained radiologist: the Pearson's correlation coefficient was r = 0.94, tICVml[manual] = 1.05 × tICVml[automated] - 33.78 (R(2) = 0.88). Bland-Altman analysis showed a bias of 31 mL and a standard deviation of 30 mL over a range of 1265 to 1526 mL. tICV measurements derived from CT using our proposed algorithm have shown to be reliable and consistent compared to manual delineation. However, it appears difficult to directly compare tICV measures between CT and MRI. • Automated estimation of tICV is in good agreement with manual tracing. • Consistent tICV estimations from repeated measurements demonstrate the robustness of the algorithm. • Automatically segmented volumes seem less variable than those from manual tracing. • Unbiased and automated tlCV estimation is possible from CT.


Implications of a Neotropical origin of the genus Leishmania.
The hypothesis of a Neotropical origin of the Leishmania/Endotrypanum clade is reviewed. The position of the L. (Sauroleishmania) external to the subgenus L. (Leishmania) is not consistent with the Neotropical origin of the latter subgenus. It is suggested that this may be a consequence of a faster evolutionary rate in the L. (Sauroleishmania). The implications for the classification of the phlebotomine sandflies of the hypothesis for a Neotropical origin of the Leishmania is also considered. The classification of Galati (1995) is proposed to be most consistent with the hypothesis of a Neotropical origin of the Leishmania, whilst classifications which place the New and Old World species in separate taxa are inconsistent with this hypothesis.


Impaired "outside-in" integrin alphaIIbbeta3 signaling and thrombus stability in TSSC6-deficient mice.
We investigated the role of the hematopoietic-specific tetraspanin superfamily member, TSSC6, in platelet function using wild-type mice and TSSC6-deficient mice. TSSC6 is expressed on the surface of murine platelets and is up-regulated by thrombin stimulation, indicating an intracellular pool of TSSC6. Immunoprecipitation/Western blot studies reveal a constitutive physical association of TSSC6 with the integrin alpha(IIb)beta(3) complex under strong detergent conditions. In vivo evaluation of hemostasis by tail bleeding revealed increased bleeding time, volume of blood lost, and evidence of tail rebleeds in TSSC6 null mice, indicating unstable hemostasis. Using ex vivo techniques, we showed that TSSC6-deficient platelets exhibited impaired kinetics of clot retraction, platelet aggregation at lower doses of PAR-4, and collagen and platelet spreading on fibrinogen in the presence of normal integrin alpha(IIb)beta(3) expression. TSSC6-deficient platelets showed normal alpha granule secretion, normal "inside-out" integrin alpha(IIb)beta(3) signaling (fluorescein isothiocyanate [FITC]-fibrinogen and JON/A binding), and normal platelet adhesion on fibrinogen. Furthermore, we show that absence of platelet TSSC6 affects the secondary stability of arterial thrombi in vivo upon vascular injury. These data demonstrate that TSSC6 appears to regulate integrin alpha(IIb)beta(3) "outside-in" signaling events in platelets and is necessary for stability of arterial thrombi in vivo.


Learning to Perceive Non-Native Tones via Distributional Training: Effects of Task and Acoustic Cue Weighting.
As many distributional learning (DL) studies have shown, adult listeners can achieve discrimination of a difficult non-native contrast after a short repetitive exposure to tokens falling at the extremes of that contrast. Such studies have shown using behavioural methods that a short distributional training can induce perceptual learning of vowel and consonant contrasts. However, much less is known about the neurological correlates of DL, and few studies have examined non-native lexical tone contrasts. Here, Australian-English speakers underwent DL training on a Mandarin tone contrast using behavioural (discrimination, identification) and neural (oddball-EEG) tasks, with listeners hearing either a bimodal or a unimodal distribution. Behavioural results show that listeners learned to discriminate tones after both unimodal and bimodal training; while EEG responses revealed more learning for listeners exposed to the bimodal distribution. Thus, perceptual learning through exposure to brief sound distributions (a) extends to non-native tonal contrasts, and (b) is sensitive to task, phonetic distance, and acoustic cue-weighting. Our findings have implications for models of how auditory and phonetic constraints influence speech learning.


Enantioselective β-Protonation of Enals via a Shuttling Strategy.
Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the β-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective β-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a β-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.


Forest Soil Phosphorus Resources and Fertilization Affect Ectomycorrhizal Community Composition, Beech P Uptake Efficiency, and Photosynthesis.
Phosphorus (P) is an important nutrient, whose plant-available form phosphate is often low in natural forest ecosystems. Mycorrhizal fungi mine the soil for P and supply their host with this resource. It is unknown how ectomycorrhizal communities respond to changes in P availability. Here, we used young beech (Fagus sylvatica L.) trees in natural forest soil from a P-rich and P-poor site to investigate the impact of P amendment on soil microbes, mycorrhizas, beech P nutrition, and photosynthesis. We hypothesized that addition of P to forest soil increased P availability, thereby, leading to enhanced microbial biomass and mycorrhizal diversity in P-poor but not in P-rich soil. We expected that P amendment resulted in increased plant P uptake and enhanced photosynthesis in both soil types. Young beech trees with intact soil cores from a P-rich and a P-poor forest were kept in a common garden experiment and supplied once in fall with triple superphosphate. In the following summer, labile P in the organic layer, but not in the mineral top soil, was significantly increased in response to fertilizer treatment. P-rich soil contained higher microbial biomass than P-poor soil. P treatment had no effect on microbial biomass but influenced the mycorrhizal communities in P-poor soil and shifted their composition toward higher similarities to those in P-rich soil. Plant uptake efficiency was negatively correlated with the diversity of mycorrhizal communities and highest for trees in P-poor soil and lowest for fertilized trees. In both soil types, radioactive P tracing (H333PO4) revealed preferential aboveground allocation of new P in fertilized trees, resulting in increased bound P in xylem tissue and enhanced soluble P in bark, indicating increased storage and transport. Fertilized beeches from P-poor soil showed a strong increase in leaf P concentrations from deficient to luxurious conditions along with increased photosynthesis. Based on the divergent behavior of beech in P-poor and P-rich forest soil, we conclude that acclimation of beech to low P stocks involves dedicated mycorrhizal community structures, low P reserves in storage tissues and photosynthetic inhibition, while storage and aboveground allocation of additional P occurs regardless of the P nutritional status.


Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer.
Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. In this single-arm, multicenter, open-label phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m(2) (first cycle dose 60 mg/m(2)) day 1 and day 8, plus capecitabine at 1000 (750 if ≥ 65 years) mg/m(2) twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for ≥ 6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8-16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile.


Vaginal apical support: cornerstone of pelvic reconstructive surgery.
Proper support of the vaginal apex is necessary to ensure successful reconstruction of pelvic prolapse. The modified McCall culdeplasty provides excellent vaginal apical support while maintaining a physiologic vaginal axis. This technique may be used transabdominally, transvaginally, or laparoscopically.


