Update on Antimicrobial Therapy in Management of Acute Odontogenic Infection in Oral and Maxillofacial Surgery.
This article focuses on the antimicrobial therapy of head and neck infections from odontogenic origin. Odontogenic infections are among the most common infections of the oral cavity. They are sourced primarily from dental caries and periodontal disease (gingivitis and periodontitis). Many odontogenic infections are self-limiting and may drain spontaneously. However, these infections may drain into the anatomic spaces adjacent to the oral cavity and spread along the contiguous facial planes, leading to more serious infections. Antibiotics are an important aspect of care of the patient with an acute odontogenic infection. Antibiotics are not a substitute for definitive surgical management.


Minimum dose requirements of steroid-dependent asthmatic patients for aerosol beclomethasone and oral prednisone.
In 34 steroid-dependent asthma patients who improved markedly during 2 mo of treatment when progressively larger doses of beclomethasone aerosol were added to their oral prednisone regimen, we subsequently reduced both steroids to ascertain the minimum dose of each needed to prevent recurrence of significant asthmatic disability. After 80 wk of follow-up, 15 patients had successfully terminated oral prednisone; 19 were better controlled with a combination of aerosol plus oral steroid than with either drug alone; all patients previously unable to convert to alternate-day prednisone did so successfully during the combined therapy. The minimum effective maintenance dosage varied greatly among these patients-the median values being 2.5 mg prednisone and 1,200 microgram beclomethasone per day. The latter ranged from 200 to 1,8000 microgram. Only 4 patients were satisfactorily controlled without prednisone on 400 microgram beclomethasone per day or less. Seven needed extra intranasal beclomethasone to help control the nasal polyps which worsened after prednisone withdrawal. Suppression of plasma cortisol levels, apparently attributable to the beclomethasone, persisted in most patients, but on the average this was no worse than before commencing this treatment and valuable clinical improvement accrued. There were no other important complications of the regimen. In most of these patients with severe chronic asthma, optimum control of the disease required combined aerosol-oral therapy and maintenance doses of beclomethasone higher than those usually recommended. In some patients, effective control of chronic asthma by beclomethasone treatment may require acceptance of some persisting suppression of adrenal function as a considered risk.


Biometry and spectral domain optical coherence tomography parameters in children with large cupping.
The purpose of this study is to investigate optic nerve head using spectral domain optical coherence tomography (SD-OCT) in children with large cupping. 111 eyes (4-10 years) were divided into three groups according to the cup to disc ratio: group 1, ≤0.3; group 2, 0.4-0.6; and group 3, ≥0.7. The rim area, disc area, average cup to disc ratio, vertical cup to disc ratio, and cup volume were investigated using SD-OCT (Cirrus HD-OCT, Carl Zeiss, Jena, Germany), and the axial length and anterior chamber depth (ACD) were measured by IOL master (IOL master 500, Carl Zeiss, Jena, Germany). Next, we compared ocular biometry and SD-OCT between the three groups. The mean age of group 1 was 6.48 ± 1.42 years, 7.00 ± 1.75 years in group 2, and 6.63 ± 1.82 years in group 3 (p = 0.370). A significant difference was seen in the spherical equivalent between the groups (p = 0.001). Group 2 had the most myopic refractive errors. As the cup to disc ratio increases, disc area, average cup to disc ratio, vertical cup to disc ratio, and cup volume increase significantly. When the results of ocular biometry and SD-OCT are adjusted for axial length, only disc area showed a significant correlation with cup to disc ratio (ACD: p = 0.473, rim area: p = 0.639, disc area: p = 0.005, and cup volume: p = 0.325). Axial length is the key factor determining disc size, which in turn is important for determining cup to disc ratio. Normal children with large cupping should be examined for axial length, myopic refractive errors, and disc size.


Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade.
MicroRNAs (miRNAs) are noncoding small RNAs that control gene expression at the posttranscriptional level. Some dysregulated miRNAs have been shown to play important roles in epileptogenesis. The aim of this study was to determine if miR-199a-5p regulates seizures and seizure damage by targeting the antiapoptotic protein silent information regulator 1 (SIRT1). Hippocampal expression levels of miR-199a-5p, SIRT1, and acetylated p53 were quantified by quantitative real-time polymerase chain reaction (RT-PCR) and Western blotting in the acute, latent, and chronic stages of epilepsy in a rat lithium-pilocarpine epilepsy model. Silencing of miR-199a-5p expression in vivo was achieved by intracerebroventricular injection of antagomirs. The effects of targeting miR-199a-5p and SIRT1 protein on seizure and epileptic damage post-status epilepticus were assessed by electroencephalography (EEG) and immunohistochemistry, respectively. miR-199a-5p expression was up-regulated, SIRT1 levels were decreased, and neuron loss and apoptosis were induced in epilepsy model rats compared with normal controls, as determined by up-regulation of acetylated p53 and cleaved caspase-3 expression. In vivo knockdown of miR-199a-5p by an antagomir alleviated the seizure-like EEG findings and protected against neuron damage, in accordance with up-regulation of SIRT1 and subsequent deacetylation of p53. Furthermore, the seizure-suppressing effect of the antagomir was partly SIRT1 dependent. The results of this study suggest that silencing of miR-199a-5p exerts a seizure-suppressing effect in rats, and that SIRT1 is a direct target of miR-199a-5p in the hippocampus. The effect of miR-199a-5p on seizures and seizure damage is mediated via down-regulation of SIRT1. The miR-199a-5p/SIRT1 pathway may thus represent a potential target for the prevention and treatment of epilepsy and epileptic damage.


Auricular chondritis and thrombotic microangiopathy: an unusual combination revealing systemic lupus erythematosus.
Thrombotic microangiopathy is a severe disorder, which is a cause of stroke in young patients. Etiologic investigations are mandatory to diagnose underlying disease. Systemic lupus erythematosus is one of the diseases, which can be associated with thrombotic microangiopathy. Although lupus diagnosis is usually easy, relying on characteristic clinical manifestations, rare symptoms can be misinterpreted. We report here a case of polychondritis, which was the first manifestation of a lupus-associated thrombotic microangiopathy.


Forkhead box protein A1 confers resistance to transforming growth factor-β-induced apoptosis in breast cancer cells through inhibition of Smad3 nuclear translocation.
Transforming growth factor-β (TGF-β) induces apoptosis of normal epithelial cells, such as mammary epithelium. Although breast cancer progression associates with acquisition of resistance to TGF-β-induced apoptosis, the molecular mechanisms underlying this resistance are largely unknown. Here, we show that forkhead box protein A1 (FOXA1), which is known as a pioneer transcription factor, suppresses TGF-β-induced apoptosis of estrogen receptor-positive breast cancer cells. FOXA1 is found to inhibit nuclear translocation of Smad3, a key transcription factor downstream of TGF-β signaling, through suppression of the binding of Smad3 to the nuclear import receptor importin7. Furthermore, RNA sequencing analyses show that knockdown of FOXA1 upregulates Smad3-mediated proapoptotic gene expression. These results demonstrate that FOXA1 as a potent survival factor that suppresses TGF-β-induced apoptosis by inhibiting Smad3 signaling in estrogen receptor-positive breast cancer cells. Thus, we provide evidence for the first time that FOXA1 localizing to the cytoplasm negatively regulates Smad3-induced apoptosis in TGF-β-mediated signal transduction.


Defibrillation by general practitioners.
To investigate the mode of cardiac arrest in patients with acute myocardial infarction attended by general practitioners, and the effectiveness of early defibrillation. Retrospective observational study. British general practice. General practitioners equipped with defibrillators by the British Heart Foundation. Cardiac rhythm when first monitored, response to defibrillation assessed by survival to reach hospital alive and survival to hospital discharge. Defibrillation and standard cardiopulmonary resuscitation in patients with cardiac arrest complicating acute myocardial infarction attended by British general practitioners. When a doctor equipped with a defibrillator witnessed an arrest or was able to initiate resuscitation within 4 min of the patient collapsing, 90% of patients were found to have developed a rhythm likely to respond to a defibrillatory shock. Defibrillation under these circumstances was very successful with more than 70% of patients subsequently admitted to hospital alive and approximately 60% surviving to be discharged alive. When the doctor commenced resuscitation later, fewer patients were found to have rhythms likely to be responsive to a DC shock. A greater proportion was in asystole and resuscitation was less frequently successful under these circumstances. When the arrest occurred in the doctor's surgery, 85% of patients were admitted to hospital alive and three quarters survived to hospital discharge. All those who provide the initial care for this vulnerable group of patients should be equipped with defibrillators. The more widespread deployment of defibrillators in the community may be a successful strategy for reducing unnecessary deaths from coronary heart disease.


Echocardiographic evaluation after blunt trauma of the chest.
We studied by cross-sectional echocardiography 27 consecutive subjects with severe blunt trauma of the chest. Inadequate studies were obtained in 6 subjects (22%). Abnormal, unexpected findings were noted in 6 of the remaining 21 subjects (29%): moderate size pericardial effusion in 3 and focal ventricular dysfunction in 4. No patient with echocardiographic abnormality was suspected clinically of having heart damage. One of the 6 subjects with abnormal echocardiographic findings died from sudden asystole 6 days later. The remaining 5 patients had normal echocardiographic findings when studied 1 week after trauma. This study shows that, following blunt chest trauma, cross-sectional echocardiography can detect unsuspected myocardial and pericardial damage in an appreciable number of patients. Ultrasonic examination of the heart complements other investigations in establishing the diagnosis of heart damage and may help improve the care of patients with heart trauma.


Pit and Fissure Sealant Retention Following Air Abrasion Preparation with Bioactive Glass and Aluminum Oxide Particles.
Alumina air abrasion is an alternative for acid-etch technique for tooth preparation before placement of a fissure sealant. The aim of this study was to compare the retention of sealants placed subsequent to air abrasion with alumina and bioactive glass (BAG) particles. Sixty-two 6-12 year old children were included in this study. Using a halfmouth design, the fissures were prepared using air abrasion with alumina particles on randomly assigned permanent mandibular or/and maxillary first molars on one side of the mouth (Group 1) and air abrasion with BAG on the contralateral side of the mouth (Group 2). Sealants were applied on 180 teeth, and were scored as missing, partially retained, and completely retained after three, six, nine and 12 months. Data were analyzed using Friedman and Wilcoxon tests (α=0.05). Sealant retention rates in the alumina group were higher than those in the BAG group at all time periods (P<0.001). Sealant retention after air abrasion with alumina particles was higher than BAG over 12 months.


