Role of the glutamate dehydrogenase reaction in furnishing aspartate nitrogen for urea synthesis: studies in perfused rat liver with 15N.
The present study was designed to determine: (i) the role of the reductive amination of alpha-ketoglutarate via the glutamate dehydrogenase reaction in furnishing mitochondrial glutamate and its transamination into aspartate; (ii) the relative incorporation of perfusate 15NH4Cl, [2-15N]glutamine or [5-15N]glutamine into carbamoyl phosphate and aspartate-N and, thereby, [15N]urea isotopomers; and (iii) the extent to which perfusate [15N]aspartate is taken up by the liver and incorporated into [15N]urea. We used a liver-perfusion system containing a physiological mixture of amino acids and ammonia similar to concentrations in vivo, with 15N label only in glutamine, ammonia or aspartate. The results demonstrate that in perfusions with a physiological mixture of amino acids, approx. 45 and 30% of total urea-N output was derived from perfusate ammonia and glutamine-N respectively. Approximately two-thirds of the ammonia utilized for carbamoyl phosphate synthesis was derived from perfusate ammonia and one-third from glutamine. Perfusate [2-15N]glutamine, [5-15N]glutamine or [15N]aspartate provided 24, 10 and 10% respectively of the hepatic aspartate-N pool, whereas perfusate 15NH4Cl provided approx. 37% of aspartate-N utilized for urea synthesis, secondary to the net formation of [15N]glutamate via the glutamate dehydrogenase reaction. The results suggest that the mitochondrial glutamate formed via the reductive amination of alpha-ketoglutarate may have a key role in ammonia detoxification by the following processes: (i) furnishing aspartate-N for ureagenesis; (ii) serving as a scavenger for excess ammonia; and (iii) improving the availability of the mitochondrial [glutamate] for synthesis of N -acetylglutamate. In addition, the current findings suggest that the formation of aspartate via the mitochondrial aspartate aminotransferase reaction may play an important role in the synthesis of cytosolic argininosuccinate.


Leukaemia, lymphoma, and multiple myeloma in seamen on tankers.
To investigate the risk of lymphatic and haematopoietic malignancies in deck crew on tankers exposed to cargo vapours. The study design was as a nested case-referent study in two cohorts of male Swedish seamen 20-64 years of age at the national census 1960 (n 13,449) and 1970 (n 11,290), respectively. Cases were detected by record linkage with the Swedish Cancer Register 1961-79 and 1971-87, respectively. For each case, three to five age matched referents from the population were selected. Exposure was assessed from data in the Swedish Registry of Seamen and from a register of Swedish ships. Seamen in the 1970 cohort, who had been exposed to cargo vapours for at least one month on chemical or product tankers, had an increased risk of lymphatic and haematopoietic malignancies (Mantel-Haenszel odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.1 to 5.9)) with a significant exposure-response relation (conditional logistic regression analysis, p = 0.04). The ORs were increased for both lymphoma (3.2), multiple myeloma (4.0), and leukaemia (1.6), but the increase was only significant for non-Hodgkin's lymphoma (OR 3.3, 95% CI 1.1 to 10.6). There were no significantly increased risks for the 1960 cohort or for seamen exposed only on crude oil tankers, but these groups had few exposed cases and low cumulative exposure to benzene and other light petroleum products. Seamen exposed to cargo vapours from gasoline and other light petroleum products on chemical or product tankers had an increased incidence of lymphatic and haematopoietic malignancies. One possible cause is exposure to benzene during loading, unloading, and tank cleaning operations.


[Acute rupture of the tibialis anterior tendon].
Tibialis anterior tendon rupture is a relatively rare injury, with diverse etiologies, that can cause significant deficits in the functionality of the ankle. These injuries are sometimes diagnosed too late, being in many occasions the alteration in walking the symptom that makes the patient go to the doctor. The six weeks will mark the limit between acute and chronic injury, requiring different therapeutic approaches, along with other parameters such as age, functional demand or concomitant pathologies. To present two cases of acute rupture, with different etiology, the surgical technique used and the final results. We present two cases of acute rupture of the tibialis anterior tendon in the critical hipovascular area, a male and a female, with posttraumatic and spontaneous etiology, respectively, in which tendon reinsertion was performed on the tarsal scaphoid with a biothenodesis screw, followed by immobilization with permission to walk at three weeks and subsequent physiotherapy. In both cases a satisfactory final functional result was obtained, with a significant improvement in the AOFAS score, returning to their work and sports activities at 3 and 4 months of surgery respectively, with a follow-up of 7.5 years and 10 months. This technique, within the variety described in the medical literature, has provided us excellent results, restoring the functionality of the anterior tibialis tendon and being reproducible for its simplicity, providing a high degree of safety when performing an early physiotherapy.


Smoking and the compression of morbidity.
To examine whether eliminating smoking will lead to a reduction in the number of years lived with disability (that is, absolute compression of morbidity). Multistate life table calculations based on the longitudinal GLOBE study (the Netherlands) combined with the Longitudinal Study of Aging (LSOA, United States of America). the Netherlands. Dutch nationals aged 30-74 years living in the city of Eindhoven and surrounding municipalities (GLOBE) and United States citizens age 70 and over (LSOA). Life expectancy with and without disability and total life expectancy at ages 30 and 70. A non-smoking population on balance spends fewer years with disability than a mixed smoking-non-smoking population. Although non-smokers have lower mortality risks and thus are exposed to disability over a longer period of time, their lower incidence of disability and higher recovery from disability yield a net reduction of the length of time spent with disability (at age 30: -0.9 years in men and -1.1 years in women) and increases the length of time lived without disability (2.5 and 1.9 years, for men and women, respectively). These outcomes indicate that elimination of smoking will extend life and the period of disability free life, and will compress disability into a shorter period. Eliminating smoking will not only extend life and result in an increase in the number of years lived without disability, but will also compress disability into a shorter period. This implies that the commonly found trade off between longer life and a longer period with disability does not apply. Interventions to discourage smoking should receive high priority.


A web-based computerized adaptive testing (CAT) to assess patient perception in hospitalization.
Many hospitals have adopted mobile nursing carts that can be easily rolled up to a patient's bedside to access charts and help nurses perform their rounds. However, few papers have reported data regarding the use of wireless computers on wheels (COW) at patients' bedsides to collect questionnaire-based information of their perception of hospitalization on discharge from the hospital. The purpose of this study was to evaluate the relative efficiency of computerized adaptive testing (CAT) and the precision of CAT-based measures of perceptions of hospitalized patients, as compared with those of nonadaptive testing (NAT). An Excel module of our CAT multicategory assessment is provided as an example. A total of 200 patients who were discharged from the hospital responded to the CAT-based 18-item inpatient perception questionnaire on COW. The numbers of question administrated were recorded and the responses were calibrated using the Rasch model. They were compared with those from NAT to show the advantage of CAT over NAT. Patient measures derived from CAT and NAT were highly correlated (r = 0.98) and their measurement precisions were not statistically different (P = .14). CAT required fewer questions than NAT (an efficiency gain of 42%), suggesting a reduced burden for patients. There were no significant differences between groups in terms of gender and other demographic characteristics. CAT-based administration of surveys of patient perception substantially reduced patient burden without compromising the precision of measuring patients' perceptions of hospitalization. The Excel module of animation-CAT on the wireless COW that we developed is recommended for use in hospitals.


Application of the 2016 EULAR/ACR/PRINTO Classification Criteria for Macrophage Activation Syndrome in Patients with Adult-onset Still Disease.
To evaluate the clinical significance of the 2016 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR)/Pediatric Rheumatology International Trials Organization (PRINTO) classification criteria for macrophage activation syndrome (MAS) in patients with adult-onset Still disease (AOSD). We performed a retrospective analysis of patients with AOSD with fever who were admitted to Severance Hospital between 2005 and 2016. The patients with AOSD were evaluated for MAS using the 2016 classification criteria for MAS. Clinical features, laboratory findings, and overall survival were analyzed. Logistic regression analysis was used to evaluate the factors associated with in-hospital mortality. Among 64 patients with AOSD, 36 (56.3%) were classified as having MAS. The overall survival rate was significantly lower in patients with MAS than in those without (67% vs 100%, p < 0.001). Multivariate analysis showed that a low erythrocyte sedimentation rate, a low albumin level, an increase in ferritin of over 2 folds, and the development of MAS on admission were significantly associated with mortality in patients with AOSD. The 2016 EULAR/ACR/PRINTO classification criteria for MAS are potentially useful for the identification of patients with AOSD at high risk for a poor outcome. Febrile patients with AOSD should be monitored with the 2016 classification criteria for MAS in the early diagnosis and proper treatment of MAS.


Capital PPS: trekking through the labyrinth.
The Health Care Financing Administration's (HCFA's) new method of paying for Medicare inpatient capital costs will pay a hospital under either a fully prospective system or a hold harmless method. The new system includes a payment floor on total capital, a revised outlier payment system, and an exceptions process by which some hospitals can receive additional capital payments. HCFA plans to phase in the new system over a 10-year period.


Nickel-Catalyzed Reductive Arylation of α-Bromo Sulfoxide.
A nickel-catalyzed cross-electrophile coupling of aryl iodides with α-bromo sulfoxide to access a diverse array of aryl benzyl sulfoxides has been discovered. These reactions occurred under mild conditions with excellent functional group tolerance so that optically enriched sulfoxides could be coupled with aryl iodides, generating corresponding sulfoxides with excellent stereochemical integrity. Furthermore, the scalability of this transformation was demonstrated. Initial mechanistic studies revealed that the reaction undergoes a radical pathway.