Fracture of pubic rami during hip fracture fixation: a rare case of traction table-related injury.
We present a case of an elderly and comorbid patient who was scheduled to undergo a hip fracture fixation using an intramedullary nail. Unfortunately, this was delayed by 3 weeks as the patient was unfit to undergo this procedure. She was placed onto the traction table and intraoperatively sustained a superior and inferior pubic rami fracture while attempting reduction on the traction table. Closed-reduction techniques using traction tables and perineal posts are not without morbidity. Risk factors such as osteoporosis and delayed-fixation should be accounted for when managing this complex and often frail group of patients.


Effect of blood activity on dosimetric calculations for radiopharmaceuticals.
The objective of this work was to investigate the influence of the definition of blood as a distinct source on organ doses, associated with the administration of a novel radiopharmaceutical for positron emission tomography-computed tomography (PET/CT) imaging-(S)-4-(3-18F-fluoropropyl)-L-glutamic acid (18F-FSPG). Personalised pharmacokinetic models were constructed based on clinical PET/CT images from five healthy volunteers and blood samples from four of them. Following an identifiability analysis of the developed compartmental models, person-specific model parameters were estimated using the commercial program SAAM II. Organ doses were calculated in accordance to the formalism promulgated by the Committee on Medical Internal Radiation Dose (MIRD) and the International Commission on Radiological Protection (ICRP) using specific absorbed fractions for photons and electrons previously derived for the ICRP reference adult computational voxel phantoms. Organ doses for two concepts were compared: source organ activities in organs parenchyma with blood as a separate source (concept-1); aggregate activities in perfused source organs without blood as a distinct source (concept-2). Aggregate activities comprise the activities of organs parenchyma and the activity in the regional blood volumes (RBV). Concept-1 resulted in notably higher absorbed doses for most organs, especially non-source organs with substantial blood contents, e.g. lungs (92% maximum difference). Consequently, effective doses increased in concept-1 compared to concept-2 by 3-10%. Not considering the blood as a distinct source region leads to an underestimation of the organ absorbed doses and effective doses. The pronounced influence of the blood even for a radiopharmaceutical with a rapid clearance from the blood, such as 18F-FSPG, suggests that blood should be introduced as a separate compartment in most compartmental pharmacokinetic models and blood should be considered as a distinct source in dosimetric calculations. Hence, blood samples should be included in all pharmacokinetic and dosimetric studies for new tracers if possible.


The implication of tissue Doppler echocardiography and cardiopulmonary exercise in early detection of cardiac dysfunction in systemic lupus erythematosus patients.
Systemic lupus erythematosus (SLE) can present limitations to exercise capacity and quality of life (QoL) because of various clinical conditions, such as pulmonary disease or heart disease. Tissue Doppler echocardiography (TDE) offers the promise of an objective measurement to quantify regional and global ventricular function through the assessment of myocardial velocity data. This study aimed to assess the intensity of left ventricular (LV) and right ventricular (RV) systolic and diastolic dysfunction in SLE patients by means of TDE and cardiopulmonary exercise (CPX) testing to determine their impact on QoL. Overall, 56 SLE patients within two tertiary healthcare centers as well as 50 healthy controls were examined with TDE after the exclusion of cardiovascular risk factors. TDE was performed for maximal systolic (S), early diastolic (E'), and late diastolic (A') velocities of the mitral and tricuspid annulus. Pulsed wave (PW) Doppler of mitral and tricuspid valve inflow was performed in addition to the estimation of the left ventricle ejection fraction and assessment of right ventricle systolic function by tricuspid annular plane systolic excursion (TAPSE). Disease activity was assessed by the Systemic Lupus Activity Measure (SLAM), and the damage index was assessed by the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). CPX tests according to the modified Bruce protocol were performed. SLE patients in both subgroups had more or less similar laboratory data and statistically higher values of ESR, CRP, and anticardiolipin (aCL) antibodies compared to the control group. LV function showed statistically insignificant EF compared to the control group, being lower in the patient group. Tissue Doppler image revealed that E' and A' of the mitral annulus were lower in the patient group than in the control group. Concerning RV, TAPSE in the patient group was statistically lower than in the control group, and there was a statistical difference between SLE groups Ia and Ib; also, S wave was lower in group Ib than in group Ia. RV diastolic dysfunction in the form of lower E' and A' values was observed for the SLE group compared to the control group, especially in the medial annulus of the tricuspid valve. A higher A wave velocity with PWD of mitral and tricuspid inflows was observed in the patient group compared to the control group. SLE patients have an increased prevalence of subclinical systolic and diastolic LV and RV dysfunction. This result advocates for regular follow-up and early screening of SLE patients. Accordingly, treatment focused on improving diastolic heart function may have a role in enhancing QoL and improving the prognosis of SLE patients.


Biomechanical considerations in the modeling of muscle function.
The instantaneous functional role of a voluntary muscle in the neighborhood of a joint is often described in clinical terms (e.g. flexor; abductor; external rotator; agonist; contracting concentrically and isokinetically) that seen sufficiently explicit and clear in certain simple situations, but have not yet been carefully defined in precise biomechanical terminology for the general case. In order to describe the functional role of a voluntary muscle as its acts to change and/or maintain the configuration of a joint, it is necessary to make certain modeling assumptions. These include modeling the joint, modeling the muscle force line of action in the joint neighborhood, and establishing the location and orientation of the three joint axes for all possible joint configurations. Modeling the joint as a point leads to simple and sensible definitions which are consistent with clinical practice. The straight line model is most conveniently used to establish the muscle force line of action. A RHO coordinate system embedded in the distal joint segment with origin at the joint center point, and with intersecting axes coincident with the F/E, A/A and I/XR axes when the joint is in the anatomical position, is the joint coordinate system of choice to describe the turning effects of the muscle about the joint. Sensible and simple biomechanical definitions for clinical terms describing muscular contractions (i.e. concentric; eccentric; isometric; isokinetic; isotonic) were presented and appear to be relatively uncontroversial. Alternative biomechanical definitions for agonistic and antagonistic muscular activity were also presented, as were arguments for choosing a simple definition based on using the joint resultant moment as the criterion measure relative to which the individual muscle's moment about J should be compared. Biomechanical definitions for determining when a muscle functions as a joint flexor or extensor, abductor or adductor, and internal or external rotator were also presented. These definitions were based on the classical concept where the muscle's instantaneous turning effect is determined by its moment about the joint center. The algebraic signs and relative magnitudes of the components of the muscle's moment about J were used to determine not only the functional behavior of the muscle (e.g. flexor vs. extensor), but also the relative contributions of the muscle to producing rotations about the three joint axes through J. A detailed critique of the restricted functional classification scheme proposed by Molbech and Carlsöö was also presented.(ABSTRACT TRUNCATED AT 400 WORDS)