Self-Waveguide Single-Benzene Organic Crystal with Ultralow-Temperature Elasticity as a Potential Flexible Material.
With the increasing popularity and burgeoning progress of space technology, the development of ultralow-temperature flexible functional materials is a great challenge. Herein, we report a highly emissive organic crystal combining ultralow-temperature elasticity and self-waveguide properties (when a crystal is excited, it emits light from itself, which travels through the crystal to the other end) based on a simple single-benzene emitter. This crystal displayed excellent elastic bending ability in liquid nitrogen (LN). Preliminary experiments on optical waveguiding in the bent crystal demonstrated that the light generated by the crystal itself could be confined and propagated within the crystal body between 170 and -196 °C. These results not only suggest a guideline for designing functional organic crystals with ultralow-temperature elasticity but also expand the application region of flexible materials to extreme environments, such as space technology.


Glomerular C3d as a novel prognostic marker for renal vasculitis.
Pauci-immune necrotizing crescentic glomerulonephritis is the histologic substrate of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Several studies in animal models have demonstrated the crucial role of complement activation in the pathogenesis of ANCA-associated vasculitis, but only small series have analyzed the prognostic implications of complement glomerular deposits. This study aimed to assess the clinical and prognostic implications of C3d- and C4d-positive glomerular staining in renal vasculitis. Eighty-five patients with a diagnosis of pauci-immune necrotizing crescentic glomerulonephritis were included in the study. C3d and C4d were analyzed by immunohistochemical staining using a polyclonal antibody. The primary predictors were glomerular C3d- and C4d-positive staining. The primary end point was the cumulative percentage of patients who developed end-stage renal disease. Glomerular staining for C3d and C4d was observed in 42 (49.4%) of 85 biopsies and 38 (44.7%) of 85 biopsies, respectively. C3d-positive staining was associated with the severity of renal impairment and with a lower response rate to treatment (P=.003 and P=.04, respectively). Renal survival at 2 and 5 years was 60.9% and 51.8% in C3d-positive patients compared with 87.7% and 78.9% in C3d-negative patients (P=.04). C4d-positive staining did not show any impact in renal outcome. When adjusted by renal function and other histologic parameters, C3d staining remained as an independent predictor for renal survival (hazard ratio, 2.5; 95% confidence interval, 1.1-5.7; P=.03). Therefore, this study demonstrates that C3d-positive glomerular staining is an independent risk factor for the development of end-stage renal disease in ANCA-associated renal vasculitis.


Characteristic of spontaneous intraperitoneal cysts in golden hamsters and European hamsters.
Epidemiological study of 340 Golden hamsters and 200 European hamsters bred as laboratory animals and necropsied between 1985 and 1989 in our facility (affiliation 2) revealed high incidence of spontaneous cysts. The incidence was in general higher in European (26 to 62%) than Golden hamsters (0 to 15%). The cysts, of different sizes, were localized first of all in the liver, and secondly (in European hamsters only), in the caecum wall. Light microscopic and electron microscopic examinations showed that the cysts are lined by flattened to cuboidal epithelial cells which, on their surface, have microvilli of different lengths and underneath a continuous basement membrane. These examinations lead further to the interpretation of the liver cysts as cystic distensions of the bile ducts. The cysts in the caecum wall could be interpreted as dilatations of the lymphatic vessels. As to the etiology, which remains unclear, several hypotheses are discussed.


Network pharmacology and molecular docking combined with widely targeted metabolomics to elucidate the potential compounds and targets of Euphorbia helioscopia seeds for the treatment of pulmonary fibrosis.
The whole herb of Euphorbia helioscopia has been traditionally used for treating pulmonary tuberculosis, malaria, warts, lung cancer and bacillary dysentery for a long time in China. However, E. helioscopia seeds are often discarded and its medicinal value is often ignored, resulting in a waste of resources. In this work, widely targeted metabolomics based on UPLC-ESI-QTRAP-MS/MS methods and metware database (MWDB) were firstly used to identify the chemical compositions of EHS. Besides, network pharmacology, molecular docking and molecular dynamics simulation were performed for elucidating the potential compounds and targets of E. helioscopia seeds for the treatment of pulmonary fibrosis via common database (like TCMSP, Genecards, DAVID, STRING) and common software (like Sybyl, Cytoscape, Pymol and Schrödinger). The results of widely targeted metabolomics showed 231 compounds including 12 categories were identified. The highest content compositions are lipids (33.89%) followed by amino acids and derivatives (21.78%), nucleotides and derivatives (15.73%), as well as the content of functional ingredients like phenolic acids (7.33%), alkaloids (7.03%) and flavonoids (4.51%) are relatively high. Besides, the results of network pharmacology and molecular docking showed that EHS presented anti-pulmonary fibrosis medicinal value through multi-ingredients, multi-targets and multi-pathways approach. Key ingredients including 9-Hydroxy-12-oxo-15(Z)-octadecenoic acid, Nordihydrocapsiate, 1-O-Salicyl-d-glucose, 9-(Arabinosyl)hypoxanthine, Xanthosine and Galangin-7-O-glucoside. Key targets including SRC, HSP90AA1, AKT1, EGFR, JUN, EP300 and VEGFA, and key signaling pathways mainly related to AGE-RAGE, EGFR tyrosine kinase inhibitor resistance, VEGF and HIF-1 signaling pathway. Molecular dynamics simulation showed that HSP90AA1 and 9-Hydroxy-12-oxo-15(Z)-octadecenoic complex (with the highest docking score) have a stable combination effect. In conclusion, this study revealed the chemical compositions of EHS and its anti-pulmonary fibrosis medicinal effect for the first time, it will provide scientific insight for the development of EHS as medicinal resource.


Locally elevated leukemia inhibitory factor in the inflamed fallopian tube resembles that found in tubal pregnancy.
To investigate the association between the expressions of leukemia inhibitory factor and the occurrence of tubal pregnancy. Prospective observational study. University-based obstetrics and gynecology hospital. Thirty women undergoing salpingectomy for tubal pregnancy and 30 nonpregnant patients with benign uterine or appendix disease. Oviduct tissues with ectopic gestation were separated into implantation sites and nonimplantation sites. Samples of ampullary fallopian tubes during midsecretory phase were collected as control groups. Immunohistochemical and Western blot analysis were performed. The differences of leukemia inhibitory factor expression between the implantation and nonimplantation sites of oviduct tissues and the normal and chronically inflamed fallopian tubes. The expression of leukemia inhibitory factor in the implantation group is significantly higher than that in the nonimplantation group or in the normal group. A statistically significant difference was also found for leukemia inhibitory factor between the chronic inflammation group and the normal group by Western blot analysis but no difference between the chronic inflammation group and the implantation group or the nonimplantation group. Leukemia inhibitory factor might be one of the reasons that cause patients with salpingitis to be more susceptible to tubal pregnancy and might be involved in the implantation process of tubal pregnancy.


Effect of sample density in prompt γ-ray analysis.
A high-accuracy analytical method is broadly required to obtain reliable research results. Thus, prompt γ-ray analysis (PGA), one of the most accurate non-destructive analytical methods, has been employed in various fields. However, the measurement accuracy of PGA is also known to degrade in hydrogenous samples. The degradation is caused by variation in the measurement sensitivity (counts per milligram) following the change in neutron energy due to scattering with hydrogen nucleus. Number of scatterings is well known to depend on the hydrogen content in a sample. However, considering multiple scatterings, hydrogen density, which has not been taken into account as yet, may also lead to the accuracy degradation. Here, we show the effect of the hydrogen density in PGA by evaluating the measurement sensitivity of samples with the same hydrogen content and different densities. We find that the measurement sensitivity varies by more than 30% depending on the hydrogen density even at the same hydrogen content. The variation is a particularly serious problem for PGA requiring a few percent accuracy in most cases. Additionally, although the variation is apparently observed in hydrogenous samples, the similar phenomenon can occur in other nuclides with a large scattering cross section; it may affect nuclear cross-section measurements using neutrons in such fields as astrophysics and nuclear energy.


Sutureless bioprosthesis for aortic valve replacement: Surgical and clinical outcomes.
Aortic valve stenosis is the most common adult valve disease in industrialized countries. The aging population and the increase in comorbidities urge the development of safer alternatives to the current surgical treatment. Sutureless bioprosthesis has shown promising results, especially in complex procedures and in patients requiring concomitant surgeries. Assess the clinical and hemodynamic performance, safety, and durability of the Perceval® prosthetic valve. This single-center retrospective longitudinal cohort study collected data from all adult patients with aortic valve disease who underwent aortic valve replacement with a Perceval® prosthetic valve between February 2015 and October 2020. Of the 196 patients included (mean age 77.20 ± 5.08 years; 45.4% female; mean EuroSCORE II 2.91 ± 2.20%), the majority had aortic stenosis. Overall mean cross-clamp and cardiopulmonary bypass times were 33.31 ± 14.09 min and 45.55 ± 19.04 min, respectively. Mean intensive care unit and hospital stay were 3.32 ± 3.24 days and 7.70 ± 5.82 days, respectively. Procedural success was 98.99%, as two explants occurred. Four valves were reimplanted due to intraoperative misplacement. Mean transvalvular gradients were 7.82 ± 3.62 mmHg. Pacemaker implantation occurred in 12.8% of patients, new-onset atrial fibrillation in 21.9% and renal replacement support was necessary for 3.1%. Early mortality was 2.0%. We report no structural valve deterioration, strokes, or endocarditis, and one successfully treated valve thrombosis. Our study confirms the excellent clinical and hemodynamic performance and safety of a truly sutureless aortic valve, up to a 5-year follow-up. These results were consistent in isolated and concomitant interventions, solidifying this device as a viable option for the treatment of isolated aortic valve disease.


Structural and functional analyses of Pcal_0917, an α-glucosidase from hyperthermophilic archaeon Pyrobaculum calidifontis.
Genome analysis of Pyrobaculum calidifontis revealed the presence of α-glucosidase (Pcal_0917) gene. Structural analysis affirmed the presence of signature sequences of Type II α-glucosidases in Pcal_0917. We have heterologously expressed the gene and produced recombinant Pcal_0917 in Escherichia coli. Biochemical characteristics of the recombinant enzyme resembled to that of Type I α-glucosidases, instead of Type II. Recombinant Pcal_0917 existed in a tetrameric form in solution and displayed highest activity at 95 °C and pH 6.0, independent of any metal ions. A short heat-treatment at 90 °C resulted in a 35 % increase in enzyme activity. A slight structural shift was observed by CD spectrometry at this temperature. Half-life of the enzyme was >7 h at 90 °C. Pcal_0917 exhibited apparent Vmax values of 1190 ± 5 and 3.9 ± 0.1 U/mg against p-nitrophenyl α-D-glucopyranoside and maltose, respectively. To the best of our knowledge, Pcal_0917 displayed the highest ever reported p-nitrophenyl α-D-glucopyranosidase activity among the characterized counterparts. Moreover, Pcal_0917 displayed transglycosylation activity in addition to α-glucosidase activity. Furthermore, in combination with α-amylase, Pcal_0917 was capable of producing glucose syrup from starch with >40 % glucose content. These properties make Pcal_0917 a potential candidate for starch hydrolyzing industry.


