Prevalence, severity and impact of chronic pain among a representative cross-sectional study of New Zealand high school students.
To report the prevalence of self-reported chronic pain and severity among young people in New Zealand and explore the relationships between pain and mental health, substance use, socialisation and school engagement. Prevalence of self-reported chronic pain frequency and severity are reported from an anonymous, representative cross-sectional self-administered health and well-being questionnaire by students aged 12-18 years in New Zealand. Multivariable models exploring chronic pain and mental health, substance use, socialisation and school engagement are reported controlling for age, sex, ethnicity, socio-economic status, disability and history of sexual abuse. Overall, 22.8% (95% confidence interval (CI) 21.2-24.5) of young people reported chronic pain for 6 months or more, with 3.2% (95% CI 3.1-4.5) reporting severe pain weekly or more often. Females and rural adolescents were more likely to report chronic and severe pain. Asian youth reported less pain than other ethnic groups. Increased severity of pain was associated more with poorer daily functioning and socialising than with frequency of pain. Severe pain occurring weekly or more often was more common among students who had a disability (2.3% 95% CI 1.8-2.7 vs. 9.8%, 95% CI 7.2-12.5) or a history of sexual abuse (2.4% 95% 1.9-2.9 vs. 8.5%, 95% CI 6.3-10.5). Those reporting chronic pain had higher proportions of self-reported significant depressive symptoms, lower well-being, lower school engagement and lower access to health care, particularly for those reporting higher levels of intensity and frequency of pain. Chronic pain is common in adolescent populations, and has a significant association with decreased daily functioning, socialising, school engagement and mental well-being. Adolescents with chronic pain report significant unmet health-care needs.


The Role of Sleep-Disordered Breathing Symptoms in Neurocognitive Function Among Youth With Sickle Cell Disease.
To examine associations between sleep-disordered breathing (SDB) and executive/attentional function in pediatric sickle cell disease (SCD). Sixty youth with SCD ages 8-18 years and caregivers completed the Pediatric Sleep Questionnaire (PSQ), Delis Kaplan Executive Function System Trail Making Test (DKEFS TMT), Psychomotor Vigilance Test (PVT), and the Behavior Rating Inventory Of Executive Function, Second Edition (BRIEF-2) Parent Report. The PSQ significantly predicted the BRIEF-2 Parent Report, F(1, 58) = 44.64, p < .001, R2 = 0.44, f2 = 0.77. Sleep-disordered breathing symptoms may predict informant-rated executive dysfunction in pediatric SCD, but not performance-based executive function.


Prejudices in pharmacology and pharmacotherapy. The so-called anticholinergic effect of antidepressants.
Imipramine and similarly acting compounds provoke a number of undesired reactions usually classified as so-called anticholinergic effects. Instances of dry mouth, disturbance of micturition and tachycardia are regularly quoted in the literature. It is contended that these effects are not necessarily due to inhibition of the vagal system, but preferentially attributable to increased activity of the sympathetic system, predominantly mediated by the beta- or the alpha-adrenergic receptors, depending on the organ affected. This hypothesis is not only theoretically interesting, but also of practical clinical significance with regard to possible remedies.


Breakfast Skipping is associated with More Deleterious Lifestyle Behaviors among Japanese Men: The TRF-Japan Study Using the Original "Taberhythm" Smartphone Application.
Time-restricted eating has been increasingly recognized as a promising option to reduce food intake and combat obesity. Especially in Asian countries such as Japan, because of the wide variety of food choices available, a dietary approach that emphasizes meal timing can be more practical and easier to implement and adhere to, compared with approaches that focus on specific dietary content, such as low-fat or low-carbohydrate diets. We aimed to identify eating patterns among Japanese men and women using a smartphone application (app) called "Taberhythm." In addition, we sought to evaluate the relationship of breakfast eating habits with lifestyle behaviors and body mass index, and determine whether sex differences were present. A total of 3369 smartphone users were eligible to participate in this observational study. Users recorded 1 mo of lifestyle logs using the app; 254 participants (178 women, 38 ± 12 y old, body mass index 23.3 ± 4.9 kg/m2) had sufficient records to calculate daily fasting duration and sleep duration, and were eligible for the analyses. Fasting duration was ∼12.6 h and was longer in women than men, among participants who never skipped breakfast. Breakfast skipping was associated with longer screen time, and more frequent snacking, only in men. Men with irregular breakfast eating patterns had a longer duration of fasting after awakening that was associated with obesity. We investigated eating patterns among Japanese people using a smartphone app and revealed that skipping breakfast was more deleterious in men than in women.


Diagnostic aspects of organophosphate poisoning.
Organophosphate (OP)-type chemical warfare agents (nerve agents) present a constant threat to the population. Sensitive and specific methods for the detection and verification of exposure to nerve agents are required for diagnosis, therapeutic monitoring, health surveillance and forensic purposes. Determination of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activity in blood remains a mainstay for the fast initial screening but lacks sensitivity and specificity. Quantitative analysis of nerve agents and their degradation products in plasma and urine by mass spectrometric methods may prove exposure but is limited to hours or days after the incident due to the short residence time of the analytes. Investigation of protein adducts extends the time interval between exposure and sampling and may be suitable to detect low-level exposure. Definitive prove of exposure requires a spectrum of different methods, expensive and sophisticated equipment and will be limited to specialized laboratories.


Meltable, Glass-Forming, Iron Zeolitic Imidazolate Frameworks.
We describe the first meltable iron-based zeolitic imidazolate framework (ZIF), denoted MUV-24. This material, elusive from direct synthesis, is obtained from the thermal treatment of [Fe3(im)6(Him)2], which yields Fe(im)2 upon loss of the neutral imidazole molecules. Different crystalline phase transformations are observed upon further heating, until the material melts at 482 °C. Vitrification upon cooling of the liquid phase gives rise to the first Fe-metal-organic framework glass. X-ray total scattering experiments show that the tetrahedral environment of the crystalline solids is maintained in the glass, whereas nanoindentation measurements reveal an increase in Young's modulus, in agreement with stiffening upon vitrification.


Effect of vermiculite modified with nano-iron-based material on stabilization of lead in lead contaminated soil.
Lead (Pb) contamination arising from the production of lead-acid batteries is getting more severe, and research on its treatment technology reflects the increasing concern worldwide. Vermiculite is a mineral with a layered structure, containing hydrated magnesium aluminosilicate and has high porosity and large specific surface area. Vermiculite has the ability of improving soil permeability and water retention performance. However, in recent studies, vermiculite is shown to be less effective than other stabilizing agents in immobilizing heavy metal Pb. Nano-iron-based materials have been widely used to adsorb heavy metals in wastewater. Therefore, vermiculite has been modified with two nano-iron-based materials-nanoscale zero-valent iron (nZVI) and nano-Fe3O4 (nFe3O4) to improve its immobilization effect for the heavy metal lead. SEM and XRD analysis confirmed that nZVI and nFe3O4 were successfully loaded on the raw vermiculite. XPS analysis was applied to further understand the composition of VC@nZVI and VC@nFe3O4. The stability and mobility of nano-iron-based materials were improved after being loaded on raw vermiculite, and the Pb immobilization effect of modified vermiculite on Pb-contaminated soil was evaluated. Adding nZVI-modified vermiculite (VC@nZVI) and nFe3O4-modified vermiculite (VC@nFe3O4) increased the immobilization effect and decreased the bioavailability of Pb. Compared with raw vermiculite, adding VC@nZVI and VC@nFe3O4 increased the amount of exchangeable Pb by 30.8% and 6.17%. After leaching ten times in soil column leaching experiments, the total concentration of Pb in the leachate of the soil with VC@nZVI and VC@nFe3O4 were reduced by 40.67% and 11.47%, compared with raw vermiculite. These results prove that the modification with nano-iron-based materials enhances the immobilization effect of vermiculite, in which the effect of VC@nZVI is significantly better than VC@nFe3O4. Vermiculite was modified with nano-iron-based materials, resulting in a better fixing effect of the modified curing agent. This study provides a new approach for the remediation of Pb-contaminated soil, but further research is needed for soil recovery and utilization of nanomaterials.


DOCK6 Mutations Are Responsible for a Distinct Autosomal-Recessive Variant of Adams-Oliver Syndrome Associated with Brain and Eye Anomalies.
The original article to which this Erratum refers was published in Human Mutation 36(6):593–598(DOI:10.1002/humu22795).The authors realized that a co-author, Nuria C. Bramswig, was left off of the title page of this article at the time of submission. This erratum serves to correct this error by including Dr. Bramswig and Dr. Bramswig's institution in the title page information.The authors regret the error.


A teratologic suppressor role for p53 in benzo[a]pyrene-treated transgenic p53-deficient mice.
DNA damage may mediate birth defects caused by many drugs and environmental chemicals, therefore p53, a tumour suppressor gene that facilitates DNA repair, may be critically embryoprotective. We have studied the effects of the environmental teratogen, benzo[a]pyrene, on pregnant heterozygous p53-deficient mice. Such mice exhibited between 2- to 4-fold higher embryotoxicity and teratogenicity than normal p53-controls. Fetal resorptions reflecting in utero death were genotyped using the polymerase chain reaction and found to be increased 2.6-fold and 3.6-fold respectively with heterozygous and homozygous p53-deficient embryos. These results provide the first direct evidence that p53 may be an important teratological suppressor gene which protects the embryo from DNA-damaging chemicals and developmental oxidative stress.


Usefulness of a new grading system based on coronary flow velocity pattern in predicting outcome in patients with acute myocardial infarction having percutaneous coronary intervention.
In acute myocardial infarction, the coronary blood flow velocity waveform changes with the damage in the infarcted myocardium. We developed a grading system using the shorter diastolic deceleration time (DDT), appearance of systolic flow reversal (SFR), and disappearance of systolic anterograde flow. We studied 72 patients with a first anterior acute myocardial infarction. Doppler guidewire monitoring and myocardial contrast echocardiography were performed 10 and 15 minutes after percutaneous coronary intervention, and left ventriculography was performed at discharge (24 +/- 2 days) to measure regional wall motion (SD/chord). Patients were classified into 4 groups according to the coronary blood flow velocity pattern: group I (n = 39), DDT >or=600 ms; group II (n = 10), DDT <600 ms; group III (n = 17), DDT <600 ms with SFR; and group IV (n = 14), DDT <600 ms with SFR and without systolic anterograde flow. The no-reflow phenomenon was observed in no patients in group I, in 3 in group II, in 11 in group III, and all 14 patients in group IV. Regional wall motion was highest in group I and decreased with increasing group number (groups I, II, III, and IV, -1.45 +/- 0.80, -2.36 +/- 0.60, -2.90 +/- 0.50, and -3.20 +/- 0.52 SD/chord, respectively). With the progression of damage in the infarcted myocardium, the DDT shortened first, followed by the appearance of SFR, and then the disappearance of systolic anterograde flow. In conclusion, analysis of the coronary blood flow velocity pattern allows assessment of the severity of microvascular dysfunction and prediction of left ventricular functional outcomes.