Production of glucaric acid from a synthetic pathway in recombinant Escherichia coli.
A synthetic pathway has been constructed for the production of glucuronic and glucaric acids from glucose in Escherichia coli. Coexpression of the genes encoding myo-inositol-1-phosphate synthase (Ino1) from Saccharomyces cerevisiae and myo-inositol oxygenase (MIOX) from mice led to production of glucuronic acid through the intermediate myo-inositol. Glucuronic acid concentrations up to 0.3 g/liter were measured in the culture broth. The activity of MIOX was rate limiting, resulting in the accumulation of both myo-inositol and glucuronic acid as final products, in approximately equal concentrations. Inclusion of a third enzyme, uronate dehydrogenase (Udh) from Pseudomonas syringae, facilitated the conversion of glucuronic acid to glucaric acid. The activity of this recombinant enzyme was more than 2 orders of magnitude higher than that of Ino1 and MIOX and increased overall flux through the pathway such that glucaric acid concentrations in excess of 1 g/liter were observed. This represents a novel microbial system for the biological production of glucaric acid, a "top value-added chemical" from biomass.


Monitoring the Formation and Reactivity of Organometallic Alkane and Fluoroalkane Complexes with Silanes and Xe Using Time-Resolved X-ray Absorption Fine Structure Spectroscopy.
Complexes with weakly coordinating ligands are often formed in chemical reactions and can play key roles in determining the reactivity, particularly in catalytic reactions. Using time-resolved X-ray absorption fine structure (XAFS) spectroscopy in combination with time-resolved IR (TRIR) spectroscopy and tungsten hexacarbonyl, W(CO)6, we are able to structurally characterize the formation of an organometallic alkane complex, determine the W-C distances, and monitor the reactivity with silane to form an organometallic silane complex. Experiments in perfluorosolvents doped with xenon afford initially the corresponding solvated complex, which is sufficiently reactive in the presence of Xe that we can then observe the coordination of Xe to the metal center, providing a unique insight into the metal-xenon bonding. These results offer a step toward elucidating the structure, bonding, and chemical reactivity of transient species by X-ray absorption spectroscopy, which has sensitivity to small structural changes. The XAFS results indicate that the bond lengths of metal-alkane (W-H-C) bond in W(CO)5(heptane) as 3.07 (±0.06) Å, which is longer than the calculated W-C (2.86 Å) for binding of the primary C-H, but shorter than the calculated W-C (3.12 Å) for the secondary C-H. A statistical average of the calculated W-C alkane bond lengths is 3.02 Å, and comparison of this value indicates that the value derived from the XAFS measurements is averaged over coordination of all C-H bonds consistent with alkane chain walking. Photolysis of W(CO)6 in the presence of HSiBu3 allows the conversion of W(CO)5(heptane) to W(CO)5(HSiBu3) with an estimated W-Si distance of 3.20 (±0.03) Å. Time-resolved TRIR and XAFS experiments following photolysis of W(CO)6 in perfluoromethylcyclohexane (PFMCH) allows the characterization of W(CO)5(PFMCH) with a W-F distance of 2.65 (±0.06) Å, and doping PFMCH with Xe allows the characterization of W(CO)5Xe with a W-Xe bond length of 3.10 (±0.02) Å.


Pilot study to determine whether transient receptor potential melastatin type 8 (TRPM8) antibodies are detected in scleroderma.
A key mediator in cold-sensation is the protein transient receptor potential melastatin 8 (TRPM8), which is expressed on sensory nerves and cutaneous blood vessels. These receptors are activated by cold temperatures and play a key role in body thermoregulation. Cold sensitivity and Raynaud's phenomenon are frequent clinical features in scleroderma, and are thought to be secondary to a local defect in cutaneous thermoregulation. We investigated whether autoantibodies targeting TRPM8 were present in the sera of patients with scleroderma as evidence for a possible mechanism for an acquired immune mediated defect in thermoregulation. Sera from 50 well-characterised scleroderma patients with Raynaud's phenomenon were studied. TRPM8 autoantibodies were assayed as follows: 1. immunoprecipitation with 35S-methionine-labelled TRPM8 generated by in vitro transcription and translation, 2. immunoblotting lysates made from cells transiently transfected with TRPM8 cDNA, 3. Immunoprecipitation of TRPM8 transfected lysates with detection by blotting and 4. flow cytometry. Fifty scleroderma patients with Raynaud's phenomenon (41 female, 39 Caucasian, 23 with limited scleroderma, and 20 with history of cancer) were studied. Four different methods to assay for TRPM8 antibodies were set up, optimised and validated using commercial antibodies. All 50 scleroderma patients' sera were assayed using each of the above methods, and all were negative for TRPM8 autoantibodies. Antibodies against TRPM8 are not found in scleroderma patient sera, suggesting that the abnormal cold sensitivity and associated abnormal vascular reactivity in scleroderma patients is not the result of an immune process targeting TRPM8.


Mechanostat parameters estimated from time-lapsed in vivo micro-computed tomography data of mechanically driven bone adaptation are logarithmically dependent on loading frequency.
Mechanical loading is a key factor governing bone adaptation. Both preclinical and clinical studies have demonstrated its effects on bone tissue, which were also notably predicted in the mechanostat theory. Indeed, existing methods to quantify bone mechanoregulation have successfully associated the frequency of (re)modeling events with local mechanical signals, combining time-lapsed in vivo micro-computed tomography (micro-CT) imaging and micro-finite element (micro-FE) analysis. However, a correlation between the local surface velocity of (re)modeling events and mechanical signals has not been shown. As many degenerative bone diseases have also been linked to impaired bone (re)modeling, this relationship could provide an advantage in detecting the effects of such conditions and advance our understanding of the underlying mechanisms. Therefore, in this study, we introduce a novel method to estimate (re)modeling velocity curves from time-lapsed in vivo mouse caudal vertebrae data under static and cyclic mechanical loading. These curves can be fitted with piecewise linear functions as proposed in the mechanostat theory. Accordingly, new (re)modeling parameters can be derived from such data, including formation saturation levels, resorption velocity moduli, and (re)modeling thresholds. Our results revealed that the norm of the gradient of strain energy density yielded the highest accuracy in quantifying mechanoregulation data using micro-finite element analysis with homogeneous material properties, while effective strain was the best predictor for micro-finite element analysis with heterogeneous material properties. Furthermore, (re)modeling velocity curves could be accurately described with piecewise linear and hyperbola functions (root mean square error below 0.2 µm/day for weekly analysis), and several (re)modeling parameters determined from these curves followed a logarithmic relationship with loading frequency. Crucially, (re)modeling velocity curves and derived parameters could detect differences in mechanically driven bone adaptation, which complemented previous results showing a logarithmic relationship between loading frequency and net change in bone volume fraction over 4 weeks. Together, we expect this data to support the calibration of in silico models of bone adaptation and the characterization of the effects of mechanical loading and pharmaceutical treatment interventions in vivo.