The Comprehensive Rheumatologic Assessment of Frailty (CRAF): development and validation of a multidimensional frailty screening tool in patients with rheumatoid arthritis.
Frailty is a topic that is gaining more and more interest in rheumatology. The aims of this study were to develop and preliminarily validate a frailty index dedicated to rheumatoid arthritis (RA) called the Comprehensive Rheumatologic Assessment of Frailty (CRAF). Ten major frailty domains of CRAF were identified: nutritional status, weakness, falls, comorbidity, polypharmacy, social activity, pain, fatigue, physical function, and depression. Convergent validity was evaluated correlating the scores of the CRAF with the Frailty Instrument for Primary Care of the Survey of Health, Ageing and Retirement in Europe (SHARE-FI). Discriminant validity was assessed using receiver operating characteristic (ROC) curve analysis. Multivariate logistic regression model procedure was used to assess the relative contribution of the individual determinants on the CRAF. Among the 219 RA patients, 79 (36.1%) were defined as non-frail (CRAF ≤0.12), 63 (28.8%) mild frail (0.12 <CRAF ≤0.24), 34 (15.5%) moderate frail (0.24 <CRAF ≤0.36), and 43 (19.6%) severe frail (CRAF >0.36). In testing for convergent validity, a significant correlation was found between CRAF and SHARE-FI (p <0.0001). The discriminatory power of CRAF was higher than those of the SHARE-FI (difference between areas under the ROC curves=0.0853± 0.0282. Variables associated with frailty at the multivariate analysis were advanced age and high disease activity (both at p<0.0001). The CRAF demonstrated a robust validity and good discriminant accuracy. Implementation of the frailty assessment into the routine rheumatological practice could represent a major advance in RA care.


A single ascending dose study of single-stranded oligodeoxyribonucleotide RO7062931 in Chinese healthy volunteers.
RO7062931 is an N-acetylgalactosamine (GalNAc)-conjugated single-stranded oligodeoxyribonucleotide complementary to hepatitis B virus RNA. GalNAc conjugation targets the liver through the asialoglycoprotein receptor (ASGPR). This phase I single ascending dose (SAD) study evaluated the safety, tolerability, and pharmacokinetics of RO7062931 in Chinese healthy volunteers. There were four SAD cohorts (0.3, 1.0, 2.0, and 4.0 mg/kg), in each of which healthy volunteers were randomized to a single subcutaneous (s.c.) injection of RO7062931 or matching placebo in a 4:1 ratio. Placebo recipients were pooled as one treatment group for safety assessments. A total of 41 healthy Chinese men received one dose of RO7062931 (n = 33) or placebo (n = 8) and completed the study (85-day follow-up). Adverse events (AEs) were reported in 22 of 33 (66.6%) RO7062931 recipients (n = 80 treatment-related) and seven of eight (87.5%) placebo recipients (n = 1 treatment-related). Apart from two moderate-intensity AEs, all AEs were mild. The most frequently reported AEs were influenza, injection-related reactions, and headache. Dose-proportional increases in plasma RO7062931 exposure were observed between the 0.3 and 1.0 mg/kg doses, whereas a supra-dose-proportional increase occurred at doses greater than or equal to 2.0 mg/kg, along with a marked increase in urinary excretion. Single s.c. dose of RO7062931 up to 4.0 mg/kg were safe and well-tolerated in healthy Chinese volunteers. Pharmacokinetic data suggested that ASGPR saturation had commenced between doses of 2.0 and 4.0 mg/kg. Results were broadly consistent with observations in primarily White subjects in the global first-in-human study of RO7062931.


Effect of repeated instillation of interstitial cystitis urine on the rabbit urinary bladder.
One theory for the etiology of interstitial cystitis (IC) proposes toxic substances in the urine. This hypothesis was tested in our laboratory by infusing urine into the bladders of rabbits twice weekly for six weeks. For the first study rabbits were treated by one-hour biweekly intravesical exposure to urine from a symptomatic interstitial cystitis patient, a normal volunteer, or physiologic saline. For the second study, animals were exposed to both a high and a low molecular weight fraction of urine pooled from 7 interstitial cystitis patients, 7 normal female volunteers, and physiologic saline. At the end of six weeks the animals were cystoscoped and the bladder was removed the following day for histologic and contractile studies. Post-distention glomerulations were observed in 3 of the 4 whole IC urine-treated animals and an ulcer identical to the classic "Hunner's ulcer" was seen in one of these animals. Post-distention petechial hemorrhages were also noted in all 5 of the high molecular weight IC urine-treated animals but in none of the others, suggesting a difference between IC and normal urine. These IC urine-treated groups also showed the greatest degree of histologic changes including edema and plasma cell infiltrates in the lamina propria, submucosa and perivascular tissue. However, there was no statistically significant difference in bladder capacity, micturition patterns, or contractile response of bladder strips. These results indicate that there are substances with nominal molecular weight greater than 10 kD in interstitial cystitis urine that induce changes in the rabbit bladder that resemble bladders of interstitial cystitis patients.


Disparate impacts on online information access during the Covid-19 pandemic.
The COVID-19 pandemic has stimulated important changes in online information access as digital engagement became necessary to meet the demand for health, economic, and educational resources. Our analysis of 55 billion everyday web search interactions during the pandemic across 25,150 US ZIP codes reveals that the extent to which different communities of internet users enlist digital resources varies based on socioeconomic and environmental factors. For example, we find that ZIP codes with lower income intensified their access to health information to a smaller extent than ZIP codes with higher income. We show that ZIP codes with higher proportions of Black or Hispanic residents intensified their access to unemployment resources to a greater extent, while revealing patterns of unemployment site visits unseen by the claims data. Such differences frame important questions on the relationship between differential information search behaviors and the downstream real-world implications on more and less advantaged populations.


Characteristics of recovery of drawing ability in left and right brain-damaged patients.
Drawings of a "person" were obtained from 21 patients with left brain damage (LBD) and 13 patients with right brain damage (RBD) at hospital discharge and 1 month postdischarge, corresponding to 2-4 and 6-8 weeks postonset, respectively. Early LBD drawings were simplistic and often incoherent. Most were placed in the upper left quadrant of the page. RBD drawings were scattered, fragmented, and elaborately detailed. Many showed evidence of left-sided neglect. The resolution of drawing disability also differed between the two groups: LBD subjects recovered drawing abilities more rapidly and more completely than RBD subjects. These differences in drawing characteristics and in the resolution of drawing disability were discernable for experienced neuropsychologists.


Association studies between chromosomal regions 1q21.3, 5q21.3, 14q21.2 and 17q21.31 and numbers of children in Poland.
Number of children is an important human trait and studies have indicated associations with single-nucleotide polymorphisms (SNPs). Aim: to give further evidence for four associations using a large sample of Polish subjects. Data from the POPULOUS genetic database was provided from anonymous, healthy, unrelated, Polish volunteers of both sexes (N = 5760). SNPs (n = 173) studied: (a) 69 from the chromosome 17 H1/H2 inversion; (b) six from 1q21.3, 5q21.3 and 14q21.2; and (c) 98 random negative controls. Zero-inflated negative-binomial regression (z.i.) was performed (0-3 numbers of children per individual (NCI) set as non-events; adjustors: year of birth, sex). Significance level p = 0.05 with Bonferroni correction. Statistically-significant differences (with data from both sexes combined) were obtained from highly-linked inversion SNPs: representative rs12373123 gave means: homozygotes TT: 2.31 NCI (n = 1418); heterozygotes CT: 2.35 NCI (n = 554); homozygotes CC: 2.44 NCI (n = 43) (genotype p = 0.01; TTvs.CC p = 0.004; CTvs.CC p = 0.009). (Male data alone gave similar results.) Recessive modeling indicated that H2-homozygotes had 0.118 more children than H1-homozygotes + heterozygotes (z.i.-count estimates ± standard errors: CT, - 0.508 ± 0.194; TT, - 0.557 ± 0.191). The non-over-dispersed count model detected no interactions: of importance there was no significant interaction with age. No positive results were obtained from negative-control SNPs or (b). Conclusions: association between the H1/H2 inversion and numbers of children (previously reported in Iceland) has been confirmed, albeit using a different statistical model. One limitation is the small amount of data, despite initially ~ 6000 subjects. Causal studies require further investigation.


Symmetric bilateral changes in dopamine release from the caudate nuclei of the cat induced by unilateral nigral application of glycine and GABA-related compounds.
The release of [3H]DA synthesized from [3H]tyrosine was estimated in the two caudate nuclei (CN) during the unilateral nigral application of glycine and GABA-related compounds in 'encéphale isolé' cats using push-pull cannulae. Glycine (10(-5) M) reduced the release of [3H]DA in both CN and these effects were antagonized by strychnine (10(-5) M). A decrease in [3H]DA release was also seen in both CN during the unilateral nigral application of diazepam (10(-5) M). In contrast, muscimol (10(-6) M) and GABA (10(-5) M) stimulated [3H]DA release on both sides. The effect of GABA was blocked by picrotoxin (10(-5) M). Picrotoxin alone stimulated the release of [3H]DA in the ipsilateral CN and was without effect in the contralateral side. Bicuculline (10(-5) M) stimulated [3H]DA release only in the contralateral CN. A symmetric increase in [3H]DA release in both CN was also observed during the unilateral nigral application of potassium (30 mM). A model involving a facilitatory polysynaptic pathway originating from the substantia nigra (SN) and acting presynaptically on ther terminals of the contralateral DA neurons is proposed to explain the changes in [3H]DA release induced in the contralateral CN in these various situations. The results are discussed taking into account previous data on the reciprocal control of the two dopaminergic pathways induced by the unilateral nigral application of dopaminergic drugs.


