[Domiciliary rehabilitation: an innovative form of outpatient medical rehabilitation].
Domiciliary rehabilitation is an innovative form of outpatient medical rehabilitation. All components of service provision are delivered in the rehabilitant's home by a multidisciplinary team headed by a physician. The key context factors in the rehab process can be taken into account firsthand. The target group of domiciliary rehabilitation consists of multimorbid patients with severe functional limitations and complex assistance needs, whose rehabilitation options would be poor without this outreach service. Here, as suggested by the WHO concept of functional health, the interaction between health condition and environmental factors is kept in view much better than in other forms of rehabilitation. The positive effects and the efficiency of the rehabilitation measures provided can be assessed very well at a high descriptive level. This fact had been a precondition for legal establishment of domiciliary rehabilitation as a regular service. Domiciliary rehabilitation not only complies with key demands in the health and social policy fields, such as priority of outpatient over inpatient treatment or rehabilitation to precede and accompany long term care, it also constitutes an alternative concept challenging the traditional inpatient rehabilitation approach. The patient, hence, no longer is to fit into the institutional framework of outpatient or inpatient rehabilitation, but the team will fit into the specifics of the patient's unique social and material situation.


GDP dissociation inhibitor 1 (GDI1) attenuates β-amyloid-induced neurotoxicity in Alzheimer's diseases.
β-Amyloid (Aβ) induced neurotoxicity is an implicated mechanism in Alzheimer's disease (AD). This study focused on the role of GDP dissociation inhibitor 1 (GDI1) in Aβ-induced neurotoxicity. Data from the GEO database for AD-related datasets GSE140829, GSE63061, GSE36980, and GSE60360 were downloaded and identified common differentially expressed genes (coDEGs). The mRNA levels of GDI1 in the serum of AD patients were analyzed by RT-qPCR. ROC curve evaluated the diagnostic value. Aβ25-35 induced SH-SY5Y cells to construct an AD cell model. CCK-8, flow cytometry, and ELISA assay were used to analyze cell viability, apoptosis, and concentrations of inflammatory factors. KEGG enrichment was employed to analyze the signal pathway of targets from GDI1 in the AD. The GEO database identifies coDEGs including GDI1. GDI1 is generally elevated in serum from AD patients as well as in Aβ-induced SH-SY5Y cells. GDI1 has 77.97% sensitivity and 84.44% specificity to identify AD patients from controls. Aβ induced decreased cell viability, increased apoptosis, and promoted over-secretion of inflammatory cytokines, but they were all partially weakened by reduced GDI1. What's more, the GDI1 interacting gene and AD target gene were co-enriched on Endocytosis and MAPK signaling pathway. Elevated GDI1 is a potential diagnostic biomarker for AD and that inhibition of GDI1 attenuates Aβ-induced neurotoxicity in AD. Our study offers new horizons for AD treatment.


[Effectiveness and duration of glucocorticoids in myocardial infarct (an experimental study)].
The authors studied the effect of prednisolone on the course of experimental myocardial infarction in rats. The results provide evidence that the effect of prednisolone on the course of experimental myocardial infarction is favourable when it is used in the first 6 days; medication with this drug over a longer period of time or its use in later stages is not recommended.


Substrate binding and catalytic mechanism in phospholipase C from Bacillus cereus: a molecular mechanics and molecular dynamics study.
For the first time a consistent catalytic mechanism of phospholipase C from Bacillus cereus is reported based on molecular mechanics calculations. We have identified the position of the nucleophilic water molecule, which is directly involved in the hydrolysis of the natural substrate phosphatidylcholine, in phospholipase C. This catalytically essential water molecule, after being activated by an acidic residue (Asp55), performs the nucleophilic attack on the phosphorus atom in the substrate, leading to a trigonal bipyramidal pentacoordinated intermediate (and structurally similar transition state). The subsequent collapse of the intermediate, regeneration of the enzyme, and release of the products has to involve a not yet identified second water molecule. The catalytic mechanism reported here is based on a series of molecular mechanics calculations. First, the x-ray structure of phospholipase C from B cereus including a docked substrate molecule was subjected to a stepwise molecular mechanics energy minimization. Second, the location of the nucleophilic water molecule in the active site of the fully relaxed enzyme-substrate complex was determined by evaluation of nonbonded interaction energies between the complex and a water molecule. The nucleophilic water molecule is positioned at a distance (3.8 A) from the phosphorus atom in the substrate, which is in good agreement with experimentally observed distances. Finally, the stability of the complex between phospholipase C, the substrate, and the nucleophilic water molecule was verified during a 100 ps molecular dynamics simulation. During the simulation the substrate undergoes a conformational change, but retains its localization in the active site. The contacts between the enzyme, the substrate, and the nucleophilic water molecule display some fluctuations, but remain within reasonable limits, thereby confirming the stability of the enzyme-substrate-water complex. The protocol developed for energy minimization of phospholipase C containing three zinc ions located closely together at the bottom of the active site cleft is reported in detail. In order to handle the strong electrostatic interactions in the active site realistically during energy minimization, delocalization of the charges from the three zinc ions was considered. Therefore, quantum mechanics calculations on the zinc ions and the zinc-coordinating residues were carried out prior to the molecular mechanics calculations, and two different sets of partial atomic charges (MNDO-Mulliken and AMI-ESP) were applied. After careful assignment of partial atomic charges, a complete energy minimization of the protein was carried out by a stepwise procedure without explicit solvent molecules. Energy minimization with either set of charges yielded structures, which were very similar both to the x-ray structure and to each other, although using AMI-ESP partial atomic charges and a dielectric constant of 4, yielded the best protein structure.


Cytomegalovirus-induced immunopathology and its clinical consequences.
Human cytomegalovirus (CMV) is a ubiquitous DNA virus that causes severe disease in patients with immature or impaired immune systems. During active infection, CMV modulates host immunity, and CMV-infected patients often develop signs of immune dysfunction, such as immunosuppression and autoimmune phenomena. Furthermore, active viral infection has been observed in several autoimmune diseases, and case reports have linked primary CMV infection and the onset of autoimmune disorders. In addition, CMV infection promotes allograft rejection and graft-versus-host disease in solid organ and bone marrow transplant recipients, respectively, further implicating CMV in the genesis and maintenance of immunopathological phenomena. The mechanisms by which CMV could induce inhibition of host defense, inflammation, and autoimmunity are discussed, as is the treatment of virus-induced immunopathology with antivirals.


Biochemical and molecular characterization of an azoreductase from Staphylococcus aureus, a tetrameric NADPH-dependent flavoprotein.
Azo dyes are a predominant class of colourants used in tattooing, cosmetics, foods and consumer products. A gene encoding NADPH-flavin azoreductase (Azo1) from the skin bacterium Staphylococcus aureus ATCC 25923 was identified and overexpressed in Escherichia coli. RT-PCR results demonstrated that the azo1 gene was constitutively expressed at the mRNA level in S. aureus. Azo1 was found to be a tetramer with a native molecular mass of 85 kDa containing four non-covalently bound FMN. Azo1 requires NADPH, but not NADH, as an electron donor for its activity. The enzyme was resolved to dimeric apoprotein by removing the flavin prosthetic groups using hydrophobic-interaction chromatography. The dimeric apoprotein was reconstituted on-column and in free stage with FMN, resulting in the formation of a fully functional native-like tetrameric enzyme. The enzyme cleaved the model azo dye 2-[4-(dimethylamino)phenylazo]benzoic acid (Methyl Red) into N,N-dimethyl-p-phenylenediamine and 2-aminobenzoic acid. The apparent Km values for NADPH and Methyl Red substrates were 0.074 and 0.057 mM, respectively. The apparent Vmax was 0.4 microM min(-1) (mg protein)(-1). Azo1 was also able to metabolize Orange II, Amaranth, Ponceau BS and Ponceau S azo dyes. Azo1 represents the first azoreductase to be identified and characterized from human skin microflora.


Pathological findings in dicephalus dipus dibrachius: implications for mechanisms in two pairs of lateral conjoined twins.
The anatomical and pathological features of two pairs of dicephalic conjoined twins (case 1 and 2) are described. Both twins showed duplicitas lateralis representing diprosopus dipus dibrachius. There were two complete heads on two necks, one thorax, one abdomen and externally normal two arms and two legs. Case 1 showed dicephalus with anencephaly, two vertebral columns and two spinal cords, which converged from the thoracic region distally. The esophagus, stomachs and partial small intestines were duplicated, which fused at yolk sac (with Meckel's diverticulum). The heart was incompletely fused. The lungs and trachea were doubled. Two spinal cords were fused from the thoracic region caudally and showed myelomeningocele and Arnold-Chiari malformation in case 2. Two larynxes and two thracheas connected with the incompletely fused three lobes of lungs. The conjoined lungs were hypoplastic. The heart was single, showing ventral septal defect, transposition of great arteries, two cuspid aortic valves and preductal aortic coarctation. The duplicated esophagi were conjoined in Y-shape and single stomach, duodenum, intestine and colon were found. There were pairs of kidneys, adrenal glands and ureters and single female genitalia in both cases. These findings indicate that the craniocaudal paleoaxes were separated in the cranial region and converted or fused under the thoracic region like a Y-shape. Further development defects and deformations might be important factors to form malformations in these case.


Active and prospective latent tuberculosis are associated with different metabolomic profiles: clinical potential for the identification of rapid and non-invasive biomarkers.
Although 23% of world population is infected with Mycobacterium tuberculosis (M. tb), only 5-10% manifest the disease. Individuals surely exposed to M. tb that remain asymptomatic are considered potential latent TB (LTB) cases. Such asymptomatic M. tb.-exposed individuals represent a reservoir for active TB cases. Although accurate discrimination and early treatment of patients with active TB and asymptomatic M. tb.-exposed individuals are necessary to control TB, identifying those individuals at risk of developing active TB still remains a tremendous clinical challenge. This study aimed to characterize the differences in the serum metabolic profile specifically associated to active TB infected individuals or to asymptomatic M. tb.-exposed population. Interestingly, significant changes in a specific set of metabolites were shared when comparing either asymptomatic house-hold contacts of active TB patients (HHC-TB) or active TB patients (A-TB) to clinically healthy controls (HC). Furthermore, this analysis revealed statistically significant lower serum levels of aminoacids such as alanine, lysine, glutamate and glutamine, and citrate and choline in patients with A-TB, when compared to HHC-TB. The predictive ability of these metabolic changes was also evaluated. Although further validation in independent cohorts and comparison with other pulmonary infectious diseases will be necessary to assess the clinical potential, this analysis enabled the discrimination between HHC-TB and A-TB patients with an AUC value of 0.904 (confidence interval 0.81-1.00, p-value < 0.0001). Overall, the strategy described in this work could provide a sensitive, specific, and minimally invasive method that could eventually be translated into a clinical tool for TB control.