Pref-1 and adipokine expression in adipose tissues of GK and Zucker rats.
In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-alpha in visceral and subcutaneous fat pads of rats with different metabolic disorders. We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-alpha mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots. These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat.


Evaluating Clostridioides difficile infection (CDI) treatment duration in hematology/oncology patients receiving concurrent non-CDI antibiotics.
To determine the impact of Clostridioides difficile infection (CDI) treatment duration on CDI recurrence in hematology/oncology patients receiving concurrent non-CDI antibiotics. This multi-site, retrospective study examined hematology/oncology patients age ≥18 years hospitalized with active CDI who received ≥1 dose of concurrent non-CDI antibiotics between September 2013 and June 2019. All patients were classified by two definitions for statistical analysis: standard (10-14 days) versus prolonged (>14 days) duration of CDI treatment and non-extended (≤24 hours after stopping non-CDI antibiotics) versus extended (>24 hours after stopping non-CDI antibiotics) CDI treatment. Primary outcome was CDI recurrence within 180 days of completing CDI treatment. Secondary outcomes included hospital length of stay (LOS) as well as mortality and incidence of vancomycin-resistant enterococcus (VRE) infections at 180 days. Of the 198 patients included, 112 were classified as prolonged versus 86 standard duration and 138 were classified as extended versus 60 non-extended duration. After accounting for demographic differences, no difference existed in the primary outcome of CDI recurrence in either prolonged versus standard or extended versus non-extended analysis (all p > 0.05). Patients who received prolonged versus standard CDI treatment had longer LOS (p < 0.0001) while no difference existed in extended versus non-extended (p > 0.05). No difference in mortality existed in prolonged versus standard (p > 0.05) while those who received extended versus non-extended CDI treatment had significantly lower mortality (p = 0.0008). Neither prolonging CDI treatment beyond standard duration nor extending duration beyond end of non-CDI antibiotics was associated with decreased CDI recurrence rate.


Partial purification of a 6-methyladenine mRNA methyltransferase which modifies internal adenine residues.
Two forms of a 6-methyladenine mRNA methyltransferase have been partially purified using a T7 transcript coding for mouse dihydrofolate reductase as an RNA substrate. Both enzyme forms modify internal adenine residues within the RNA substrate. The enzymes were purified 357- and 37-fold respectively from nuclear salt extracts prepared from HeLa cells using DEAE-cellulose and phosphocellulose chromatography. The activity of the first form of the enzyme eluted from DEAE-cellulose (major form) was at least 3-fold greater than that of the second (minor form). H.p.l.c. analysis of the hydrolysed, methylated mRNA substrates demonstrated that both forms of the enzyme produced only 6-methyladenine. The two forms of the enzyme differed in their RNA substrate specificity as well as in the dependence for a 5' cap structure. The 6-methyladenine mRNA methyltransferase activity was found to be elevated in HeLa nuclei as compared with nuclear extracts from rat kidney and brain. Enzymic activity could not be detected in nuclei from either normal rat liver or regenerating rat liver. In the case of the HeLa cell, activity could only be detected in nuclear extracts, with a small amount in the ribosomal fraction. Other HeLa subcellular fractions were void of activity.


Evaluation of collaborative models of care in the management of patients with depression: protocol and progress.
Introduction Depression is highly prevalent and has a considerable impact on the quality of life of affected individuals, and on healthcare resources. Evidence indicates that collaborative care models can improve patient outcomes within a primary care setting. The Primary Care Services Improvement Project (PCSIP) aims to investigate the costs and outcomes of different models of care for the management of patients with depression. These models have been defined based on the level of involvement of practice nurses in management processes within the primary care setting in Australia. This paper describes our study protocol and its progress. Methods PCSIP is an observational study that will link retrospective data from a range of sources to estimate costs and intermediate outcomes (such as relapse rate) over a 3-year time horizon. The main sources of primary data include the medical records of patients held at participating practices and Medicare Australia. Initial report We recruited 15 practices from a metropolitan area and allocated them to three models of care. Two hundred and sixty-one patients agreed to participate. Appropriate regression-based analyses will be used to evaluate the association between different models of care and patient-level outcomes while controlling for several covariates such as age and gender. Discussion/conclusions This project will generate the knowledge required to promote investment in the most cost-effective initiatives, and to ensure that waste of resources due to the implementation of comparatively inefficient interventions is minimised. Given the scarcity of resources, the increasing costs of providing healthcare and the increasing prevalence of chronic diseases, such research is essential.


Glucose stimulates protein synthesis in skeletal muscle of neonatal pigs through an AMPK- and mTOR-independent process.
Skeletal muscle protein synthesis is elevated in neonates in part due to an enhanced response to the rise in insulin and amino acids after eating. In vitro studies suggest that glucose plays a role in protein synthesis regulation. To determine whether glucose, independently of insulin and amino acids, is involved in the postprandial rise in skeletal muscle protein synthesis, pancreatic-substrate clamps were performed in neonatal pigs. Insulin secretion was inhibited with somatostatin and insulin was infused to reproduce fasting or fed levels, while glucose and amino acids were clamped at fasting or fed levels. Fractional protein synthesis rates and translational control mechanisms were examined. Raising glucose alone increased protein synthesis in fast-twitch glycolytic muscles but not in other tissues. The response in muscle was associated with increased phosphorylation of protein kinase B (PKB) and enhanced formation of the active eIF4E.eIF4G complex but no change in phosphorylation of AMP-activated protein kinase (AMPK), tuberous sclerosis complex 2 (TSC2), mammalian target of rapamycin (mTOR), 4E-binding protein-1 (4E-BP1), ribosomal protein S6 kinase (S6K1), or eukaryotic elongation factor 2 (eEF2). Raising glucose, insulin, and amino acids increased protein synthesis in most tissues. The response in muscle was associated with phosphorylation of PKB, mTOR, S6K1, and 4E-BP1 and enhanced eIF4E.eIF4G formation. The results suggest that the postprandial rise in glucose, independently of insulin and amino acids, stimulates protein synthesis in neonates, and this response is specific to fast-twitch glycolytic muscle and occurs by AMPK- and mTOR-independent pathways.