A pharmacokinetic analysis of posaconazole oral suspension in the serum and alveolar compartment of lung transplant recipients.
Invasive fungal infections cause significant morbidity and mortality after lung transplantation. Fungal prophylaxis following lung transplantation is not standardised, with transplant centres utilising a variety of regimens. Posaconazole is a broad-spectrum antifungal triazole that requires further investigation within the setting of lung transplantation. This prospective, single-centre, observational study explored the pharmacokinetics of posaconazole oral suspension (POS) in the early perioperative period following lung transplantation in 26 patients. Organ recipients were scheduled to receive 400mg POS twice daily for 6 weeks as primary antifungal prophylaxis. Therapeutic drug monitoring (TDM) of serum posaconazole levels was performed in accordance with local clinical protocols. Bronchoalveolar lavage fluid (BALF) was sampled during routine bronchoscopies. Posaconazole levels were measured both in serum and BALF using mass spectrometry. Posaconazole levels were highly variable within lung transplant recipients during the perioperative period and did not achieve 'steady-state'. Serum posaconazole concentrations positively correlated with levels within the BALF (r=0.5527; P=0.0105). Of the 26 patients, 10 failed to complete the study for multiple reasons and so the trial was terminated early. Unlike study findings in stable recipients, serum posaconazole levels rarely achieved steady-state in the perioperative period; however, they do reflect the concentrations within the airways of newly transplanted lungs. The role of POS as primary prophylaxis in the perioperative period is uncertain, but if used TDM may be helpful for determining attainment of therapeutic levels.


[Immune tolerance and active suppression in oncology. Immunological principles and therapeutic options].
In view of the fact that conventional therapies continue to yield unsatisfactory results, a therapy based on tumor immunology is of increasing interest. The results of some clinical immunotherapy studies have shown that the mechanism of tolerance induced by tumors is of critical importance. There are several mechanisms to be recognized by the tumor, such asanergy, immunosuppressive cytokines, immunodeviation and dysfunction of the T-lymphocytes. The so-called tumor escape mechanisms, which often refer to molecules that contribute to the recognition of antigens and activation of specific T cells, also lead to immunological tolerance. Immunotherapies based on gene-modified tumor cells, peptide-pulsed antigen presenting cells (APC) or antibody therapies to activate immune cells, have a fairly reasonable chance of being successful if immunological tolerance can be understood and influenced. Time will show if combining all sorts of immunotherapy that are based on different strategies, can induce tumor rejection more efficiently. In the scope of multimodal therapy concepts, immunotherapy only seems to be reasonable if the immunological tolerance that was induced by tumors can be overcome. Immunological markers are of crucial importance, not only for the therapy but also for the diagnosis and prognosis of cancer patients.


Analysis of olive allergens.
Olive pollen is one of the most important causes of seasonal respiratory allergy in Mediterranean countries, where this tree is intensely cultivated. Besides this, some cases of contact dermatitis and food allergy to the olive fruit and olive oil have been also described. Several scientific studies dealing with olive allergens has been reported, being the information available about them constantly increasing. Up to date, twelve allergens have been identified in olive pollen while just one allergen has been identified in olive fruit. This review article describes considerations about allergen extraction and production, also describing the different methodologies employed in the physicochemical and immunological characterization of olive allergens. Finally, a revision of the most relevant studies in the analysis of both olive pollen and olive fruit allergens is carried out.


Severe impairment battery. A neuropsychological test for severely demented patients.
Patients with progressive dementia invariably evolve to a stage where they can no longer be tested by standard neuropsychological tests. We studied the use of the Severe Impairment Battery (SIB) in such patients. Case series. Geriatric long-term facility. Sixty-nine patients who met the criteria of the Diagnostic and Statistical Manual for Mental Disorders, Revised Third Edition, for dementia were selected. The diagnosis of probable Alzheimer's disease was established according to the guidelines suggested by the National Institute of Neurologic and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association. There were 18 men and 51 women. The mean age of the population was 82.99 +/- 5.66 years. The mean Mini-Mental State Examination (MMSE) score was 10.71 +/- 6.14. To characterize the cognitive profile and evolution of severely demented patients by means of the SIB. The mean score on the SIB was 92.52 +/- 31.92, with a possible maximum of 133 points. Subgroups of patients with the most severe degree of dementia (MMSE scores of 0 to 5 and 6 to 11) showed significant differences in their scores on the SIB. In contrast, no differences were found between subgroups with MMSE scores of 6 to 11, 12 to 17, and greater than 17. Fifteen patients who had MMSE scores of less than 6 had SIB scores ranging from 7 to 81. All cognitive domains showed a deterioration across the four severity groups as determined by the MMSE scores and also during a longitudinal study performed on 26 patients. Our study indicates that the SIB is useful for the neuropsychological evaluation of severely demented patients and for their follow-up.


Recombinant live virus vaccines.
Many successful vaccines are based on live attenuated viruses. An attractive idea is to genetically engineer these live attenuated vaccines so that they express protective antigens from other pathogens. Vaccinia virus, the smallpox vaccine, can be considered as the prototype for this sort of approach. Over one hundred examples of vaccinia virus recombinants are recorded in the literature and many of these have been shown to protect animals against challenge with the appropriate pathogen. Several problems need to be overcome before these recombinants can be tested in humans; however, the potential advantages of this approach ensure vigorous study of these difficulties. Vaccinia virus recombinants can also be used to dissect the cell-mediated and humoral immune responses to pathogens, and have thus proved to be valuable laboratory tools. However, it remains to be seen if they will also be used in other than experimental situations.


Effect of Bdellovibrio bacteriovorus infection on the phosphoenolpyruvate:sugar phosphotransferase system in Escherichia coli: evidence for activation of cytoplasmic proteolysis.
Intact cells of Bdellovibrio bacteriovorus strain 109J were found to be incapable of taking up 14C-methyl alpha-glucoside, mannitol or fructose, and extracts derived from these cells exhibited negligible activities of the protein components of the phosphoenolpyruvate:sugar phosphotransferase system (PTS). Escherichia coli strain ML35 cells exhibited high in vivo sugar uptake activities that were progressively lost over a period of 2 h at 30 degrees C following the entry of B. bacteriovorus into the periplasm of E. coli. In vitro complementation assays revealed that the E. coli PTS enzymes, enzyme I, HPr, and the glucose- and mannitol-specific enzymes II, were all lost almost in parallel with the disappearance of uptake activity. Thus, loss of activity in vivo was not due to membrane leakiness, energy depletion, or preferential inhibition or inactivation of any one protein component of the PTS. Instead, loss of PTS activity was attributed to digestion of the protein constituents of the system by proteases present in the cytoplasm of the host cell after bdellovibrio entry. Both ethylenediaminetetraacetate and phenylmethylsulphonyl fluoride partially protected against inactivation in vitro, and the two inhibitors together gave full protection, suggesting that both metallo- and seryl-proteases were responsible for the inactivation. Protease activity increased progressively with time following bdellovibrio entry and appeared to degrade the E. coli PTS enzymes in vivo. Preliminary evidence suggested that the proteases responsible for PTS enzyme degradation may be encoded by the B. bacteriovorus chromosome.


Gate-Tunable Plasmon-Induced Transparency Modulator Based on Stub-Resonator Waveguide with Epsilon-Near-Zero Materials.
We demonstrate an electrically tunable ultracompact plasmonic modulator with large modulation strength (>10 dB) and a small footprint (~1 μm in length) via plasmon-induced transparency (PIT) configuration. The modulator based on a metal-oxide-semiconductor (MOS) slot waveguide structure consists of two stubs embedded on the same side of a bus waveguide forming a coupled system. Heavily n-doped indium tin oxide (ITO) is used as the semiconductor in the MOS waveguide. A large modulation strength is realized due to the formation of the epsilon-near-zero (ENZ) layer at the ITO-oxide interface at the wavelength of the modulated signal. Numerical simulation results reveal that such a significant modulation can be achieved with a small applied voltage of ~3V. This result shows promise in developing nanoscale modulators for next generation compact photonic/plasmonic integrated circuits.


The intrinsic and extrinsic elements regulating inflammation.
Inflammation is a sophisticated biological tissue response to both extrinsic and intrinsic stimuli. Although the pathological aspects of inflammation are well appreciated, there are still rooms for understanding the physiological functions of the inflammation. Recent studies have focused on mechanisms, context and the role of physiological inflammation. Besides, there have been progress in the comprehension of commensal microbiota, immunometabolism, cancer and intracellular signaling events' roles that impact on the regulation of inflammation. Despite the fact that inflammatory responses are vital through tissue damage, understanding the mechanisms to turn off the finished or unnecessary inflammation is crucial for restoring homeostasis. Inflammation seems to be a smart process that acts like two edges of a sword, meaning that it has both protective and deleterious consequences. Knowing both edges and the regulation processes will help the future understanding and therapy for various diseases.


Sex and haemodynamics in pulmonary arterial hypertension.
Female sex is a risk factor for pulmonary arterial hypertension (PAH), yet females have better survival than males. We sought to determine if sex was associated with baseline haemodynamics in subjects with PAH, and whether age modified these relationships. We conducted a pooled analysis from 11 randomised trials submitted to the US Food and Drug Administration. The study sample included 1211 subjects with idiopathic PAH, 25% of whom were males, and 489 subjects with connective tissue disease-associated PAH, 13% of whom were males. After multivariable adjustment, right atrial pressure was 1.36 mmHg higher (95% CI 0.44-2.27, p=0.004), cardiac index was -0.14 L · min(-1) · m(-2) lower (95% CI -0.23-0.04, p=0.01) and pulmonary vascular resistance was 1.23 Wood units higher (95% CI 0.18-2.27, p=0.02) in males compared with females. Younger males had 5.43 mmHg (95% CI 2.20-8.66, p=0.001) higher mean pulmonary arterial pressures than younger females, but these relationships were attenuated after age 45 years. In the subgroup of connective tissue disease-associated PAH, males may have had higher right atrial pressure. These findings implicate age as a modifier and provide further evidence of sexual dimorphism in PAH.


Hand-held toy squeaker during carotid endarterectomy in the awake patient.
A toy squeaker held by the patient in the contralateral hand is used to monitor cerebral circulation during carotid endarterectomy. Regional anesthesia--cervical plexus block--allowed the patient to cooperate and give useful information, especially during the crucial period of test clamping. In a series of 300 cases, during a period of five years, it was instrumental in avoiding brain damage in 6% of the cases.