Sensitive and precise visually guided drug delivery nanoplatform with dual activation of pH and light.
Controlled-release drug carriers in cancer therapy are the most ideal way to reduce toxicity and improve drug efficacy. Since light stimulation is precise and operable, most multi-stimulation response carriers utilize phototherapy to enhance release efficiency. However, phototoxicity severely limits the application of phototherapy. Herein, we designed and synthesized a Cou-ONB lipid with sensitive fluorescence feedback and multi-stimulus response. COBL liposomes prepared from Cou-ONB lipids will passively aggregate at the tumor and guide phototherapy by fluorescence. More importantly, it can reflect the drug release effect in vivo through its own sensitive fluorescence changes, further enabling precise phototherapy and reducing phototoxicity. In this paper, the multi-stimulus superimposed response and precise fluorescence-guided performance of COBL liposomes were investigated at the molecular, liposome, cellular, and animal levels. Finally, tumor treatment experiments showed that the d-COBL-UV group had the best tumor suppression effect (5.3-fold). This paper highlights a real-time fluorescence-guided multi-stimulus superposition strategy and provides a design idea to precisely implement exogenous stimuli by displaying the degree of drug release, aiming to achieve less toxic and more efficient cancer therapy through timely and precise multi-stimulation. STATEMENT OF SIGNIFICANCE: Multi-stimulus responsive drug carriers have been extensively developed in the last decade. Visual guidance is an important tool to achieve precision medicine and precise control of drug release. However, the available visualization materials are more aimed at directing stimulation at the optimal moment. There is little discussion on when to stop exogenous stimulation and how to minimize the damage of stimulation to the patient. Here, we provide a Cou-ONB lipid that not only responds to multiple stimuli, but also provides sensitive feedback on its own dissociation with a fluorescent signal so that physicians can adjust exogenous stimuli in a timely manner. This paper provides insights to facilitate precision drug delivery systems, providing viable design ideas for precise, efficient, and less toxic cancer therapies.


A new device for the quantitative assessment of dopaminergic drug effects in unilateral MPTP-lesioned monkeys.
Non-human primates exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have been employed to study the clinical features of parkinsonism. Monkeys lesioned by unilateral intracarotid administration of MPTP display spontaneous and drug responsive turning behavior. However this seems to correlate poorly with their clinical deficits. We describe an objective measurement of arm movement velocity, applied in 4 cynomolgus monkeys before and after unilateral administration of MPTP. Reduced movement velocities correlated with clinical signs of unilateral flexed arm posture, rigidity, tremor and bradykinesia and could be reversed with L-DOPA therapy. This measurement technique has advantages for the quantitative assessment of parkinsonian deficits and will permit the evaluation of dopaminergic therapy and transplantation in non-human primates.


Osteosarcoma of the limbs. Report of the EORTC-SIOP 03 trial 20781 investigating the value of adjuvant treatment with chemotherapy and/or prophylactic lung irradiation.
The European Organization for Research on Treatment of Cancer (EORTC) trial 20781, concerning osteosarcoma of the limbs is reported. After definitive treatment of the primary tumor with amputation or irradiation, adjuvant treatment was given, randomized into either 9 months of chemotherapy according to a modified Rosen schedule, or elective bilateral lung irradiation of 20 Gy, or 3 months of chemotherapy followed by lung irradiation. The 4-year disease-free survival and total survival were 24% and 43%, respectively, with no difference between the treatment arms. In the radiotherapy arms the lung metastases were more frequently suitable for surgical treatment. The survival of patients with either tibia localizations or higher age was somewhat better. Local recurrences occurred in 16% of patients, 50% of them with distant metastases. The trial was executed from 1978 to 1983; 205 patients were evaluable and eligible, and three toxic deaths occurred in the chemotherapy arms. Elective lung irradiation provided the same survival as the adjuvant chemotherapy given in that time.


Management of an Immunocompromised Pediatric Patient With Multiple Hospitalizations for Symptomatic COVID-19.
Relapse of infection due to SARS-CoV-2 has been rarely described and there is little guidance regarding the management of such cases in immunocompromised hosts. We present a case of an adolescent female with B-cell acute lymphoblastic leukemia hospitalized multiple times for symptomatic SARS-CoV-2 infection who was safely treated with 2 courses of remdesivir (RDV) and has had no additional readmissions to date. Though additional studies are needed to confirm the safety and efficacy of an additional course of RDV in the setting of relapsed or prolonged severe COVID-19, our observations suggest that a second course of RDV may be considered.


Chemical stability of caesium iodide deposits in air/steam atmosphere.
Iodine compounds that may be released in case of severe nuclear accident will have important radiotoxicity if they are disseminated in air. One of the most important iodine species is CsI that is deposited on the surfaces of the reactor coolant system. However, depending on the conditions, CsI can volatilize or react with oxidants to produce I2(g). Theoretical and experimental studies demonstrate that the oxidation of iodide depends on the temperature and in the presence of oxidants in the gas. It is also slightly influenced by the crystallinity of the CsI particles and the nature of the support. In case of a high temperature deposition, the iodine release started at temperature lower than 300 °C. For the CsI vapour and aerosol depositions, the iodine is detected only at temperature above 450 °C and become very important above 550 °C.


Ultrasonic control of ceramic membrane fouling by particles: effect of ultrasonic factors.
Ultrasound at 20 kHz was applied to a cross-flow ultrafiltration system with gamma-alumina membranes in the presence of colloidal silica particles to systematically investigate how ultrasonic factors affect membrane cleaning. Based on imaging of the ultrasonic cavitation region, optimal cleaning occurred when the membrane was outside but close to the cavitation region. Increasing the filtration pressure increased the compressive forces driving cavitation collapse and resulted in fewer cavitation bubbles absorbing and scattering sound waves and increasing sound wave penetration. However, an increased filtration pressure also resulted in greater permeation drag, and subsequently less improvement in permeate flux compared to low filtration pressure. Finally, pulsed ultrasound with short pulse intervals resulted in permeate flux improvement close to that of continuous sonication.


[MicroPET's development and progress].
As technologies are progressing rapidly in many aspects, microPET has been developing worldwide at present. The principle, up-to-date status and development of microPET, as well as its existing problems which should be solved, have been introduced in this paper.


Cascade screening and genetic diagnosis of familial hypercholesterolemia in clusters of the Southeastern region from Brazil.
Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by high levels of low-density lipoprotein-cholesterol (LDLc), associated to premature cardiovascular disease. The detection of the variants related to FH is important to improve the early diagnosis in probands / index-cases (ICs) and their relatives. We included ICs with FH and their relatives, living in a small region of Minas Gerais state-Brazil, which were classified according to Dutch Lipid Clinic Network Criteria (DLCNC) and submitted to sequencing of genes related to FH (LDLR, APOB, PCSK9, LDLRAP1, LIPA, STAP1, APOE, ABCG5 e ABCG8). In a total of 143 subjects (32 ICs and 111 relatives), eight variants were identified in 91 individuals. From these variants, five were in LDLR [p.(Asp224Asn), p.(Ser854Gly), p.(Cys34Arg), p.(Asp601His), deletion of exon15 in LDLR)], one in APOB [p.(Met499Val)], one in PCSK9 [p.(Arg237Trp)] and one in APOE [p.(Pro28Leu)] genes. The variants were detected in 100% of those subjects classified as definitive, 87% as probable and 69% as possible FH cases based on DLCNC. The LDLc level was higher in individuals with corneal arch and xanthomas or xanthelasmas, as well as in pathogenic or probably pathogenic variants carriers. This study showed higher frequency of LDLR gene variants compared to other genes related to LDL metabolism in individuals with FH in Minas Gerais - Brazil and the presence of FH in relatives without previous diagnosis. Our data reinforce the importance of molecular and clinical evaluation of FH relatives in order to early diagnosis the FH, as well as cardiovascular diseases prevention.


Scrub typhus associated acute kidney injury--a study from a tertiary care hospital from western Himalayan State of India.
To report the clinical profile of acute kidney injury (AKI) associated with scrub typhus. Retrospective study of hospitalized patients of acute febrile illness who were diagnosed scrub typhus and had AKI. 174 (35%) patients (75.9% female), mean age (41.4 ± 15.9 years) were studied. The laboratory abnormalities were: anemia (63.2%), leukocytosis (44.3%), thrombocytopenia (61.5%), hyponatremia (35.6%), hypernatremia (2.9%), and hypokalemia (12.1%), hyperkalemia (11.5%), hypoalbuminemia (56.9%), hepatic dysfunction (70%) and metabolic acidosis (28.7%). The complications of hypotension (5.7%), septic shock (3.4%), pneumonia (10.9%), acute respiratory distress syndrome (ARDS) (11.5%), meningoencephalitis (6.9%), encephalopathy (5.2%), gastrointestinal bleed (1.3%), myocarditis (3.4%), disseminated intravascular coagulation (2.9%) and multi organ failure (MOF) (10.3%) developed during course of hospitalization in these patients. Twenty-five (14.4%) patients required intensive care support (ICU) support and seven (4%) patients were dialyzed. 146 (83.9%) patients survived. Twenty-eight (16.1%) patients died. There was a significant difference in the age, various hematological & biochemical abnormalities, complications and need for ICU support in the non-survival group as compared the survival group. This study shows that AKI in scrub typhus is common and a severe disease. Age, a shorter hospital stay, severities of leukocytosis, thrombocytopenia, azotemia, hypoalbuminemia, hepatic dysfunction and the complications of ARDS, encephalopathy, MOF and need for ICU support are the factors associated with mortality.


Biliary cystadenoma of the liver.
Hepatobiliary cystadenoma is an uncommon lesion that is difficult to diagnose preoperatively. Here we report a 34-year-old woman who presented with enlargement of a cyst that had been observed for the previous 6 months. Diagnostic imaging revealed a 7-cm diameter cystic mass with irregular multiple septation in her liver. All laboratory test results were normal except for serum carbohydrate antigen (CA) 19-9 (62.5 U/ml). Because of the malignant potential and the history of enlargement, a complete surgical excision was performed. The patient was discharged after a good recovery; 2 months after surgery her serum CA19-9 level had returned to normal (32.9 U/ml). Regardless of the diagnostic modalities used, cystadenoma and cystadenocarcinoma cannot be differentiated with accuracy. Therefore complete surgical resection is the recommended therapy.