Yellow fever virus envelope protein has two discrete type-specific neutralizing epitopes.
Two monoclonal antibody neutralization resistant (MAbR) variants of the yellow fever (YF) 17D-204 vaccine virus strain were selected using YF type-specific MAb B39. These B39R variants were compared with the variant virus selected by Lobigs et al. (Virology 161, 474-478, 1987) using a second YF-type specific MAb (2E10) which mapped to amino acid position 71/72 in the envelope (E) protein. Neutralization assays with a panel of MAbs suggested that these two YF-type-specific epitopes are located in two discrete regions of the folded E protein. Each of the B39R variants had a single nucleotide mutation which encoded an amino acid substitution at either position E-155 or E-158. Thus, YF type-specific epitopes map to both domain I (B39) and II (2E10) of the YF virus E protein. The B39 defined epitope represents the first flavivirus neutralizing epitope localized to this region of domain I of the E protein.


[A rapid and precise determination of fibrinogen and its cleavage products (author transl)].
A method is described for the quantitative determination of fibrinogen equivalents in citrated blood before and after removal of the fibrinogen by coagulation. The method employs an immunological reaction, which is measured by mechanized nephelometry. Thus the sum of all the fibrinogen equivalents can be compared with the concentration of "cleavage products". The difference between the two readings represents the concentration of coagulable fibrinogen. For the fibrinogen concentration of 11.15 mg/l, variation coefficients of 2.81% in series and 3.31% for day to day were obtained. The accuracy of a new method was tested under conditions of fibrinogenolysis, and in the presence of heparin, by comparison with simple radial immunodiffusion, and with the "coagulation physiological rapid method for the determination of fibrinogen" after Clauss ((1957), Acta-Haematol, 17, 237-246). In addition 180 citrated blood samples of different patients were compared with the simple radial immunodiffusion, the method of Clauss and the new method. Only the new rapid method appears to measure plausible fibrinogen values, and permits a clear differentiation between coagulable and non-coagulable fibrinogen equivalents. It can be recommended for clinical practice.


Fecundability of female twins.
Animal studies have shown evidence of prenatal hormonal interaction between unlike sexed fetuses, including reduced fertility among females. We evaluated whether the fecundability of female twins is different from that of singletons and whether it differs according to the sex of the co-twin. The study was based on a questionnaire survey of 12,681 female twins born in the period 1953-1976 and an interview survey of 760 female controls born in the period 1953-1966, both in Denmark. Outcome of the first try ever to become pregnant (pregnant, still trying, stopped trying, pregnant despite contraception, and never tried) and the waiting time to pregnancy distribution did not differ among monozygotic, dizygotic same sexed, and dizygotic unlike sexed twins. More twins had a waiting time of less than 2 months, compared with singletons. This difference probably reflects an artifact due to the data collection method, because it disappeared when the cutoff point was changed to include 2 months for singletons, and we found no difference for longer waiting times. Hence, we found no increase in fecundability for twins compared with singletons, nor any reduced fecundability among female twins from unlike sexed pairs.


Exploring the relation between learning style and cognitive impairment in patients with acquired brain injury.
The way a patient prefers to approach or choose a learning situation represents the patient's learning style. The objective of this chart review study was to explore the relation between learning style and cognitive impairment in patients with acquired brain injury (ABI). We used data from files of 92 adult patients with ABI referred to inpatient rehabilitation, who completed the Adapted Learning Style Inventory (A-LSI) and at least one of the following neuropsychological tests: Trail Making Test, Rey Auditory Verbal Learning Test, WAIS-III Digit Span, Rey-Osterrieth Complex Figure Test-Copy, Stroop Color-Word Test, or the Brixton Spatial Anticipation Test. The A-LSI yielded the following distribution of learning styles: 4 doers, 48 observers, 2 deciders and 38 thinkers. No significant correlation coefficients were found between the neuropsychological tests and the A-LSI. Furthermore, Chi-square tests revealed no significant associations between learning style (observer, thinker) and cognitive impairment. The results of this exploratory study suggest that learning style and cognitive impairment are independent in patients with ABI.


The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development.
Craniofacial development depends on cell-cell interactions, coordinated cellular movement and differentiation under the control of regulatory gene networks, which include the distal-less (Dlx) gene family. However, the functional significance of Dlx5 in patterning the oropharyngeal region has remained unknown. Here, we show that loss of Dlx5 leads to a shortened soft palate and an absence of the levator veli palatini, palatopharyngeus and palatoglossus muscles that are derived from the 4th pharyngeal arch (PA); however, the tensor veli palatini, derived from the 1st PA, is unaffected. Dlx5-positive cranial neural crest (CNC) cells are in direct contact with myoblasts derived from the pharyngeal mesoderm, and Dlx5 disruption leads to altered proliferation and apoptosis of CNC and muscle progenitor cells. Moreover, the FGF10 pathway is downregulated in Dlx5-/- mice, and activation of FGF10 signaling rescues CNC cell proliferation and myogenic differentiation in these mutant mice. Collectively, our results indicate that Dlx5 plays crucial roles in the patterning of the oropharyngeal region and development of muscles derived from the 4th PA mesoderm in the soft palate, likely via interactions between CNC-derived and myogenic progenitor cells.


[A Dutch family with familial Mediterranean fever].
Familial mediterranean fever (or recurrent hereditary polyserositis) is a genetic disorder with an autosomal recessive pattern of inheritance which occurs mostly in patients with eastern Mediterranean origin. Two Dutch patients are described, a 25-year-old women and her 58-year-old father, who suffered from recurring abdominal complaints, fever, and increased erythrocyte sedimentation rate, without evidence of Middle Eastern ancestry or hyperimmunoglobulinemia D.


Diet quality and weight gain among black and white young adults: the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1985-2005).
Little is known about the long-term health consequences of following the 2005 Dietary Guidelines for Americans (DGA; Washington, DC: US Government Printing Office, 2005). The objective was to examine the longitudinal association between diets consistent with the 2005 DGA and subsequent weight gain. We used data from the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a cohort of black and white men and women aged 18-30 y at baseline who attended ≤7 examinations from 1985-1986 to 2005-2006 (n = 4913). We created a 100-point Diet Quality Index (2005 DQI) to rate participants' diets based on meeting the 2005 DGA key recommendations. Longitudinal models of weight gain were adjusted for physical activity, smoking, energy intake, age, education, sex, and initial body mass index (BMI) and included interaction terms of DQI by race and initial BMI (if statistically significant). We found effect modification by race (likelihood ratio test, P < 0.03 in all models). The mean adjusted 20-y weight change was +19.4 kg for blacks and +11.2 kg for whites with high diet quality (DQI >70) and +17.8 for blacks and +13.9 for whites with a DQI <50 (P < 0.05). In race-specific Cox models (with interaction terms for DQI × initial BMI, P < 0.05), a 10-point increase in DQI score was associated with a 10% lower risk of gaining 10 kg in whites with an initial BMI (in kg/m(2)) <25 but with a 15% higher risk in blacks with baseline obesity (P < 0.001). Our findings do not support the hypothesis that a diet consistent with the 2005 DGA benefits long-term weight maintenance in American young adults. Greater need for attention to obesity prevention in future DGAs is warranted.


Impact of irradiation and thermal processing on the immunochemical detection of milk and egg allergens in foods.
There is little information available on the antigenicity of allergens in foods subjected to gamma irradiation and thermal processes. The objective of the study was to evaluate the effects of gamma irradiation and thermal processing on the recovery of milk and egg allergens in foods prepared using irradiated wheat flour incurred with these allergens. Bread, boiled pasta and extruded cereal were selected as food matrices for the study. Allergen detection was performed using Surface Plasmon Resonance (SPR) and commercially available enzyme linked immunosorbent assay (ELISA) kits. Protein structure was characterized using differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, and circular dichroism (CD) spectroscopy. The ELISA kits performed well in detecting allergens in the unprocessed flours with recoveries ranging from 63-120%. The results for dough and uncooked pasta were similar to those of unprocessed flours. Recoveries for boiled pasta were significantly (p≤0.05) reduced. The lowest allergen recoveries were obtained in bread samples. Allergen recoveries in gamma irradiated samples depended on the irradiation dose, the type of ELISA kit used, the tested matrix, and the processing method. FTIR and CD results showed that among the allergens casein was the most thermostable followed by ovomucoid. β-Lg and ovalbumin showed thermal sensitivity. In conclusion, gamma irradiation may affect the antigenicity of allergenic food residues at low levels depending on the food matrices and the processing methods.


Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis.
There is increasing evidence that autoantibodies and immune complexes (ICs) contribute to synovitis in rheumatoid arthritis (RA), yet the autoantigens incorporated in ICs in RA remain incompletely characterised. We used the C1q protein to capture ICs from plasma derived from human RA and control patients. Antibodies specific for immunoglobulin were used to detect ICs, and fibrinogen antibodies were used to detect fibrinogen-containing ICs. RA and control plasma were separated by liquid chromatography, and fractions then characterised by ELISA, immunoblotting and mass spectrometry. Immunohistochemical staining was performed on rheumatoid synovial tissue. C1q-immunoassays demonstrated increased levels of IgG (p = 0.01) and IgM (p = 0.0002) ICs in plasma derived from RA patients possessing anti-cyclic citrullinated peptide (CCP+) autoantibodies as compared with healthy controls. About one-half of the anti-CCP+ RA possessed circulating ICs containing fibrinogen (p = 0.0004). Fractionation of whole RA plasma revealed citrullinated fibrinogen in the high molecular weight fractions that contained ICs. Positive correlations were observed between fibrinogen-containing ICs and anti-citrullinated fibrinogen autoantibodies, anti-CCP antibody, rheumatoid factor and certain clinical characteristics. Immunohistochemical staining demonstrated co-localisation of fibrinogen, immunoglobulin and complement component C3 in RA pannus tissue. Mass spectrometry analysis of immune complexes immunoprecipitated from RA pannus tissue lysates demonstrated the presence of citrullinated fibrinogen. Circulating ICs containing citrullinated fibrinogen are present in one-half of anti-CCP+ RA patients, and these ICs co-localise with C3 in the rheumatoid synovium suggesting that they contribute to synovitis in a subset of RA patients.


EAHP European Statements Survey 2018, focusing on Section 1: Introductory Statements and Governance, Section 3: Production and Compounding, and Section 4: Clinical Pharmacy Services.
The 2018 EAHP European Statements Survey focused on sections 1, 3 and 4 of the European Statements of Hospital Pharmacy. Statistical data on the level of implementation and on the main barriers to implementation of the Statements were collected. A further aim was to identify barriers in general, such as lack of awareness. An online questionnaire was sent to all hospital pharmacies in EAHP member countries. Data were analysed at Keele University School of Pharmacy, UK. As with previous reports, the survey was divided into three sections: section A, asking general questions about the hospital pharmacy; Section B, addressing questions about the current activity of pharmacists around each statement from Sections 1, 3 and 4; and Section C, focusing on their ability to implement the statements. 719 complete responses were obtained from a sample of 5164 hospital pharmacies, giving a response rate of 14% (719/5164). Section A results indicated that 45% (323/719) of responders worked in teaching hospitals, 79% (568/719) of hospital pharmacies had 10 or fewer pharmacists, and 48% (345/719) of hospital pharmacies served over 500 beds. Section B results found a high percentage of positive responses for activity in section 1 (introductory statements and governance) and section 3 (production and compounding). However, responses to questions in section 4 (clinical pharmacy services) were more variable, with 6 of the 15 questions being answered positively by less than half of respondents. The five questions that revealed the lowest implementation levels were then analysed in greater detail. These questions corresponded to Statements 4.4, 4.5, 4.8, 1.1, and 4.2, which need the greatest effort for implementation. The major identified barriers to implementation were 'lack of capacity' and that 'other health professionals in the hospital fulfil the tasks'. This survey provides useful information on the implementation status (and the barriers to, and drivers of implementation) of sections 1, 3 and 4 of the Statements. This will allow the EAHP to plan its implementation support programme for its members. To increase the quality of data, as well as the feedback to hospital pharmacies, the EAHP is planning to combine the survey with the self-assessment tool of the European Statements of Hospital Pharmacy.


Pathogenesis of hypertensive retinopathy. An experimental study in the monkey.
Retinal changes in accelerated hypertension were studied in seventeen monkeys with experimental hypertension by means of ophthalmoscopy and colour and flourescence photography during life, and by injection and digest preparations and light and electron microscopy after the animals had been killed. Cotton-wool spots developed in all but three monkeys. The arteries became tortuous and dilated and the light reflex decreased in those animals that became hypertensive. The earliest abnormality was a development of many points of fluorescein leakage on terminal arterioles or small arteries. Such leaking points were always present in relation to cotton-wool spots but were not confined to such areas. Focal narrowing of arteries was not observed but arteriolar occlusion and retrograde filling of the distal segment was present in three animals. Superficial linear haemorrhages were noted in five animals. Light microscopy revealed cotton-wool spots which were identical to those observed in man with a collection of swollen axons containing densely staining pseudonuclei. Study of the arterioles by electron microscopy showed findings ranging from normality to extensive necrosis. Many precapillary arteries were constricted and some were virtually occluded. Degenerative changes were present in smooth muscle cells in the wall of many of the constricted arterioles. Many arteries also showed insudation into their wall of plasma which had seeped into the muscular coat displacing and sometimes entirely replacing the smooth muscle cells. Except for arterioles with advanced necrosis, there was no indication of how plasma insudation occurred. Two arterioles with extensive necrosis showed a break within the endothelial cell cytoplasm through which penetration of plasma proteins had probably occurred. The extravascular tissues showed collections of amorphous material, sone of it with the typical banded configuration of fibrin. The sequence of events proposed to explain these features is as follows: (1) The arterioles constrict as the pressure rises, most likely as a result of vascular autoregulation. This may head to occlusion of the precapillary arterioles and is associated with necrosis of vascular smooth muscle. (2) Dilatation then occurs with insudation of plasma into the unsupported wall through a damaged endothelium. This stage probably corresponds to the autoregulatory break-point and is evidenced clinically by focal leakage of fluorescein. (3) Progressive plasma insudation into the vessel wall with further muscle necrosis results in secondary occlusion and the typical picture of advanced fibrinoid necrosis.


Labetalol, a combined alpha- and beta-blocker, in hypertension of pregnancy.
Labetalol was given to women with hypertension of pregnancy in their last trimester to study its acute effect on circulation and metabolism. Seven women were given 50 mg labetalol i v. There was a significant decrease of blood pressure from a mean of 143/101 +/- 4/2 (SEM) to 127/88 +/- 5/2 mm Hg. Maternal heart rate fell significantly from 77 +/- 5 to 68 +/- 3 beats per min. These changes persisted during a three-hour observation period. The hypotensive response was accompanied by a significant increase in plasma noradrenaline from 1.54 +/- 0.16 to 2.37 +/- 0.41 nmol/l, suggesting sympathetic activation. Plasma cyclic AMP, which is increased by beta 2-adrenoceptor stimulation, was significantly elevated after labetalol. This supports the hypothesis of partial beta-agonist activity of labetalol. Lipid metabolism, as judged from measurements of plasma FFA, glycerol and 3-hydroxybuturic acid, showed little change. The acute effect of labetalol on uteroplacental blood flow was determined in eight women with pregnancy hypertension using a gammacamera on line with a computer. 0.5 mCi indium-113m was given i v before and 30 min after labetalol was administered i v in a dose of 1 mg per kg body weight. After the injections of indium-113m, serial scintigrams were recorded during 10 s periods for 240 s. By computerized summation of the scintigrams, an image was obtained in which the placenta could be outlined for time-activity analysis of the isotope accumulation curve. From this curve a uteroplacental blood flow index could be calculated. Labetalol induced a significant drop of mean arterial blood pressure from 114 +/- mm Hg to 100 +/- 3 mm Hg after 30 min in this group of women. However, the uteroplacental blood flow index did not change. As we have earlier shown with this technique that uteroplacental blood flow can be severely impaired in hypertension of pregnancy, the finding of substained uteroplacental blood flow simultaneously with a decrease in blood pressure should be of clinical importance. Taken together with other studies of clinical effects, these results indicate that labetalol is useful in the treatment of hypertension of pregnancy.


Secular trends in the body mass index of Canadian children.
Various changes in society have created the opportunity for more sedentary behaviour and the consumption of food that is high in kilojoules, which may lead to a progressive increase in body mass over time. The purpose of this study was to examine secular changes in the body mass index (BMI) of Canadian children between 1981 and 1996. Nationally representative data from the 1981 Canada Fitness Survey, the 1988 Campbell's Survey on the Well-being of Canadians and the 1996 National Longitudinal Survey of Children and Youth were used in the analysis. Regression analyses were used to assess population changes in BMI from 1981 to 1996 for children aged 7-13 years. Changes in the distribution of BMI results were evaluated by plotting the residuals from regression analyses of BMI on age, assessed separately by sex, using the 1981 data as baseline. The proportions of children exceeding the 85th and 95th age- and sex-specific percentiles from the 1981 (baseline) data were also calculated. Since 1981, BMI has increased at the rate of nearly 0.1 kg/m2 per year for both sexes at most ages, indicating a clear secular trend toward an increase in BMI of Canadian children. The prevalence of overweight among boys increased from 15% in 1981 to 28.8% in 1996 and among girls from 15% to 23.6%. The prevalence of obesity in children more than doubled over that period, from 5% to 13.5% for boys and 11.8% for girls. Secular trends indicate that Canadian children aged 7-13 years are becoming progressively overweight and obese.


Norepinephrine-sensitive adenylate cyclase system in rat brain: role of adrenal corticosteroids.
Two weeks after bilateral adrenalectomy, the responsiveness of the norepinephrine (NE)-sensitive adenylate cyclase system in the rat frontal cortex was increased. This effect was restricted to the non-beta-component of the system as no change was observed in the cyclic AMP response elicited by isoproterenol after bilateral adrenalectomy, thus indicating that subpopulations of cortical NE receptor systems are under separate endocrine control. The effect of adrenalectomy on the NE-sensitive adenylate cyclase system could be completely reversed by administering corticosterone for 3 days. No changes in the cyclic AMP response to NE were observed 2 weeks after bilateral medullectomy. Furthermore, an increase in the responsiveness of the system was also observed 2 weeks after hypophysectomy. These results suggest that the effects observed in the NE-sensitive adenylate cyclase system after adrenalectomy are mediated by the loss of adrenal corticosteroids. Adrenalectomy did not alter the activities of either adenylate cyclase or phosphodiesterase. No apparent changes were observed in the maximum binding or dissociation constant values of either beta or alpha adrenoceptors as assessed with [3H]alprenolol, [3H]WB-4101 and [ [3H]clonidine. Furthermore, the effects of adrenalectomy cannot be accounted for by a shift in the diurnal variation of the system as the cyclic AMP response to NE in tissue from adrenalectomized animals was higher than that in tissue from shamoperated rats throughout a 24-hr period.