Brain region-dependent differential expression of alpha-synuclein.
α-Synuclein, the major constituent of Lewy bodies (LBs), is normally expressed in presynapses and is involved in synaptic function. Abnormal intracellular aggregation of α-synuclein is observed as LBs and Lewy neurites in neurodegenerative disorders, such as Parkinson's disease (PD) or dementia with Lewy bodies. Accumulated evidence suggests that abundant intracellular expression of α-synuclein is one of the risk factors for pathological aggregation. Recently, we reported differential expression patterns of α-synuclein between excitatory and inhibitory hippocampal neurons. Here we further investigated the precise expression profile in the adult mouse brain with special reference to vulnerable regions along the progression of idiopathic PD. The results show that α-synuclein was highly expressed in the neuronal cell bodies of some early PD-affected brain regions, such as the olfactory bulb, dorsal motor nucleus of the vagus, and substantia nigra pars compacta. Synaptic expression of α-synuclein was mostly accompanied by expression of vesicular glutamate transporter-1, an excitatory presynaptic marker. In contrast, expression of α-synuclein in the GABAergic inhibitory synapses was different among brain regions. α-Synuclein was clearly expressed in inhibitory synapses in the external plexiform layer of the olfactory bulb, globus pallidus, and substantia nigra pars reticulata, but not in the cerebral cortex, subthalamic nucleus, or thalamus. These results suggest that some neurons in early PD-affected human brain regions express high levels of perikaryal α-synuclein, as happens in the mouse brain. Additionally, synaptic profiles expressing α-synuclein are different in various brain regions.


Insights into manganese(VII) enhanced oxidation of benzophenone-8 by ferrate(VI): Mechanism and transformation products.
Benzophenones (BPs) are commonly used as UV filters in cosmetics and plastics products and are potentially toxic to the environment. This paper presents kinetics and products of BPs oxidation by ferrate(VI) (FeO42-, Fe(VI)) promoted by permanganate (Mn(VII)) . Degradation of 10.0 µM 2,2'-dihydroxy-4-methoxybenzophenone (BP-8)were determined under different experimental conditions ([Mn(VII)] = 0.5-1.5 µM, [Fe(VI)] = 50-150 µM, and pH = 7.0-10.0). The addition of Mn(VII) traces to Fe(VI)-BP-8 solution enhanced kinetics and efficiency of the removal. Similar enhanced removals were also seen for other BPs (BP-1, BP-3, and BP-4) under optimized conditions. The second-order rate constants (k, M-1s-1) of the degradation of BPs showed positive relationship with the energy of the highest occupied orbital (EHOMO). The possible interaction between Mn(VII) and BP-8 and the enhanced generation of Fe(V)/Fe(IV) and •OH was proposed to facilitate the oxidation of the target benzophenone, supported by in-situ electrochemical measurements, theoretical calculations and reactive species quenching experiments. Thirteen oxidation products of BP-8 suggested hydroxylation, bond breaking, polymerization and carboxylation steps in the oxidation. Toxicity assessments by ECOSAR program showed that the oxidized intermediate products posed a tapering ecological risk during the degradation process. Overall, the addition of Mn(VII) could improve the oxidation efficiency of Fe(VI).


Degree and correlates of cardiac knowledge and awareness among cardiac inpatients.
To investigate the degree of CHD awareness as well as symptom, risk factor, and treatment knowledge in a broad sample of cardiac inpatients, and to examine its sociodemographic, clinical and psychosocial correlates. 1308 CHD inpatients (351 [27.0%] female), recruited from 11 acute care sites in Ontario, participated in this cross-sectional study. Participants were provided with a survey which included a knowledge questionnaire among other measures, and clinical data were extracted from medical charts. 855 (68.8%) respondents cited heart disease as the leading cause of death in men, versus only 458 (37.0%) in women. Participants with less than high school education (p<.001), an annual family income less than $50,000CAD (p=.022), low functional capacity (p=.042), who were currently smoking (p=.022), who had no family history of heart disease (p<.001), and who had a perception of low personal control (p=.033) had significantly lower CHD knowledge. Awareness of CHD is not optimal, especially among women, South Asians, and those of low socioeconomic status. CHD patients have a moderate level of disease knowledge overall, but greater education is needed. Tailored educational approaches may be necessary for those of low socioeconomic status, particularly with regard to the nature of CHD, tests and treatments.


Single and multiple ascending-dose study of glucagon-receptor antagonist RN909 in type 2 diabetes: a phase 1, randomized, double-blind, placebo-controlled trial.
This first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects. This study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks. RN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change -20.6 to -97.5 mg/dL) and day 85 (mean change; -27.2 to -43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change -0.30% to -1.44%), and multiple doses (-0.83% to -1.56%). RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.


Prediction of valve-related complications for artificial heart valves using adaptive neural networks: a preliminary study.
A novel approach to the prediction of valve-related complications in patients with implanted artificial heart valves is discussed. Adaptive artificial neural networks were used to identify patients at high risk of valve-related events based on preoperative data. Data from a clinical trial on 789 subjects with Carpentier-Edwards pericardial bioprostheses were used. Patients' records were divided into two groups, one of which was used for training the neural network and the other for testing the trained network and determining error rates. Patient information such as age, sex, NYHA class and anticoagulation therapy, as well as valve information such as size and the date of implant, were used as the network inputs. The neural net had a single output variable indicating the risk that an individual patient would develop a valve-related complication resulting in death. The results show that a trained neural network was able to predict valve-related deaths in the specified time interval of 1981-1991 with a high degree of accuracy. The neural network was also successful in classifying patients into high and low risk categories.


Thermal stability of UV-irradiated collagen in bovine lens capsules and in bovine cornea.
The thermal stability of UVB irradiated collagen in bovine lens capsules and in bovine cornea has been investigated by differential scanning calorimetry (DSC). During UVB irradiation the lens capsules and cornea were immersed in water to keep the collagen in a fully hydrated condition at all times. UV irradiation induced changes in collagen which caused both stabilization and destabilization of the collagen structure. The helix-coil transition for non-irradiated collagen in cornea occurred near 66 degrees C, instead for the irradiated one for 3h it occurred at 69 degrees C. After irradiating for longer times (20-96h) the helix-coil transition peak occurred at much lower temperatures. The peak was very broad and suggested that collagen was reduced by UV to different polypeptides of different molecular weight and different lower thermal stabilities. The irradiation of lens capsules with UVB light in vitro resulted in changes in the thermal properties of type-IV collagen consistent with increased cross-linking. DSC of lens capsules showed two major peaks at melting temperatures at 54 degrees C Tm1 and 78 degrees C Tm2, which can be attributed to the denaturation of the triple helix and 7S domains, respectively. UVB irradiation of lens capsules in vitro for 6 h caused an increase in Tm1 from 54 to 57 degrees C. The higher temperature required to denature the type-IV collagen after irradiation in vitro suggested an increase of intermolecular cross-linking.


Chronic hepatitis B in children after e antigen seroclearance: final report of a 29-year longitudinal study.
Chronic hepatitis B is usually a benign disease in Caucasian children; however, the long-term prognosis remains unsettled. This report describes the results of a 29-year longitudinal study including 99 white children with chronic hepatitis B, mainly acquired horizontally: 91 were hepatitis B e antigen (HBeAg) positive (4 had cirrhosis), and 8 were HBeAg negative at presentation. Of the 91 HBeAg-positive children, 89 underwent HBeAg seroconversion after a mean period of 5.2 +/- 4.0 years and were included in the study. Of the 85 children without cirrhosis, one had HBeAg-negative hepatitis and the other 84 became inactive carriers. During a mean follow-up of 14.5 +/- 6.1 years after HBeAg seroclearance, 4 carriers experienced reactivation, and 3 of them had HBeAg-negative hepatitis at the last follow-up. Of the 8 initially HBeAg-negative children, 2 had HBeAg-negative hepatitis, and 6 were inactive carriers. Of the 4 children with cirrhosis, 2 had hepatocellular carcinoma (HCC) and remained alive and 2 lost the histological features of cirrhosis in adulthood. Two patients with HBeAg-negative hepatitis and 1 with cirrhosis had experienced drug abuse. At the end of follow-up, 15 of the 89 initially HBeAg-positive patients and 2 of 8 initially HBeAg-negative children had cleared hepatitis B surface antigen. In conclusion, the overall prognosis for chronic hepatitis B in horizontally infected Caucasian children is favorable; however, some patients progress to HCC and HBeAg-negative hepatitis. Long-term monitoring is important, as is counseling on cofactors of liver damage, such as alcohol and drug abuse.


The use of calcium ions instead of heat treatment for β-1,3-glucan gelation improves biocompatibility of the β-1,3-glucan/HA bone scaffold.
The aim of this study was to determine which procedure for β-1,3-glucan gelation - newly developed dialysis against calcium salt or described in the literature thermal technique - is more appropriate for fabrication of a biomaterial designed for bone tissue engineering applications. Thus, β-1,3-glucan/hydroxyapatite scaffolds were prepared based on two different methods and their physicochemical, microstructural, and biological properties were compared. Obtained results demonstrated that unlike thermal method-prepared β-1,3-glucan/hydroxyapatite material (glu/HAT), bone scaffold fabricated via dialysis method (glu/HA D) possessed rough surface resulting from the presence of CaCl2 precipitates as proven by SEM and EDS analysis. As a consequence, glu/HA D scaffold released Ca2+ ions to the surrounding environment positively affecting osteoblast behaviour and biomineralization in vitro. Since glu/HA D material exhibited better bioactivity and biocompatibility compared to the glu/HA T scaffold, it may be concluded that the dialysis method is more suitable for β-1,3-glucan/hydroxyapatite biomaterial fabrication.


Adenovirus vector infection of non-small-cell lung cancer cells is a trigger for multi-drug resistance mediated by P-glycoprotein.
P-glycoprotein (P-gp) is an ATP-binding cassette protein involved in cancer multi-drug resistance (MDR). It has been reported that infection with some bacteria and viruses induces changes in the activities of various drug-metabolizing enzymes and transporters, including P-gp. Although human adenoviruses (Ad) cause the common cold, the effect of Ad infection on MDR in cancer has not been established. In this study, we investigated whether Ad infection is a cause of MDR in A549, H441 and HCC827 non-small-cell lung cancer (NSCLC) cell lines, using an Ad vector system. We found that Ad vector infection of NSCLC cell lines induced P-gp mRNA expression, and the extent of induction was dependent on the number of Ad vector virus particles and the infection time. Heat-treated Ad vector, which is not infectious, did not alter P-gp mRNA expression. Uptake experiments with doxorubicin (DOX), a P-gp substrate, revealed that DOX accumulation was significantly decreased in Ad vector-infected A549 cells. The decrease of DOX uptake was blocked by verapamil, a P-gp inhibitor. Our results indicated that Ad vector infection of NSCLC cells caused MDR mediated by P-gp overexpression. The Ad vector genome sequence is similar to that of human Ad, and therefore human Ad infection of lung cancer patients may lead to chemoresistance in the clinical environment.