Diuretic Doppler sonography following successful repair of renal obstruction in children.
The measurement of resistive index (RI = [peak systolic velocity--end diastolic velocity]/peak systolic velocity) by Doppler sonography has demonstrated variable reliability as an indicator of pediatric urinary obstruction. By modifying Doppler studies with the addition of furosemide (diuretic Doppler sonography), we previously found significant differences between 10 nonobstructed and 10 obstructed kidneys in children (median age 7 months). The obstructed kidneys have since undergone surgical repair, and postoperative reevaluation has been performed by diuretic Doppler sonography and diuretic renography. Diuretic Doppler sonography was performed on well hydrated catheterized patients, with resistive index measurement of the renal interlobar and arcuate arteries obtained before and 10 minutes after 1 mg./kg. furosemide infusion. Following surgical repair of obstruction all 10 kidneys had stable glomerular filtration rate with improved pelvic emptying times as demonstrated by half-time. Of 6 kidneys evaluated by diuretic Doppler sonography before 3 months 2 had resistive index levels greater than 75. Of the 9 kidneys measured at 3 months or more postoperatively all had resistive index values of less than 75, even after furosemide infusion (5 kidneys underwent repeat evaluation). In our study the previously demonstrated post-diuretic elevation of resistive index in pediatric urinary obstruction was eventually reversed following surgical repair. Diuretic Doppler sonography appears to be a promising noninvasive method for evaluating pediatric hydronephrosis, providing an alternative physiological parameter with which to measure renal obstruction.


Educational disparities in disability-free life expectancy across Europe: A focus on the East-West gaps from a gender perspective.
Education plays a crucial role in shaping the health outcomes of adults. This study examines the relationship between educational attainment and health across Europe. Using data from the Survey of Health, Ageing and Retirement in Europe (SHARE), we estimate educational inequalities in disability-free life expectancy (DFLE) by gender in seven Western European (2004-2019) and three Central and Eastern European (CEE) (2010-2019) countries. We exploit a novel approach that combines the Sullivan method and multivariate life tables to calculate DFLE using SHARE data. We find that educational differences in DFLE favoring the better-educated exist in both CEE and Western European countries, but also that the differences across countries are more pronounced among the low-educated. While the absolute gaps in DFLE between low- and high-educated individuals in CEE and Western European countries are similar, the educational disparities in DFLE impose a more significant burden on the CEE populations due to their overall lower life expectancy. Educational inequalities are larger among women than among men in CEE countries, while the results for Western European countries are mixed. Our findings further highlight the important role of the institutional context in mitigating or exacerbating educational inequalities in health.


Mapping and identification of essential gene functions on the X chromosome of Drosophila.
The Drosophila melanogaster genome consists of four chromosomes that contain 165 Mb of DNA, 120 Mb of which are euchromatic. The two Drosophila Genome Projects, in collaboration with Celera Genomics Systems, have sequenced the genome, complementing the previously established physical and genetic maps. In addition, the Berkeley Drosophila Genome Project has undertaken large-scale functional analysis based on mutagenesis by transposable P element insertions into autosomes. Here, we present a large-scale P element insertion screen for vital gene functions and a BAC tiling map for the X chromosome. A collection of 501 X-chromosomal P element insertion lines was used to map essential genes cytogenetically and to establish short sequence tags (STSs) linking the insertion sites to the genome. The distribution of the P element integration sites, the identified genes and transcription units as well as the expression patterns of the P-element-tagged enhancers is described and discussed.


Radiotherapy for Hepatocellular Carcinoma in Russia: a Survey-Based Analysis of Current Practice and the Impact of an Educational Workshop on Clinical Expertise.
Radiation therapy (RT) is an effective treatment modality for hepatocellular carcinoma (HCC), but globally, it is underutilized. In Russia, practice patterns with regard to liver-directed radiation are unknown. Under the auspices of Russian Society of Clinical Oncology (RUSSCO), our team conducted an IRB-approved contouring workshop for Russian radiation oncologists. Pre- and post-workshop surveys were analyzed to determine baseline clinical experience and patterns of care for liver-directed RT among Russian providers. The effect of the contouring workshop on participants' knowledge was tested using mixed effects model. Forty pre-workshop and 24 post-workshop questionnaires were analyzable with a 100% response rate. Sixty percent of respondents had never evaluated a patient with HCC and only 8% (3 out of 40) reported treating an HCC patient with liver-directed RT. Nonetheless, 73% of respondents were comfortable offering liver-directed RT prior to the workshop. After the workshop, 85% of respondents felt comfortable treating a patient with HCC with liver-directed RT and 50% were comfortable recommending stereotactic body radiation therapy (SBRT). Measures of knowledge pertaining to evaluation of HCC patients and selection for appropriate liver-directed therapies were dramatically improved after the workshop. Liver-directed RT is not commonly used in Russia in the management of patients with HCC, and few centers are equipped for motion management. Our contouring workshop resulted in dramatically improved understanding of the evaluation and management of HCC patients. We recommend starting with a more protracted fractionated RT and building experience through attendance of additional educational activities, participation in multidisciplinary liver tumor boards, and prospective analysis of treatment toxicity and outcomes.


Basilar invagination: Surgical results.
Basilar invagination (BI) is a congenital craniocervical junction (CCJ) anomaly represented by a prolapsed spine into the skull-base that can result in severe neurological impairment. In this paper, we retrospective evaluate the surgical treatment of 26 patients surgically treated for symptomatic BI. BI was classified according to instability and neural abnormalities findings. Clinical outcome was evaluated using the Nürick grade system. A total of 26 patients were included in this paper. Their age ranged from 15 to 67 years old (mean 38). Of which, 10 patients were male (38%) and 16 (62%) were female. All patients had some degree of tonsillar herniation, with 25 patients treated with foramen magnum decompression. Nine patients required a craniocervical fixation. Six patients had undergone prior surgery and required a new surgical procedure for progression of neurological symptoms associated with new compression or instability. Most of patients with neurological symptoms secondary to brainstem compression had some improvement during the follow-up. There was mortality in this series, 1 month after surgery, associated with a late removal of the tracheal cannula. Management of BI requires can provide improvements in neurological outcomes, but requires analysis of the neural and bony anatomy of the CCJ, as well as occult instability. The complexity and heterogeneous presentation requires attention to occult instability on examination and attention to airway problems secondary to concomitant facial malformations.


Optimizing brain MR imaging protocols with gadopentetate dimeglumine: enhancement of intracranial lesions on spin-density- and T2-weighted images.
To determine whether long TR MR imaging is best performed before or after IV administration of gadopentetate dimeglumine, we obtained spin-density- and T2-weighted images before and after contrast administration in 21 patients with known intracranial enhancing lesions. Of 25 lesions demonstrating enhancement on T1-weighted sequences, 21 showed mild or moderate enhancement on spin-density-weighted sequences and 20 showed mild enhancement on T2-weighted sequences. Importantly, no spin-density or T2 information was obscured by the administration of gadopentetate dimeglumine, and no T2 shortening effects were visible. Two new foci of enhancement were visible on postcontrast spin-density- and T2-weighted images that were missed on postcontrast T1-weighted images and on precontrast spin-density- and T2-weighted studies. Visualization of new areas of enhancement is the main advantage provided by the long TR images obtained after IV injection of gadopentetate dimeglumine. The most likely reason for the appearance of these newly visualized lesions is thought to be delayed enhancement. This imaging protocol also allows the display of adjacent edema or gliosis and enhancing lesions on a single image. Additionally, in three cases, posterior fossa phase-shift artifacts raised the suspicion of an enhancing lesion on postcontrast T1-weighted images, but the cerebellum was shown to be normal on the postcontrast spin-density- and T2-weighted studies. On the basis of our results, we recommend obtaining long TR images after rather than before the administration of gadopentetate dimeglumine in patients with intracranial enhancing lesions.