Effects of nitroglycerin on transmural myocardial blood flow in the unanesthetized dog.
This study was designed to determin the effect of nitroglycerin upon transmural distribution of myocardial blood flow in the awake dog during normal conditions and in the presence of ischemia-induced coronary vasodilation. Studies were performed in chronically prepared dogs with electromagnetic flowmeters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was estimated by using radionuclide-labeled microspheres, 7-10 mum in diameter, injected into the left atrium. During control conditions endocardial flow (0.86 plus or minus SEM 0.05 ml/min per g) slightly exceeded epicardial flow (0.72 plus or minus 0.03 ml/min per g, P smaller than 0.05), and this distribution of flow was not significantly altered by nitroglycerin. After a 5-s coronary artery occlusion, reactive hyperemia occurred with excess inflow of arterial blood effecting 360 plus or minus 15% repayment of the blood flow debt incurred during occlusion. When arterial inflow was limited to the preocclusion rate during coronary vasodilation after a 5-s total coronary artery occlusion, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium, and the delayed reactive hyperemia was markedly augmented (mean blood flow debt repayment =775plus or minus 105%, P smaller than 0.01). Tese data suggested that subendocardial underperfusion during the interval of coronary vasodilation in the presence of a flow-limiting proximal coronary artery stenosis caused continuing subendocardial ischemia which resulted in augmentation of the reactive hyperemic response. In this experimental model both the redistribution of myocardial blood flow which occurred during an interval of restricted arterial inflow after a 5-s coronary artery occlusion and augmentation of the subsequent reactive hyperemic response were returned toward normal by nitroglycerin. This effect of nitroglycerin may have resulted, at least in part, from its ability to vasodilate the penetrating arteries which deliver blood from the epicardial surface to the subendocardium.


Use of the ornithine decarboxylase promoter to achieve N-MYC-mediated overexpression of a rabbit carboxylesterase to sensitize neuroblastoma cells to CPT-11.
Overexpression of specific transcription factors by tumor cells can be exploited to regulate expression of proteins that induce apoptosis or activate prodrugs, thereby producing tumor-selective toxicity. A majority of advanced-stage neuroblastomas overexpress the transcription factor N-MYC, and this overexpression is associated with poor prognosis. This study describes regulation of expression by N-MYC, via the ornithine decarboxylase (ODC) promoter, of a rabbit liver carboxylesterase (CE) that activates the prodrug CPT-11. Chloramphenicol acetyltransferase reporter assays and CE activity assays in transiently transfected neuroblastoma cell lines (SJNB-1, SJNB-4, NB-1691) and rhabdomyosarcoma cell lines (JR1neo20, JR1Nmyc6, JR1Nmyc9) support this approach as a potential method for sensitizing tumor cells to CPT-11. Clonogenic assays with IMR32 human neuroblastoma cells which express N-MYC and that had been stably transfected with a plasmid containing an ODC promoter/CE cassette corroborated results of enzyme activity assays. Specifically, IMR32.ODC.CE cells expressed approximately eightfold more CE activity than IMR32.CMV.neo cells; and 5 microM CPT-11 reduced the clonogenic potential of IMR32.ODC.CE cells to zero, while 50 microM CPT-11 was required to produce the same effect with IMR32.CMV.neo cells. Current experiments focus on adenoviral delivery of an ODC promoter/CE cDNA cassette for potential virus-directed enzyme prodrug therapy applications.


Algorithm and data structures for efficient energy maintenance during Monte Carlo simulation of proteins.
Monte Carlo simulation (MCS) is a common methodology to compute pathways and thermodynamic properties of proteins. A simulation run is a series of random steps in conformation space, each perturbing some degrees of freedom of the molecule. A step is accepted with a probability that depends on the change in value of an energy function. Typical energy functions sum many terms. The most costly ones to compute are contributed by atom pairs closer than some cutoff distance. This paper introduces a new method that speeds up MCS by exploiting the facts that proteins are long kinematic chains and that few degrees of freedom are changed at each step. A novel data structure, called the ChainTree, captures both the kinematics and the shape of a protein at successive levels of detail. It is used to efficiently detect self-collision (steric clash between atoms) and/or find all atom pairs contributing to the energy. It also makes it possible to identify partial energy sums left unchanged by a perturbation, thus allowing the energy value to be incrementally updated. Computational tests on four proteins of sizes ranging from 68 to 755 amino acids show that MCS with the ChainTree method is significantly faster (as much as 10 times faster for the largest protein) than with the widely used grid method. They also indicate that speed-up increases with larger proteins.


Cleavage site mutations in the encephalomyocarditis virus P3 region lethally abrogate the normal processing cascade.
Site-specific mutations within the proteinase 3C-dependent P3 region cleavage sequences of encephalomyocarditis virus have been constructed. The mutations altered the normal QG cleavage site dipeptide pairs of the 2C/3A, 3A/3B, 3B/3C, and 3C/3D junctions into QV, QC, QF, QY, and RG sequences. When translated in vitro in the context of full-length viral polyproteins, all mutations blocked endogenous 3C-mediated processing at their engineered sites and produced stable forms of the expected viral P3 precursors that were also resistant to cleavage by exogenously added recombinant 3C. Relative to wild-type viral sequences, each mutant form of P3 had a somewhat different ability to mediate overall polyprotein processing. Mutations at the 2C/3A, 3A/3B, and 3B/3C sites, for example, were generally less impaired than 3C/3D mutations, when the cleavage reactions were quantitated with cotranslated L-P1-2A precursors. A notable exception was mutant 3B3C(QG-->RG), which proved far less active than sibling mutants 3B3C(QG-->QF) and 3B3C(QG-->QV), a finding that possibly implicates this segment in the proper folding of an active 3C. When transfected into HeLa cells, all mutant sequences were lethal, presumably because of the reduced L-P1-2A processing levels or reduced RNA synthesis capacity. However, when specifically tested for the latter activity, all mutations except those at the 3C/3D cleavage site were indeed able to initiate and perpetuate viral RNA replication in transfected cells, albeit to RNA accumulation levels lower than those produced by wild-type sequences. The transfection effects could be mimicked with cell-free synthesized proteins, in that translation samples containing locked 3CD polymerase precursors were catalytically inactive in poly(A)-oligo(U)-dependent assays, while all other mutant processing samples initiated detectable RNA synthesis. Surprisingly, not only did the 3B/3C mutant sequences prove capable of directing RNA synthesis, but the viral RNA thus synthesized could be immunolabeled and precipitated with 3C-specific monoclonal antibody reagents, indicating an unexpected covalent attachment of the proteinase to the RNA product whenever this cleavage site was blocked.


[Energy requirement for the maintenance and utilization of energy convertible to protein and fat deposits in piglets].
In respiration experiments with 16 piglets the effect of feeding level on energy metabolism was studied with the aim of estimating energy requirement and costs of protein and fat deposition. Four groups of 4 animals each were fed on different levels of digestible protein and metabolisable energy (ME). Group 1 was fed intensively, whereas the piglets of group 2, 3 and 4 received 92, 76 and 55% respectively of the amounts given to group 1. In the group 1-4 mean daily weight gain was 457, 437, 360 and 205 g respectively. As a consequence the rearing period increased from 44 days to 46, 56 and 98 days. The variation in feed intake affected not only significant differences in energy deposition but also changes in gain composition. In the groups 1-4 the average energy deposition was 4.2 MJ, 4.0 MJ, 3.0 MJ and 1.4 MJ per day and protein gain exceeded fat gain in all groups. Estimations of energy requirement for maintenance were carried out by means of multiple regression analysis using different models. As a result a value of 428 MJ ME per kg live weight 0.75 was obtained and the models used have hardly shown any influence. It seems that higher values for maintenance requirement, as formerly published, are due to different conditions of livestock management, such as temperature. For all groups the average efficiency of ME-utilisation for growth was 0.77, ranging from 0.73 to 0.82. The variation can be attributed to the changes in protein and fat formation. The groups with a higher proportion of protein in the accretion utilised metabolisable energy more efficiently than the intensively fed group 1 with the highest proportion of fat, the difference between the groups being in the range from 0.73 to 0.82. The efficiency of ME-utilisation for protein deposition was calculated to be 0.83 and for fat deposition 0.73. As a higher coefficient for fat formation may be expected in the light of the high fat content in the ration, calculations with an assumed coefficient from 0.75 and 0.80 had been carried out, showing that the efficiency of ME-utilisation for protein gain would only decrease to 0.79 and 0.73 respectively. According to these results the statement must be called in question, that the energetic efficiency of protein deposition of about 50 to 55% - as measured in numerous experiments mainly with older pigs - can generally be accepted.


Test-retest reliability of selected items of Health Behaviour in School-aged Children (HBSC) survey questionnaire in Beijing, China.
Children's health and health behaviour are essential for their development and it is important to obtain abundant and accurate information to understand young people's health and health behaviour. The Health Behaviour in School-aged Children (HBSC) study is among the first large-scale international surveys on adolescent health through self-report questionnaires. So far, more than 40 countries in Europe and North America have been involved in the HBSC study. The purpose of this study is to assess the test-retest reliability of selected items in the Chinese version of the HBSC survey questionnaire in a sample of adolescents in Beijing, China. A sample of 95 male and female students aged 11 or 15 years old participated in a test and retest with a three weeks interval. Student Identity numbers of respondents were utilized to permit matching of test-retest questionnaires. 23 items concerning physical activity, sedentary behaviour, sleep and substance use were evaluated by using the percentage of response shifts and the single measure Intraclass Correlation Coefficients (ICC) with 95% confidence interval (CI) for all respondents and stratified by gender and age. Items on substance use were only evaluated for school children aged 15 years old. The percentage of no response shift between test and retest varied from 32% for the item on computer use at weekends to 92% for the three items on smoking. Of all the 23 items evaluated, 6 items (26%) showed a moderate reliability, 12 items (52%) displayed a substantial reliability and 4 items (17%) indicated almost perfect reliability. No gender and age group difference of the test-retest reliability was found except for a few items on sedentary behaviour. The overall findings of this study suggest that most selected indicators in the HBSC survey questionnaire have satisfactory test-retest reliability for the students in Beijing. Further test-retest studies in a large and diverse sample, as well as validity studies, should be considered for the future Chinese HBSC study.


Conducting Science in Disasters: Recommendations from the NIEHS Working Group for Special IRB Considerations in the Review of Disaster Related Research.
Research involving human subjects after public health emergencies and disasters may pose ethical challenges. These challenges may include concerns about the vulnerability of prospective disaster research participants, increased research burden among disaster survivors approached by multiple research teams, and potentially reduced standards in the ethical review of research by institutional review boards (IRBs) due to the rush to enter the disaster field. The NIEHS Best Practices Working Group for Special IRB Considerations in the Review of Disaster Related Research was formed to identify and address ethical and regulatory challenges associated with the review of disaster research. The working group consists of a diverse collection of disaster research stakeholders across a broad spectrum of disciplines. The working group convened in July 2016 to identify recommendations that are instrumental in preparing IRBs to review protocols related to public health emergencies and disasters. The meeting included formative didactic presentations and facilitated breakout discussions using disaster-related case studies. Major thematic elements from these discussions were collected and documented into 15 working group recommendations, summarized in this article, that address topics such as IRB disaster preparedness activities, informed consent, vulnerable populations, confidentiality, participant burden, disaster research response integration and training, IRB roles/responsibilities, community engagement, and dissemination of disaster research results. https://doi.org/10.1289/EHP2378.