A ribonuclease with antimicrobial, antimitogenic and antiproliferative activities from the edible mushroom Pleurotus sajor-caju.
A 12 kDa ribonuclease preferential for poly U and with much lower activity toward poly A, poly G and poly C was isolated from fresh fruiting bodies of the mushroom Pleurotus sajor-caju. A purification procedure involving ion exchange chromatography on CM-cellulose, affinity chromatography on Red-Sepharose and Heparin-Sepharose, and fast protein liquid chromatography-gel filtration on Superdex 75 was used. The ribonuclease was adsorbed on all of the first three types of chromatographic media. It exhibited some activity toward herring sperm DNA and calf thymus DNA. The ribonuclease activity was unaffected in the presence of KCl (10 and 100 mM) and NaCl (100 mM and 1 M), but was strongly inhibited by CuSO4 (0.01 and 0.1 mM) and less potently inhibited by other divalent salts including MgCl2, CaCl2, ZnCl2, ZnSO4 and FeSO4. The optimal pH was 5.5 and the ribonuclease was stable up to 60 degrees C for 1 h. The ribonuclease inhibited mycelial growth in the fungi Fusarium oxysporum and Mycosphaerella arachidicola with an IC50 value of 95 and 72 microM, respectively. Out of the 12 species of bacteria tested, only Pseudomonas aeruginosa and Staphylococcus aureus were inhibited in growth by the ribonuclease. Viability of the tumor cells HepG2 (hepatoma) and L1210 (leukemia) was reduced with an IC50 of 0.22 and 0.1 microM, respectively in the presence of the ribonuclease. The ribonuclease inhibited translation in a cell-free rabbit reticulocyte lysate system with an IC50 of 158 nM and 3H-methyl-thymidine uptake by murine splenocytes with an IC50 of 65 nM.


Genetic diversity among some canola cultivars as revealed by RAPD, SSR and AFLP analyses.
To assess the genetic diversity among four canola cultivars (namely, Serw-3, Serw-4, Misser L-16 and Semu 249), random amplified polymorphic DNA (RAPD), simple sequence repeat polymorphism (SSR) and amplified fragment length polymorphism (AFLP) analyses were performed. The data indicated that all of the three molecular markers gave different levels of polymorphism. A total of 118, 31 and 338 markers that show 61, 67.7 and 81 % polymorphism percentages were resulted from the RAPD, SSR and AFLP analyses, respectively. Based on the data obtained the three markers can be used to differentiate between the four canola cultivars. The genotype-specific markers were determined, 18 out of the 72 polymorphic RAPD markers generated were found to be genotype-specific (25 %). The highest number of RAPD specific markers was scored for Semu 249 (15 markers), while Serw-4 scored two markers. On the other hand, Serw-3 scored one marker. The cultivar Semu 249 scored the highest number of unique AFLP markers, giving 57 unique markers, followed by Misser L-16 which was characterized by 40 unique AFLP markers, then Serw-3 giving 31 unique markers. While Serw-4 was characterized by the lowest number producing 14 unique positive markers. The dendrogram built on the basis of combined data from RAPD, SSR and AFLP analysis represents the genetic distances among the four canola cultivars. Understanding the genetic variability among the current canola cultivars opens up a possibility for developing a molecular genetic map that will lead to the application of marker-assisted selection tools in genetic improvement of canola.


Does periodontal treatment have an effect on clinical and immunological parameters of periodontal disease in obese subjects? A systematic review and meta-analysis.
The aim of this study was to systematically review the literature to answer the questions: (i) "Is periodontal treatment effective to improve clinical and immunological conditions in obese subjects?"; (ii) "Do obese subjects present different clinical and immunological response after periodontal therapy when compared to non-obese subjects?" Searches were performed in six databases up to August 2014. Interventional studies were included if the following data were described: (1) Obesity/overweight assessment; (2) definition of periodontal disease; (3) periodontal therapy; (4) inflammatory marker in serum/plasma, and/or clinical parameters of periodontal disease. Assessment of quality was performed with the Downs and Black scale. Meta-analyses were conducted with the available data. Of 489 articles, 5 were included, and only 3 proceeded to meta-analysis of clinical outcomes. Included studies presented fair methodological quality. Statistical analysis demonstrated that periodontal therapy in obese subjects was effective to improve clinical outcomes. No clinical differences between post-therapy results of obese and non-obese were observed. Effects of periodontal therapy on inflammatory markers remain unclear. Periodontal treatment seems to be effective to improve healing in obese individuals. No differences on periodontal healing between obese and non-obese subjects were observed; however, only limited and fragile base of evidence was available for analysis. Periodontal treatment is effective to improve clinical and immunological periodontal parameters in adults. Also, obesity seems to not modify the periodontal healing after treatment.


Association Between Severe Vitamin D Deficiency, Lung Function and Asthma Control.
To examine the relationship between severe vitamin D deficiency, asthma control, and pulmonary function in Turkish adults with asthma. One hundred six asthmatic patients underwent pulmonary function tests skin prick test, peripheral blood eosinophil counts, IgE, body mass index and vitamin D levels were determined. Patients were divided into 2 subgroups according to vitamin D levels (vitamin D level<10ng/ml and vitamin D level≥10 ng/ml). Asthma control tests were performed. The mean age of subgroup i (vitamin D level<10) was 37±10 and the mean age of subgroup ii (vitamin D level≥10ng/ml) was 34±8. Sixty-six percent of patients had severe vitamin D deficiency (vitamin D level<10 ng/ml). There was a significant trend towards lower absolute FEV1 (L) values in patients with lower vitamin D levels (P=.001). Asthma control test scores were significantly low in the severe deficiency group than the other group (P=.02). There were a greater number of patients with uncontrolled asthma (asthma control test scores<20) in the severe vitamin D deficiency group (P=.040). Patients with severe vitamin D deficiency had a higher usage of inhaled corticosteroids than the group without severe vitamin D deficiency (P=.015). There was a significant trend towards lower absolute FEV1 (L) (P=.005, r=.272) values in patients with lower vitamin D levels. Vitamin D levels were inversely related with body mass index (P=.046). The incidence of severe vitamin D deficiency was high in adult Turkish asthmatics. In addition, lower vitamin D levels were associated with poor asthma control and decreased pulmonary function.


Mechanistic insight into light-dependent recognition of Timeless by Drosophila Cryptochrome.
Cryptochrome (CRY) entrains the fly circadian clock by binding to Timeless (TIM) in light. Undocking of a helical C-terminal tail (CTT) in response to photoreduction of the CRY flavin cofactor gates TIM recognition. We present a generally applicable select western-blot-free tagged-protein interaction (SWFTI) assay that allowed the quantification of CRY binding to TIM in dark and light. The assay was used to study CRY variants with residue substitutions in the flavin pocket and correlate their TIM affinities with CTT undocking, as measured by pulse-dipolar ESR spectroscopy and evaluated by molecular dynamics simulations. CRY variants with the CTT removed or undocked bound TIM constitutively, whereas those incapable of photoreduction bound TIM weakly. In response to the flavin redox state, two conserved histidine residues contributed to a robust on/off switch by mediating CTT interactions with the flavin pocket and TIM. Our approach provides an expeditious means to quantify the interactions of difficult-to-produce proteins.


Alterations in the Menstrual Cycle as a Peculiar Sign of Type 1 Diabetes Mellitus: A Meta-analytic Approach.
Menstrual irregularities are present in >30% of women with type 1 diabetes mellitus (T1DM). These abnormalities will likely lead to reduced fertility and earlier menopause. T1DM management has changed over time, with even more emphasis on stringent levels of glycemic control. Thus, we investigated whether therapeutic T1DM changes have an influence on the proportion of menstrual disorders in women with T1DM. A meta-analysis was performed that included clinical trials in which menstrual abnormalities in women with T1DM were studied. The literature was checked for studies in which women with T1DM were compared with healthy, age-matched controls. Case-control, cohort, and cross-sectional studies were included. The primary endpoint was rate of menstrual dysfunction. Menstrual dysfunction was higher in women with T1DM compared with controls (odds ratio 2.08, 95% confidence interval [CI] 1.43 to 3.03, p<0.001), even when sensitivity analysis was performed, considering only studies published after 2000. The age at menarche was higher for women with T1DM compared with controls (mean difference 0.53, 95% CI 0.32 to 0.74 year, p<0.001). The proportion of menstrual abnormalities in T1DM was inversely related to diabetes duration, but was unrelated to both body mass index and glycated hemoglobin. The meta-analytic approach used confirmed the correlation between T1DM and menstrual irregularities. T1DM menstrual dysfunction seemed unrelated to change in therapeutic management across years, as well as to glycemic control and body weight. The underlying pathogenetic mechanisms are not fully understood.


Gender differences in symptoms associated with acute myocardial infarction: a review of the research.
Recognizing similarities and differences in symptom experiences of acute myocardial infarction (AMI) between men and women has implications for both health care providers and the general public. Rapid accurate diagnosis is necessary to implement timely lifesaving treatment. The purpose of this article is to critically review and evaluate studies that have compared symptoms of AMI between men and women. Research to date has demonstrated that during AMI, women are more likely than men to report shortness of breath, nausea, vomiting, back pain, jaw pain, neck pain, cough, and fatigue, but less likely than men to report chest pain and sweating. However, the findings were inconsistent across studies. These inconsistent findings could be attributable to methodological issues such as collecting data from medical records, small sample sizes, and controversial eligibility criteria for studies. More studies are needed to confirm gender differences in symptom experiences of AMI.


Identification and characterization of the iron compounds in bone marrow by means of Mössbauer spectrometry.
In order to determine and to demonstrate the cellular iron molecular states in hematopoietic bone marrow, direct investigations were performed by means of different and complementary spectroscopic techniques: optical absorption, electron spin resonance and Mössbauer spectrometry. In fact, the latter appears to have been the most informative. In addition to the hemoglobin forms, five- and six-coordination ligand protoporphyrins IX (monomeric and polymeric stacking, respectively) were observed. A small amount of non-hemic high-spin iron III storage component (ferritin) was measured. No diferric transferrin was detected. A ferrous compound was also observed and attributed to the mitochondrial iron pool.