Layer-specific cholinergic control of human and mouse cortical synaptic plasticity.
Individual cortical layers have distinct roles in information processing. All layers receive cholinergic inputs from the basal forebrain (BF), which is crucial for cognition. Acetylcholinergic receptors are differentially distributed across cortical layers, and recent evidence suggests that different populations of BF cholinergic neurons may target specific prefrontal cortical (PFC) layers, raising the question of whether cholinergic control of the PFC is layer dependent. Here we address this issue and reveal dendritic mechanisms by which endogenous cholinergic modulation of synaptic plasticity is opposite in superficial and deep layers of both mouse and human neocortex. Our results show that in different cortical layers, spike timing-dependent plasticity is oppositely regulated by the activation of nicotinic acetylcholine receptors (nAChRs) either located on dendrites of principal neurons or on GABAergic interneurons. Thus, layer-specific nAChR expression allows functional layer-specific control of cortical processing and plasticity by the BF cholinergic system, which is evolutionarily conserved from mice to humans.


Synaptotagmin IV is an immediate early gene induced by depolarization in PC12 cells and in brain.
Subtractive library construction and differential screening were used to identify a cDNA for a cell type-specific immediate early gene induced in rat PC12 pheochromocytoma cells. Sequencing identified the protein product of this gene as rat synaptotagmin IV (SytIV). Synaptotagmins are synaptic vesicle proteins thought to play a role in depolarization-induced, calcium-mediated exocytosis and neurotransmitter release. SytIV mRNA accumulation is transiently induced in PC12 cells by potassium depolarization, calcium ionophore, ATP, and forskolin. In contrast, growth factors and phorbol 12-myristate 13-acetate induce little or no SytIV mRNA accumulation. Kainic acid-induced seizures in rats are followed by accumulation of SytIV message in the hippocampus and piriform cortex. The SytIV gene may provide a direct link between depolarization-induced neuronal gene expression and subsequent modulation of synaptic structure and function.


Vitamin E and platelets: cooperative interactions with nitroblue tetrazolium on inhibition of adhesion, aggregation and secretion.
We have evaluated the influence of NBT, vitamin E, and the combination of NBT and vitamin E on the fine structure and biochemistry of platelets during incubation, and the effects of these compounds on the aggregation and secretion of platelets stimulated by collagen, thrombin, epinephrine, and ADP. Results demonstrate that NBT and vitamin E, rather than injuring platelets, appear to protect them during incubation. Togheter NBT and vitamin E blockedaggregation by epinephrine, collagen, and thrombin, but permitted a small first wave stimulated by ADP. This pattern of response to aggregating agents was similar to reactions observed in platelets pretreated with aspirin and indomethacin, both potent inhibitors of platelet prostaglandin synthesis. The findings support the concept that conversion of arachidonic acid to an activated state is an important step in prostaglandin synthesis and that electron transfer or oxidation--reduction reactions are intimately involved in the development of platelet stickiness. Although vitamin E alone does not block prot to regulate formation of endoperoxides and thromboxanes.


Geographic variations in eosinophil concentration in normal colonic mucosa.
We reviewed 256 mucosal biopsy specimens from the descending and sigmoid colon obtained from surgical pathology departments in several areas of the United States. Only specimens of normal colonic mucosa were included, i.e., no specimens with acute or chronic colitis or adenomatous change, or in which eosinophils invaded the crypts or muscularis mucosae. The mean number of eosinophils per intercryptal space was highest in the southern United States, and there was a 35-fold difference between the mean eosinophil concentrations of patients in New Orleans and Boston. The reason for geographic variation is unknown, but it might be related to allergens in the environment or diet. Normal variations in mucosal eosinophil concentrations should be measured within a specific region before evaluating colonic biopsy specimens for eosinophilia.


Stacking Faults Assist Lithium-Ion Conduction in a Halide-Based Superionic Conductor.
In the pursuit of urgently needed, energy dense solid-state batteries for electric vehicle and portable electronics applications, halide solid electrolytes offer a promising path forward with exceptional compatibility against high-voltage oxide electrodes, tunable ionic conductivities, and facile processing. For this family of compounds, synthesis protocols strongly affect cation site disorder and modulate Li+ mobility. In this work, we reveal the presence of a high concentration of stacking faults in the superionic conductor Li3YCl6 and demonstrate a method of controlling its Li+ conductivity by tuning the defect concentration with synthesis and heat treatments at select temperatures. Leveraging complementary insights from variable temperature synchrotron X-ray diffraction, neutron diffraction, cryogenic transmission electron microscopy, solid-state nuclear magnetic resonance, density functional theory, and electrochemical impedance spectroscopy, we identify the nature of planar defects and the role of nonstoichiometry in lowering Li+ migration barriers and increasing Li site connectivity in mechanochemically synthesized Li3YCl6. We harness paramagnetic relaxation enhancement to enable 89Y solid-state NMR and directly contrast the Y cation site disorder resulting from different preparation methods, demonstrating a potent tool for other researchers studying Y-containing compositions. With heat treatments at temperatures as low as 333 K (60 °C), we decrease the concentration of planar defects, demonstrating a simple method for tuning the Li+ conductivity. Findings from this work are expected to be generalizable to other halide solid electrolyte candidates and provide an improved understanding of defect-enabled Li+ conduction in this class of Li-ion conductors.


Processes of change after a sudden gain and relation to treatment outcome-Evidence for an upward spiral.
Sudden gains are sudden symptom improvements from 1 psychotherapy session to the next. This study investigates the processes that may facilitate treatment outcome after a sudden gain occurred. A sample of 211 depressed patients who underwent cognitive-behavioral therapy was analyzed. Sudden gains were identified using a session-by-session self-report symptom measure. Patient ratings of general change factors (therapeutic alliance; coping skills) in the sessions before and after a sudden gain were investigated as predictors of outcome. Propensity score matching was used to compare sudden gain patients with similar patients who did not experience a sudden gain. Therapeutic alliance and coping skills increased in the postgain sessions. There were no comparable processes of change among patients without sudden gains. The therapeutic alliance was found to moderate the association between sudden gains and treatment outcome. Results suggest that sudden gains trigger change factors that facilitate the association between gains and treatment outcome. Patient-therapist dyads should work with sudden gains to consolidate symptom relief. (PsycINFO Database Record


Experience with MR-guided therapy.
The use of magnetic resonance imaging (MRI) for the real time guidance of surgical procedures is now undergoing clinical trials. Among the many procedures explored, open craniotomy neurosurgery appears to be among the most promising. Over 50 such cases have been done at the Brigham and Women's Hospital (BWH) in Boston. We review the technical approach used in these and related procedures. We consider the way in which imaging is used to augment and improve the procedures. As well, the implications of these protocols for remote diagnosis and telesurgery are explored. Finally, the implications of this experience for the insertion of new technology into medicine are discussed.