A Cross-Sectional Study of Nemaline Myopathy.
Nemaline myopathy (NM) is a rare neuromuscular condition with clinical and genetic heterogeneity. To establish disease natural history, we performed a cross-sectional study of NM, complemented by longitudinal assessment and exploration of pilot outcome measures. Fifty-seven individuals with NM were recruited at 2 family workshops, including 16 examined at both time points. Participants were evaluated by clinical history and physical examination. Functional outcome measures included the Motor Function Measure (MFM), pulmonary function tests (PFTs), myometry, goniometry, and bulbar assessments. The most common clinical classification was typical congenital (54%), whereas 42% had more severe presentations. Fifty-eight percent of individuals needed mechanical support, with 26% requiring wheelchair, tracheostomy, and feeding tube. The MFM scale was performed in 44 of 57 participants and showed reduced scores in most with little floor/ceiling effect. Of the 27 individuals completing PFTs, abnormal values were observed in 65%. Last, bulbar function was abnormal in all patients examined, as determined with a novel outcome measure. Genotypes included mutations in ACTA1 (18), NEB (20), and TPM2 (2). Seventeen individuals were genetically unresolved. Patients with pathogenic ACTA1 and NEB variants were largely similar in clinical phenotype. Patients without genetic resolution had more severe disease. We present a comprehensive cross-sectional study of NM. Our data identify significant disabilities and support a relatively stable disease course. We identify a need for further diagnostic investigation for the genetically unresolved group. MFM, PFTs, and the slurp test were identified as promising outcome measures for future clinical trials.


[Tumoral form of cerebral cysticercosis: diagnosis by computerized tomography].
Solitary granulomatous lesions due to cysticercosis in the brain were found by computed tomography in six patients. The CT images were in all cases very similar to those from brain neoplasms. The cerebrospinal fluid complement fixation test for cysticercosis was negative in all of the cases. The definite etiological diagnosis could only be made by craniotomy in this series.


Reconstitution of cytochrome b-560 (QPs1) of bovine heart mitochondrial succinate-ubiquinone reductase.
The QPs1 subunit of bovine heart mitochondrial succinate-ubiquinone reductase was overexpressed in Escherichia coli DH5 alpha cells as a glutathione S-transferase fusion protein (GST-QPs1) using the expression vector, pGEX/QPs1. The yield of soluble active recombinant GST-QPs1 fusion protein depends on the IPTG concentration, induction growth time, temperature, and medium. Maximum yield of recombinant fusion protein was obtained from cells harvested 3 h postinduction of growth with 0.5 mM IPTG at 27 degrees C in an enriched medium containing betaine and sorbitol. QPs1 is released from the fusion protein by proteolytic cleavage with thrombin. Isolated recombinant QPs1 shows one protein band in SDS-polyacrylamide gel electrophoresis corresponding to subunit III of mitochondrial succinate-ubiquinone reductase. However, partial N-terminal amino acid sequence analysis of recombinant QPs1 shows two extra amino acid residues, glycine and serine, at the N-terminus of mature QPs1, resulting from the recombinant manipulation. When isolated recombinant QPs1 is dispersed in 0.01% dodecyl maltoside, it is in a highly aggregated form with an apparent molecular mass of over 1 million. Recombinant GST-QPs1 contains little cytochrome b-560 heme. However, addition of hemin chloride restores the spectral characteristics of cytochrome b-560. Cytochrome b-560 restoration varies with the amount of hemin used. Maximum reconstitution is obtained when the molar ratio of heme to fusion protein used in the system is 0.6. Reconstituted cytochrome b-560 shows a EPR signal at g = 2.91 which corresponds to one of the EPR signals of cytochrome b-560 in a QPs preparation. When GST-QPs1 with reconstituted cytochrome b-560 is treated with thrombin to cleave GST from QPs1, no change in the absorption and EPR characteristics of cytochrome b-560 is observed, indicating that the bis-histidine ligands of reconstituted cytochrome b-560 are provided by QPs1.


[Preparation to motherhood by the group structure].
The authors, who are undergraduate nursing students, describe a method they have employed to prepare pregnant women and "pregnant comples" for delivery. This method, which includes individual and group sessions, is centered on the patients' needs and emphasizes the importance of understanding the anatomical, physiological and psychological changes occurring in pregnancy.


[An evaluation of the services of state hospital pharmacies in Rio de Janeiro, Brazil].
This article presents an evaluation of state-run hospital pharmacies in Rio de Janeiro. For the regulatory evaluation, 62 indicators of structure and procedures were used in order to establish the adequacy of the activities of the hospital pharmacy. The services were then stratified by level of complexity of the hospital. A scaled rating algorithm was applied to each stratum in accordance with the activities carried out. The hospitals were then hierarchically grouped for each stratum and the best and worst services at each level of complexity were chosen for the multiple case study, resulting in a total of six units. In these units 16 result indicators were applied and analysis of the resulting data was conducted by cross-case synthesis. The performance evaluation revealed that only one unit performed management and forecasting activities satisfactorily. Four units administered medication procurement inadequately. The worst results in terms of performance in the six hospitals studied were related to stock management and the best to distribution activities. The data are a cause for concern, since these are considered the core activities of the hospital pharmacy.


Electoral incentives to combat mosquito-borne illnesses: Experimental evidence from Brazil.
Mosquito-borne illnesses present significant health challenges to the developing world. If citizens are informed about their government's efforts to combat these diseases, will they reward incumbents who have performed well and punish those who have done poorly at this task? Electoral sanctioning requires that combatting disease be a sufficiently salient concern, which, in turn, is likely to depend upon subjective perceptions of the risks posed by particular illnesses. Epidemics typically prompt stronger risk perceptions than endemic diseases, but where both types circulate jointly, the more familiar endemic disease may determine public reactions. The salience of health threats also varies among individuals; those with a self-interest in prevention or a personal connection to the effects of mosquito-borne illnesses may react more strongly. This study presents the results of a face-to-face survey experiment in Pernambuco, Brazil, informing subjects about their mayor's use of federal funds to combat mosquito-borne illnesses such as dengue (an endemic disease) and Zika and chikungunya (both epidemics). We examine the effect of this information on intended vote for the mayor's reelection. For the full sample, the treatment has no significant effect. However, we find a large and significant punishment effect among voters who know someone affected by microcephaly or the Zika virus. Drawing on survey and focus group evidence, we argue that most voters fail to act upon our treatment information because mosquito control is a low-salience concern primarily associated with endemic rather than epidemic diseases. Our study constitutes the first experimental evidence as to whether informing citizens about government public health efforts affects voting behavior. Our results suggests that, where similar epidemic and endemic diseases circulate together, informational campaigns aiming to induce electoral accountability should also seek to boost the salience of the information by educating the public about the difference between familiar and newer threats.


The treatment landscape of advanced angiosarcoma in Asia-A multi-national collaboration from the Asian Sarcoma Consortium.
Angiosarcoma (AS) is a rare disease with a dismal prognosis. The treatment landscape and prognostic factors for advanced AS, including locally advanced, unresectable, and metastatic disease remain elusive. The Asian Sarcoma Consortium is an international collaborative effort to understand the sarcoma treatment landscape in Asia. We undertook a retrospective chart review of AS patients seen in 8 sarcoma academic centers across Asia. Patients with complete clinical, treatment, and follow-up data were enrolled. Overall, 276 advanced AS patients were included into this study; 84 (30%) of the patients had metachronous metastatic AS. The median age was 67 y; primary sites of AS was cutaneous in 55% and visceral in 45% of patients. In total, 143 (52%) patients received at least 1 line of systemic chemotherapy. The most common first-line chemotherapy regimen used was paclitaxel (47.6%) followed by liposomal doxorubicin (19.6%). The median overall survival (OS) was 7.8 mo. Significant prognostic factors for OS included age > 65 (hazard ratio (HR) 1.54, P = .006), male gender (HR 1.39, P = .02), and a cutaneous primary AS site (HR 0.63, P = .004). The median progression-free survival (PFS) for first-line chemotherapy was 3.4 mo. PFS for single vs combination or paclitaxel vs liposomal doxorubicin chemotherapy regimens were comparable. This study provides an insight into the treatment patterns and prognostic factors of advanced AS patients in Asia. Prognosis of advanced AS remains poor. Data from this study serve as a benchmark for future clinical study design.


The stromal microenvironment and ovarian aging: mechanisms and therapeutic opportunities.
For decades, most studies of ovarian aging have focused on its functional units, known as follicles, which include oocytes and granulosa cells. However, in the ovarian stroma, there are a variety of somatic components that bridge the gap between general aging and ovarian senescence. Physiologically, general cell types, microvascular structures, extracellular matrix, and intercellular molecules affect folliculogenesis and corpus luteum physiology alongside the ovarian cycle. As a result of damage caused by age-related metabolite accumulation and external insults, the microenvironment of stromal cells is progressively remodeled, thus inevitably perturbing ovarian physiology. With the established platforms for follicle cryopreservation and in vitro maturation and the development of organoid research, it is desirable to develop strategies to improve the microenvironment of the follicle by targeting the perifollicular environment. In this review, we summarize the role of stromal components in ovarian aging, describing their age-related alterations and associated effects. Moreover, we list some potential techniques that may mitigate ovarian aging based on their effect on the stromal microenvironment.


Pharmacokinetic evaluation of dosing regimens for insulin in diabetic ketoacidosis.
A pharmacokinetic model of the insulin-glucose system was used to examine the effectiveness of insulin administered by a variety of routes and regimens for diabetic ketoacidosis. The blood plasma concentration of glucose was set at 1,000 mg. per dl., and the effects of the following insulin regimens on the glucose plasma level were compared: low dose (90mU. per kg. per hr.) administered by hourly intramuscular injection, constant-rate infusion, hourly intravenous bolus, constant-rate infusion with intravenous loading dose, and high dose (2 U. per kg.) with half given as an intravenous bolus and the remainder administered subcutaneously. Computer simulations showed that the high-dose regimen reduced the plasma glucose concentration rapidly to a hypoglycemic level (less than 34 mg. per dl. at three hours postadministration). The low-dose regimens reduced the plasma glucose level more slowly than did the high-dose regimen. Differences among the low-dose regimens were noted. The initial decline of the plasma glucose level was relatively slow with both the intramuscular and constant-rate infusion regimens. An additional problem with the intramuscular regimen was the accumulation of insulin at sites of administration. This accumulation could make judgment of the appropriate time to discontinue insulin difficult. Both the hourly intravenous bolus and the constant-rate infusion with loading-dose regimens caused a prompt decline in the plasma glucose level. Their potential for causing hypoglycemia was low provided insulin was discontinued when the plasma glucose level reached 180 mg. per dl.