Arachidonic acid down-regulates the insulin-dependent glucose transporter gene (GLUT4) in 3T3-L1 adipocytes by inhibiting transcription and enhancing mRNA turnover.
Chronic exposure of fully differentiated 3T3-L1 adipocytes to 50 microM arachidonic acid (AA) resulted in an inhibition (approximately 91%) in cellular GLUT4 mRNA content after a 48-h exposure, without similarly affecting the mRNA content of the ubiquitous glucose transporter, GLUT1. Subsequent investigations revealed that transcription of the GLUT4 gene was reduced by approximately 50% in response to AA treatment and the half-life of GLUT4 mRNA decreased from 8.0 to 4.6 h. By contrast, AA increased the accumulation of GLUT1 mRNA by 65%, by a mechanism that also involved regulation at both transcriptional and mRNA stability levels. Western blot analysis revealed that AA was specifically reducing the insulin-responsive glucose transporter (GLUT4) in both plasma and intracellular membranes. Subsequently, AA was observed to alter the ability of the GLUT4 transporter to respond to insulin and mediate a significant enhancement of glucose uptake. The results presented in this study indicate that AA can partially mimic the effects of both tumor necrosis factor-alpha and insulin which, when chronically supplied to 3T3-L1 adipocytes, also down-regulate GLUT4 gene expression. Therefore, these data may have relevance to the insulin-resistance associated with non-insulin-dependent diabetes mellitus.


Early results for anatomic correction of transposition of the great arteries and for double-outlet right ventricle with subpulmonary ventricular septal defect.
Fifty patients, 21 with transposition of the great arteries plus ventricular septal defect, four with double-outlet right ventricle plus ventricular septal defect, and 25 with transposition of the great arteries plus intact ventricular septum, have undergone anatomic correction. There were four hospital deaths, all in the patients with ventricular septal defects (overall mortality rate 8%). The Lecompte maneuver was used in all patients, and in the last 25 patients the coronary arteries were transposed to medially hinged trapdoor flaps created in the neoaorta. In 10 patients (20%) intraoperative adjustments were necessary to the great vessels and coronary arteries to achieve unobstructed coronary artery flow. There have been no late deaths. Postoperative cardiac catheterization in 19 patients has revealed stenosis on the new main pulmonary artery suture line to be the main early problem. Anatomic correction of transposition (with or without ventricular septal defect) and double-outlet right ventricle septal defect would seem to be a good operative alternative to the Mustard or Senning operation, with the advantage of incorporating the left ventricle into the systemic circulation.


Studies on the central nervous system: visually evoked cortical responses in sheep.
Several factors which were thought to affect the magnitude of flash evoked cortical potentials were examined in halothane-anaesthetised sheep. The proximity of the electrodes to the cortex and the patency of the eye which was contralateral to the recording electrodes had the greatest effect on the excursion distance of the visually evoked response. The choice of upper frequency filter (70 vs 700 Hz), the patency of the ipsilateral eye and closure of both eyelids resulted in relatively smaller reductions in excursion distance of the response. The importance of these findings in studies using evoked potentials for assessing sensibility and brain death in animals is discussed.


Association of sICAM-1 and MCP-1 with coronary artery calcification in families enriched for coronary heart disease or hypertension: the NHLBI Family Heart Study.
Data accumulated from mouse studies and in vitro studies of human arteries support the notion that soluble intercellular adhesion molecule-1 (sICAM-1) and monocyte chemoattractant protein-1 (MCP-1) play important roles in the inflammation process involved in atherosclerosis. However, at the population level, the utility of sICAM-1 and MCP-1 as biomarkers for subclinical atherosclerosis is less clear. In the follow-up exam of the NHLBI Family Heart Study, we evaluated whether plasma levels of sICAM-1 and MCP-1 were associated with coronary artery calcification (CAC), a measure of the burden of coronary atherosclerosis. CAC was measured using the Agatston score with multidetector computed tomography. Information on CAC and MCP-1 was obtained in 2246 whites and 470 African Americans (mean age 55 years) without a history of coronary heart disease (CHD). Information on sICAM-1 was obtained for white participants only. In whites, after adjustment for age and gender, the odds ratios (ORs) of CAC (CAC > 0) associated with the second, third, fourth, and fifth quintiles of sICAM-1 compared to the first quintile were 1.22 (95% confidence interval [CI]: 0.91-1.63), 1.15 (0.84-1.58), 1.49 (1.09-2.05), and 1.72 (1.26-2.36) (p = 0.0005 for trend test), respectively. The corresponding ORs for the second to fifth quintiles of MCP-1 were 1.26 (0.92-1.73), 0.99 (0.73-1.34), 1.42 (1.03-1.96), and 2.00 (1.43-2.79) (p < 0.0001 for trend test), respectively. In multivariable analysis that additionally adjusted for other CHD risk factors, the association of CAC with sICAM-1 and MCP-1 was attenuated and no longer statistically significant. In African Americans, the age and gender-adjusted ORs of CAC associated with the second and third tertiles of MCP-1 compared to the first tertile were 1.16 (0.64-2.08) and 1.25 (0.70-2.23) (p = 0.44 for trend test), respectively. This result did not change materially after additional adjustment for other CHD risk factors. Test of race interaction showed that the magnitude of association between MCP-1 and CAC did not differ significantly between African Americans and whites. Similar results were obtained when CAC > or = 10 was analyzed as an outcome for both MCP-1 and sICAM-1. This study suggests that sICAM-1 and MCP-1 are biomarkers of coronary atherosclerotic burden and their association with CAC was mainly driven by established CHD risk factors.


High prevalence of rat hepatitis E virus in wild rats in China.
Serum samples from a total of 713 wild rats captured in Zhanjiang city in China from December 2011 to September 2012 were investigated for the prevalence of rat hepatitis E virus (HEV) by exploring rat HEV-specific antibodies and RNA. By an ELISA based on recombinant rat HEV-like particles (HEV-LPs), 23.3% (166/713) of the rats were positive for anti-HEV IgG, and 8.3% (59/713) were positive for anti-HEV IgM. The IgG-positive rates in Rattus norvegicus, Bandicota indica, Rattus flavipectus, Rattus rattoides losea, and Rattus rattus hainanus, were 27.8% (64/230), 23.0% (40/174), 19.9% (34/171), 21.5% (26/121), and 11.8% (2/17), while the IgM-positive rates were 8.3% (19/230), 6.9% (12/174), 8.2% (14/171), 10.7% (13/121), and 5.9% (1/17), respectively. The IgG-positive rate of the rats captured in rural areas, 24.1% (84/348), was higher than that in the central area of Zhanjiang city, 15.1% (32/212). The highest IgG-positive rates, as high as 45.3% (39/86), were detected in wild rats trapped in the garbage dump. Twelve of the 59 IgM-positive serum samples were positive for HEV RNA, which was detected in all of the wild rat species except R. rattus hainanus. A phylogenetic analysis of the partial genome of rat HEV ORF1 indicated that all of the 12 HEV strains belong to rat HEV, and no other genotype HEV were detected. The rat HEV from Zhangjiang city could be classified into three separated clusters, suggesting that the infection due to rat HEV with a variety of genome entities occurs extensively among wild rats in China.


Optogenetic Stimulation for Restoring Vision to Patients Suffering From Retinal Degenerative Diseases: Current Strategies and Future Directions.
Optogenetic strategies for vision restoration involve photosensitizing surviving retinal neurons following retinal degeneration, using emerging optogenetic techniques. This approach opens the door to a minimally-invasive retinal vision restoration approach. Moreover, light stimulation has the potential to offer better spatial and temporal resolution than conventional retinal electrical prosthetics. Although proof-of-concept studies in animal models have demonstrated the possibility of restoring vision using optogenetic techniques, and initial clinical trials are underway, there are still hurdles to pass before such an approach restores naturalistic vision in humans. One limitation is the development of light stimulation devices to activate optogenetic channels in the retina. Here we review recent progress in the design and implementation of optogenetic stimulation devices and outline the corresponding technological challenges. Finally, while most work to date has focused on providing therapy to patients suffering from retinitis pigmentosa, we provide additional insights into strategies for applying optogenetic vision restoration to patients suffering from age-related macular degeneration.


Development of a 2-sludge, 3-stage system for nitrogen and phosphorous removal from nutrient-rich wastewater using granular sludge and biofilms.
A novel 2-sludge 3-stage process using a combination of granular sludge and biofilm was developed to achieve biological removal of nitrogen and phosphorus from nutrient-rich wastewater. The system consists of a granular sequencing batch reactor (SBR) working under alternating anaerobic/anoxic conditions supplemented with a short aerobic phase and an aerobic biofilm SBR. The wastewater is first fed to the granular SBR reactor, where easily biodegradable carbon sources are taken up primarily by polyphosphate accumulating organisms (PAOs). The supernatant resulting from quick settling of the granular sludge is then fed to the biofilm SBR for nitrification, which produces oxidized nitrogen that is returned to the granular reactor for simultaneous denitrification and phosphorus removal. While maximizing the utilization of organic substrates and reducing operational costs, as do other 2-sludge processes previously reported in literature, the proposed system solves the bottleneck problem of traditional 2-sludge systems, namely high effluent ammonia concentration, due to its high-volume exchange ratios. An ammonia oxidation rate of 32 mg N/Lh was achieved in the biofilm SBR, which produced nitrite as the final product. This nitrite stream was found to cause major inhibition on the anoxic P uptake and also to result in the accumulation of N(2)O. These problems were solved by feeding the nitrite-containing stream continuously to the granular reactor in the anoxic phase. With a nitrogen and phosphorus removal efficiency of 81% and 94%, respectively, the system produces an effluent that is suitable for land irrigation from a wastewater stream containing 270 mg N/L of total nitrogen and 40 mg P/L of total phosphorus.