Myc-induced microRNAs integrate Myc-mediated cell proliferation and cell fate.
The Myc pathway, often deregulated in cancer, is critical in determining cell fate by coordinating a gene expression program that links the control of cell proliferation with cell fate decisions. As such, precise control of the Myc pathway activity must be achieved to ensure faithful execution of appropriate cellular response and to prevent progressing toward a malignant state. With recent highlighted roles of microRNAs (miRNA) as critical components of gene control, we sought to evaluate the extent to which miRNAs may contribute in the execution of Myc function. Combined analysis of mRNA and miRNA expression profiles reveals an integration whereby the Myc-mediated induction of miRNAs leads to the repression of various mRNAs encoding tumor suppressors that block cell proliferation including p21, p27, and Rb. In addition, the proapoptotic PTEN tumor suppressor gene is also repressed by Myc-induced miRNAs, suggesting that Myc-induced miRNAs contribute to the precise control of a transcriptional program that coordinates the balance of cell proliferation and cell death.


Of language knowledge, apes, and brains.
Man's language ability is due to a more general, deep-seated cognitive ability characteristic of the species. It is argued that man's ability for mathematical thinking is a product of the same species-specific form of cerebration as language. The basis for mathematical constructs seems to be contained in the basis for language constructs; apparently, for every mathematical notion there is a homologous one in the sphere of language, the former always being more restricted and well defined than the latter. Mathematical ability may therefore be regarded as a special case of the more general ability that also generates language, and this point is further emphasized by certain similarities in the formal structure of mathematics (arithmetic in particular) and language. Taking advantage of the commonalities between language and arithmetic, it is possible to use the latter to illustrate important general characteristics of the former. The insights gained are relevant to biology at large, and to comparative zoology and neurology in particular. The zoologist who wishes to compare animal communication with language must know what the nature of language is-how (or whether) one might analyze it into components. He must know what might constitute a primitive or simple language. It is shown that the irreducible elements of the two systems under study (language and arithmetic) are processes (i.e., processes of "relating," or simply "relations") and that these processes combine into interrated systems. The systems have ontogenetic histories that might, perhaps, furnish a criterion for the notion of simplicity. We do not yet know what might be a homologous phylogenetic "cousin" of the basic human ability under consideration; howerver, we should expect it to be "homeomorphic" to the human system if it is derived from a common ancestral ability. Homeomorphic mapping is therefore the most reliable criterion so far for phylogenetic relatedness. By characterizing language and arithmetic simultaneously (in order to get at their common biological foundations) it is also possible to sharpen up the questions that the student of language should put to the neurophysiologist. The quest for innovation or differences in brain processes and functions now appears to be the primary one, whereas a description of structural changes in the human brain would be of interest only insofar as this would elucidate how brain functions might have become modified by them.


Neoadjuvant Radiotherapy Improves Survival in Patients With T2b/T3 Bladder Cancer: A Population-Based Analysis.
Neoadjuvant radiotherapy (NART) for muscle-invasive bladder cancer (MIBC) is currently underused. However, the outcomes for MIBC have remained suboptimal. We investigated the relationship of NART to cause-specific mortality (CSM) and overall mortality (OM) among patients with a diagnosis of MIBC. The patients diagnosed with primary invasive urothelial carcinoma of the bladder from 1983 to 2008 with localized disease were included. Patients aged > 90 years, those diagnosed with T1 or T4 BC, and those with no information on tumor grade were excluded from the analysis. Kaplan-Meier, Cox regression, and competing risk methods were used in the analysis of OM and CSM. A total of 5562 patients were included in the cohort (115 NART and 5447 surgery alone). On univariate analysis, NART significantly decreased the OM for patients with high-grade BC (hazard ratio [HR], 0.8), stage T2b (HR, 0.74), and stage T2b/T3 (HR, 0.74). CSM was also lower for those with stage T2b disease (HR, 0.63). Multivariable analysis revealed that NART was associated with a significant decrease in CSM (P = .043) and OM (P = .0462) for those with T2b. Likewise, an improvement was seen in OM (P = .0337) for patients with T2b/T3 who had received NART. NART was significantly associated with decreased CSM and OM in patients with clinical T2b/T3 BC and OM for patients with T2b/T3. These data suggest that NART could be beneficial in patients with T2b/T3 BC. In the modern era, the greatest utility would potentially be for patients with an incomplete response to neoadjuvant chemotherapy or as an adjunct to chemotherapy to improve the complete response rates.


Improved insulin sensitivity in patients with type I diabetes mellitus after CSII.
Tissue sensitivity to insulin was studied using the euglycemic insulin clamp technique (delta plasma insulin above basal 90 microU/ml) in eight patients with type I diabetes mellitus (IDDM) before and after 4-8 mo of continuous subcutaneous insulin infusion (CSII) and in 36 age-matched control subjects. Institution of CSII was associated with significant improvements in glycosylated hemoglobin (HbA1) (11.2 +/- 0.6% versus 8.1 +/- 0.4%; P less than 0.001) and mean 24-h plasma glucose concentrations (239 +/- 23 mg/dl versus 106 +/- 18 mg/dl; P less than 0.001). Insulin-mediated glucose metabolism in the diabetic patients pre-CSII (3.92 +/- 0.36 mg/kg X min) was reduced by 44% compared with controls (7.03 +/- 0.22 mg/kg X min; P less than 0.001). After 4-8 mo of improved glycemic control, improved tissue sensitivity to insulin was observed (5.33 +/- 0.75 mg/kg X min; P less than 0.05 versus pre-CSII). However, insulin-mediated glucose utilization still remained significantly below control values (P less than 0.01). During hyperinsulinemia, hepatic glucose production (3-3H-glucose) was suppressed by over 90% in diabetic patients (pre- and post-CSII) and in control subjects. We conclude that near-normalization of glucose metabolism with CSII partially corrects, but does not restore to normal, insulin-stimulated glucose uptake in IDDM. Our failure to totally reverse the impaired response of peripheral tissues to insulin in IDDM patients may be attributed to inadequate metabolic correction, the peripheral route of insulin administration, or a primary defect in glucose metabolism.