Variation of Anatomical and Physiological Parameters that Affect Estimates of ACL Loading During Drop Landing.
Anterior cruciate ligament (ACL) loading during drop landing has been recently studied with a sagittal plane knee model developed by Kernozek and Ragan using mean anatomical and physiological parameters obtained from cadaveric and clinical data. It is unknown how estimates in ACL load may be altered due to variations in anatomical and physiological parameters used from other research. USING THE SAME MODEL, THESE PARAMETERS WERE SYSTEMATICALLY VARIED, INCLUDING: tibial slope, moment arms of the patellar tendon, hamstring, and gastrocnemius at the knee and ankle, patellar tendon and hamstring line of force, ACL stiffness, and nonlinear muscle activation parameters. To determine the sensitivity of the model to changes in these parameters, each was varied independently by ±5% and by ranges reported in the literature. Changes in maximum ACL load and shear force components of the patellar tendon, hamstring, and tibio-femoral contact force were calculated from drop landing data of 21 subjects. The variation in ACL load during drop landing from its nominal value was largest (-100% to 176%) when extremes in reported tibial slope values were utilized. Variation in the next most important parameter, patellar tendon line of force, affected ACL load by -72% to 88%. Variations in tibial slope and patellar tendon line of force had the greatest influence on estimated ACL loading during drop landing. Differences in these parameters between subjects may be just as important to ACL loading as the kinematic and kinetic performance differences observed in landing.


Ultrastructural Abnormalities in Induced Pluripotent Stem Cell-Derived Neural Stem Cells and Neurons of Two Cohen Syndrome Patients.
Cohen syndrome is an autosomal recessive disorder caused by VPS13B (COH1) gene mutations. This syndrome is significantly underdiagnosed and is characterized by intellectual disability, microcephaly, autistic symptoms, hypotension, myopia, retinal dystrophy, neutropenia, and obesity. VPS13B regulates intracellular membrane transport and supports the Golgi apparatus structure, which is critical for neuron formation. We generated induced pluripotent stem cells from two patients with pronounced manifestations of Cohen syndrome and differentiated them into neural stem cells and neurons. Using transmission electron microscopy, we documented multiple new ultrastructural changes associated with Cohen syndrome in the neuronal cells. We discovered considerable disturbances in the structure of some organelles: Golgi apparatus fragmentation and swelling, endoplasmic reticulum structural reorganization, mitochondrial defects, and the accumulation of large autophagosomes with undigested contents. These abnormalities underline the ultrastructural similarity of Cohen syndrome to many neurodegenerative diseases. The cell models that we developed based on patient-specific induced pluripotent stem cells can serve to uncover not only neurodegenerative processes, but the causes of intellectual disability in general.


Sequential purification of human apolipoprotein B-100, albumin, and fibrinogen by immunoaffinity chromatography for measurement of protein synthesis.
A determinant of the accuracy of protein synthesis measurement using stable isotope is the purity of the protein under study. An Immunoaffinity chromatographic technique to sequentially purify human plasma albumin, fibrinogen, and apolipoprotein B-100 (ApoB-100) was developed to measure isotopic enrichment in these proteins. The technique, utilizing immobilized mouse monoclonal antibodies specific to human plasma ApoB-100, albumin, and fibrinogen onto an affinity matrix, allowed purification of very low density lipoprotein (VLDL) ApoB-100, albumin, and fibrinogen from 1- to 2-ml plasma samples. Analytical sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining demonstrated consistent purity of the three purified proteins. The identity and the purity of the proteins separated by this technique were also confirmed by amino acid sequence analysis. This technique was applied to sequentially purify and measure the isotopic enrichment in those proteins by mass spectrometry from human plasma samples collected after orally ingesting L[1-13C]-leucine. Reproducibility of the enrichment measurements is within 5% of the coefficient of variation. Measurements [13C]leucine in these proteins purified from plasma samples collected during a 10-h primed continuous intravenous infusion of L-[1-13C]leucine confirmed that this technique provides an efficient way to purify plasma VLDL ApoB-100, albumin, and fibrinogen for measuring their synthetic rates in human metabolism studies.


[Improvement in the control of the water supply in military posts].
The control at water supply on criteria of quantitative and qualitative adequacy--one the major sections of sanitary-and-epidemiologic supervision. To radical improvement of water supply of the population of the country, army and fleet are called to serve entered in action since July 1, 1997 Sanitary rules and norms 188.8.131.529-96 "Drinking water. The hygienic requirement to quality of water of centralized systems of drinking water supply. Quality surveillance". In the interest of increase of epidemiologic safety of drinking water in comparison with GOST 2874-82 specifications of microbiological parameters are severed and a parasitologic parameter is entered. The new document changes accepted early classification of chemical structure of water.


Assessing Student Readiness to Work with People Who Use Drugs: Development of a Multi-disciplinary Addiction Educational Survey.
As health profession schools implement addiction curricula, they need survey instruments to evaluate the impact of the educational interventions. However, existing measures do not use current non-stigmatizing language and fail to capture core concepts. To develop a brief measure of health profession student readiness to work with people who use drugs (PWUDs) and establish its content validity. We conducted a literature review of existing instruments and desired clinical competencies related to providing care to PWUD and used results and expert feedback to create and revise a pool of 72 items. We conducted cognitive interviews with ten pre-clinical health profession students from various US schools of nursing, pharmacy, and medicine to ensure the items were easy to understand. Finally, we used a modified Delphi process with twenty-four health professions educators and addiction experts (eight each from nursing, pharmacy, and medicine) to select items for inclusion in the final scale. We analyzed expert ratings of individual items and interdisciplinary agreement on ratings to decide how to prioritize items. We ultimately selected 12 attitudes and 12 confidence items to include in the REadiness to Discuss Use, Common Effects, and HArm Reduction Measure (REDUCE-HARM). Experts rated their overall assessment of the final scale. Twenty-two of twenty-four experts agreed or strongly agreed that the attitudes scale measures student attitudes that impact readiness to work with PWUDs. Twenty-three of twenty-four experts agreed or strongly agreed that the confidence scale measures student self-efficacy in competencies that impact readiness to work with PWUDs. Seven of 72 initial items and none of the 24 selected items had statistically significant differences between disciplines. The REDUCE-HARM instrument has strong content validity and may serve as a useful tool in evaluating addiction education. Additional research is needed to establish its reliability, construct validity, and responsiveness to change.


A mammalian cytochrome fused to a chloroplast transit peptide is a functional haemoprotein and is imported into isolated chloroplasts.
The small subunit of ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) is a major chloroplast stromal protein that is cytosolically synthesized as a precursor with an N-terminal extension, known as the transit sequence or transit peptide (Tp). The Tp is essential for the post-translational uptake of the precursor by the chloroplast. The Tp is thought to influence the conformation of the precursor protein and to facilitate polypeptide translocation across the chloroplast envelope barrier via a Tp-selective translocon. To address these issues we have devised a novel strategy to generate substrate amounts of a chloroplast targeting sequence as a fusion with the chromogenic globular domain of cytochrome b(5) (Cyt). The chimaeric protein is an ideal probe for investigating the conformation of a preprotein and events surrounding protein import into isolated chloroplasts. The Cyt of liver endoplasmic reticulum was fused at its N-terminus with the Tp of the small subunit of Rubisco of Pisum sativum (pea). To enhance its production by clearance from the cytoplasm of Escherichia coli, the chimaera was engineered by further N-terminal linkage of a prokaryotic secretory signal. Expression of this tripartite fusion resulted in mg quantities of the signal sequence-processed Tp-Cyt protein, which was eventually targeted to the membranes. The chromogenic nature of the chimaera and its localization to the bacterial membrane facilitated the biochemical isolation of the precursor in a soluble and functional form. The purified preprotein displayed spectral and enzymic properties that were indistinguishable from the native parental Cyt, implying an absence of observable influence of the Tp on the conformation of the haemoprotein. The chimaeric precursor was imported into the stroma of the isolated chloroplasts in a dose-dependent manner. Import was also strongly dependent upon exogenously supplied ATP. The stromally imported chimaeric precursor protein was processed to a size characteristic of Cyt.


Counterpulsation and dobutamine. Their use in treatment of cardiogenic shock due to right ventricular infarct.
A patient had right ventricular infarction complicated by cardiogenic shock. Volume expansion along with high doses of dopamine hydrochloride successfully alleviated hypotension in this patient. However, he had persistent mental obtundation and low cardiac output, and adverse chronotropic responses to high doses of dopamine developed. Counterpulsation effectively maintained an adequate arterial pressure and dopamine therapy was discontinued. Counterpulsation, however, failed to augment cardiac output. Simultaneous use of dobutamine hydrochloride along with counterpulsation was associated with a noticeable increase in cardiac output. To our knowledge, this is the first reported case of right ventricular infarct complicated by shock in which the simultaneous use of counterpulsation and dobutamine therapy resulted in a substantial increase in cardiac output.