Measuring perceived effects of drinking an extract of basidiomycetes Agaricus blazei Murill: a survey of Japanese consumers with cancer.
To survey cancer patients who consume an extract of the Basidiomycetes Agaricus blazei Murill mushroom (Sen-Sei-Ro) to measure their self-assessment of its effects and to develop an instrument for use in future randomized trials. We designed, translated and mailed a survey to 2,346 Japanese consumers of Sen-Sei-Ro self-designated as cancer patients. The survey assessed consumer demographics, cancer history, Sen-Sei-Ro consumption, and its perceived effects. We performed exploratory psychometric analyses to identify distinct, multi-item scales that could summarize perceptions of effects. We received completed questionnaires from 782 (33%) of the sampled Sen-Sei-Ro consumers with a cancer history. Respondents represented a broad range of cancer patients familiar with Sen-Sei-Ro. Nearly all had begun consumption after their cancer diagnosis. These consumers expressed consistently positive views, though not extremely so, with more benefit reported for more abstract benefits such as emotional and physical well-being than relief of specific symptoms. We identified two conceptually and empirically distinct and internally consistent summary scales measuring Sen-Sei-Ro consumers' perceptions of its effects, Relief of Symptoms and Functional Well-being (Cronbach's alpha: Relief of Symptoms, alpha = .74; Functional Well-Being, alpha = .91). Respondents to our survey of Sen-Sei-Ro consumers with cancer reported favorable perceived effects from its use. Our instrument, when further validated, may be a useful outcome in trials assessing this and other complementary and alternative medicine (CAM) substances in cancer patients.


Reintervention after valve-sparing aortic root replacement: A comprehensive analysis of 781 David V procedures.
Studies of reintervention after valve-sparing aortic root replacement (VSRR) are limited by sample size and failure to evaluate all types of reinterventions, including distal aorta and transcatheter interventions. In this report, reintervention after VSRR using a large patient cohort was comprehensively analyzed. In a series involving 2 academic aortic centers, 781 consecutive patients from 2005 to 2020 undergoing David V VSRR for aortic aneurysm (91%) or dissection (9%) were included. Median age was 50 years, and 23% had a bicuspid aortic valve (AV). Median follow-up was 7.0 years. Open or transcatheter reintervention on the AV, proximal, or distal thoracic aorta was identified. Cumulative incidence was calculated, and subdistribution hazard models identified factors associated with reintervention. Time-dependent incidence of reintervention was plotted using risk-hazard functions. Sixty-eight reinterventions (57 open, 11 transcatheter) were performed. Reinterventions were divided by indication into degenerative AV (n = 26, including 1 transcatheter aortic valve replacement), endocarditis (n = 11), proximal aorta (n = 8), and distal aorta (n = 23, including 10 thoracic endovascular aortic repairs). Risk of reintervention for endocarditis peaked 1 to 3 years after VSRR, whereas other indications had stable, low rates of occurrence throughout the follow-up period. The cumulative incidence of reintervention was 12.5% whereas the cumulative incidence of AV reintervention was 7.0% at 10 years and was associated with residual postoperative aortic insufficiency. In-hospital mortality after reintervention was 3%. Reintervention rates after VSRR are relatively low in long-term follow-up and can be performed with acceptable operative risk. The majority of reinterventions are performed for indications other than AV degeneration, with the timing of reintervention varying by the specific clinical indication.


Adrenal and juxta-adrenal schwannomas: A single-centre study.
Adrenal schwannomas and juxta-adrenal schwannomas are rare tumours. We aimed to summarise their clinical, biochemical and imaging characteristics. Single-centre retrospective study of eligible patients between 1995 and 2022. Patients with a histopathologic diagnosis of adrenal or juxta-adrenal schwannoma. Twenty-four patients were diagnosed with either primary adrenal schwannoma (8, 33%) or juxta-adrenal schwannoma (16, 67%). Most tumours (21, 88%) were discovered incidentally on imaging. All tumours were unilateral, with 15 (62%) on the left and 9 (38%) on the right. At diagnosis, the median tumour size was 4 cm (range, 2-13 cm). Adrenal schwannomas were smaller when compared to juxta-adrenal schwannomas (median of 3.1 cm [range, 2-9 cm] vs. 4.6 cm [range, 2.3-13.3 cm], p = .037). On imaging, the tumours were round or oval in shape in 16 (70%), lobulated in 7 (30%), solid in 15 (68%), solid-cystic in 7 (32%), heterogeneous in 14 (61%) and homogeneous in 9 (39%). The median unenhanced computed tomography attenuation was 30 Hounsfield units (HU) (range, 12-38 HU). Of the 20 patients who underwent complete hormonal testing, all had nonfunctioning tumours. There was no recurrence or new tumour development in our cohort. Adrenal and juxta-adrenal schwannomas are nonfunctioning benign tumours that present with indeterminate radiographic features, including large tumour size and increased unenhanced CT attenuation. We did not find an imaging phenotype that was diagnostic of schwannoma. The diagnosis of this rare tumour is based on biopsy or resection.


[Impacted maxillary cuspid. II. Releasing by means of a modified fenestration technique].
A review of the treatment of the impacted upper cuspid is presented. A description of a modified exposure technique is given. Up to the present day more than 400 impacted cuspids have been treated with this technique.


Rapid enzyme immunoassay for measurement of bovine progesterone.
Reproductive management is a primary financial concern of the dairy industry with missed estrus detection one of the major causes of lost income. A rapid enzyme immunoassay (EIA) was developed for on-line measurement of progesterone in bovine milk with a biosensor for detection of estrus. The EIA was developed using covalent binding microtiter wells, monoclonal antibody, horseradish peroxidase, and 3,3',5,5'-tetramethylbenzidine (TMB). The EIA took 8 min and had a dynamic response for progesterone in buffer and milk between 0.2 and 20 ng/ml.


Cognitive impairment in Alzheimer's disease correlates with ventricular width and atrophy-corrected cortical glucose metabolism.
We compared the correlation of PET and MRI with neuropsychological tests in 26 patients with probable Alzheimer's disease (AD). The width of the temporal horns and the third ventricle, regional metabolic rates of glucose (rCMRGlu) and the proportion of cerebrospinal fluid space in mesial temporal and temporoparietal cortical regions were measured with three-dimensionally coregistered PET and MRI in two planes perpendicular to the Sylvian fissure. Highly significant correlations between rCMRGlu and neuropsychological tests were found mainly in the temporoparietal cortex, with and without correction for atrophy. Correlations of similar magnitude were seen also between most tests and the width of the temporal horns and third ventricle. Changes in the third ventricle and mesial temporal lobe were best seen with MRI, whereas PET most clearly depicted alterations in neocortical association areas. These two aspects of the disease correlated with the severity of dementia to a similar degree.


Influence of vasodilators used in the therapy of heart failure on platelet aggregation.
Of the vasodilators used at present in the treatment of heart failure, only nitroprusside and phentolamine inhibit platelet aggregation at therapeutic dose levels. The other vasodilators studied, viz. nitroglycerin, isosorbide dinitrate, hydrallazine, dihydrallazine and prazosin, only inhibit platelet aggregation at relatively high concentrations, well above those reached in vivo. The exact nature of the platelet receptor, stimulation and blockade of which respectively initiate and inhibit aggregation, is not yet know, but it would appear to resemble the presynaptic alpha-receptors of other tissues.


[Off-label therapy: current problems from the perspective of the Pharmaceutical Commission of the German Medical Profession].
The off-label use of approved pharmaceuticals outside the authorized status is implemented in pharmacotherapy of many diseases, especially for rare diseases and in cases of therapy resistance. The German regulations are presented and analyzed and the relative literature is discussed.


Technology-assisted cognitive-behavior therapy delivered by peers versus standard cognitive behavior therapy delivered by community health workers for perinatal depression: study protocol of a cluster randomized controlled non-inferiority trial.
The lack of trained mental health professionals is a key barrier to scale-up of evidence-based psychological interventions in low and middle-income countries. We have developed an app that allows a peer with no prior experience of health-care delivery to deliver the cognitive therapy-based intervention for perinatal depression, the Thinking Healthy Programme (THP). This trial aims to assess the effectiveness and cost-effectiveness of this Technology-assisted peer-delivered THP versus standard face-to-face Thinking Healthy Programme delivered by trained health workers. We will employ a non-inferiority stratified cluster randomized controlled trial design comparing the two formats of intervention delivery. A total of 980 women in the second or third trimester of pregnancy with a diagnosis of Major Depressive Episode, evaluated with the Structured Clinical Interview for DSM-V Disorders (SCID), will be recruited into the trial. The unit of randomization will be 70 village clusters randomly allocated in a 1:1 ratio to the intervention and control arms. The primary outcome is defined as remission from major depressive episode at 3 months postnatal measured with the SCID. Data will also be collected on symptoms of anxiety, disability, quality of life, service use and costs, and infant-related outcomes such as exclusive breastfeeding and immunization rates. Data will be collected on the primary outcome and selected secondary outcomes (depression and anxiety scores, exclusive breastfeeding) at 6 months postnatal to evaluate if the improvements are sustained in the longer-term. We are especially interested in sustained improvement (recovery) from major depressive episode. This trial will evaluate the effectiveness and cost-effectiveness of a technology-assisted peer-delivered cognitive behavioral therapy-based intervention in rural Pakistan. If shown to be effective, the novel delivery format could play a role in reducing the treatment gap for perinatal depression and other common mental disorders in LMIC. The trial was registered at Clinicaltrials.gov (NCT05353491) on 29 April 2022.


Million spot binding array platform for exploring and optimizing multiple simultaneous detection events.
Large-scale, high-throughput specificity assays to characterize binding properties within a competitive and complex environment of potential binder-target pairs remain challenging and cost prohibitive. Barcode cycle sequencing (BCS) is a molecular binding assay for proteins, peptides, and other small molecules that is built on a next-generation sequencing (NGS) chip. BCS uses a binder library and targets labeled with unique DNA barcodes. Upon binding, binder barcodes are ligated to target barcodes and sequenced to identify encoded binding events. For complete details on the use and execution of this protocol, please refer to Hong et al. (2022).