Clinic and patient variation in intermediate clinical outcomes for type 2 diabetes: a multilevel analysis.
Variation at different levels of diabetes care has not yet been quantified for low- and middle-income countries. Understanding this variation and its magnitude is important to guide policy makers in designing effective interventions. This study aims to quantify the variation in the control of glycated haemoglobin (HbA1c), systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) for type 2 diabetes (T2D) patients at the clinic and patient level and determine patient and clinic factors associated with control of these outcomes in T2D. This is a cross-sectional study within the baseline data from the impact evaluation of the Enhanced Primary Health Care (EnPHC) intervention on 40 public clinics in Malaysia. Patients aged 30 and above, diagnosed with T2D, had a clinic visit for T2D between 01 Nov 2016 and 30 April 2017 and had at least one HbA1c, SBP and LDL-C measurement within 1 year from the date of visit were included for analysis. Multilevel linear regression adjusting for patient and clinic characteristics was used to quantify variation at the clinic and patient levels for each outcome. Variation in intermediate clinical outcomes in T2D lies predominantly (93% and above) at the patient level. The strongest predictors for poor disease control in T2D were the proxy measures for disease severity including duration of diabetes, presence of microvascular complications, being on insulin therapy and number of antihypertensives. Among the three outcomes, HbA1c and LDL-C results provide greatest opportunity for improvement. Clinic variation in HbA1c, SBP and LDL-C accounts for a small percentage from total variation. Findings from this study suggest that standardised interventions need to be applied across all clinics, with a focus on customizing therapy based on individual patient characteristics.


Gaps in quality of diabetes care in internal medicine residency clinics suggest the need for better ambulatory care training.
To ensure that medical residents will be prepared to deliver consistently high-quality care, they should be trained in settings that provide such care. Residents in internal medicine, particularly, need to learn good care habits in order to meet the needs of patients with diabetes and other common chronic and high-impact illnesses. To assess the strength of such training, we compared the quality of medical care provided in sixty-seven US internal medicine residency ambulatory clinics with the quality of care provided by 703 practicing general internists. We found significant quality gaps in process, intermediate outcome, and patient-experience measures. These inadequacies in ambulatory training for internal medicine residents must be addressed by policy makers and educators-for example, by accelerating the movement toward new residency curricula that emphasize competency-based training.


Inhibition of T-cell acute lymphoblastic leukemia proliferation in vivo by re-expression of the p16INK4a tumor suppressor gene.
T-cell acute lymphoblastic leukemia (T-ALL) is characterized by the presence of differentiation-inhibited pro- and pre-T-cell blasts. The p16INK4a tumor suppressor gene has been shown to be frequently deleted in human T-ALL cases. Deletion of p16INK4a may be associated with poor prognosis and relapse of the disease. Radiation-induced murine T-ALL in C57B1/6 mice shares pathogenetic and molecular characteristics with the human disease. We used the murine disease as a model to study the status of the INK4/ARF gene locus and to examine the effect of p16INK4a-re-expression in T-ALL cells on their leukemic potential in vivo. In 9 of 17 radiation-induced murine T-ALL cell lines, the p16INK4a protein was not expressed as determined by immunoblotting. Southern blot analysis revealed homozygous deletions of the p16INK4a gene locus in three of the nine lines, along with the genes encoding p15INK4b and p19ARF. Transduction of p16INK4a-negative T-ALL lines with retrovirus encoding p16INK4a significantly inhibited their in vitro proliferation by inducing G1-arrest. Importantly, re-expression of p16INK4a in p16INK4a-negative T-ALL cells obliterated the induction of lethal disseminated leukemia in syngeneic mice. This is the first demonstration that re-establishment of p16INK4a expression is critical for in vivo growth regulation of T-ALL cells.


Splicing of plant pre-mRNAs in animal systems and vice versa.
To investigate similarities and differences of pre-mRNA splicing between higher plants and animals, we tested whether pre-mRNAs of higher plants can be accurately spliced in animal systems, and whether an animal pre-mRNA can be spliced in plant cells. Pre-mRNAs of the maize bronze locus and oat phytochrome type 3 are accurately spliced with moderate efficiency in a human (HeLa cell) nuclear extract. The first intervening sequence (IVS1) of bean phaseolin pre-mRNA is not excised in the human nuclear extract, but is removed (although at low efficiency) in intact monkey cells. However, the IVS1 of human alpha-globin pre-mRNA is not removed in tobacco cells. Our data suggest that the mechanisms of pre-mRNA splicing are similar, but not identical, in plants and animals.


Fungal levels in the home and allergic rhinitis by 5 years of age.
Studies have repeatedly demonstrated that sensitization to fungi, such as Alternaria, is strongly associated with allergic rhinitis and asthma in children. However, the role of exposure to fungi in the development of childhood allergic rhinitis is poorly understood. In a prospective birth cohort of 405 children of asthmatic/allergic parents from metropolitan Boston, Massachusetts, we examined in-home high fungal concentrations (> 90th percentile) measured once within the first 3 months of life as predictors of doctor-diagnosed allergic rhinitis in the first 5 years of life. In multivariate Cox regression analyses, predictors of allergic rhinitis included high levels of dust-borne Aspergillus [hazard ratio (HR) = 3.27; 95% confidence interval (CI), 1.50-7.14], Aureobasidium (HR = 3.04; 95% CI, 1.33-6.93), and yeasts (HR = 2.67; 95% CI, 1.26-5.66). The factors controlled for in these analyses included water damage or mild or mildew in the building during the first year of the child's life, any lower respiratory tract infection in the first year, male sex, African-American race, fall date of birth, and maternal IgE to Alternaria > 0.35 U/mL. Dust-borne Alternaria and nonsporulating and total fungi were also predictors of allergic rhinitis in models excluding other fungi but adjusting for all of the potential confounders listed above. High measured fungal concentrations and reports of water damage, mold, or mildew in homes may predispose children with a family history of asthma or allergy to the development of allergic rhinitis.


Effectiveness of a novel cellular therapy to treat multidrug-resistant tuberculosis.
We urgently need novel treatments for multidrug-resistant tuberculosis (MDR-TB). Autologous mesenchymal stromal cell (MSC) infusion is one such possibility due to its potential to repair damaged lung tissue and boost immune responses. We aimed to assess the effectiveness of MSC to improve outcomes among MDR-TB patients. We analyzed outcomes for 108 Belarussian MDR-TB patients receiving chemotherapy. Thirty-six patients ("cases") also had MSCs extracted, cultured and re-infused (average time from chemotherapy start to infusion was 49 days); another 36 patients were "study controls". We identified another control group: 36 patients from the Belarussian surveillance database ("surveillance controls") 1:1 matched to cases. Of the cases, 81% had successful outcomes versus 42% of surveillance controls and 39% of study controls. Successful outcome odds were 6.5 (95% Confidence Interval: 1.2-36.2, p=0.032) times greater for cases than surveillance controls (age-adjusted). Radiological improvement was more likely in cases than study controls. Culture analysis prior to infusion demonstrated a poorer initial prognosis in cases, yet despite this they had better outcomes than the control groups. MSC treatment could vastly improve outcomes for MDR-TB patients. Our findings could revolutionize therapy options and have strong implications for future directions of MDR-TB therapy research.


[Cloning, expression and purification of His-tagged mouse mitochondrial transcription factor A and preparation of its polyclonal antibody].
To express and purify the fusion protein of His-tagged mouse mitochondrial transcription factor A (mtTFA) in prokaryocytes and prepare rabbit anti-mtTFA polyclonal antibody. The total RNA was extracted from mouse liver cells, and the coding sequence of mtTFA without signal peptides was amplified with reverse transcriptional (RT)-PCR. The PCR product was then cloned into the prokaryotic expression vector pET14b. After enzyme digestion and DNA sequencing, the plasmid was transformed into BL21(DE3) competent cells, and IPTG was used to induce the expression of His-tagged mtTFA. The expressed fusion protein was purified with Ni(2+)-NTA His-bind resin and quantified with Bradford method. The amplified product was confirmed as the coding sequence of mtTFA without signal peptides by DNA sequencing, and the recombinant expression vector could express His-tagged mtTFA in E.coil following the induction by IPTG. The fusion protein of high purity and rabbit anti-mtTFA serum with high specificity were obtained. The prokaryotic expression vector for mtTFA is successfully constructed and His-tagged mtTFA protein and specific polyclonal antibody are obtained, which can be helpful for further investigation of the biological function and signaling pathways involved in the regulation of functional cooperation between the nucleus and mitochondria.


Suppression of A549 cell proliferation and metastasis by calycosin via inhibition of the PKC-α/ERK1/2 pathway: An in vitro investigation.
Mol Med Rep 12:[Related article:] 7992–8002, 2015; DOI: 10.3892/mmr.2015.4449 Following the publication of this article, an interested reader drew to our attention an anomaly associated with the presentation of Fig. 2; essentially, an image had been inadvertently selected from the same original photomicrograph to represent Fig. 2D, the centre panel [+80 nM phorbol-12-myristate-13-acetate (TPA), + 20 μM calycosin (Cal)] and Fig. 2F, the second panel from the right (+ 80 nM TPA, + 30 μM Cal). After having re-examined our original data, the panel originally featured in Fig. 2F was identified as having been selected incorrectly for the Figure. A corrected version of Fig. 2 is presented on next page, which features the proper data for Fig. 2F. Fig. 2D and F showed the effect of different concentrations of Cal on the migration and invasive ability of the TPA-treated A549 cells, respectively; Cal was demonstrated to inhibit the migration, and to suppress the invasive ability, of the A549 cells induced by TPA. Therefore, this error did not affect the overall conclusions reported in the present study. We sincerely apologize for this mistake, and thank the reader of our article who drew this matter to our attention. Furthermore, we regret any inconvenience this mistake has caused.


ATP-dependent chromatin remodeling enzymes: two heads are not better, just different.
ATP-dependent chromatin remodeling complexes enable rapid rearrangements in chromatin structure in response to developmental cues. The ATPase subunits of remodeling complexes share homology with the helicase motifs of DExx box helicases. Recent single-molecule experiments indicate that, like helicases, many of these complexes use ATP to translocate on DNA. Despite sharing this fundamental property, two key classes of remodeling complexes, the ISWI class and the SWI/SNF class, generate distinct remodeled products. SWI/SNF complexes generate nucleosomes with altered positions, nucleosomes with DNA loops and nucleosomes that are capable of exchanging histone dimers or octamers. In contrast, ISWI complexes generate nucleosomes with altered positions but in standard structures. Here, we draw analogies to monomeric and dimeric helicases and propose that ISWI and SWI/SNF complexes catalyze different outcomes in part because some ISWI complexes function as dimers while SWI/SNF complexes function as monomers.


The effect of hemoglobin F-Chesapeake (alpha 2 92 Arg. leads to Leu gamma 2) on fetal oxygen affinity and erythropoiesis.
A carrier of hemoglobin Chesapeake, born of a normal mother, had a cord-blood hematocrit of 60%. The oxygen affinity of his blood was increased. Hemoglobin F-Chesapeake (alpha 2 Ches gamma 2), partially purified from the infant's blood, had oxygen affinity greater than that of hemoglobin A, but less than that of the adult form of the abnormal hemoglobin (alpha 2 Ches beta 2). These findings suggest that the conformation of that part of the gamma chain which contacts the site of amino acid substitution in Hb F-Chesapeake is similar to the analogous region of hemoglobin F. They also support the hypothesis that regulation of erythropoiesis in late fetal life is similar to that of the adult, and is under fetal control.