Clinical stage and grade migration of localized prostate cancer at diagnosis during the past decade.
Early 2010s data suggest a reverse stage and grade migration towards more aggressive prostate cancer (PCa) at diagnosis, accelerated by the 2012 US Preventive Services Task Force recommendation against PSA screening. Using the National Cancer Database, we investigated the impact of the 2018 USPSTF recommendation and the COVID-19 outbreak on this shift. We hypothesized that the COVID-19 outbreak would further contribute to a stage and grade migration towards more aggressive disease. We identified men with localized PCa diagnosed between 2010 and 2020. We analyzed the shift in the proportion of PCa stratified according to D'Amico risk classification. We used multivariable logistic regression models to assess the association between year of diagnosis and dichotomous variables related to clinical stage and grade of PCa. Predicted probabilities with 95% CI were computed through marginal effect analyses. We identified 910,898 men with localized PCa. The proportion of low-risk PCa almost halved from 34.9% in 2010 to 17.7% in 2020 (P < 0.001). Compared to 2010, we found in each year increased odds of: PSA≥10 ng/dL starting from 2012 (aOR2012 1.05; 95% CI, 1.02-1.08); cT3-T4 starting from 2015 (aOR2015 1.10; 95% CI, 1.03-1.17); ISUP GG 3-5 starting from 2011 (aOR2011 1.06; 95% CI, 1.03-1.08); and consequently, D'Amico intermediate/high-risk class starting from 2011 (aOR2011 1.03; 95% CI, 1.01-1.05). Fluctuations in the probabilities of PSA≥10 ng/dL and cT3-T4 at diagnosis were observed over time (all P < 0.001). The probability of PSA≥10 ng/dL peaked at 29.0% (95% CI, 28.0%-29.0%) in 2018, while the probability of cT3-T4 peaked at 3.7% (95% CI, 3.6%-3.8%) in 2020. All other outcome variables demonstrated a consistent upward shift (all P < 0.001), with the highest probabilities in 2020 for ISUP GG 3-5 (42.3%, 95% CI, 41.9%-42.6%) and D'Amico intermediate/high-risk (81.3%, 95% CI, 81.0%-81.6%). Our study confirms an enduring shift towards a higher proportion of aggressive PCa at diagnosis, likely influenced by the COVID-19 pandemic. The impact of the 2018 USPSTF PCa screening recommendation on the proportion of aggressive PCa seems restricted and likely affected by the pandemic outbreak. Future investigations should evaluate the long-term effects of the 2018 USPSTF recommendations in the postpandemic setting.


Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonist-treated monkeys.
Both follicle stimulating hormone (FSH) and luteinizing hormone (LH) are proposed requirements for follicular growth and steroidogenesis; however, the role of LH in primate folliculogenesis is unclear. Follicular stimulation by recombinant human FSH (n = 5) with and without recombinant LH (1:1; n = 6) following 90 days of gonadotrophin-releasing hormone (GnRH) antagonist (Antide) treatment in macaques was evaluated. Human chorionic gonadotrophin (HCG) was administered when six follicles > or = 4 mm were observed. Oocytes were aspirated 27 h later and inseminated in vitro. Chronic Antide reduced serum oestradiol and bioactive LH to concentrations observed in hypophysectomized rhesus monkeys. Multiple follicular growth required a longer interval following recombinant FSH (12 +/- 1 days) than recombinant FSH+recombinant LH (9 +/- 0.2 days), but the total number of follicles/animal did not differ between groups. The day prior to HCG, oestradiol concentrations were 4-fold less following recombinant FSH compared to recombinant FSH+recombinant LH. With recombinant FSH, more oocytes completed meiosis to metaphase II (51%) and fertilized (89 +/- 5%) relative to recombinant FSH+recombinant LH (12 and 52 +/- 11% respectively). Follicular growth and maturation in LH-deficient macaques occurred with FSH alone. Thus, LH is not required for folliculogenesis in primates. Higher fertilization rates following follicular stimulation with FSH alone suggest that the presence of LH with FSH (1:1) during the pre-ovulatory interval impairs gametogenic events in the periovulatory period.


Gut microbiota changes in inflammatory bowel diseases and ankylosing spondilytis.
Both inflammatory bowel diseases (IBD) and ankylosing spondylitis (AS) can be considered chronic immune disorders sharing common etiopathogenetic mechanisms. Changes in the composition of the intestinal microbiota, which can lead to an abnormal mucosal response, could be the missing link between these two diseases. Our study evaluate the composition of intestinal microbiota and to characterize gut dysbiosis in patients with IBD and AS. We conducted a prospective case-control study that enrolled 124 patients [20 Crohn's disease (CD), 27 ulcerative colitis (UC), 28 AS, 17 IBD + AS and 32 controls). Intestinal microbiota analysis was performed by real-time polymerase chain reaction in stool samples. The total quantity of bacteria was decreased in all investigated groups compared to the control group. In studied groups, we noticed an increased percentage of Bacteroides and Escherichia coli (E.coli) and a decreased percentage of Clostridium coccoides, Clostridium leptum, and Faecalibacterium prausnitzii compared to the control group. The percentages of Bifidobacterium (p=0.010) as well as Lactobacillus group (p=0.023) were higher in the L3 form of CD patients. In the E2 form of UC, the quantity of Bacteroides was much higher compared to the E3 form (p=0.004). In AS patients, significant correlations were observed only for the Bifidobacterium species, significantly increased in the axial form compared to peripheral disease (p=0.035). Statistically significant correlations were demonstrated between the Crohn Disease Activity Index score and the total bacterial group (p=0.023, r=-0.507), respectively Bacteroides (p=0.021, r=-0.511) and between the Mayo score and Lactobacillus (p=0.001), respectively E. coli (p=0.001). In IBD + AS group, the Crohn Disease Activity Index score was inversely correlated with the total bacterial group (p=0.010) and directly correlated with Lactobacillus (p=0.047). Intestinal dysbiosis is associated with both IBD and AS. In the association of IBD with AS, dysbiosis is intermediate, but it is associated with the more severe articular disease. Bifidobacterium and Lactobacillus (commonly used as probiotics!) were found to be increased in the association between active IBD and active AS. Further studies are needed to understand how dysbiosis regulates the gut immune system and contributes to intestinal and articular inflammation.


Use of learner-driven, formative, ad-hoc, prospective assessment of competence in physical therapist clinical education in the United States: a prospective cohort study.
The purpose of this project was to implement a process for learner-driven, formative, prospective, ad-hoc, entrustment assessment in Doctor of Physical Therapy clinical education. Our goals were to develop an innovative entrustment assessment tool, and then explore whether the tool detected (1) differences between learners at different stages of development and (2) differences within learners across the course of a clinical education experience. We also investigated whether there was a relationship between the number of assessments and change in performance. A prospective, observational, cohort of clinical instructors (CIs) was recruited to perform learner-driven, formative, ad-hoc, prospective, entrustment assessments. Two entrustable professional activities (EPAs) were used: (1) gather a history and perform an examination and (2) implement and modify the plan of care, as needed. CIs provided a rating on the entrustment scale and provided narrative support for their rating. Forty-nine learners participated across 4 clinical experiences (CEs), resulting in 453 EPA learner-driven assessments. For both EPAs, statistically significant changes were detected both between learners at different stages of development and within learners across the course of a CE. Improvement within each CE was significantly related to the number of feedback opportunities. The results of this pilot study provide preliminary support for the use learner-driven, formative, ad-hoc assessments of competence based on EPAs with a novel entrustment scale. The number of formative assessments requested correlated with change on the EPA scale, suggesting that formative feedback may augment performance improvement.


Immunoglobulin and lymphocyte responses following silica exposure in New Zealand mixed mice.
Epidemiological studies have shown strong associations between silica exposure and several autoimmune diseases, including scleroderma and systemic lupus erythematosus. We previously reported that the New Zealand mixed (NZM) mouse develops silicosis and exacerbated autoimmunity following crystalline silica exposure, including increased levels of autoantibodies, proteinuria, circulating immune complexes, pulmonary fibrosis, and glomerulonephritis. In this study, the NZM mouse was used to examine changes in immune activation following silica exposure by measuring levels of immunoglobulin, cytokines and lymphocyte populations. Levels of immunoglobulin (Ig) G1 were significantly decreased from 1124 +/- 244 microg/ml in saline exposed mice to 614 +/- 204 microg/ml in silica-exposed mice, suggesting a decrease in the Th2 response. The levels of tumor necrosis factor (TNF)-alpha were significantly increased (1.5-fold) in the bronchoalveolar lavage fluid of the silica-exposed mice as compared to the saline-exposed mice. The number of B1a B cells were significantly increased sixfold within the superficial cervical lymph nodes of silica-exposed mice as compared with saline-exposed mice. Following silica exposure, CD4+ T cells significantly increased threefold within the superficial cervical lymph nodes. During this increase in the number of CD4+ T cells, the number of CD4+CD25+ regulatory T cells was not significantly changed, altering the ratio of regulatory T cells to T helper cells from 1:5 to 1:8 following silica exposure. Therefore, the silica-induced alterations in immunoglobulin levels, increased TNF-alpha, increased B1a B cells and CD4+ T cells, with decreased regulatory T cells, may provide an environment that allows for increased autoreactivity. These studies begin to provide possible mechanisms for environmentally induced autoimmune diseases that have been reported in many epidemiological studies.


Initial validation and clinical experience with 3D optical-surface-guided whole breast irradiation of breast cancer.
We had introduced 3D optical surface-guided radiotherapy (SGRT) of the breast cancer (BC). We then initiated the feasibility, accuracy, and precision studies of stereovision in detection of any breast displacement through the course of treatment for total thirty breasts undertaken whole breast irradiation (WBI). In the SGRT, CT-based plan data were parsed into an in-house computer program through which the reference surfaces were generated in 3D video format. When patients were positioned on treatment Tables, real-time stereovisions were rapidly acquired while the live surface tracking shown steady thorax motion. The real-time surface images were automatically aligned with the reference surface and detected shape and location changes of the breast were online corrected through the Table and beam adjustments. Accumulated dose to each patient was computed according to the frequency distribution of the measured breast locations during beam on time. Application of SGRT had diminished large skin-marking errors of > 5-mm and daily breast-setup errors of >10-mm that occurred on half of cases. Accuracy (mean) and precision (two standard deviations) of the breast displacements across the tangential field edges in the (U, V) directions were improved from (-0.5 ± 8.8, 2.2 ± 10.8) mm in conventional setup to (0.4 ± 4.6, 0.7 ± 4.4) mm in the final position while intra-fractional motion contributed only (0.1 ± 2.8, 0.0 ± 2.2) mm in free breathing. Dose uniformity and coverage to targets had both been increased by up to 10% and the lung or heart intersections have been decreased by half of those volumes if they were irradiated at the initial positions. SGRT of BC appears to be feasible regardless of skin tones, as fast as a snapshot for 3D imaging, and very accurate and precise for daily setup of flexible breast targets. Importantly, the technique allows us to verify the breast shape and position during beam-on time.