Heart rate recovery after the 6 min walk test rather than distance ambulated is a powerful prognostic indicator in heart failure with reduced and preserved ejection fraction: a comparison with cardiopulmonary exercise testing.
Heart rate recovery (HRR) appears to be a robust prognostic marker in heart failure (HF). When using the 6 min walk test (6MWT) in HF, distance ambulated is generally the reference prognostic variable. We hypothesized that HRR after the 6MWT would be a better prognostic measure than distance ambulated. A 6MWT and cardiopulmonary exercise testing (CPX) were randomly performed in 258 HF patients [216 HF with reduced EF (HFrEF) and 42 HF preserved EF (HFpEF)], after which HRR was measured. HRR was defined as the difference between heart rate at peak exercise and 1 min following test termination. Patients were assessed for major cardiac events during a mean follow-up period of 22.8 ± 22.1 months. There were 50 major cardiac events during the tracking period. Univariate Cox regression analysis results identified HRR after both the 6MWT and CPX as a significant (P < 0.001) predictor of adverse events. Multivariate Cox regression analysis revealed that dichotomized HRR after the 6MWT and CPX was the strongest predictor of survival (χ(2) 61.1 and 53.8, respectively; P < 0.001), with LVEF (residual χ(2) 6.1, P < 0.05) adding significant prognostic value to the 6MWT model and ventilatory efficiency (the VE/VCO2 slope) (residual χ(2) 6.6, P < 0 .05) adding significant prognostic value to the CPX model. HRR after the 6MWT is a powerful prognosticator that performs similarly to HRR after maximal exercise. If confirmed in subsequent studies, 6MWT HRR should replace 6MWT distance as the reference criterion 6MWT measure to consider when grading cardiovascular risk in HF patients.


[Safety of nanoparticles and nanomaterials for environmental and occupational space].
National and international experience, international standards, reports and recommendations relating to the assessment of harm to health, safety in the new nanoscale production for environmental and occupational space (ISO / TR 12885:2008 (E), BSI PD 6699-1:2007, etc .) have been analyzed.


The link between interoceptive processing and anxiety in children diagnosed with autism spectrum disorder: Extending adult findings into a developmental sample.
Anxiety is a major associated feature of autism spectrum disorders. The incidence of anxiety symptoms in this population has been associated with altered interoceptive processing. Here, we investigated whether recent findings of impaired interoceptive accuracy (quantified using heartbeat detection tasks) and exaggerated interoceptive sensibility (subjective sensitivity to internal sensations on self-report questionnaires) in autistic adults, can be extended into a school-age sample of children and adolescents (n = 75). Half the sample had a verified diagnosis of an Autism Spectrum Disorder (ASD) and half were IQ- and age-matched children and adolescents without ASD. The discrepancy between an individual's score on these two facets of interoception (interoceptive accuracy and interoceptive sensibility), conceptualized as an interoceptive trait prediction error, was previously found to predict anxiety symptoms in autistic adults. We replicated the finding of reduced interoceptive accuracy in autistic participants, but did not find exaggerated interoceptive sensibility relative to non-autistic participants. Nonetheless, the positive association between anxiety and interoceptive trait prediction error was replicated. However, in this sample, the best predictor of anxiety symptoms was interoceptive sensibility. Finally, we observed lower metacognitive accuracy for interoception in autistic children and adolescents, relative to their non-autistic counterparts. Despite their reduced interoceptive accuracy on the heartbeat tracking task and comparable accuracy on the heartbeat discrimination task, the autistic group reported higher confidence than the typical group in the discrimination task. Findings are consistent with theories of ASD as a disorder of interoceptive processing, but highlight the importance of validating cognitive models of developmental conditions within developmental populations.


RG108 induces the apoptosis of endometrial cancer Ishikawa cell lines by inhibiting the expression of DNMT3B and demethylation of HMLH1.
The effects of DNA methyltransferase (DNMT) inhibitor RG108 on the proliferation and apoptosis of endometrial cancer was investigated, and whether its mechanism was related to the inhibition of DNMT3B, thereby affecting the human mutL homolog 1 (hMLH1) methylation status and its expression, was further studied. Culture of human endometrial cancer Ishikawa cell lines: cells grew adhering to the wall in Roswell Park Memorial Institute-1640 (RPMI-1640) medium (supplemented with 10% fetal bovine serum (FBS) and 2 mM L-glutamic acid). After the cells were treated with RG108, the changes in cell viability were detected via methyl thiazolyl tetrazolium (MTT) assay. The effect of RG108 on cell cycle was detected via flow cytometry, and its effect on cell apoptosis was detected via flow cytometry and TUNEL. Moreover, the methylation status of hMLH1gene in endometrial cancer cells was detected via methylation specific-PCR (MSP), and the changes in DNMT3Band hMLH1 expressions were detected via RT-PCR and Western blotting, respectively. MTT results showed that RG108 inhibited the cell viability in a dose-dependent and time-dependent manner. Flow cytometry revealed that RG108 blocked the cell cycle in G2/M phase and promoted the apoptosis, and TUNEL assay further proved that RG108 promoted the apoptosis. It was found in the detection via MSP that the methylated hMLH1 gene was significantly reduced after 72 h of treatment with RG108. Besides, RT-PCR and Western blotting showed that RG108 inhibited the DNMT3B expression and activated the hMLH1 expression. The demethylation drug RG108 can significantly inhibit the proliferation of endometrial cancer cells, block the cell cycle in the G2/M phase and induce the cell apoptosis, which is a new candidate drug in the treatment of endometrial cancer. RG108 realizes the hMLH1 demethylation and increases the hMLH1 expression through inhibiting the expression of DNMT3B.


The Genetic and Environmental Relationship Between Childhood Behavioral Inhibition and Preadolescent Anxiety.
This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9-13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.


Utilization of orange peel, a food industrial waste, in the production of exo-polygalacturonase by pellet forming Aspergillus sojae.
The production of exo-polygalacturonase (exo-PG) from orange peel (OP), a food industrial waste, using Aspergillus sojae was studied in submerged culture. A simple, low-cost, industrially significant medium formulation, composed of only OP and (NH4)2SO4 (AS) was developed. At an inoculum size of 2.8 × 10(3) spores/mL, growth was in the form of pellets, which provided better mixing of the culture broth and higher exo-PG activity. These pellets were successfully used as an inoculum for bioreactors and 173.0 U/mL exo-PG was produced. Fed-batch cultivation further enhanced the exo-PG activity to 244.0 U/mL in 127.5 h. The final morphology in the form of pellets is significant to industrial fermentation easing the subsequent downstream processing. Furthermore, the low pH trend obtained during this fermentation serves an advantage to fungal fermentations prone to contamination problems. As a result, an economical exo-PG production process was defined utilizing a food industrial by-product and producing high amount of enzyme.