Autogenous iliac crest bone graft. Complications and functional assessment.
Functional outcomes and complications experienced by adult patients who underwent iliac crest bone grafting were evaluated to assess the effect of bone grafts on patient function. In addition to retrospective chart reviews, patients completed the Sickness Impact Profile and a detailed questionnaire on pain. One hundred ninety-two patients met study inclusion criteria. Major complications were recorded in four (2.4%) patients in whom infections developed requiring readmission. Thirty-seven (21.8%) patients had minor complications. One hundred nineteen of 170 patients were available for followup; of these 119 patients, 87 (73.1%) returned completed questionnaires. Thirty-three of 87 (37.9%) patients reported pain 6 months postoperatively. The incidence of pain decreased with time, with 16 of 87 (18.7%) patients continuing to report pain more than 2 years postoperatively. Proportionately more spine patients reported pain at all time points. The mean Sickness Impact Profile score for patients completing questionnaires was nine, suggesting most patients were functioning well 2 years postoperatively. The morbidity of iliac crest grafting remains substantial. Pain symptoms in this study sample seemed to last longer in more patients than earlier series have indicated. Minimizing muscle dissection around donor sites and the advent of bone graft substitutes may help alleviate these problems.


A functional link between glucokinase binding to insulin granules and conformational alterations in response to glucose and insulin.
Glucokinase (GK) activity is essential for the physiological regulation of insulin secretion by glucose. Because the enzyme exerts nearly total control over glucose metabolism in the beta-cell, even small changes in GK activity exert effects on glucose-stimulated insulin secretion and, consequently, the blood glucose concentration. Using quantitative imaging of multicolor fluorescent proteins fused to GK, we found that the association of GK with insulin granules is regulated by glucose in the beta-cell. Glucose stimulation increased the rate of fluorescence recovery after photobleaching of GK to insulin granules, indicating that GK is released into the cytoplasm after glucose stimulation. Changes in fluorescence resonance energy transfer between two different fluorescent protein variants inserted on opposing ends of GK were observed after glucose stimulation and correlated with increased enzyme activity. Furthermore, glucose-stimulated changes in GK regulation were blocked by two inhibitors of insulin secretion. Insulin treatment restored GK regulation in inhibited cells and stimulated GK translocation and activation by itself. Together, these data support a model for post-translational regulation of GK whereby insulin regulates both the association of GK with secretory granules and the activity of the enzyme within the pancreatic beta-cell.


Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome.
Mitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation. The clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations. Analysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation. Individuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.


Characterization of Trypanosoma congolense serodemes in stocks isolated from Chipata District, Zambia.
Six stocks of Trypanosoma congolense were cloned from 17 stocks isolated from Eastern Zambia and used to initiate insect-form in vitro cultures producing metacyclic trypanosomes. Serological assays were then developed using these in vitro-derived metacyclics as a reference collection of antigens. Monoclonal antibodies recognized 8 metacyclic variable antigen types (M-VATs) of one stock, T. congolense TREU 1885, representing 70-80% of that stock's M-VAT repertoire, and in an indirect fluorescent antibody test (IFAT) there were no cross-reactions between them and the metacyclic trypanosomes of the other 5 stocks. Cross-protection assays between the 6 stocks in mice showed that the stocks cultured in vitro were serologically distinct. In order to facilitate serological typing for serodeme characterization, an IFAT was developed using formalin-fixed metacyclic trypanosomes to identify VAT specific immune responses using 21 day post-infection antisera. The cultured stocks reacted only with their homologous antisera thus confirming the results obtained in the cross-protection assays. No cross-reactions were observed with the 6 cloned stocks and antisera against the 11 stocks of T. congolense isolated in the same area at the same time suggesting that these stocks were different from the reference collection of cultured metacyclics. Hence, at least 7 serodemes of T. congolense have been identified from the 17 stocks isolated.


Insights into the adaptive significance of vertical pupil shape in snakes.
Pupil shape in vertebrates ranges from circular to vertical, with multiple phylogenetic shifts in this trait. Our analyses challenge the widely held view that the vertical pupil evolved as an adaptation to enhance night vision. On functional grounds, a variable-aperture vertical pupil (i) allows a nocturnal species to have a sensitive retina for night vision but avoid dazzle by day by adjusting pupil closure, and (ii) increases visual acuity by day, because a narrow vertical pupil can project a sharper image onto the retina in the horizontal plane. Detection of horizontal movement may be critical for predators that wait in ambush for moving prey, suggesting that foraging mode (ambush predation) as well as polyphasic activity may favour the evolution of vertical pupil shape. Camouflage (disruption of the circular outline of the eye) also may be beneficial for ambush predators. A comparative analysis in snakes reveals significant functional links between pupil shape and foraging mode, as well as between pupil shape and diel timing of activity. Similar associations between ambush predation and vertically slit pupils occur in lizards and mammals also, suggesting that foraging mode has exerted major selective forces on visual systems in vertebrates.


P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury.
Extracellular nucleotides have been implicated as signaling molecules used by microglia to sense adverse physiological conditions, such as neuronal damage. They act through purinoceptors, especially the G-protein-coupled P2Y receptor P2Y(12)R. Emerging evidence has indicated that activated spinal microglia responding to nerve injury are key cellular intermediaries in the resulting highly debilitating chronic pain state, namely neuropathic pain. However, the role of microglial P2Y(12)Rs in neuropathic pain remains unknown. Here, we show that the level of P2Y(12)R mRNA expression was markedly increased in the spinal cord ipsilateral to the nerve injury and that this expression was highly restricted to ionized binding calcium adapter molecule 1-positive microglia. An increase in the immunofluorescence of P2Y(12)R protein in the ipsilateral spinal cord was also observed after nerve injury, and P2Y(12)R-positive cells were double labeled with the microglial marker OX-42. Blocking spinal P2Y(12)R by the intrathecal administration of its antagonist AR-C69931MX prevented the development of tactile allodynia (pain hypersensitivity to innocuous stimuli), a hallmark of neuropathic pain syndrome. Furthermore, mice lacking P2ry(12) (P2ry(12)(-/-)) displayed impaired tactile allodynia after nerve injury without any change in basal mechanical sensitivity. Moreover, a single intrathecal administration of AR-C69931MX or oral administration of clopidogrel (a P2Y(12)R blocker clinically in use) to nerve-injured rats produced a striking alleviation of existing tactile allodynia. Together, our findings indicate that activation of P2Y(12)Rs in spinal microglia may be a critical event in the pathogenesis of neuropathic pain and suggest that blocking microglial P2Y(12)R might be a viable therapeutic strategy for treating neuropathic pain.


[Computer-assisted documentation and therapy planning in pediatric oncology--introduction of a nationwide solution].
In Pediatric Oncology in Germany, 90% of the patients are treated according to multicenter clinical trials, which means an enormous effort for documentation in the participating clinics. In order to enable multiple use of data for patient records as well as for clinical trials a computer-based documentation system for pediatric oncology (DOSPO) is being developed, which can be used nationwide. DOSPO currently comprises a minimum basic data set, which represents the common core of all multicenter trials and which has been approved by the German Society for Pediatric Oncology and Hematology (GPOH). It is intended to enhance the documentation by specific items of each clinical trial. Functions for computer-aided chemotherapy planning and medical report writing have already been implemented in the documentation system. Various centers in Germany are currently validating the system in routine use.


Gamma Knife radiosurgery in pituitary adenomas: Why, who, and how to treat?
Pituitary adenomas are benign tumors that can be either secreting (acromegaly, Cushing's disease, prolactinomas) or non-secreting. Transsphenoidal neurosurgery is the gold standard treatment; however, it is not always effective. Gamma Knife radiosurgery is a specific modality of stereotactic radiosurgery, a precise radiation technique. Several studies reported the efficacy and low risk of adverse effects induced by this technique: in secreting pituitary adenomas, hypersecretion is controlled in about 50% of cases and tumor volume is stabilized or decreased in 80-90% of cases, making Gamma Knife a valuable adjunctive or first-line treatment. As hormone levels decrease progressively, the main drawback is the longer time to remission (12-60 months), requiring an additional treatment during this period. Hypopituitarism is the main side effect, observed in 20-40% cases. Gamma Knife is thus useful in the therapeutic algorithms of pituitary adenomas in well-defined indications, mainly low secreting small lesions well identified on magnetic resonance imaging (MRI).


NF-κB-inducing kinase increases renal tubule epithelial inflammation associated with diabetes.
The impact of increased NF-κB-inducing kinase (NIK), a key component of the NF-κB activation pathways, on diabetes-induced renal inflammation remains unknown. We overexpressed NIK wild type (NIKwt) or kinase-dead dominant negative mutants (NIKdn) in HK-2 cells and demonstrated that RelB and p52, but not RelA, abundance and DNA binding increased in nuclei of NIKwt but not NIKdn overexpressed cells, and this corresponded with increases in multiple proinflammatory cytokines. Since TRAF3 negatively regulates NIK expression, we silenced TRAF3 by >50%; this increased nuclear levels of p52 and RelB, and transcript levels of proinflammatory cytokines and transcription factors. In HK-2 cells and mouse primary proximal tubule epithelial cells treated with methylglyoxal-modified albumin, multiple proinflammatory cytokines and NIK were increased in association with increased nuclear RelB and p52. These observations indicate that NIK regulates proinflammatory responses of renal proximal tubular epithelial cells via mechanisms involving TRAF3 and suggest a role for NF-κB noncanonical pathway activation in modulating diabetes-induced inflammation in renal tubular epithelium.