Coronary artery thrombus as a risk factor for acute vessel occlusion during percutaneous transluminal coronary angioplasty: improving results.
Early experience with percutaneous transluminal coronary angioplasty (from October 1979 to March 1983 inclusive) showed that pre-existing coronary artery thrombus was associated with a significant increase in the incidence of acute coronary occlusion during angioplasty. Acute occlusion occurred in 11 (73%) of 15 patients with pre-existing thrombus compared with 18 (8%) of 223 patients without thrombus. The effect of improved technology (steerable guiding systems) and altered dilatation strategy (full intravenous heparinisation for 24 hours after the procedure and more intensive use of antiplatelet medications) was studied by review of angiograms from 297 consecutive patients without evidence of acute myocardial infarction who underwent angioplasty from April 1983 to March 1985 inclusive. Coronary artery thrombus was present in 34 (11%) patients, eight (24%) of whom had complete occlusion during or immediately after the procedure compared with 34 (13%) of 263 patients without thrombus. Patients with pre-existing coronary artery thrombus continue to be at greater risk of complete occlusion than patients without thrombus, but this risk has declined significantly since the modification of the angioplasty procedure.


Long-term associative learning predicts verbal short-term memory performance.
Studies using tests such as digit span and nonword repetition have implicated short-term memory across a range of developmental domains. Such tests ostensibly assess specialized processes for the short-term manipulation and maintenance of information that are often argued to enable long-term learning. However, there is considerable evidence for an influence of long-term linguistic learning on performance in short-term memory tasks that brings into question the role of a specialized short-term memory system separate from long-term knowledge. Using natural language corpora, we show experimentally and computationally that performance on three widely used measures of short-term memory (digit span, nonword repetition, and sentence recall) can be predicted from simple associative learning operating on the linguistic environment to which a typical child may have been exposed. The findings support the broad view that short-term verbal memory performance reflects the application of long-term language knowledge to the experimental setting.


Polyethyleneimine coated Fe3O4 magnetic nanoparticles induce autophagy, NF-κB and TGF-β signaling pathway activation in HeLa cervical carcinoma cells via reactive oxygen species generation.
Fe3O4 magnetic nanoparticles (MNPs), as one of the most intensively researched NPs, have a range of applications in cancer treatments. In current research, we have focused on the influences of MNPs on cancer cells. We chose polyethyleneimine (PEI) coated MNPs (PEI-MNPs) as a model and they are colloidally stable in biological media. It can be proved that PEI-MNPs result in autophagy induction via mTOR-Akt-p70S6 K and ATG7 signaling pathways. For the first time, we have reported that PEI-MNPs activate both NF-κB and TGF-β signaling, two key pro-inflammatory pathways, in cancer cells. More significantly, we have found that autophagy induction and NF-κB and TGF-β activation can be efficiently suppressed through the inhibition of PEI-MNP dependent reactive oxygen species (ROS) over-production. ROS are deemed as a 'double edge sword' for cancer cells, owing to the cancer-suppressing and cancer-promoting actions. Our findings would be useful for designing MNPs induced ROS anti-cancer strategies or diminishing long-term toxic effects.


Measuring concentration fields in microfluidic channels in situ with a Fabry-Perot interferometer.
Recent advancements in microfluidic technology have allowed for the generation and control of complex chemical gradients; however, few general techniques can measure these spatio-temporal concentration profiles without fluorescent labeling. Here we describe a Fabry-Perot interferometric technique, capable of measuring concentration profiles in situ, without any chemical label, by tracking Fringes of Equal Chromatic Order (FECO). The technique has a sensitivity of 10(-5) RIU, which can be used to track local solute changes of ~0.05% (w/w). The technique is spatially resolved (1 μm) and easily measures evolving concentration fields with ~20 Hz rate. Here, we demonstrate by measuring the binary diffusion coefficients of various solutes and solvents (and their concentration-dependence) in both free solution and in polyethylene glycol diacrylate (PEG-DA) hydrogels.


A first-level evaluation of a family intervention for adolescent social, emotional and behavioural difficulties in Child and Adolescent Mental Health Services.
This study is a first-level evaluation of a family intervention targeted at adolescents with social, emotional and behavioural difficulties (SEBD) attending Child and Adolescent Mental Health Services (CAMHS) in Ireland. It is a combined implementation of the Working Things Out adolescent programme and the Parents Plus Adolescent Programme (WTOPPAP). A total of 93 adolescents aged 11-17 years (M = 14.64, SD = 1.31; 39% male) and their parents took part in the study. The study used a quasi-experimental One-Group Pretest-Posttest design to assess change from pre- to post-intervention using the Strengths and Difficulties Questionnaire, the McMaster General Functioning Scale, Goal Attainment, Parent Stress Scale and the Kansas Parenting Satisfaction Scale. Both parent- and adolescent-rated goal attainment and general family functioning improved from pre- to post-intervention. Parents also rated their satisfaction with parenting as having significantly improved. Adolescent-rated emotional difficulties significantly improved for the overall sample and parent-rated child total difficulties for female adolescents significantly improved from pre-test to post-test. Parents of female adolescents also reported a significant drop in parental stress. These findings indicate that the WTOPPAP may be an effective intervention for adolescents with SEBD, particularly females, and their parents. Further implications are discussed.


Functional Geometry of Human Connectomes.
Mapping the brain imaging data to networks, where nodes represent anatomical brain regions and edges indicate the occurrence of fiber tracts between them, has enabled an objective graph-theoretic analysis of human connectomes. However, the latent structure on higher-order interactions remains unexplored, where many brain regions act in synergy to perform complex functions. Here we use the simplicial complexes description of human connectome, where the shared simplexes encode higher-order relationships between groups of nodes. We study consensus connectome of 100 female (F-connectome) and of 100 male (M-connectome) subjects that we generated from the Budapest Reference Connectome Server v3.0 based on data from the Human Connectome Project. Our analysis reveals that the functional geometry of the common F&M-connectome coincides with the M-connectome and is characterized by a complex architecture of simplexes to the 14th order, which is built in six anatomical communities, and linked by short cycles. The F-connectome has additional edges that involve different brain regions, thereby increasing the size of simplexes and introducing new cycles. Both connectomes contain characteristic subjacent graphs that make them 3/2-hyperbolic. These results shed new light on the functional architecture of the brain, suggesting that insightful differences among connectomes are hidden in their higher-order connectivity.


Effects of feedback frequency and timing on acquisition, retention, and transfer of speech skills in acquired apraxia of speech.
Two studies examined speech skill learning in persons with apraxia of speech (AOS). Motor-learning research shows that delaying or reducing the frequency of feedback promotes retention and transfer of skills. By contrast, immediate or frequent feedback promotes temporary performance enhancement but interferes with retention and transfer. These principles were tested in the context of a common treatment for AOS. Two studies (N = 4, N = 2) employed single-subject treatment designs to examine acquisition and retention of speech skills in adults with AOS under different feedback conditions. Reduced-frequency or delayed feedback enhanced learning in 3 participants with AOS. Feedback manipulation was not an influential variable in 3 other cases in which stimulus-complexity effects may have masked treatment effects. These findings demonstrate that individuals with AOS can benefit from structured intervention. They provide qualified support for reduction and delay of feedback, although interaction with other factors such as stimulus complexity or task difficulty needs further exploration. This study adds to the growing body of literature investigating the use of principles of motor learning in treating AOS and provides impetus for consideration of pre-treatment variables that affect outcome in treatment studies.


Endovascular embolization of varicoceles using n-butyl cyanoacrylate (NBCA) glue.
Varicoceles are abnormally dilated veins within the pampiniform plexus. They are caused by reflux of blood in the internal spermatic vein. The incidence of varicoceles is approximately 10-15% of the adolescent male population. The etiology of varicoceles is probably multifactorial. The diagnosis is based on Doppler US. Treatment could be endovascular or surgical. The aim of the study was to describe and evaluate a novel method of endovascular embolization of varicoceles using n-butyl cyanoacrylate (NBCA) glue. 17 patients were subjected to endovascular treatment of varicoceles using NBCA. A 2.8 Fr microcatheter and a 1:1 mixture of NBCA and lipiodol were used for embolization of the spermatic vein. All 17 procedures were successful. There were no complications. Embolization of varicoceles using NBCA glue is efficient and safe for all patients. The method should be considered as a method of choice in all patients. Phlebography and Valsalva maneuver are crucial for technical success and avoidance of complications. Endovascular treatment of varicoceles using NBCA glue is very effective and safe.


Identification multiplex assay of 19 terrestrial mammal species present in New Zealand.
An identification assay has been developed that allows accurate detection of 19 of the most common terrestrial mammals present in New Zealand (cow, red deer, goat, dog, horse, hedgehog, cat, tammar wallaby, mouse, weasel, ferret, stoat, sheep, rabbit, Pacific rat, Norway rat, ship rat, pig, and brushtail possum). This technique utilizes species-specific primers that, combined in a multiplex PCR, target small fragments of the mitochondrial cytochrome b gene. Each species, except hedgehog, produces two distinctive species-specific fragments, making the assay self-confirmatory and enabling the identification of multiple species simultaneously in DNA mixtures. The multiplex assay detects as little as 100 copies of mitochondrial DNA, which makes it a very reliable tool for degraded and trace samples. Reliability, accuracy, reproducibility, and sensitivity tests to validate the technique were performed. The technique featured here enabled a prompt response in a predation specific event, but can also be useful for wildlife management and conservation, pest incursions detection, forensic, and industrial purposes in a very simple and cost-effective manner.


Novel Pulse Oximetry Sonifications for Neonatal Oxygen Saturation Monitoring: A Laboratory Study.
We aimed to test whether the use of novel pulse oximetry sounds (sonifications) better informs listeners when a neonate's oxygen saturation (SpO2) deviates from the recommended range. Variable-pitch pulse oximeters do not accurately inform clinicians via sound alone when SpO2 is outside the target range of 90% to 95% for neonates on supplemental oxygen. Risk of blindness, organ damage, and death increase if SpO2 remains outside the target range. A more informative sonification may improve clinicians' ability to maintain the target range. In two desktop experiments, nonclinicians' ability to detect SpO2 range and direction of change was tested with novel versus conventional sonifications of simulated patient data. In Experiment 1, a "shoulder" sonification used larger pitch differences between adjacent saturation percentages for SpO2 values outside the target range. In Experiment 2, a "beacon" sonification used equal-appearing pitch differences, but when SpO2 was outside the target range, a fixed-pitch reference tone from the center of the target SpO2 range preceded every fourth pulse tone. The beacon sonification improved range identification accuracy over the control display (85% vs. 60%; p < .001), but the shoulder sonification did not (55% vs. 52%). The beacon provided a distinct auditory alert and reference that significantly improved nonclinical participants' ability to identify SpO2 range. Adding a beacon to the variable-pitch pulse oximeter sound may help clinicians identify when, and by how much, a neonate's SpO2 deviates from the target range, particularly during patient transport situations when auditory information becomes essential.