High-voltage 10 ns delayed paired or bipolar pulses for in vitro bioelectric experiments.
Recent studies proved that classical bio-effects induced by nanosecond pulsed electric field (nsPEF) can be reduced by the delivery of a negative polarity pulse generated immediately after a positive polarity pulse. This phenomenon is known as "bipolar cancellation" and it was reported for a wide range of bipolar pulses with pulse duration from 2 ns to 900 ns. On the contrary, paired pulses, i.e., two identical pulses with the same polarity, increased traditional nsPEF outcomes. Herein, we propose a novel robust and flexible generator, based on the frozen-wave concept, able to produce a broad range of pulses with the duration of 10 ns and delay between 17 and 360 ns. Numerical simulations and experimental measurements were performed to fully characterize the proposed generator. YO-PROTM-1 uptake was investigated in the U87-MG human glioblastoma cell line as a marker of membrane permeabilization in response to 10 ns, 11.5MV/m nsPEF. Our results showed that bipolar cancellation occurred for delays of 0-30 ns and decreased as a function of the interphase interval. In addition, we observed that cellular response following the application of paired nsPEF was more than two-fold compared to the unipolar pulse response and was independent from the interphase interval.


Radiation dose response of normal lung assessed by Cone Beam CT - a potential tool for biologically adaptive radiation therapy.
Density changes of healthy lung tissue during radiotherapy as observed by Cone Beam CT (CBCT) might be an early indicator of patient specific lung toxicity. This study investigates the time course of CBCT density changes and tests for a possible correlation with locally delivered dose. A total of 665 CBCTs in 65 lung cancer patients treated with IMRT/VMAT to 60 or 66 Gy in 2 Gy fractions were analyzed. For each patient, CBCT lung density changes during the treatment course were related to the locally delivered dose. A dose response is observed for the patient population at the end of the treatment course. However, the observed dose response is highly variable among patients. Density changes at 10th and 20th fraction are clearly correlated to those observed at the end of the treatment course. CBCT density changes in healthy lung tissue during radiotherapy correlate with the locally delivered dose and can be detected relatively early during the treatment. If these density changes are correlated to subsequent clinical toxicity this assay could form the basis for biological adaptive radiotherapy.


Anion transport in rat brain mitochondria: fumarate uptake via the dicarboxylate carrier.
Penetration of fumarate into rat brain mitochondria has been investigated, as required in brain ammoniogenesis. Mitochondria swell in ammonium fumarate and this swelling is increased by both Pi and malate. According to a carrier mediated process, fumarate translocation, which occurs in exchange with intramitochondrial malate or Pi shows saturation characteristics. By photometrically investigating the kinetics of fumarate/malate, fumarate/Pi and malate/Pi exchanges, different Km values were obtained (10, 22 and 250 microM, respectively), whereas no significant difference was found for Vmax values (40 nmol NAD(P)+ reduced/min X mg protein). This suggests that fumarate and malate share a single carrier to enter mitochondria, namely the dicarboxylate carrier. Both comparison made of the Vmax values and inhibition studies exclude a fumarate translocation via either the tricarboxylate carrier, whose occurrence in brain is here demonstrated, or oxodicarboxylate carrier. Kinetic investigation of the dicarboxylate translocator shows the existence of thiol group/s and metal ion/s at or near the substrate binding sites. The experimental findings are discussed in the light of fumarate uptake in vivo in brain ammoniogenesis.


Accuracy of the American Association of Endodontists diagnostic criteria for assessing pulp health in primary teeth.
There is a lack of studies evaluating the accuracy of the 2009 American Association of Endodontists (AAE) diagnostic criteria for diagnosing pulpal health in primary teeth. This study aimed to estimate and correlate the diagnostic accuracy of clinical diagnosis of reversible and irreversible pulpitis using the 2009 AAE criteria with histological findings in primary teeth. Eighty primary teeth that were clinically diagnosed with normal pulp (n = 10), reversible pulpitis (n = 30), irreversible pulpitis (n = 30) and pulp necrosis (n = 10) were collected. The teeth were histo-processed, and pulp tissues were diagnosed histologically as uninflamed pulp, reversible or irreversibly inflamed and necrosis based on previously proposed criteria. The clinical diagnosis of pulp necrosis (sensitivity 70%, specificity 96%) and normal pulp (sensitivity 91%, specificity 100%) matched the histological diagnosis of necrosis and uninflamed pulp in 70% and 100%, respectively. The clinical diagnosis of irreversible pulpitis (sensitivity 64%, specificity 72%) matched the histological diagnosis of irreversible pulp inflammation for 47% of teeth evaluated. For the clinical diagnosis of reversible pulpitis (sensitivity: 65%, specificity: 86%), 80% matched the histological diagnosis of reversible pulp inflammation. Teeth with histologically diagnosed irreversible pulp inflammation were more likely to have lingering (OR 5.08; 95% CI 1.48-17.46, P = 0.010) and nocturnal tooth pain (OR 15.86; 95% CI 1.57-160.47, P = 0.019) when compared to teeth with reversible pulp inflammation. Using the classification and regression tree model, the presence of widened periodontal ligament space and nocturnal tooth pain were useful predictors of irreversible pulp inflammation with an accuracy of 78%. The 2009 AAE criteria was acceptable for primary teeth with pulp necrosis and normal pulp but poor for reversible pulpitis and irreversible pulpitis.


Breaking prolonged sitting increases 24-h physical activity and self-perceived energy levels but does not acutely affect cognition in healthy adults.
It is unknown whether predetermined (un)interrupted sitting within a laboratory setting will induce compensatory changes in human behaviours (energy intake and physical activity) once people return to a free-living environment. The effects of breaking up prolonged sitting on cognition are also unclear. Twenty-four (male = 13) healthy participants [age 31 ± 8 y, BMI 22.7 ± 2.3 kg/m2 (mean ± SD)] completed 320 min mixed-feeding trials under prolonged sitting (SIT) or with 2 min walking at 6.4 km/h every 20 min (ACTIVE), in a randomised crossover design. Human behaviours were recorded post-trial under free-living conditions until midnight. Cognitive performance was evaluated before and immediately after SIT and ACTIVE trials. Self-perceived sensations (appetite, energy and mood) and finger prick blood glucose levels were collected at regular intervals throughout the trials. There were no differences between trials in eating behaviour and spontaneous physical activity (both, p > 0.05) in free-living conditions, resulting in greater overall total step counts [11,680 (10740,12620) versus 6049 (4845,7253) steps] and physical activity energy expenditure (PAEE) over 24-h period in ACTIVE compared to SIT (all, p < 0.05). Greater self-perceived levels of energy and lower blood glucose iAUC were found in ACTIVE trial compared to SIT trial (both, p < 0.05). No differences were found in cognitive performance between trials (all, p > 0.05). Breaking up sitting does not elicit subsequent behavioural compensation, resulting in greater 24-h step counts and PAEE in healthy adults. Breaking up sitting reduces postprandial glucose concentrations and elicits greater self-perceived energy levels, but these positive effects do not acutely translate into improved cognitive function.


Effects of milk diet on gastrointestinal absorption of cadmium in adult mice.
Effect of milk diet on absorption of cadmium were investigated in a 6-week study. Forty adult male mice were divided into groups of 10 and treated with different foodstuffs (I: mouse pellets and deionized water; II: mouse pellets and water containing cadmium chloride: III: milk only: IV: milk containing cadmium chloride). The intake of cadmium and milk was regulated during the experiment to make sure that the animal groups received the same amounts of cadmium andmilk respectively. After 2 weeks the mice were exposed to a single oral dose via stomach tube of 109CdCl2, the fate of which was followed by whole body counting. A markedly higher whole body retention of 109CdCl2 was observed in animals given milk diet compared to other groups. Total cadmium concentrations in different organs measured by atomic absorption spectrophotometry were twice as high in milk-fed mice compared to mice fed on R35 mouse pellets.


Application of Centrifugal Partition Chromatography for Bioactivity-Guided Purification of Antioxidant-Response-Element-Inducing Constituents from Atractylodis Rhizoma Alba.
Activity-guided separation of antioxidant response element (ARE)-inducing constituents from the rhizomes of Atractylodis Rhizoma Alba was performed by the combination of centrifugal partition chromatography (CPC) and an ARE luciferase reporter assay. From 3 g of the active n-hexane fraction, one polyacetylene, (6E,12E)-tetradeca-6,12-dien-8,10-diyne-1,3-diyl diacetate (47.3 mg), and two sesquiterpenes, atractylenolide I (40.9 mg), and selina-4(14),7(11)-dien-8-one (6.0 mg) were successfully isolated by CPC with n-hexane⁻ethyl acetate⁻methanol⁻water (8:2:8:2, v/v). The chemical structures of the isolated compounds were determined by ¹H- and 13C-NMR and ESI-MS. Among the isolated compounds, (6E,12E)-tetradeca-6,12-diene-8,10-diyne-1,3-diol diacetate and selina-4(14),7(11)-dien-8-one increased ARE activity 32.9-fold and 16.6-fold, respectively, without significant cytotoxicity, when 5 µM sulforaphane enhanced ARE activity 27.1-fold. However, atractylenolide I did not increase ARE activity at 100 µM, and showed cytotoxicity at concentrations over 10 µM.


An evaluation of the safety and immunogenicity of MVC-COV1901: Results of an interim analysis of a phase III, parallel group, randomized, double-blind, active-controlled immunobridging study in Paraguay.
Data from previous studies of the MVC-COV1901 vaccine, a subunit vaccine against SARS-CoV-2 based on the stable prefusion spike protein (S-2P) adjuvanted with CpG 1018 adjuvant and aluminum hydroxide, suggest that the vaccine is generally safe and elicits a good immune response in healthy adults and adolescents. By comparing with AZD1222, this study adds to the findings from previous trials and further evaluates the breadth of protection offered by MVC-COV1901. In this phase 3, parallel group, randomized, double-blind, active-controlled trial conducted in 2 sites in Paraguay, we assigned adults aged 18-91 years in a 1:1 ratio to receive intramuscular doses of MVC-COV1901 or AZD1222 administered as scheduled in the clinical trial. Serum samples were collected on the day of vaccination and 14 days after the second dose. Primary and secondary safety and immunogenicity endpoints were assessed. In addition, other outcomes investigated were cross-reactive immunity against the Omicron strain and the induction of IgG subclasses. A total of 1,030 participants underwent randomization. Safety data was derived from this set while primary immunogenicity data involved a per-protocol immunogenicity (PPI) subset including 225 participants. Among the participants, 58% are seropositive at baseline. When compared against AZD1222, MVC-COV1901 exhibited superiority in terms of neutralizing antibody titers and non-inferiority in terms of seroconversion rates. Reactogenicity was generally mild and no serious adverse event was attributable to MVC-COV1901. Both vaccines have a Th1-biased response predominated by the production of IgG1 and IgG3 subclasses. Omicron-neutralizing titers were 44.5 times lower compared to wildtype-neutralizing titers among seronegative individuals at baseline. This fold-reduction was 3.0 times among the seropositive. Safety and immunogenicity data of MVC-COV1901 from the study in Paraguay confirm previous results. The previous infection coupled with vaccination of this vaccine may offer protection against the Omicron strain though its durability is still unknown.


Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat.
1. Soleus, extensor digitorum longus (EDL) or hemi-diaphragm muscles of the rat were incubated in the presence of insulin and rates of the processes of glycolysis and glycogen synthesis were measured. 2. The concentrations of insulin required to cause half-maximal stimulation of glycolysis in both soleus and EDL preparations were significantly decreased by the presence of adenosine deaminase in the medium. 3. Adenosine deaminase increased the sensitivity of the process of hexose transport to insulin (in an identical manner to the change in sensitivity of glycolysis) in the EDL preparation. 4. None of the adenosine mediated effects on insulin-stimulated rates of glycolysis were observed in the hemi-diaphragm preparation or on the rates of glycogen synthesis in any of the three muscle preparations. 5. Therefore, changes in the adenosine system in skeletal muscle influence insulin sensitivity regardless of fibre type composition of the muscle.


Observed use of voluntary controls to reduce physical exposures among sheet metal workers of the mechanical trade.
Little is known about the transfer into the workplace of interventions designed to reduce the physical demands of sheet metal workers. We reviewed videos from a case series of 15 sheet metal worksite assessments performed in 2007-2009 to score postures and physical loads, and to observe the use of recommended interventions to reduce physical exposures in sheet metal activities made by a NIOSH stakeholder meeting in 2002. Workers showed consistent use of material handling devices, but we observed few uses of recommended interventions to reduce exposures during overhead work. Workers spent large proportions of time in awkward shoulder elevation and low back rotation postures. In addition to the development of new technologies and system designs, increased adoption of existing tools and practices could reduce time spent in awkward postures and other risks for musculoskeletal disorders in sheet metal work.


Mechanisms and management of chemotherapy-induced nausea and vomiting.
Only in recent years has serious attention been given to the control of chemotherapy-induced emesis (CIE) which is to the patient a most obnoxious side-effect. Important advances in the understanding of the mechanisms of CIE have led to the scientific appraisal of potential anti-emetics whilst additional, useful anti-emetics have appeared by serendipity. CIE has largely been studied in trials separating either cis-platinum (severely emetic) or non-cis-platinum(moderately emetic)-induced emesis. In the evolution of these trials the difficulty and importance of accurate evaluation of emesis has been revealed and the whole area of psychogenic emesis opened to investigation and treatment. Phenothiazines and butyrophenones have a definite modest anti-emetic role against moderately emetogenic chemotherapy but increasingly corticosteroids, benzodiazepines, high dose metoclopramide and cannabinoids are being used with great effect even with severely emetic drugs. Combination anti-emesis has further improved control rates and new schedules of currently available anti-emetics are now proving their worth. Major advances in anti-emetic control have been achieved recently and every patient at risk of CIE should have good control, if not total abolition, of emesis with appropriate use of anti-emetics.


Alcohol consumption and high-density lipoprotein levels: the effect of ADH1C genotype, gender and menopausal status.
We previously demonstrated that a functional polymorphism in alcohol dehydrogenase type 1C (ADH1C, also known as ADH3) modifies the association between moderate alcohol consumption and high-density lipoprotein (HDL) levels and risk of myocardial infarction among older men. In this study, we investigated the effect of the ADH1C gamma(1) and gamma(2) alleles on the relationship between alcohol consumption and HDL levels among four populations with varied exposure to endogenous and exogenous estrogens: premenopausal women, middle-to-older aged men, postmenopausal women currently using postmenopausal hormones (PMH) and postmenopausal women not currently using PMH. We observed an interaction between moderate alcohol consumption and ADH1C genotype on HDL level that was similar among middle-to-older aged men and postmenopausal women not using PMH. Among the moderate drinkers (approximately a half a drink per day for women and a full drink per day for men), there was a significant 5.3mg/dL (P=0.02) higher level of multivariate adjusted HDL level comparing the gamma(2) homozygotes (slow oxidizers) to the gamma(1) homozygotes (fast oxidizers). This interaction was not present among premenopausal women or postmenopausal women using PMH, who had higher overall HDL levels irrespective of alcohol consumption. Our results confirm that ADH1C genotype modifies the association between alcohol consumption and HDL levels among men and postmenopausal women not using PMH who drink moderately. However, this was not observed among individuals with estrogen-elevated HDL levels, specifically premenopausal women and postmenopausal women taking PMH, suggesting that these populations may benefit less from alcohol consumption with respect to coronary heart disease.


Tissue fatty acid changes and tumor incidence in C3H mice ingesting cottonseed oil.
The incidence of spontaneous mammary tumors in C3H mice at 35 wk was higher in mice fed rations containing cottonseed oil than in mice fed fats of comparable fatty acid composition. The time to 50% (T50) incidence was also shorter in the first group. The fatty acid composition of tissue lipids from mice fed the cottonseed oil showed changes indicating the presence of cyclopropene fatty acids-higher levels of saturates and lower oleate/stearate and palmitoleate/palmitate ratios. A possible association between the development of a spontaneous mammary tumor in the C3H mouse and the presence of cyclopropene fatty acids in the cottonseed oil is indicated.


The prevalence and significance of abnormal vital signs prior to in-hospital cardiac arrest.
Patients suffering in-hospital cardiac arrest often show signs of physiological deterioration before the event. The purpose of this study was to determine the prevalence of abnormal vital signs 1-4h before cardiac arrest, and to evaluate the association between these vital sign abnormalities and in-hospital mortality. We included adults from the Get With the Guidelines(®)- Resuscitation registry with an in-hospital cardiac arrest. We used two a priori definitions for vital signs: abnormal (heart rate (HR) ≤ 60 or ≥ 100 min(-1), respiratory rate (RR) ≤ 10 or >20 min(-1) and systolic blood pressure (SBP) ≤ 90 mm Hg) and severely abnormal (HR ≤ 50 or ≥ 130 min(-1), RR ≤ 8 or ≥ 30 min(-1) and SBP ≤ 80 mm Hg). We evaluated the association between the number of abnormal vital signs and in-hospital mortality using a multivariable logistic regression model. 7851 patients were included. Individual vital signs were associated with in-hospital mortality. The majority of patients (59.4%) had at least one abnormal vital sign 1-4h before the arrest and 13.4% had at least one severely abnormal sign. We found a step-wise increase in mortality with increasing number of abnormal vital signs within the abnormal (odds ratio (OR) 1.53 (CI: 1.42-1.64) and severely abnormal groups (OR 1.62 (CI: 1.38-1.90)). This remained in multivariable analysis (abnormal: OR 1.38 (CI: 1.28-1.48), and severely abnormal: OR 1.40 (CI: 1.18-1.65)). Abnormal vital signs are prevalent 1-4h before in-hospital cardiac arrest on hospital wards. In-hospital mortality increases with increasing number of pre-arrest abnormal vital signs as well as increased severity of vital sign derangements.


Aspects regarding renal morphophysiology of fruit-eating and vampire bats.
Bats have adapted to many different feeding habits, which are known to induce morphophysiological adaptations in several tissues, especially those particularly involved with absorption, metabolism and excretion. The common vampire bat (Desmodus rotundus) has a very unique diet (blood), which, among other challenges, seems to pose a risk to their kidneys, due to the increased nitrogen excretion imposed by their remarkably high protein meal. Fruit-eating bats (Artibeus lituratus) consume a high carbohydrate diet and may be taken as a suitable species for this dietary comparative study. Here we aimed at investigating the renal morphology and stereology, kidneys antioxidant capacity, and plasma antidiuretic hormone (ADH) concentrations in adult fruit-eating and vampire bats. Sixteen animals were captured and used in this study, being 8 adult males from each species. Our results showed higher morphological standards of glomerular area, volumetric density of glomeruli, and renal somatic index for vampire bats, as well as higher reactive species of oxygen (ROS) production, such as nitric oxide (NO), higher plasma iron reduction ability (FRAP), higher activity of the antioxidant enzyme glutathione-S-transferase (GST) and a higher malondialdehyde production (MDA) in vampires' kidneys, compared to the fruit-eating species. The activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) were higher in fruit-eating bats. Plasma ADH concentrations were not different between species. Taken together, the renal morphophysiology conditions presented by vampire bats might be associated with a high demand for nitrogenous products excretion imposed by protein and iron overload. These features may play an important role on preventing protein-overload nephropathy, allowing vampires to survive under such a unique diet.


Changes in quality of life among low-income men treated for prostate cancer.
To investigate as the primary objective changes over time in general and disease-specific health-related quality of life (HRQOL) among low-income men treated for prostate cancer in a longitudinal prospective study. Study participants were recruited from a state-funded program providing free prostate cancer treatment to impoverished men. We included men who completed telephone interviews and self-administered questionnaires at study enrollment and 6 months of follow-up. Covariates univariately associated with HRQOL change scores were included in multivariate linear regression models. All HRQOL models were controlled for age at enrollment, race, baseline HRQOL, and treatment effects at baseline and follow-up. Subjects with greater baseline Gleason scores experienced more negative changes in their physical health than did men with lower Gleason scores. Men with less than a high school education experienced greater improvement in their mental well-being than did men with more than a high school education. Those experiencing treatment effects at baseline displayed greater positive changes in their urinary function than did those without treatment effects at baseline. Finally, men experiencing treatment effects at follow-up were characterized by profound reductions in sexual function compared with those free of treatment effects at follow-up. This work provides new insights into HRQOL over time in a low-income, multiethnic group of patients with prostate cancer.


Infection with Candida albicans of a total knee arthroplasty. Case report and review of the literature.
Infection with Candida albicans of a total knee arthroplasty developed in an immunosuppressed 52-year-old woman with rheumatoid arthritis who initially presented with clear drainage from the incision, which cultured negative initially. Successful treatment consisted initially of debridement and a course of intravenous antibiotics, followed by staged arthrodesis with an intramedullary rod.