Effect of nesiritide on renal function in patients admitted for decompensated heart failure.
Studies addressing the effect of nesiritide on renal function in patients hospitalized for decompensated heart failure (HF) are limited, with conflicting results. To study the effect of nesiritide on renal function in patients admitted for acute decompensated HF. We retrospectively reviewed charts of patients admitted with decompensated HF, comparing those who received nesiritide along with conventional therapy vs. those who received conventional therapy alone. Serum creatinine levels and body weight were measured on admission, and were compared with levels at day 3 to estimate deterioration in renal function. Worsening renal function (WRF) was defined as a rise in serum creatinine of > or =0.3 mg/dl from baseline, with final creatinine level >1.5 mg/dl. We reviewed 206 charts (116 controls, 90 nesiritide group). WRF developed in 28/90 (31.1%) in the nesiritide group and 37/116 (31.9%) controls (p = 1.0). Mean change in creatinine in the nesiritide group was 0.15 +/- 0.37 mg/dl, compared to 0.17 +/- 0.25 mg/dl in controls (p = 0.75). Using an alternative cut-off increase in serum creatinine of > or =0.5 mg/dl, 16/90 (17.7%) patients in the nesiritide group developed WRF compared to 18/116 (15.5%) controls (p = 0.80). If WRF was defined as elevation in serum creatinine levels by > or =0.3 mg/dl anytime during hospitalization, the incidence of WRF in the nesiritide group remained similar to that of controls (42.2% vs. 41.3%, p = 0.90). On multivariate analysis, nesiritide therapy was not associated with WRF (OR 0.8, 95% CI 0.4-1.6, p = 0.48). We failed to detect any significant risk of WRF in patients treated with nesiritide compared to conventional therapy in patients with decompensated HF during index hospitalization. Larger randomized, placebo-controlled trials are required to further elucidate the effect of nesiritide on renal function in these patients.


Reduced Breastfeeding Rates in Firstborn Late Preterm and Early Term Infants.
The primary objective was to determine the rate of breastfeeding by gestational age reported by new mothers 1 month postpartum, with particular focus on early term newborns (37-38(6)/7 weeks). Three thousand six primiparous women aged 18-36 years were interviewed during their third trimester and again 1 month postpartum. Logistic regression analysis was used to model the association between gestational age and breastfeeding 1 month postpartum among those who reported that they planned to breastfeed, controlling for potentially confounding variables. Two thousand seven hundred seventy-two women planned to breastfeed (92.2%), among whom 116 (4.2%) delivered late preterm (34-36(6)/7 weeks), 519 (18.7%) early term (37-38(6)/7 weeks), and 2,137 (77.1%) term or postterm (39+ weeks). Among those who delivered late preterm, 63.8% were breastfeeding 1 month postpartum, early term 72.6%, and term or postterm 76.5%. This relationship was verified by a multivariate logistic regression analysis; late preterm newborns were significantly less likely to be breastfeeding 1 month postpartum than the term or postterm newborns (odds ratio [OR] 0.44; 95% confidence interval [CI] 0.28-0.69; p ≤ 0.0001), as were early term newborns (OR 0.77; 95% CI 0.60-0.99; p = 0.038). In this large prospective study of first-time mothers and newborns, gestational age was significantly associated with breastfeeding 1 month postpartum; highlighting late preterm and early term infants as populations at risk for shortened breastfeeding duration and the need to create specific breastfeeding support and education.


Giant cell tumor of the larynx: a case of malignant sarcomatous transformation.
We report what is to the best of our knowledge the first case of malignant transformation of a giant cell tumor of the larynx. The patient, a 34-year-old man, presented to our tertiary care university teaching hospital where he underwent hemilaryngopharyngectomy with radial forearm free flap reconstruction and 11 of 15 cycles of chemotherapy. He remained disease-free at approximately 6 years and 4 months of follow-up. The patient is decannulated and continues to have a good voice with excellent quality of life to this day. We discuss the patient's clinical course and subsequent treatment within the context of a review of the current literature regarding this disease entity. Our experience demonstrates that giant cell tumor of the larynx may present as a malignant neoplasm without adversely affecting the patient's prognosis when treated aggressively with surgical resection and adjunct chemotherapy.


Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53.
It has been well known that curcumin is a powerful inhibitor of proliferation of several tumor cells. However, the molecular basis of the anti-proliferative effect of curcumin has not been investigated in detail. In this paper, we present evidence to show that curcumin inhibited proliferation of a variety of B lymphoma cells. At low concentrations curcumin inhibited the proliferation of BKS-2, an immature B cell lymphoma, more effectively than that of normal B lymphocytes and caused the apoptosis of BKS-2 cells in a dose- and time-dependent manner. Furthermore, curcumin downregulated the expression of survival genes egr-1, c-myc, and bcl-X(L) as well as the tumor suppressor gene p53 in B cells. In addition, NF-kappaB binding activity was also downregulated almost completely by curcumin. Stimulation with CpG oligonucleotides or anti-CD40 overcame growth inhibition induced by low concentrations of curcumin. Our results suggest that curcumin caused the growth arrest and apoptosis of BKS-2 immature B cell lymphoma by downregulation of growth and survival promoting genes.


Shear wave velocity measurements using acoustic radiation force impulse in young children with normal kidneys versus hydronephrotic kidneys.
To measure shear wave velocities (SWVs) by acoustic radiation force impulse (ARFI) ultrasound elastography in normal kidneys and in hydronephrotic kidneys in young children and to compare SWVs between the hydronephrosis grades. This study was approved by an institutional review board, and informed consent was obtained from the parents of all the children included. Children under the age of 24 months were prospectively enrolled. Hydronephrosis grade was evaluated on ultrasonography, and three valid ARFI measurements were attempted using a high-frequency transducer for both kidneys. Hydronephrosis was graded from 0 to 4, and high-grade hydronephrosis was defined as grades 3 and 4. Fifty-one children underwent ARFI measurements, and three valid measurements for both kidneys were obtained in 96% (49/51) of the patients. Nineteen children (38.8%) had no hydronephrosis. Twenty-three children (46.9%) had unilateral hydronephrosis, and seven children (14.3%) had bilateral hydronephrosis. Seven children had ureteropelvic junction obstruction (UPJO). Median SWVs in kidneys with high-grade hydronephrosis (2.02 m/sec) were higher than those in normal kidneys (1.75 m/sec; P=0.027). However, the presence of UPJO did not influence the median SWVs in hydronephrotic kidneys (P=0.362). Obtaining ARFI measurements of the kidney is feasible in young children with median SWVs of 1.75 m/sec in normal kidneys. Median SWVs increased in high-grade hydronephrotic kidneys but were not different between hydronephrotic kidneys with and without UPJO.


Platelet function testing and prediction of procedural bleeding risk.
The essential role of platelets in haemostasis underlies the relationship between platelet function and spontaneous or procedure-related bleeding, which has important prognostic implications. Although not routinely undertaken, platelet function testing offers the potential to tailor antiplatelet therapy for individual patients. However, uncertainties remain about how well platelet function testing may predict haemostasis and guide management of bleeding risk. Studies of aspirin, P2Y12 inhibitors and other antiplatelet drugs clearly demonstrate how inhibition of platelet function increases bleeding risk. More potent antiplatelet drugs are associated with higher bleeding rates, consistent with the levels of platelet inhibition achieved by these drugs. Studies of patients treated with clopidogrel, which is associated with wide inter-individual variation in antiplatelet effect, suggest that platelet function testing may predict bleeding risk related to coronary artery bypass grafting (CABG) surgery and potentially guide the timing of surgery following discontinuation of clopidogrel. Similarly, some studies have demonstrated a relationship between clopidogrel response and bleeding in patients undergoing percutaneous coronary intervention (PCI), although other studies have not supported this. Carriage of the *17 allele of cytochrome P450 2C19, which is associated with gain of function and enhanced response to clopidogrel, seems to be associated with increased bleeding risk, although studies showing lack of apparent effect of loss-of-function alleles provide contradictory evidence. Further large studies are needed to guide best practice in the application of platelet function testing in the clinical management of patients treated with antiplatelet drugs in order to optimise individual care.


Scanning Micromirror Platform Based on MEMS Technology for Medical Application.
This topical review discusses recent development and trends on scanning micromirrors for biomedical applications. This also includes a biomedical micro robot for precise manipulations in a limited volume. The characteristics of medical scanning micromirror are explained in general with the fundamental of microelectromechanical systems (MEMS) for fabrication processes. Along with the explanations of mechanism and design, the principle of actuation are provided for general readers. In this review, several testing methodology and examples are described based on many types of actuators, such as, electrothermal actuators, electrostatic actuators, electromagnetic actuators, pneumatic actuators, and shape memory alloy. Moreover, this review provides description of the key fabrication processes and common materials in order to be a basic guideline for selecting micro-actuators. With recent developments on scanning micromirrors, performances of biomedical application are enhanced for higher resolution, high accuracy, and high dexterity. With further developments on integrations and control schemes, MEMS-based scanning micromirrors would be able to achieve a better performance for medical applications due to small size, ease in microfabrication, mass production, high scanning speed, low power consumption, mechanical stable, and integration compatibility.


Does endoscopic sinus surgery alter the biomechanics of the orbit?
The purpose of this study is to determine if removal of ethmoid cell septations as commonly performed in endoscopic sinus surgery leads to a change in orbital wall fracture patterns and the force required to create them. Six fresh-frozen cadaveric heads were acquired and underwent endoscopic uncinectomy, maxillary antrostomy, and anterior and posterior ethmoidectomy on one, randomized, side. The contralateral sinuses were used as intra-specimen control. Hyaluronic acid gel globe injections were performed to simulate normal intra-ocular pressure. Post-op CT scans confirmed no orbital fractures or violation of the lamina papyracea prior to trauma testing. Orbital trauma was induced using a guided weight-drop technique. Both orbits were tested in random order, and sequentially higher drops were performed until both the test and control side demonstrated an orbital fracture on CT scan. In all six heads, the post-sinus surgery side incurred a medial orbital wall fracture, and no orbital floor fractures were identified. On the other hand, on the control side, all six heads incurred orbital floor fractures at drop heights equal to, or higher than, the surgical side. Fisher's exact test demonstrated a significant difference in fracture pattern (p < 0.001). To our knowledge, this is the first demonstration that the structures removed during sinus surgery may act as a buttress for the medial orbital wall. The anatomic changes of sinus surgery may alter the biomechanics of the orbit and affect the pattern of subsequent traumatic blowout fractures.


Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review.
Ototoxicity has been reported after administration of aminoglycosides and glycopeptides. To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children. Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies. Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%-57%, whereas the frequency of tinnitus and vertigo ranged between 0%-53% and 0%-79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication. In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.