The PICO strategy for the research question construction and evidence search.
Evidence based practice is the use of the best scientific evidence to support the clinical decision making. The identification of the best evidence requires the construction of an appropriate research question and review of the literature. This article describes the use of the PICO strategy for the construction of the research question and bibliographical search.


Analytical model of large data transactions in CoAP networks.
We propose a novel analytical model to study fragmentation methods in wireless sensor networks adopting the Constrained Application Protocol (CoAP) and the IEEE 802.15.4 standard for medium access control (MAC). The blockwise transfer technique proposed in CoAP and the 6LoWPAN fragmentation are included in the analysis. The two techniques are compared in terms of reliability and delay, depending on the traffic, the number of nodes and the parameters of the IEEE 802.15.4 MAC. The results are validated trough Monte Carlo simulations. To the best of our knowledge this is the first study that evaluates and compares analytically the performance of CoAP blockwise transfer and 6LoWPAN fragmentation. A major contribution is the possibility to understand the behavior of both techniques with different network conditions. Our results show that 6LoWPAN fragmentation is preferable for delay-constrained applications. For highly congested networks, the blockwise transfer slightly outperforms 6LoWPAN fragmentation in terms of reliability.


In vivo short-term precision of hip structure analysis variables in comparison with bone mineral density using paired dual-energy X-ray absorptiometry scans from multi-center clinical trials.
Hip structural analysis (HSA) is a technique for extracting strength-related structural dimensions of bone cross-sections from two-dimensional hip scan images acquired by dual energy X-ray absorptiometry (DXA) scanners. Heretofore the precision of the method has not been thoroughly tested in the clinical setting. Using paired scans from two large clinical trials involving a range of different DXA machines, this study reports the first precision analysis of HSA variables, in comparison with that of conventional bone mineral density (BMD) on the same scans. A key HSA variable, section modulus (Z), biomechanically indicative of bone strength during bending, had a short-term precision percentage coefficient of variation (CV%) in the femoral neck of 3.4-10.1%, depending on the manufacturer or model of the DXA equipment. Cross-sectional area (CSA), a determinant of bone strength during axial loading and closely aligned with conventional DXA bone mineral content, had a range of CV% from 2.8% to 7.9%. Poorer precision was associated with inadequate inclusion of the femoral shaft or femoral head in the DXA-scanned hip region. Precision of HSA-derived BMD varied between 2.4% and 6.4%. Precision of DXA manufacturer-derived BMD varied between 1.9% and 3.4%, arising from the larger analysis region of interest (ROI). The precision of HSA variables was not generally dependent on magnitude, subject height, weight, or conventional femoral neck densitometric variables. The generally poorer precision of key HSA variables in comparison with conventional DXA-derived BMD highlights the critical roles played by correct limb repositioning and choice of an adequate and appropriately positioned ROI.


The CRISPR-associated gene cas2 of Legionella pneumophila is required for intracellular infection of amoebae.
Recent studies have shown that the clustered regularly interspaced palindromic repeats (CRISPR) array and its associated (cas) genes can play a key role in bacterial immunity against phage and plasmids. Upon analysis of the Legionella pneumophila strain 130b chromosome, we detected a subtype II-B CRISPR-Cas locus that contains cas9, cas1, cas2, cas4, and an array with 60 repeats and 58 unique spacers. Reverse transcription (RT)-PCR analysis demonstrated that the entire CRISPR-Cas locus is expressed during 130b extracellular growth in both rich and minimal media as well as during intracellular infection of macrophages and aquatic amoebae. Quantitative reverse transcription-PCR (RT-PCR) further showed that the levels of cas transcripts, especially those of cas1 and cas2, are elevated during intracellular growth relative to exponential-phase growth in broth. Mutants lacking components of the CRISPR-Cas locus were made and found to grow normally in broth and on agar media. cas9, cas1, cas4, and CRISPR array mutants also grew normally in macrophages and amoebae. However, cas2 mutants, although they grew typically in macrophages, were significantly impaired for infection of both Hartmannella and Acanthamoeba species. A complemented cas2 mutant infected the amoebae at wild-type levels, confirming that cas2 is required for intracellular infection of these host cells. Given that infection of amoebae is critical for L. pneumophila persistence in water systems, our data indicate that cas2 has a role in the transmission of Legionnaires' disease. Because our experiments were done in the absence of added phage, plasmid, or nucleic acid, the event that is facilitated by Cas2 is uniquely distinct from current dogma concerning CRISPR-Cas function.


Estimating energy expenditure in vascular surgery patients: Are predictive equations accurate enough?
Malnutrition is prevalent in vascular surgical patients who commonly seek tertiary care at advanced stages of disease. Adjunct nutrition support is therefore pertinent to optimise patient outcomes. To negate consequences related to excessive or suboptimal dietary energy intake, it is essential to accurately determine energy expenditure and subsequent requirements. This study aims to compare resting energy expenditure (REE) measured by indirect calorimetry, a commonly used comparator, to REE estimated by predictive equations (Schofield, Harris-Benedict equations and Miller equation) to determine the most suitable equation for vascular surgery patients. Data were collected from four studies that measured REE in 77 vascular surgery patients. Bland-Altman analyses were conducted to explore agreement. Presence of fixed or proportional bias was assessed by linear regression analyses. In comparison to measured REE, on average REE was overestimated when Schofield (+857 kJ/day), Harris-Benedict (+801 kJ/day) and Miller (+71 kJ/day) equations were used. Wide limits of agreement led to an over or underestimation from 1552 to 1755 kJ. Proportional bias was absent in Schofield (R2 = 0.005, p = 0.54) and Harris-Benedict equations (R2 = 0.045, p = 0.06) but was present in the Miller equation (R2 = 0.210, p < 0.01) even after logarithmic transformation (R2 = 0.213, p < 0.01). Whilst the Miller equation tended to overestimate resting energy expenditure and was affected by proportional bias, the limits of agreement and mean bias were smaller compared to Schofield and Harris-Benedict equations. This suggested that it is the preferred predictive equation for vascular surgery patients. Future research to refine the Miller equation to improve its overall accuracy will better inform the provision of nutritional support for vascular surgery patients and subsequently improve outcomes. Alternatively, an equation might be developed specifically for use with vascular surgery patients.


The nature of early intraluminal thrombosis in terminal aneurysms occluded with guglielmi detachable coils.
To investigate the early intraluminal thrombotic events after endovascular treatment of terminal aneurysms with detachable coils, and to assess the biological changes over the first three weeks, terminal arterial bifurcation aneurysms were produced microsurgically in 20 rabbits. After a healing period of three weeks, transfemoral angiography was performed and all aneurysms were occluded with Guglielmi Detachable Coils (GDC). Complete (i.e. 100%) occlusion was achieved in ten aneurysms. About 95% occlusion (only a small neck remnant) was seen in eight cases. In two cases, occlusion was about 70 - 80%. Half of the animals were treated by anticoagulation during and continuously two days after occlusion therapy. Angiographic studies and histological analysis were done for four aneurysms (two without and two with anticoagulation) after 24 - 48 hours, 3 - 4 days, 6 - 7 days, 14 days, and 21 days after the treatment. On macroscopic examination, complete occlusion of the aneurysms by early thrombus formation was found in all cases during the first two days. After three to seven days, recanalization and fibrinolysis were observed, leading to a reopening of the neck, and part of the dome. After three weeks recanalization was found in six out of eight aneurysms, regardless of whether the animal was under anticoagulation. In nine cases, the degree of occlusion was overestimated by angiography compared to the pathological findings. During the early phase after occlusion of an aneurysm with platinum coils, extensive clot formation is induced. Over time due to the natural fibrinolysis, continuous recanalization beginning at the neck takes place. These findings can explain the clinical phenomenon of early thromboembolic complications, and the reopening and regrowth of aneurysms occluded with metallic coils observed at later stages.


Peptides of Matrix Gla protein inhibit nucleation and growth of hydroxyapatite and calcium oxalate monohydrate crystals.
Matrix Gla protein (MGP) is a phosphorylated and γ-carboxylated protein that has been shown to prevent the deposition of hydroxyapatite crystals in the walls of blood vessels. MGP is also expressed in kidney and may inhibit the formation of kidney stones, which mainly consist of another crystalline phase, calcium oxalate monohydrate. To determine the mechanism by which MGP prevents soft-tissue calcification, we have synthesized peptides corresponding to the phosphorylated and γ-carboxylated sequences of human MGP in both post-translationally modified and non-modified forms. The effects of these peptides on hydroxyapatite formation and calcium oxalate crystallization were quantified using dynamic light scattering and scanning electron microscopy, respectively. Peptides YGlapS (MGP1-14: YγEpSHEpSMEpSYELNP), YEpS (YEpSHEpSMEpSYELNP), YGlaS (YγESHESMESYELNP) and SK-Gla (MGP43-56: SKPVHγELNRγEACDD) inhibited formation of hydroxyapatite in order of potency YGlapS > YEpS > YGlaS > SK-Gla. The effects of YGlapS, YEpS and YGlaS on hydroxyapatite formation were on both crystal nucleation and growth; the effect of SK-Gla was on nucleation. YGlapS and YEpS significantly inhibited the growth of calcium oxalate monohydrate crystals, while simultaneously promoting the formation of calcium oxalate dihydrate. The effects of these phosphopeptides on calcium oxalate monohydrate formation were on growth of crystals rather than nucleation. We have shown that the use of dynamic light scattering allows inhibitors of hydroxyapatite nucleation and growth to be distinguished. We have also demonstrated for the first time that MGP peptides inhibit the formation of calcium oxalate monohydrate. Based on the latter finding, we propose that MGP function not only to prevent blood-vessel calcification but also to inhibit stone formation in kidney.