Caries prevalence and tooth loss in Hungarian adult population: results of a national survey.
Oral health is basically important for the well-being of people. Thus, it is strongly suggested to organize epidemiological surveys in order to gain representative data on oral condition of the given population. The purpose of the cross-sectional study was to determine the results on tooth loss and caries prevalence of Hungarian adults in different age groups. Altogether 4606 persons (2923 women, 1683 men) participated in the study who were classified into different age groups: 19 [less than or equal to], 20-24, 35-44, 45-64, 65-74, [greater than or equal to]75 year olds. Probands were selected randomly from the population attending the compulsory lung screening examinations. The participants were examined by calibrated dentists, according to the WHO (1997) criteria. In order to produce representative data, the chosen localities for these examinations covered the capital, the largest towns, the villages, and case weights were used for the statistical evaluation. The mean values of DMF-T were found between 11.79+/-5.68 and 21.90+/-7.61 These values were significantly higher in women compared to men (p < 0.05). In all age groups the values of M were the highest. Except for the women in the groups of 35-44 and 45-64 year olds, these values showed an increasing tendency both in women and men by age (from 5.50+/-6.49, and 4.70+/-4.08 to 21.52+/-9.07 and 18.41+/-8.89 respectively). The values of D components reached the highest values in 45-64 year olds (4.54+/-2.12 and 4.22+/-2.81, by gender, respectively), then in the older age groups there was a high reduction in these values (in 65-74 year olds: 2.72+/-1.88 and 1.36+/-2.48; in 75 or more than 75 year olds: 1.05+/-1.41 and 1.03+/-1.76 by gender, respectively). The ratio of D and F values was the highest in the age group of 65-74 year olds (2.12), the lowest ratio could be calculated in 20-34 year olds (0.65).Data showed some decrease in caries experience in 35-44 years of age between 2000 and 2004. The prevalence of persons with 21 or more teeth had been increased from 65.6% to 73.1%. This positive tendency has not been occured in prevalence of edentulousness in this age group: the prevalence of edentulous persons changed from 1.4 to 1.9%. In 65-74 year olds the level of edentulousness became lower, from 25.9 to 14.8% and the prevalence of persons with 21 or more teeth is higher (22.6%) than it was in 2000 (13.0%). Present data from Hungary show some slight decrease in caries experience between 35-44 years of age, although this positive tendency has not been occured in prevalence of edentulousness in this age group. A positive tendency could be experienced in the group of 65-74 year olds in edentulousness and in number of teeth, but further efforts are needed to reach a better situation.


An examination of effects of intimate partner violence on children: A cross-sectional study conducted in a paediatric emergency unit in Turkey.
Intimate partner violence (IPV) against women causes inadequate and unbalanced nutrition in children aged 0-5 years and adversely affects their growth. To examine the impact of intimate partner violence on a child's growth regarding the medical diagnosis in paediatric patients under 5 years of age, growth of the child, and the mother's exposure to intimate partner violence. This descriptive cross-sectional study included 166 children admitted to a paediatric emergency department, and their mothers. Women exposed to emotional violence and controlling behaviour during pregnancy had children prone to being overweight and obese. A mothers lifetime exposure to physical violence had an adverse effect on their children's wasting and moderate wasting. In contrast, mothers' exposure to emotional violence had a direct impact on a child's wasting and moderate wasting. The lifetime effect of domestic violence may begin at birth. This vulnerability leads to negative outcomes in both children and women regarding biopsychosocial development. Nurses and midwives in primary health care services and one-on-one care should be trained to evaluate prospective mothers and children aged 0-5 regarding violence and its effects on the child's growth.


Glycerol stimulates innate chaperoning, proteasomal and stress-resistance functions: implications for geronto-manipulation.
Aging is associated with accumulation of toxic intracellular and extracellular protein aggregates. Cells manage "aged" proteins by mobilizing their molecular chaperones or heat shock proteins that are also considered as determinants of lifespan in diverse species. In this study, we tested whether an exogenous addition of the non-toxic chemical chaperone 'glycerol' could elicit stress and geronto-protective activities. We found that glycerol enhanced chaperoning of heat-denatured proteins. In addition to stimulating proteasome activity, glycerol led to an increased expression of the stress chaperone 'mortalin' and decreased p53 function in human cells. Glycerol-fed worms exhibited thermo-tolerance and lower level of age-associated auto-fluorescence. Through the combined stimulation of the proteasome and chaperoning activities of mortalin, in particular, glycerol treatment resulted in increased survival and fitness against oxidative- and heat-stress. These results may have significant implications in the use of glycerol as a candidate geronto-modulator in development of practical interventions for "healthy aging".


Fluorescence in situ hybridization analysis of chromosome 1p36 deletions in human MYCN amplified neuroblastoma.
Deletion of the short arm of chromosome 1 (1p) is one of the poor prognostic factors in human neuroblastomas. Recent studies have suggested that one or more of the neuroblastoma tumor suppressor genes reside in this region and have identified the shortest region of overlap (SRO) on 1p36. The purpose of this study was to examine deletions of 1p in human neuroblastomas by fluorescence in situ hybridization (FISH). Two-color FISH analysis was performed to detect chromosome 1p36 abnormalities in 42 MYCN-amplified neuroblastomas. Four different probes from the 1p36 region, the E2F2, NPPA, D1S160, and CDC2L1 loci were used for detection of 1p abnormalities. A repeat sequence probe, which is specific for the heterochromatic region of chromosome 1 (pUC1.77), was used as a control. Large deletions of 1p36 were observed in 31 (73.8%) of 42 tumors, whereas the remaining 11 (26.2%) showed no deletion. In these 11 tumors, a translocation of 1p was found in one and a duplication of 1p was detected in another. A strong correlation between 1p abnormalities and MYCN amplification was found in this study. MYCN-amplified neuroblastomas were found to show large deletions of 1p encompassing the SRO. FISH provided a rapid and reliable method to detect hemizygous deletions of 1p.


Neurologic complications of thyrotoxicosis: case report.
Weakness accompanying hyperthyroidism may be due to a variety of causes. A case is presented of a patient who, during management of thyrotoxicosis, became quadriparetic due to a unique combination of axonal neuropathy, myopathy, and pyramidal tract dysfunction. Electrodiagnostic, muscle biopsy, and nerve biopsy results are presented.


Ginsenosides from Korean red ginseng modulate T cell function via the regulation of NF-AT-mediated IL-2 production.
Korean red ginseng is a traditional health food frequently used to prevent or treat various diseases worldwide. In this study, we evaluated the immunomodulatory activities of eleven compounds (1-11) isolated from Korean red ginseng, focusing on T cell function. First, the effects of the eleven compounds were studied on the regulation of IL-2, a potent T cell growth factor. Compounds 5, 7, and 9 significantly increased IL-2 secretion in phorbol 12-myristate 13-acetate (PMA)/ionomycin (Io)-induced EL-4 T cells. Next, we examined the effects of compounds 5, 7, and 9 on the regulation of transcription factors related to IL-2 production in T cells. Compound 9 significantly increased the PMA/Io-induced promoter activity of nuclear factor of activated T cells (NF-AT) in EL-4 T cells, but did not have any significant effects on the promoters of NF- κB. These results suggest that compound 9 activates T cell function via the regulation of NF-AT-mediated IL-2 production.


Diagnosis of Hepatozoon spp. in Amblyomma ovale and its experimental transmission in domestic dogs in Brazil.
Transmission of Hepatozoon spp. to dogs was investigated using four species of ixodid ticks: Rhipicephalus sanguineus, Amblyomma aureolatum, Amblyomma ovale and Amblyomma cajennense. We collected completely or partially engorged adult ticks of these species from dogs that were naturally infested and positive for Hepatozoon spp. We selected some of these ixodids and inoculated them orally in four negative dogs. The other ticks were dissected and examined for oocysts. Of all dogs inoculated orally with R. sanguineus, A. aureolatum, A. cajennense and A. ovale, only the animal that received the macerate of A. ovale was positive; evidence (gametocytes in peripheral blood) of infection was found 63 days after inoculation. Among all dissected ticks, we found only two oocysts; these were similar to those of Hepatozoon canis, and both were recovered from a single A. ovale specimen. We inoculated sporozoites recovered from the oocysts intraperitoneally into a Hepatozoon spp. negative dog, and circulating gametocytes were detected 84 days later. Our study demonstrated that A. ovale can be a vector of Hepatozoon spp. in Brazil.


Identification and characterization of peptide mimics of blood group A antigen.
In order to investigate peptide mimics of carbohydrate blood group A antigen, a phage display 12-mer peptide library was screened with a monoclonal antibody against blood group A antigen, NaM87-1F6. The antibody-binding properties of the selected phage peptides were evaluated by phage ELISA and phage capture assay. The peptides were co-expressed as glutathione S-transferase (GST) fusion proteins. RBC agglutination inhibition assay was performed to assess the natural blood group A antigen-mimicking ability of the fusion proteins. The results showed that seven phage clones selected bound to NaM87-1F6 specifically, among which, 6 clones bore the same peptide sequence, EYWYCGMNRTGC and another harbored a different one QIWYERTLPFTF. The two peptides were successfully expressed at the N terminal of GST protein. Both of the fusion proteins inhibited the RBC agglutination mediated by anti-A serum in a concentration-dependent manner. These results suggested that the fusion proteins based on the selected peptides could mimic the blood group A antigen and might be used as anti-A antibody-adsorbing materials when immunoabsorption was applied in ABO incompatible transplantation.


Cell imaging and manipulation by nonlinear optical microscopy.
Advances in the technologies for labeling and imaging biological samples drive a constant progress in our capability of studying structures and their dynamics within cells and tissues. In the last decade, the development of numerous nonlinear optical microscopies has led to a new prospective both in basic research and in the potential development of very powerful noninvasive diagnostic tools. These techniques offer large advantages over conventional linear microscopy with regard to penetration depth, spatial resolution, three-dimensional optical sectioning, and lower photobleaching. Additionally, some of these techniques offer the opportunity for optically probing biological functions directly in living cells, as highlighted, for example, by the application of second harmonic generation to the optical measurement of electrical potential and activity in excitable cells. In parallel with imaging techniques, nonlinear microscopy has been developed into a new area for the selective disruption and manipulation of intracellular structures, providing an extremely useful tool of investigation in cell biology. In this review we present some basic features of nonlinear microscopy with regard both to imaging and manipulation, and show some examples to illustrate the advantages offered by these novel methodologies.


Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition.
The aim of this study is to derive and evaluate an equilibrium model of a previously developed general pharmacokinetic model for drugs exhibiting target-mediated drug disposition (TMDD). A quasi-equilibrium solution to the system of ordinary differential equations that describe the kinetics of TMDD was obtained. Computer simulations of the equilibrium model were carried out to generate plasma concentration-time profiles resulting from a large range of intravenous bolus doses. Additionally, the final model was fitted to previously published pharmacokinetic profiles of leukemia inhibitory factor (LIF), a cytokine that seems to exhibit TMDD, following intravenous administration of 12.5, 25, 100, 250, 500, or 750 microg/kg in sheep. Simulations show that pharmacokinetic profiles display steeper distribution phases for lower doses and similar terminal disposition phases, but with slight underestimation at early time points as theoretically expected. The final model well-described LIF pharmacokinetics, and the final parameters, which were estimated with relatively good precision, were in good agreement with literature values. An equilibrium model of TMDD is developed that recapitulates the essential features of the full general model and eliminates the need for estimating drug-binding microconstants that are often difficult or impossible to identify from typical in vivo pharmacokinetic data.