Adjustment of children and adolescents to parental cancer. Parents' and children's perspectives.
Little empirical evidence exists to address the impact of a diagnosis of cancer of a father or mother on his or her children. Previous studies have found inconsistencies in the levels of distress reported for children of a parent with cancer, which may be a function of who (parent or child) was reporting on the child's symptoms and when the reports were taken (near diagnosis or months or years later). This study examined parents' and children's reports of emotional and behavioral problems in children and adolescents from 76 patient families in which a mother or father was recently diagnosed with cancer. Parents' reports indicated little or no evidence of emotional distress or disruptive behavior in their children regardless of the child's age or sex, or whether the mother or father was ill. Children's reports differed significantly from those of their parents, with adolescent girls reporting the highest levels of symptoms of anxiety/depression and aggressive behavior. Children's reports of their emotional distress declined from an initial assessment 10 weeks after their parents' diagnosis to a follow-up 4 months later, whereas parents' reports of their children's distress did not change with time. Children's symptoms of psychologic distress varied considerably according to their age, sex, whether their mother or father had cancer, and whether they themselves or their parents were reporting the symptoms. Adolescent girls whose mothers had cancer reported the highest levels of distress. When children did report elevated levels of psychologic symptoms, their parents did not appear to be aware of their distress and rated their children as asymptomatic. These findings suggest that health professionals may need to assist parents in recognizing and coping with their children's distress when it is present.


New Approaches to Target T-ALL.
Acute lymphoblastic leukemia is the most common malignancy in children. Although it is now curable in 80-90% of cases, patients with T-cell acute lymphoblastic leukemia (T-ALL) experience a higher frequency of induction failure and early relapse. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-ALL will not be cured. As such, we are in need of new targeted therapies for the disease. Recent advances in the molecular characterization of T-ALL have uncovered a number of new therapeutic targets. This review will summarize recent advancements in the study of inhibiting the NOTCH1, PI3K-AKT, and Cyclin D3:CDK4/6 pathways as therapeutic strategies for T-ALL. We will focus on pre-clinical studies supporting the testing of small-molecule inhibitors targeting these proteins and the rationale of combination therapies. Moreover, epigenetic approaches to modulate T-ALL are rapidly emerging. Here, we will discuss the data supporting the role of bromodomain and extra-terminal bromodomain inhibitors in human T-ALL.


Double-lock ratchet mechanism revealing the role of alphaSER-344 in FoF1 ATP synthase.
In a majority of living organisms, FoF1 ATP synthase performs the fundamental process of ATP synthesis. Despite the simple net reaction formula, ADP+Pi→ATP+H2O, the detailed step-by-step mechanism of the reaction yet remains to be resolved owing to the complexity of this multisubunit enzyme. Based on quantum mechanical computations using recent high resolution X-ray structures, we propose that during ATP synthesis the enzyme first prepares the inorganic phosphate for the γP-OADP bond-forming step via a double-proton transfer. At this step, the highly conserved αS344 side chain plays a catalytic role. The reaction thereafter progresses through another transition state (TS) having a planar ion configuration to finally form ATP. These two TSs are concluded crucial for ATP synthesis. Using stepwise scans and several models of the nucleotide-bound active site, some of the most important conformational changes were traced toward direction of synthesis. Interestingly, as the active site geometry progresses toward the ATP-favoring tight binding site, at both of these TSs, a dramatic increase in barrier heights is observed for the reverse direction, i.e., hydrolysis of ATP. This change could indicate a "ratchet" mechanism for the enzyme to ensure efficacy of ATP synthesis by shifting residue conformation and thus locking access to the crucial TSs.


Preclinical antitumor activity of the azonafide series of anthracene-based DNA intercalators.
The azonafides are a series of anthracene-based DNA intercalators which inhibit tumor cell growth in vitro at low nanomolar concentrations and are not affected by the multidrug resistance phenomenon (MDR). Prior studies have described antitumor efficacy in murine tumor models including L-1210 and P-388 leukemias, and B-16 melanoma. The current results extend these cell line observations to human tumors tested in the NCI panel of 56 cell lines, in freshly isolated tumors tested in colony-forming assays in soft agar and in several animal models. In the NCI panel, the overall mean 50% cell kill (LC50) for the unsubstituted azonafide, AMP-1, was 10(-5.53) M, with some selectivity noted in melanomas (10(-6.22) M). The mean LC50 for the 6-ethoxy substituted analog, AMP-53, was 10(-5.53) M, with some selectivity found in non-small cell lung cancer (10(-5.91)) and renal cell carcinoma (10(-5.84)). In freshly isolated human tumors tested in soft agar, there was marked activity (mean IC50 in microg/ml) for AMP-53 in four cell types: breast cancer (0.09), lung cancer (0.06), renal cell carcinomas (0.06) and multiple myeloma (0.03). These effects were superior to doxorubicin and to several other azonafides, including AMP-1, AMP-104 and the 6-hydroxyethoxy derivative, AMP-115. Compound AMP-1 was shown to be superior to amonafide in the mammary 16C breast cancer model in B6CF31 mice, but it had little activity in Colon-38 nor in M5076 ovarian sarcomas in vivo. Nine azonafides were evaluated in the Lewis lung cancer model in C57/bl mice, but only AMP-53 demonstrated significant efficacy with a treated/control x 100% (T/C) value of 30%. Because AMP-53 demonstrated the greatest breadth of activity, it was then evaluated in several human tumor cell lines growing in mice with severe combined immunodeficiency disease (SCID). Only three tumors were sensitive (T/C<42%), including HL-60 leukemia (T/C=39%), MCF-7 breast cancer (T/C=39%) and A549 non-small cell lung cancer (T/C=37%). Overall, these results demonstrate that the 6-ethoxy substituted azonafide, AMP-53, has consistent (in vitro and in vivo) experimental antitumor activity in human breast and lung cancer, and could be considered for clinical testing in patients with MDR tumors.


Backward position shift in apparent motion.
We investigated the perceived position of visual targets in apparent motion. A disc moved horizontally through three positions from -10° to +10° in the far periphery (20° above fixation), generating a compelling impression of apparent motion. In the first experiment, observers compared the position of the middle of the three discs to a subsequently presented reference. Unexpectedly, observers judged its position to be shifted backward, in the direction opposite that of the motion. We then tested the middle disc in sequences of 3, 5, and 7 discs, each covering the same spatial and temporal extents (similar speeds). The backwards shift was only found for the three-disc sequence. With the extra discs approaching more continuous motion, the perceived shift was in the same direction as the apparent motion. Finally, using a localization task with constant static references, we measured the position shifts of all the disc locations for two-disc, three-disc and four-disc apparent motion sequences. The backward shift was found for the second location of all sequences. We suggest that the backward shift of the second element along an apparent motion path is due to an attraction effect induced by the initial point of the motion.


Community perceptions of childbearing and use of safer conception strategies among HIV-discordant couples in Kisumu, Kenya.
Safer conception strategies (SCS) have the potential to decrease HIV transmission among HIV-discordant couples who desire children. Community perceptions of SCS may influence the scale-up and uptake of these services, but little is known about how communities will react to these strategies. Without community support for SCS, their success as an HIV prevention tool may be limited. The objective of this study is to characterize community perceptions of SCS for HIV-discordant couples in Kisumu, Kenya, to inform ongoing and future safer conception intervention studies in low-resource settings. We conducted six focus group discussions and 11 in-depth-interviews in Kisumu, Kenya, among a diverse group (N=59) of community members, including men, women, youth (age 19-25), community health workers and local leaders. An iterative qualitative analysis using a grounded theory approach was employed. All participants emphasized the importance of childbearing in their society and the right to have children, regardless of an individual's HIV status. While most participants believed that HIV-discordant couples should be allowed to have children, they discussed several barriers to the uptake of SCS such as HIV-related stigma, fear of HIV transmission to the uninfected partner and child, fear of unfamiliar medical procedures and lack of information among community members and health care providers about HIV prevention interventions that allow safer conception. Access to information, community experiences with successful safer conception interventions, healthcare provider training, male engagement and community mobilization may help overcome these barriers. Though assisted reproduction strategies generated the most negative reactions from participants, our results suggest that with education and explanation of these services, participants express interest in these strategies and want them to be offered in their community. Many community members noted a need and desire for safer conception education and services in Kisumu. However, community barriers such as fear, stigma and lack of information should be addressed before safer conception interventions can be successfully implemented and delivered. Further research focused on community education, male engagement and healthcare provider training is a crucial next step in delivering safer conception in this region.


Timeline of heparin-induced thrombocytopenia seroconversion in serial plasma samples tested using an automated latex immunoturbidimetric assay.
HIT is caused by platelet-activating IgG that recognize multimolecular PF4/heparin complexes. HIT antibodies are generally detectable by PF4-dependent enzyme immunoassay (EIA) and by platelet serotonin-release assay (SRA) at the beginning of the HIT-related platelet count fall. We determined whether an automated immunoassay for HIT, the latex immunoturbidimetric assay (LIA), also detects antibodies early during the course of HIT. The LIA was also used to evaluate a patient with putative SRA-negative HIT. We evaluated the timing and magnitude of LIA reactivity in serial plasma samples obtained from 19 SRA-positive patients (17 with abnormal platelet count changes indicating HIT; two with subclinical seroconversion) and one putative SRA-negative HIT patient, all obtained from patients who participated in a clinical trial of heparin thromboprophylaxis. We determined LIA status at the onset of the HIT-related platelet count fall. The LIA was positive in all 19 SRA-positive patients (median value, 7.3 U/mL [range, 1.2-35.5]; cutoff, 1.0 U/mL); for all 13 evaluable patients for whom an informative plasma sample was available at (or shortly before) the onset of the HIT-related platelet count fall, LIA reactivity was positive. Heterogeneity in seroconversion using the LIA was observed; some patients exhibited gradual increases in reactivity, whereas other patients showed rapid increase in reactivity over a few days. The single clinical trial patient who met clinical-pathological criteria for "SRA-negative HIT" tested LIA-positive. The LIA detects HIT antibodies at the beginning of the HIT-associated platelet count fall. The LIA was also positive in a patient with SRA-negative HIT.