Information Safety Assurances Increase Intentions to Use COVID-19 Contact Tracing Applications, Regardless of Autonomy-Supportive or Controlling Message Framing.
Promoting the use of contact tracing technology will be an important step in global recovery from the COVID-19 pandemic. Across two studies, we assessed two messaging strategies as motivators of intended contact tracing uptake. In one sample of 1117 Australian adults and one sample of 888 American adults, we examined autonomy-supportive and controlling message framing and the presence or absence of information safety as predictors of intended contact tracing application uptake, using an online randomized 2 × 2 experimental design. The results suggested that the provision of data safety assurances may be key in affecting people's intentions to use contact tracing technology, an effect we found in both samples regardless of whether messages were framed as autonomy-supportive or controlling. Those in high information safety conditions consistently reported higher intended uptake and more positive perceptions of the application than those in low information safety conditions. In Study 2, we also found that perceptions of government legitimacy related positively to intended application uptake, as did political affiliation. In sum, individuals appeared more willing to assent to authority regarding contact tracing insofar as their data safety can be assured. Yet, public messaging strategies alone may be insufficient to initiate intentions to change behavior, even in these unprecedented circumstances.


Microbial induction of vascular pathology in the CNS.
The central nervous system (CNS) is a finely tuned organ that participates in nearly every aspect of our day-to-day function. Neurons lie at the core of this functional unit and maintain an active dialogue with one another as well as their fellow CNS residents (e.g. astrocytes, oligodendrocytes, microglia). Because of this complex dialogue, it is essential that the CNS milieu be tightly regulated in order to permit uninterrupted and efficient neural chemistry. This is accomplished in part by anatomical barriers that segregate vascular components from the cerebral spinal fluid (CSF) and brain parenchyma. These barriers impede entry of noxious materials and enable the CNS to maintain requisite protein and ionic balances for constant electrochemical signaling. Under homeostatic conditions, the CNS is protected by the presence of specialized endothelium/epithelium, the blood brain barrier (BBB), and the blood-CSF barrier. However, following CNS infection these protective barriers can be comprised, sometimes resulting in severe neurological complications triggered by an imbalance or blockage of neural chemistry. In some instances, these disruptions are severe enough to be fatal. This review focuses on a selection of microbes (both viruses and parasites) that compromise vascular barriers and induce neurological complications upon gaining access to the CNS. Emphasis is placed on CNS diseases that result from a pathogenic interplay between host immune defenses and the invading microbe.


Epidemiology underpinning research in the aetiology of orofacial clefts.
Epidemiological information gathered through birth defects surveillance is an important adjunct to carrying out clinical and aetiological research. Information on the incidence in the population, causative risk factors and providing baseline data prior to intervention are all important elements. Under the auspices of the World Health Organisation, it was agreed that a global registry and database on craniofacial anomalies should be created and this, the International Database on Craniofacial Anomalies (ICDFA) was designed to gather information on craniofacial abnormalities from existing birth defects registries and databases around the world to become a resource underpinning research. There are currently 62 registries covering 2 million births per year contributing to a database along with information on the size and type of studies used to collect the information, any variation in ascertainment and on the inclusion of syndromes and associated abnormalities. From the epidemiological data collected it is possible to carry out meta-analysis and to search for trends and consistencies in the data that enable hypothesis to be generated. Issues such as geographical distribution, ethnicity, gender, associated abnormalities and clefts in stillbirths can all be examined in a meta-analytical approach. Collection of information on risk factors such as maternal illnesses, medications, lifestyle factors, nutrition and perhaps occupational exposures enables investigation into environmental contribution to causality and genetic predisposition. A range of techniques are currently being used to identify new candidate genes and ultimately it will be necessary to test genetic and environmental hypothesis in the context of human population studies. It is only by consistency of association between different populations with different gene pools and maternal exposures, lifestyles, nutrition etc that conclusive evidence regarding causality will be found. It is therefore essential, and a major objective of the WHO that international multicentre collaborative studies are setup to gather the appropriate evidence and improve knowledge and the cause of birth defects in general and orofacial clefts in particular, with the ultimate humanitarian and scientific objective of the WHO being primary prevention. This IDCFA project fulfils three basic objectives namely to enable global surveillance of CFA; to create online access to those who wish to contribute to the IDCFA, and to develop an online directory of resources on craniofacial anomalies for the support of research and improving quality of care. The next steps for IPDTOC are to expand the number of participating registries and to actively collect data on other craniofacial birth defects.


Biosurfactants in plant-Pseudomonas interactions and their importance to biocontrol.
Production of biosurfactants is a common feature in bacteria, and in particular in plant-associated species. These bacteria include many plant beneficial and plant pathogenic Pseudomonas spp., which produce primarily cyclic lipopeptide and rhamnolipid type biosurfactants. Pseudomonas-derived biosurfactants are involved in many important bacterial functions. By modifying surface properties, biosurfactants can influence common traits such as surface motility, biofilm formation and colonization. Biosurfactants can alter the bio-availability of exogenous compounds, such as nutrients, to promote their uptake, and of endogenous metabolites, including phenazine antibiotics, resulting in an enhanced biological activity. Antibiotic activity of biosurfactants towards microbes could play a role in intraspecific competition, self-defence and pathogenesis. In addition, bacterial surfactants can affect plants in different ways, either protecting them from disease, or acting as a toxin in a plant-pathogen interaction. Biosurfactants are involved in the biocontrol activity of an increasing number of Pseudomonas strains. Consequently, further insight into the roles and activities of surfactants produced by bacteria could provide means to optimize the use of biological control as an alternative crop protection strategy.


Simultaneously promoting the surface/bulk structural stability of Fe/Mn-based layered cathode for sodium ion batteries.
Layered sodium iron manganese oxide cathodes have attracted great interest owing to their high specific capacity and cost-effective metal resources, while the detrimental phase transitions and surface structural degradation severely limit their commercial applications. In this work, the bulk and surface structure stability of a P2-Na0.67Fe0.5Mn0.5O2 cathode can be synergically enhanced by a one-step Li/Nb co-doping strategy. Structural characterizations reveal that Li doping promotes the formation of P2/O3 biphasic structure and makes the unfavorable P2-OP4 phase transition convert into a smooth solid-solution reaction. Nb doping enhances the mobility of sodium ions and forms strong Nb-O bonds, thereby enhancing the stability of the TMO2 layer structure. In particular, the Nb element induces the surface reorganization of an atomic-scale NaNbO3 coating layer, which could effectively prevent the dissolution of metals and surface side reactions. The synergistic mechanism of enhanced electrochemical performance is proved by multiple characterizations during cycling. As a result, the as-prepared Na0.67Li0.1Fe0.5Mn0.38Nb0.02O2 exhibits improved capacity retention of 85.4 % than raw material (45.7 %) after 100 cycles at 0.5C (1C = 174 mA g-1) within 2.0-4.0 V. This co-regulating strategy provides a promising approach to designing highly stable sodium-ion battery cathodes. Furthermore, a full cell of Na0.67Li0.1Fe0.5Mn0.38Nb0.02O2 with hard carbon displays excellent cycling stability (85.1 % capacity retention after 100 cycles), making its commercial operation possible. This synergistic strategy of biphasic structure and surface reorganization is a critical route to accelerate the application of layer oxide cathodes.


[Changes in the intensity of lipid peroxidation in the blood plasma of sheep under repeat gamma irradiation after chronic gamma exposure].
The indices of lipid peroxidation and the contents of alpha-tocopherol and retinol in the blood plasma of sheep exposed to repeated gamma irradiations were studied. It was shown that a repeated acute gamma irradiation of sheep with sublethal and lethal doses after 9 months of chronic low-dose gamma irradiation adversely affected the activity of the lipid free-radical oxidation. A radiologic pathology in the repeatedly irradiated animals developed as a decrease in the intensity of spontaneous chemiluminescence. Also, a tendency to an increase in the concentration of malonic dialdehyde was observed along with weak changes in the contents of triene and diene conjugates and the levels of alpha-tocopherol and retinol.


Altered oral microbiota and immune dysfunction in Chinese elderly patients with schizophrenia: a cross-sectional study.
Schizophrenia (SZ) is a complex psychiatric neurodevelopmental disorder with uncertain etiology and pathogenesis. Increasing evidence has recognized the key role of the gut microbiota in SZ. However, few studies have investigated the potential link between oral microbiota and SZ. We studied the tongue coating microbiota and inflammatory profiles of 118 elderly SZ patients and 97 age-matched healthy controls using Illumina MiSeq sequencing and multiplex immunoassays, respectively. Reduced α-diversity, along with a significant difference in β-diversity, were observed in patients with SZ. We have identified SZ-associated oral dysbiosis, characterized by increased Streptococcus and Fusobacterium, as well as decreased Prevotella and Veillonella. These differential genera could potentially serve as biomarkers for SZ, either alone or in combination. Additionally, an elevated Streptococcus/Prevotella ratio could indicate oral dysbiosis. These differential genera formed two distinct clusters: Streptococcus-dominated and Prevotella-dominated, which exhibited different correlations with the altered immunological profiles. Furthermore, we also observed disruptions in the inferred microbiota functions in SZ-associated microbiota, particularly in lipid and amino acid metabolism. Our study provides novel insights into the characteristics of tongue coating microbiota and its associations with immunological disturbances in elderly SZ patients, which offer new targets for the diagnosis and treatment of SZ in the elderly.


Mechanism of renin release in exercising dog.
Exercise is associated with an increase in plasma renin activity (PRA). The purpose of this study was to determine the role of the prostaglandin (PG) and adrenergic pathways in the renin release with exercise in the dog. One group of animals (n = 4) was exercised under control untreated and indomethacin- and meclofenamate- (2 mg/kg) treated conditions. A 155% increase in PRA was not influenced by PG inhibition. In a second group (n = 7) PRA was 1.22 +/- 0.32, 3.29 +/- 1.59, 6.28 +/- 2.85, and 5.30 +/- 2.00 ng ANG I X ml-1 X h-1 at rest and during light, moderate, and heavy exercise, respectively. Guanethidine treatment (15 mg/kg) decreased mean PRA by 41, 50, 70, and 73% at rest and during the three levels of exercise, respectively. In a third group (n = 5) control exercise runs were repeated after metoprolol treatment. Selective beta 1-blockade completely abolished the increment in PRA observed with exercise. These data demonstrate that the elevation of PRA during exercise in the dog is mediated by increased sympathetic nerve activity involving beta 1-receptors and that it is not dependent on alterations in PG synthesis.