Bacterial air counts obtained with a centrifugal (RCS) sampler and a slit sampler--the influence of aerosols.
Samples of air collected from an air-conditioned hospital room with a 'Biotest RCS' centrifugal air sampler yielded (assuming a sampling rate of 40 l/min) air counts that were approximately twice those obtained with a modified conventional ' Casella ' slit sampler. However, for samples taken during the generation of an aerosol of spores of Bacillus globigii, the slit sampler gave counts that were apparently three- to tenfold higher than those with the centrifugal sampler. For a few minutes after switching off the nebulizer, higher counts were still obtained with the slit sampler, but then the centrifugal sampler again gave consistently higher counts. Our results illustrate that attempts to measure the number of bacteria in air are influenced by the size of the bacterial particles and the sampler that is used.


Dexamethasone-induced sodium influx in human lymphocytes.
We evaluated the direct effects of glucocorticoids on intracellular sodium content and cellular transport systems. Cytosolic free sodium concentration ([Na+]i) was measured in intact human lymphocytes using the sodium-sensitive fluorescent dye sodium-binding benzofuran-isophthalate. Administration of dexamethasone for 60 min increased lymphocytic [Na+]i from 17.6 +/- 2.0 mmol/L to 24.3 +/- 3.9 nmol/L (n = 12; P < 0.01). The dexamethasone-induced [Na+]i increase was abolished in the absence of extracellular sodium, by mifepristone and by actinomycin D. The dexamethasone-induced [Na+]i increase was also seen after inhibition of Na+,K(+)-ATPase by 1 mmol/L ouabain. The present results indicate that dexamethasone produces a trans-plasma membrane sodium influx probably by early occurring genomic effects.


Neuroticism and Individual Differences in Neural Function in Unmedicated Major Depression: Findings from the EMBARC Study.
Personality dysfunction represents one of the only predictors of differential response between active treatments for depression to have replicated. In this study, we examine whether depressed patients with higher neuroticism scores, a marker of personality dysfunction, show differences versus depressed patients with lower scores in the functioning of two brain regions associated with treatment response, the anterior cingulate and anterior insula cortices. Functional magnetic resonance imaging data during an emotional Stroop task were collected from 135 adults diagnosed with major depressive disorder at four academic medical centers participating in the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) study. Secondary analyses were conducted including a sample of 28 healthy individuals. In whole-brain analyses, higher neuroticism among depressed adults was associated with increased activity in and connectivity with the right anterior insula cortex to incongruent compared to congruent emotional stimuli (ks>281, ps<0.05 FWE corrected), covarying for concurrent psychiatric distress. We also observed an unanticipated relationship between neuroticism and reduced activity in the precuneus (k=269, p<0.05 FWE corrected). Exploratory analyses including healthy individuals suggested that associations between neuroticism and brain function may be nonlinear over the full range of neuroticism scores. This study provides convergent evidence for the importance of the right anterior insula cortex as a brain-based marker of clinically meaningful individual differences in neuroticism among adults with depression. This is a critical next step in linking personality dysfunction, a replicated clinical predictor of differential antidepressant treatment response, with differences in underlying brain function.


High-frequency oscillatory ventilation in adult acute respiratory distress syndrome.
This study examined whether ARDS patients in whom predefined ventilator settings fail to maintain oxygenation and CO2 removal can be safely transitioned to high-frequency oscillatory ventilation (HFOV), and whether HFOV use is efficacious. Prospective observational study in the 14-bed intensive care unit of a university hospital. 42 patients with ARDS (APACHE II score 28 (IQR 24-37) and ventilation time prior HFOV 3.0 days (0.7-9.1). Gas exchange parameters and ventilator data were recorded before and during HFOV treatment (-12 h, -6 h, baseline, 10 min, 1 h, 6 h, 12 h, 24 h). Primary endpoints included: (a) PaO2/FIO2 ratio 24 h after start of HFOV treatment or the last point of measurement if HFOV ended within the first 24 h; (b) HFOV-related complications. Post hoc analysis assessed the relationship between outcome and the response to HFOV, and between outcome and time of mechanical ventilation prior to HFOV. At baseline the median PaO2/FIO2 ratio was 95 (IQR 62-129); after 24 h of HFOV the PaO2/FIO2 ratio had increased significantly to 165 (88-225); only one patient developed a unilateral pneumothorax. Of the 42 patients 18 (43%) had died by day 30. Subset analyses showed a significantly higher 30-day mortality rate in patients with at least 3 days of mechanical ventilation prior to HFOV (64%) and in patients without oxygenation improvement after 24 h on HFOV (71%). HFOV is an effective and safe method to ventilate ARDS patients. Failure to improve oxygenation within 24 h of HFOV is associated with high mortality.


Factors influencing myopia stabilisation in young myopic adult Singaporeans.
To evaluate factors influencing stabilisation of myopia in the Singapore Cohort of Risk factors for Myopia. We evaluated the longitudinal natural history of 424 myopic participants from 1999 to 2022. The outcome was the change in myopia from the adolescence follow-up visit (aged 12-19 years) to the adulthood follow-up visit (aged 26-33 years). Association of predictive factors, including baseline spherical error, gender, ethnicity, parental myopia, time outdoor, near work and age at adolescence, was examined with the dichotomous outcome of adult myopia progression (≤ -1.00 dioptres (D) over 10 years) using multiple logistic regression and progression in linear regression models. For the primary outcome, the mean rate of progression of the outcome was found to be -0.04±0.09 D per year from the adolescent to the adulthood follow-up visits. 82.3% (95% CI 78.3% to 85.8%) had myopia stabilisation, with progression of less than 1.00 D over 10 years while 61.3% (95% CI 56.5% to 66.0%) of the subjects had progression of less than 0.50 D. In logistic regression models, both male gender (p=0.035) and non-Chinese ethnicity (p=0.032) were more likely to achieve myopia stabilisation while in linear multivariate regression models, males had a significantly slower degree of myopia progression (p=0.021). 5 in 6 Singaporean young adults had myopia stabilisation. Male gender is 2 times and non-Chinese ethnicities are 2.5 times more likely to achieve myopia stabilisation. However, a proportion of myopes continue to exhibit a clinically significant degree of progression in adulthood.


Excessive S-adenosyl-L-methionine-dependent methylation increases levels of methanol, formaldehyde and formic acid in rat brain striatal homogenates: possible role in S-adenosyl-L-methionine-induced Parkinson's disease-like disorders.
Excessive methylation may be a precipitating factor for Parkinson's disease (PD) since S-adenosylmethionine (SAM), the endogenous methyl donor, induces PD-like changes when injected into the rat brain. The hydrolysis of the methyl ester bond of the methylated proteins produces methanol. Since methanol is oxidized into formaldehyde, and formaldehyde into formic acid in the body, we investigated the effects of SAM on the production of methanol, formaldehyde and formic acid in rat brain striatal homogenates and the toxicity of these products in PC12 cells. Radio-enzymatic and colorimetric assays, cell viability, Western blot. SAM increased the formation of methanol, formaldehyde and formic acid in a concentration and time-dependent manner. Concentrations of [3H-methyl]-SAM at 0.17, 0.33, 0.67 and 1.34 nM produced 3.8, 8.0, 18.3 and 34.4 fmol/mg protein/h of [3H] methanol in rat striatal homogenates, respectively. SAM also significantly generated formaldehyde and formic acid in striatal homogenates. Formaldehyde was the most toxic metabolite to differentiated PC12 pheochromocytoma cells in cell culture studies, indicating that formaldehyde formed endogenously may contribute to neuronal damage in excessive methylation conditions. Subtoxic concentration of formaldehyde decreased the expression of tyrosine hydroxylase, the limiting factor in dopamine synthesis. Formaldehyde was more toxic to catecholaminergic PC12 cells than C6 glioma cells, indicating that neurons are more vulnerable to formaldehyde than glia cells. We suggest that excessive carboxylmethylation of proteins might be involved in the SAM-induced PD-like changes and in the aging process via the toxic effects of formaldehyde.


Psychostimulants, antidepressants and neurokinin-1 receptor antagonists ('motor disinhibitors') have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD.
Both psychostimulants and antidepressants target monoamine transporters and, as a consequence, augment monoamine transmission. These two groups of drugs also increase motor activity in preclinical behavioural screens for antidepressants. Substance P-preferring receptor (NK1R) antagonists similarly increase both motor activity in these tests and monoamine transmission in the brain. In this article, the neurochemical and behavioural responses to these three groups of drugs are compared. It becomes evident that NK1R antagonists represent a distinct class of compounds ('motor disinhibitors') that differ substantially from both psychostimulants and antidepressants, especially during states of heightened arousal or stress. Also, all three groups of drugs influence the activation of voltage-gated Ca(v)1.2 and Ca(v)1.3 L-type channels (LTCCs) in the brain, albeit in different ways. This article discusses evidence that points to disruption of these functional interactions between NK1R and LTCCs as a contributing factor in the cognitive and behavioural abnormalities that are prominent features of Attention Deficit Hyperactivity Disorder (ADHD). Arising from this is the interesting possibility that the hyperactivity and impulsivity (as in ADHD) and psychomotor retardation (as in depression) reflect opposite poles of a behavioural continuum. A better understanding of this pharmacological network could help explain why psychostimulants augment motor behaviour during stress (e.g., in preclinical screens for antidepressants) and yet reduce locomotor activity and impulsivity in ADHD. This article is part of the Special Issue entitled 'CNS Stimulants'.


An enhanced mitochondrial function through glutamine metabolism in plasmablast differentiation in systemic lupus erythematosus.
To evaluate the dysfunction of B-cell metabolism and its involvement in SLE pathology. We assessed the expression of metabolic markers of B cells in the peripheral blood of healthy controls (HCs) and SLE patients by using flow cytometry. In vitro, peripheral B cells were isolated from HCs and SLE patients to investigate the metabolic regulation mechanisms involved in their differentiation. The expression level of DiOc6 (mitochondrial membrane hyperpolarization) was higher in B cells from SLE patients than in HCs, and correlated to the percentage of plasmablasts in CD19+ cells and with SLEDAI, a disease activity score. Stimulation of CD19+ cells with the Toll-like receptor 9 (TLR9) ligand CpG and IFN-α enhanced glycolysis, oxidative phosphorylation (OXPHOS), DiOc6 expression, and plasmablast differentiation in vitro. In the absence of glutamine, both glycolysis and OXPHOS were reduced, and plasmablast differentiation was suppressed, whereas there was no change in the absence of glucose. As glutamine is an important nutrient for protein synthesis, we further investigated the effect of the glutaminase inhibitor BPTES, which inhibits glutamine degradation, on metabolic regulation. BPTES reduced DiOc6 expression, OXPHOS, reactive oxygen species (ROS) production, adenosine triphosphate (ATP) production, plasmablast differentiation without affecting glycolysis. Metformin inhibited CpG- and IFN-α-induced glutamine uptake, mitochondrial functions and suppressed plasmablast differentiation. Mitochondrial dysfunction in B cells is associated with plasmablast differentiation and disease activity in SLE. Enhanced mitochondrial functions mediated by glutamine metabolism are important for plasmablast differentiation, which may be a potential therapeutic target for SLE.