Demonstration of alpha 1-acid glycoprotein (orosomucoid) by double one-dimensional slab gel electrophoresis: evidence for intra- and interindividual variability of the microheterogeneity pattern in health and disease.
This double one-dimensional slab gel electrophoresis technique, in the sequence polyacrylamide gel electrophoresis followed by isoelectric focusing in polyacrylamide gels, permits the selective demonstration and comparison of the micro-heterogeneity pattern of alpha 1-acid glycoprotein (orosomucoid) in as many as 96 human plasma or serum samples on one gel. The electrophoretic analysis is performed on 8 microL of serum or plasma without prior purification. Several hundred samples can be analyzed by one investigator during a working day. Densitometric evaluation of the patterns revealed two new findings: 1) The microheterogeneity pattern can be described by a parameter that is independent of the concentration of orosomucoid in plasma: the center of density of the pattern, with the peak number as coordinate. 2) There is a considerable average shift of the center of density towards more basic components among the patterns obtained for samples from hospital patients. The results suggest that followup of the intra-individual variation of the orosomucoid pattern in health and disease might help in studying the still-uncertain function of this protein as well as the diseases affecting the pattern.


Early ischemia after complete coronary ligation in the rabbit, dog, pig, and monkey.
The character and extent of the myocardial ischemic "borderzone" was assessed in the rabbit, dog, pig, and monkey. A fluorophotographic technique permitting high resolution (+/- 50 micrometers) display of myocardial ischemia has been developed. Reduced intracellular NADH (ischemia) fluoresces and may be photographed while oxidized NAD (perfused tissue) does not. A coronary artery was ligated for 5 min in open-chest rabbits, dogs, pigs, and monkeys. A fluorescent dye was injected into the left atrium as a coronary vascular marker, and the tissue was quick-frozen. The ischemic margin was well seen and was jagged in all species. The distance from anoxic to perfused tissue (borderzone) was less than 50 micrometers in all species. A narrow "oxygen-diffusion zone" of nonperfused non-anoxic tissue is visible in isolated heart perfused with blood-free solution. The width of this zone is inversely related to myocardial oxygen consumption and is less than 50 micrometers in a working blood-perfused heart. We have not yet correlated the oxygen diffusion zone with the clinically defined salvageable borderzone. In dogs, collateral vessels provide a heterogeneous border to the ischemic region so that the canine ischemic pattern differs from that of pigs, rabbits, and monkeys.


The posterior skeletal thorax: rib-vertebral angle and axial vertebral rotation asymmetries in adolescent idiopathic scoliosis.
The deformity of the ribcage in thoracic adolescent idiopathic scoliosis (AIS) is viewed by most as being secondary to the spinal deformity, though a few consider it primary or involved in curve aggravation. Those who consider it primary ascribe pathogenetic significance to rib-vertebra angle asymmetry. In thoracic AIS, supra-apical rib-vertebra angle differences (RVADs) are reported to be associated with the severity of the Cobb angle. In this paper we attempt to evaluate rib and spinal pathomechanisms in thoracic and thnoracolumbar AIS using spinal radiographs and real-time ultrasound. On the radiographs by costo-vertebral angle asymmetries (rib-vertebral angle differences RVADs, and rib-spinal angle differences RSADs), apical vertebral rotation (AV) and apical vertebral translation (AVT) were measured; and by ultrasound, spine-rib rotation differences (SRRDs) were estimated. RVADs are largest at two and three vertebral levels above the apex where they correlate significantly and positively with Cobb angle and AVT but not AVR. In right thoracic AIS, the cause(s) of the RVA asymmetries is unknown: it may result from trunk muscle imbalance, or from ribs adjusting passively within the constraint of the fourth column of the spine to increasing spinal curvature from whatever cause. Several possible mechanisms may drive axial vertebral rotation including, biplanar spinal asymmetry, relative anterior spinal overgrowth, dorsal shear forces in the presence of normal vertebral axial rotation, asymmetry of rib linear growth, trunk muscle imbalance causing rib-vertebra angle asymmetry weakening the spinal rotation-defending system of bipedal gait, and CNS mechanisms.


Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Moderna COVID-19 Vaccine - United States, December 21, 2020-January 10, 2021.
As of January 20, 2021, a total of 24,135,690 cases of coronavirus disease 2019 (COVID-19) and 400,306 associated deaths had been reported in the United States (https://covid.cdc.gov/covid-data-tracker/#cases_casesper100klast7days). On December 18, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Moderna COVID-19 vaccine administered as 2 doses, 1 month apart to prevent COVID-19. On December 19, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of Moderna COVID-19 vaccine (1). As of January 10, 2021, a reported 4,041,396 first doses of Moderna COVID-19 vaccine had been administered in the United States, and reports of 1,266 (0.03%) adverse events after receipt of Moderna COVID-19 vaccine were submitted to the Vaccine Adverse Event Reporting System (VAERS). Among these, 108 case reports were identified for further review as possible cases of severe allergic reaction, including anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that occurs rarely after vaccination, with onset typically within minutes to hours (2). Among these case reports, 10 cases were determined to be anaphylaxis (a rate of 2.5 anaphylaxis cases per million Moderna COVID-19 vaccine doses administered), including nine in persons with a documented history of allergies or allergic reactions, five of whom had a previous history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 7.5 minutes (range = 1-45 minutes). Among eight persons with follow-up information available, all had recovered or been discharged home. Among the remaining case reports that were determined not to be anaphylaxis, 47 were assessed to be nonanaphylaxis allergic reactions, and 47 were considered nonallergic adverse events. For four case reports, investigators have been unable to obtain sufficient information to assess the likelihood of anaphylaxis. This report summarizes the clinical and epidemiologic characteristics of case reports of allergic reactions, including anaphylaxis and nonanaphylaxis allergic reactions, after receipt of the first dose of Moderna COVID-19 vaccine during December 21, 2020-January 10, 2021, in the United States. CDC has issued updated interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States (3) and interim considerations for preparing for the potential management of anaphylaxis (4).


The Emergency Surgery Score accurately predicts the need for postdischarge respiratory and renal support after emergent laparotomies: A prospective EAST multicenter study.
The Emergency Surgery Score (ESS) was recently validated as an accurate mortality risk calculator for emergency general surgery. We sought to prospectively evaluate whether ESS can predict the need for respiratory and/or renal support (RRS) at discharge after emergent laparotomies (EL). This is a post hoc analysis of a 19-center prospective observational study. Between April 2018 and June 2019, all adult patients undergoing EL were enrolled. Preoperative, intraoperative, and postoperative variables were systematically collected. In this analysis, patients were excluded if they died during the index hospitalization, were discharged to hospice, or transferred to other hospitals. A composite variable, the need for RRS, was defined as the need for one or more of the following at hospital discharge: tracheostomy, ventilator dependence, or dialysis. Emergency Surgery Score was calculated for all patients, and the correlation between ESS and RRS was examined using the c-statistics method. From a total of 1,649 patients, 1,347 were included. Median age was 60 years, 49.4% were men, and 70.9% were White. The most common diagnoses were hollow viscus organ perforation (28.1%) and small bowel obstruction (24.5%); 87 patients (6.5%) had a need for RRS (4.7% tracheostomy, 2.7% dialysis, and 1.3% ventilator dependence). Emergency Surgery Score predicted the need for RRS in a stepwise fashion; for example, 0.7%, 26.2%, and 85.7% of patients required RRS at an ESS of 2, 12, and 16, respectively. The c-statistics for the need for RRS, the need for tracheostomy, ventilator dependence, or dialysis at discharge were 0.84, 0.82, 0.79, and 0.88, respectively. Emergency Surgery Score accurately predicts the need for RRS at discharge in EL patients and could be used for preoperative patient counseling and for quality of care benchmarking. Prognostic and epidemiological, level III.


Changes in glottal contact quotient during resonance tube phonation and phonation with vibrato.
Phonating into narrow hard-walled tubes of varying diameters and length as an extension of the vocal tract is considered a semioccluded vocal tract exercise. Semioccluded vocal tract postures have been postulated to have a therapeutic effect during the treatment of the dysphonic patient. They appear to affect at least two components of the voice source (1) glottal flow pulse and (2) vibrational characteristics of the vocal folds. Vibrato also has been described as a possible therapeutic tool and may decrease phonatory hyperfunction. The aim of this study was to determine the influence of resonance tubes and phonation with vibrato on the closed quotient. Thirty-six adult classical singers were recruited for this study. Subjects were asked to produce four phonatory tasks at comfortable pitch and loudness: sustained vowel [a:] without vibrato, sustained vowel [a:] with vibrato, sustained phonation into a straw without vibrato, and sustained phonation into a straw with vibrato. Computer analysis of the contact quotient (CQ) was performed for each type of phonation in every participant. An increase in CQ variability was observed during tube phonation when compared with vowel phonation. Although there was a decrease in the mean CQ values when comparing vowel phonation without vibrato with the other three phonatory tasks, the difference was not statistically significant. Intrasubject analysis demonstrated a decrease in the CQ during tube and vibrato phonation in most of the participants. Although a causal relationship is not proven, this finding suggests that the use of straws and vibrato during phonation may have potential therapeutic value in the treatment of patients with hyperfunctional voice disorders.


[The dorsal hippocampus injury influences chronobiological effects of depressants and antidepressants in rats].
The administration of depressant reserpine and antidepressant imipramine in rats is manifested by opposite trends in the chronobiological aspect of behavior. Reserpine disorganizes the circadian locomotion rhythm and increases the rhythmological index of depression in the forced swim test. In contrast, imipramine increases the circadian rhythm contrast and decreases the index of depression. A bilateral lesion of the dorsal hippocampus attenuates both pharmacological effects, but the general trend has an antidepressant character: the effect of reserpine decreases, while the effect of imipramine increases. It is suggested that hippocampus probably plays an important role in the origin of depression and related chronobiological manifestations.


Association of objectively measured sedentary behaviour and physical activity with cardiovascular disease risk.
Background We evaluated the association of accelerometer-based sedentary behaviour and physical activity with the risk of cardiovascular disease. Design The design of this study used a population-based, cross-sectional sample. Methods A subsample of participants in the Health 2011 Study in Finland used the tri-axial accelerometer (≥4 days, >10 h/day, n = 1398). Sedentary behaviour (sitting, lying) and standing still in six-second epochs were recognised from raw acceleration data based on intensity and device orientation. The intensity of physical activity was calculated as one-minute moving averages of mean amplitude deviation of resultant acceleration and converted to metabolic equivalents. Metabolic equivalents were categorised to light physical activity (1.5-2.9 metabolic equivalents) and moderate-to-vigorous physical activity (moderate-to-vigorous physical activity≥3.0 metabolic equivalents). Daily sedentary behaviour, standing still, light physical activity and moderate-to-vigorous physical activity were expressed as mean daily total time, accumulated time and number of different bouts (from 30 s to >30 min), mean daily metabolic equivalent and weekly peak metabolic equivalent levels of different bout lengths and number of breaks in sedentary behaviour. The ten-year cardiovascular disease risk was based on the Framingham risk model. Results The mean number of daily sedentary behaviour bouts was more strongly associated with cardiovascular disease risk than mean daily total time. In the best model, smaller waist circumference, greater value of mean daily metabolic equivalent levels of one-minute bouts, higher accumulated time of moderate-to-vigorous physical activity lasting ≤30 min, higher number of >5 min standing bouts and a higher number of long (>30 min) bouts of light physical activity were significantly associated with lower cardiovascular disease risk (R2 = 0.836). Conclusions The objectively measured number and accumulated time from different bout lengths of physical activity and sedentary behaviour were associated with cardiovascular disease risk, which is considered relevant for estimating cardiovascular diseases and for devising preventive actions.


An Unusual Presentation of Insulinoma: Confusion With Psychiatric Symptoms.
Insulinoma is a rare but common functional neuroendocrine tumor that secretes an excess amount of insulin resulting in mostly fasting hypoglycemia but can also cause postprandial hypoglycemia. It usually presents with neuroglycopenic and autonomic sympathetic symptoms that resolve following the administration of dextrose. The patients may remain symptomatic from 1 week to as long as several decades before diagnosis. Insulinoma presenting with psychiatric symptoms has been documented in case/case series reports. Laboratory findings of elevated insulin and C-peptide level in the presence of hypoglycemia and absence of plasma sulfonylurea are suggestive of the diagnosis. Localization of the tumor is essential preoperatively. Surgery usually cures most of the patients, but a minority will have a recurrence especially with malignant insulinoma. The manuscript presents a case of insulinoma presenting with psychiatric symptoms without sympathetic symptoms that led to the delay of the diagnosis for 3 months as initially thought to be related to psychiatric problems. Pancreatic insulinoma was localized by computed tomography (CT) scan and confirmed with endoscopic ultrasound (EUS). The patient underwent successful resection of the tumor, and her symptoms were completely resolved.


A carbon dot-based fluorescent nanoprobe for the associated detection of iron ions and the determination of the fluctuation of ascorbic acid induced by hypoxia in cells and in vivo.
Maintaining the redox balance of biological systems is a key point to maintain a healthy physiological environment. Excessive iron ions (Fe3+) can cause apoptosis, tissue damage and death. Fortunately, ascorbic acid (AA) as a reducing agent has been evaluated for the reduction of Fe3+. Moreover, AA plays an important role in relieving hypoxia-induced oxidative stress. Therefore, the real-time imaging of the Fe3+ and AA fluctuations is important for understanding their biofunctions in cells and in vivo. In this work, we developed a fluorescent nanoprobe carbon dot-desferrioxamine B (CD-DB) by the conjugate connection of CDs and desferrioxamine B (a complexing agent for Fe3+) for the associated detection of Fe3+ and AA. CD-DB exhibited excellent sensitivity and selectivity for the detection of Fe3+ and AA. The nanoprobe CDs-DB@Fe obtained by the reaction of CD-DB and Fe3+ was suitable for tracing the dynamic changes of AA in cells and in vivo. Therefore, CDs-DB@Fe was used for monitoring the fluctuation of AA in hypoxic cell models, hypoxic zebrafish models and liver ischemia mice models. These results exhibited the decrease in AA under hypoxic conditions because AA was consumed to neutralize free radicals and relieve hypoxia-induced oxidative stress damage. The ideal biocompatibility and low toxicity make our nanoprobe a potential candidate for the research of the physiological effects of AA in vivo.


An acute osteomyelitis model in traumatized rat tibiae involving sand as a foreign body, thermal injury, and bimicrobial contamination.
The multfactorial nature of bone injuries in modern warfare and emergency trauma patients warrants enhancement of existing models. To develop a more appropriate model, rat tibiae (n = 195) were mechanically injured, divided into 2 groups (with or without thermal injury), and contaminated with a range of Staphylococcus aureus (Cowan 1) inocula. In some experiments, S. aureus inocula also contained Escherichia coli or foreign bodies (sand or soil). The primary outcome measure was the amount of S. aureus remaining in the tibia (tibial bacterial load) 24 h after contamination, reported as log10 cfu/g bone. S. aureus showed ID50 and ID95 values of 72 and 977 cfu, respectively. Values were lower than seen previously by using S. aureus strain SMH. S. aureus tibial bacterial loads were higher in tibiae with mechanical and thermal injury (log10 4.15 +/- 0.27 cfu/g) versus mechanical injury alone (log10 3.1 +/- 0.47 cfu/g, P = 0.028). The addition of E. coli to the S. aureus inoculum had no effect on tibial bacterial loads (S. aureus only, log10 4.24 +/- 0.92 cfu/g; S. aureus + E. coli, log10 4.1 +/- 1.0 cfu/g, P = 0.74). Sand, added as a foreign body, increased tibial bacterial load. Combined mechanical and thermal trauma of the tibia is associated with increased S. aureus tibial bacterial loads, increasing the risk of acute osteomyelitis. Understanding the interplay of mechanical and thermal injuries, bimicrobial contamination, and foreign bodies may improve our understanding of traumatic bone injuries and the pathogenesis of osteomyelitis.


Polynitroethyl- and fluorodinitroethyl substituted boron esters.
The reaction of boron oxide with various nitro-substituted ethanols (2-nitroethanol, 2-fluoro-2,2-dinitroethanol, 2,2,2-trinitroethanol) furnished the corresponding nitroethyl borates B(OCH2CH2NO2)3 (1), B(OCH2CF(NO2)2)3 (2), and B(OCH2C(NO2)3)3 (3). Fluorination of the anion [(NO2)2CCH2OH](-) (4) resulted in 2-fluoro-2,2-dinitroethanol (5), a precursor for 2, and was thoroughly characterized. An interesting condensation was observed with the anion 4 to form the unusual dianion [(NO2)2CCH2C(NO2)2](2-) (6). All compounds were fully characterized by multinuclear NMR spectroscopy, vibrational spectroscopy (IR, Raman), mass spectrometry and elemental analysis. The chemical, physical and energetic properties of 1-3 and 5 are reported, as well as quantum chemical calculations at the CBS-4M level of theory to predict the enthalpies and energies of formation. X-ray diffraction studies were performed, and the crystal structures for compounds 1-6 were determined and discussed thoroughly. The boron esters 1-3 are of interest as possible candidates for smoke-free, green colorants in pyrotechnic applications, and in case of 2 and 3 also as promising high energy oxidizers.


Prescription of antibiotics in Riga and Vilnius tertiary children's hospitals.
The aim of this study was to compare the use of antibiotics among hospitalised children in Riga (Latvia) and in Vilnius (Lithuania) at two tertiary paediatric centres. A point prevalence survey (PPS) was conducted using validated and standardised Antibiotic Resistance and Prescribing in European Children (ARPEC) project methodology during November 2012. All inpatients less than 18 years old were included in the study. All data were recorded for patients with active antimicrobial prescriptions at 8 am on the day of the survey. Data were entered into the ARPEC-webPPS programme and were validated online for accuracy. The proportion of patients receiving antimicrobial therapy was statistically different: 128 (37.0%) patients in Riga and 83 (26.3%) in Vilnius. The most common age group in Riga and Vilnius was 1-5 years. The most commonly used antibiotic classes for the treatment and prophylaxis of infection were third-generation cephalosporins (38; 25.5% prescriptions) in Riga and second-generation cephalosporins (16; 19.8%) in Vilnius. Parenteral use of antimicrobials was higher in Riga than in Vilnius: 111 (74.5%) prescriptions to paediatric patients in Riga and 45 (55.6%) prescriptions in Vilnius. The PPS identified differences in antibiotic use in both hospitals and problem areas for improvement: high use of third-generation cephalosporins for paediatric patients (in Riga) and predominant use of parenteral antibiotics. Further collaboration between both centres is needed because sharing audit data and antimicrobial stewardship initiatives may encourage further changes in practice at both institutions.


Utilization of paraoptometrics in contact lens practice.
The author discusses the many types of paraoptometrics used in a busy contact lens practice and how to integrate them into a professional team that offers quality care in a well-managed practice.


Locomotor activity and behavior of mutant mice deleted for gastrin gene expression.
The current studies were initiated to investigate the role of brain-gut peptide, gastrin, on locomotor activity and anxiety-like behavior. Young, male mutant mice, lacking gastrin gene expression (GAS-KO mice), were used in the experiments. The locomotor activity of GAS-KO vs wild type (WT) mice was compared by open field test. The anxiety-like behavior was examined using elevated plus maze. The time and entries to the open arms of the elevated plus maze were used as an indicator for the anxiety-like behavior and the data were analyzed using Hindsight program. On the open field test, locomotor activity of GAS-KO mice was similar to that of the WT mice for the first 10 min of the test, but decreased significantly after that. Anxiety-like behavior was more evident in the GAS-KO vs WT mice in the elevated plus maze experiments. The number of entries to and time spent on the open arms of plus-maze were significantly reduced for the GAS-KO vs WT mice suggesting an increased anxiety-like behavior of GAS-KO mice. Our studies suggest that normal circulating levels of gastrins may play a direct or indirect role in the regulation of locomotor activity and anxiety-like behavior.