Fall-related injuries in anticoagulated stroke patients during inpatient rehabilitation.
To compare the frequency and severity of fall-related injuries in anticoagulated patients undergoing rehabilitation after stroke to nonanticoagulated stroke patients undergoing rehabilitation. Retrospective chart review. Free-standing rehabilitation hospital. 264 patients who sustained falls while undergoing intensive inpatient rehabilitation after stroke. Injuries, categorized as minor (abrasions and bruises) or major (intracranial hemorrhage, fracture, major bleeding). A total of 400 falls in 264 patients undergoing inpatient stroke rehabilitation were reviewed. One hundred thirty-one falls were sustained by 93 patients receiving anticoagulation, whereas 269 falls were sustained by 175 patients not receiving anticoagulation. In both the anticoagulation group and the control (nonanticoagulated) group, approximately one in five falls resulted in minor injuries (abrasions or bruises). Three fractures occurred, but no major bleeding events or intracranial hemorrhage occurred in either group. The risk for minor injury secondary to fall is comparable between the two groups, and the risk is low in this setting for hemorrhagic injuries in stroke patients falling while receiving anticoagulation.


The role of neuropeptide Y and aquaporin 4 in the pathogenesis of intestinal dysfunction caused by traumatic brain injury.
Although the exact incidence is unknown, traumatic brain injury (TBI) can lead to intestinal dysfunction. It has important influence on the early nutrition and prognosis of TBI patients. Experiments were designed to study the roles of neuropeptide Y (NPY) and aquaporin 4 (AQP4) in the pathogenesis of intestinal dysfunction caused by TBI and to find some new solutions for the treatment of intestinal dysfunction after TBI. Forty adult male Wistar rats were randomly divided into control, mild trauma, moderate trauma, and severe trauma groups. TBI was induced by Feeney's impact method. Control animals were sham operated but not subjected to the impact test. All rats were killed 24 h after surgery. Blood samples were obtained from the abdominal aorta for enzyme-linked immunosorbent assay measurement of NPY concentrations. Jejunum segments 15 cm distal to the Treitz ligament were taken for analysis of NPY and AQP4 expression by polymerase chain reaction, Western blot, and immunohistochemistry. Pathologic changes in intestinal cell structure and ultrastructure were studied by light microscopy and transmission electron microscopy. The specimens from different groups showed different degrees of structural changes, ranging from swelling and degeneration of villous epithelial cells to extensive denudation and collapse of the villi. The more severe the trauma, the more serious the degree of intestinal mucosal injury. Intestinal smooth muscle also showed varying degrees of edema and structural disorder. Electron microscopy showed that intestinal mitochondria had varying degrees of swelling and the structure of mitochondrial crista was disordered and even fractured. Plasma concentrations of NPY and jejunal gene and protein expressions of NPY and AQP4 increased significantly following TBI (P < 0.05), with greater increases at higher levels of injury. Moreover, there were positive correlations between NPY and AQP4 (P < 0.05). Increasing grades of TBI caused increasing degrees of intestinal ischemia and edema, and thus caused increasingly severe intestinal dysfunction. AQP4 and NPY may be involved in the pathogenesis of intestinal dysfunction after TBI. Increased NPY levels may be responsible for intestinal ischemia and hypoxia, and AQP4 may play an important role in intestinal edema. Increased NPY levels may be one of the main causes for the increase in AQP4 after TBI.


X-ray diffractometric analysis of L-cystine stones in 12 patients.
In 12 of 21 cystinuric patients, the components of cystine stones, either previously passed or removed at surgery, were studied by X-ray diffractometry and chemical analysis. The results of diffractometry suggested that, in addition to cystine, the stones contained sodium urate and ammonium magnesium orthophosphate hydrate, although chemical analysis was negative for these components. The role of uric acid in cystinuria is discussed.


Vaccines: predicting the risk of allergy and autoimmunity.
The field of vaccines is markedly evolving with the introduction and development of many new concepts and formulations, as well as new indications. Based on the current clinical experience, vaccines can be considered safe in most cases. Nevertheless, allergy and, to a lesser extent, autoimmunity have repeatedly been described or suspected as rare adverse consequences of human vaccines. The mechanisms of these adverse reactions are ill-elucidated, if at all. No animal models have been adequately standardized and validated to predict the risk of allergy and autoimmunity associated with vaccines. However, a number of existing models can be considered for use, but need refinement to be applied to vaccine evaluation. Finally, because the preclinical safety evaluation has not received much attention in the past, efforts should be paid to design specific and cost-effective procedures to meet the current expectations.


Impact of Disease Activity on Physical Activity in Patients With Psoriatic Arthritis.
The purpose of this study was to compare physical activity (PA) in a group of patients with psoriatic arthritis (PsA) versus healthy controls and to determine whether the mobility of these patients is affected by disease activity. A group of 52 patients with PsA and 53 controls were included in this case-control study. PA was assessed by accelerometry in both groups and additionally with the International Physical Activity Questionnaire (IPAQ) in patients with PsA. Multiple regression analysis was used to compare PA between groups and to determine the relationship between PA and PsA features, including disease activity, as assessed by the 28-joint Disease Activity Score (DAS28) and the Disease Activity Index for Psoriatic Arthritis (DAPSA) score. In a group of 36 patients, a test-retest study was carried out after 6 months. The time engaged in moderate-to-vigorous physical activity (MVPA) per day, as evaluated by accelerometry, and adjusted by confounders, proved similar in patients with PsA and controls. In patients with PsA, disease activity was inversely related to PA as assessed either by IPAQ or accelerometry. When PA was compared in patients with PsA between the 2 visits, a significant difference in the amount of time doing MVPA was found (42 ± 33 versus 30 ± 22 minutes/day; P = 0.004). Interestingly, in the test-retest study, variations in disease activity over time based on DAPSA scores (r = -0.49, P = 0.002) and DAS28 using the C-reactive protein level (r = -0.4, P = 0.017) were inversely correlated with changes in PA, as determined by accelerometry. Patients with PsA show levels of PA like healthy controls. In patients with PsA, disease activity and PA are inversely correlated and the evaluation of PA by accelerometry is sensitive to changes in disease activity.


Capecitabine as first-line treatment in colorectal cancer. Pooled data from two large, phase III trials.
The oral, tumour-selective fluoropyrimidine capecitabine represents a major new strategy for the treatment of colorectal cancer. Pooled results from two large, multicentre, open-label, phase III studies comparing oral capecitabine (1250 mg/m2 twice daily for 14 days every 3 weeks) with the Mayo Clinic regimen (5-fluorouracil [5-FU] 425 mg/m2 plus leucovorin 20 mg/m2 days 1-5, every 4 weeks) provide information on over 1200 patients receiving first-line chemotherapy for metastatic colorectal cancer. Analysis of all randomised patients demonstrated a significantly superior overall response rate as assessed by the investigator for capecitabine compared with 5-FU/leucovorin (25.7% versus 16.7%, P<0.0002), reinforcing the individual trial results. Median time to disease progression, overall survival and duration of response were equivalent in the two treatment groups. Furthermore, capecitabine showed a superior safety profile compared with 5-FU/leucovorin, with a significantly lower incidence (P<0.001) of diarrhoea, stomatitis, nausea and alopecia, together with a reduced treatment-related hospitalisation rate. In addition, the incidence of neutropenic fever/sepsis was significantly lower in patients receiving capecitabine.


The BCR/ABL hybrid gene.
A DNA region on chromosome 22, designated M-BCR, contains the chromosomal breakpoint of the Philadelphia (Ph) translocation in all Ph positive CML patients studied to date. M-BCR is part of a gene, BCR, oriented with its 5' end towards the centromere of chromosome 22. All of the CML DNAs analysed have a breakpoint within introns of the BCR gene. As a consequence of the Ph translocation the 3' end of the BCR gene has been translocated to chromosome 9, while the 5' part remains on the Ph chromosome. The remaining BCR sequences act as an acceptor for a chromosome 9 gene, the ABL oncogene: the ABL oncogene is fused in a head-to-tail fashion to the chromosome 22 sequences. This genomic configuration results in the transcription of a novel chimeric mRNA consisting of 5' BCR sequences and 3' ABL oncogene sequences. In K562, a cell line derived from a CML patient, and in five CML patients such chimeric BCR/ABL transcripts have been demonstrated. An abnormally sized ABL protein has been detected in the cell line K562 and in leukaemic cells from patients. This protein represents the translational product of the chimeric mRNA. The role of the BCR part of the fusion protein is unknown; it is possible that the BCR moiety could alter the structure of the ABL protein and unmask its tyrosine kinase activity. By analogy with the gag/v-abl polyprotein, the CML-specific BCR/ABL protein might have transforming activity and could play an essential role in the generation and/or maintenance of CML.


Adjusting for global effects in voxel-based morphometry: gray matter decline in normal aging.
Results from studies that have examined age-related changes in gray matter based on structural MRI scans have not always been consistent. Reasons for this variability likely include small or unevenly-distributed samples, different methods for tissue class segmentation and spatial normalization, and the use of different statistical models. Particularly relevant to the latter is the method of adjusting for global (total) gray matter when making inferences about regionally-specific changes. In the current study, we use voxel-based morphometry (VBM) to explore the impact of these methodological choices in assessing age-related changes in gray matter volume in a sample of 420 adults evenly distributed between the ages of 18-77 years. At a broad level, we replicate previous findings, showing age-related gray matter decline in nearly all parts of the brain, with particularly rapid decline in inferior regions of frontal cortex (e.g., insula and left inferior frontal gyrus) and the central sulcus. Segmentation was improved by increasing the number of tissue classes and using less age-biased templates, and registration was improved by using a diffeomorphic flow-based algorithm (DARTEL) rather than a "constrained warp" approach. Importantly, different approaches to adjusting for global effects--not adjusting, Local Covariation, Global Scaling, and Local Scaling--significantly affected regionally-specific estimates of age-related decline, as demonstrated by ranking age effects across anatomical ROIs. Split-half cross-validation showed that, on average, Local Covariation explained a greater proportion of age-related variance across these ROIs than did Global Scaling. Nonetheless, the appropriate choice for global adjustment depends on one's assumptions and specific research questions. More generally, these results emphasize the importance of being explicit about the assumptions underlying key methodological choices made in VBM analyses and the inferences that follow.