Can the response to 23-valent pneumococcal vaccine in splenectomised patients be predicted?
The 23-valent pneumococcal vaccine has unequal effectiveness in splenectomised patients. We performed a longitudinal study (2005-2008) whose main objective was to characterize the profile of non-responders among splenectomised patients treated at our institution and identify potential predictive indicators of the response to the vaccine. The immune response was evaluated in 96 subjects. The proportion of responders was 70% (95% CI: 60-78%). Immunosuppression (OR=3.19, 95% CI 1.04-9.73) and the reason for splenectomy (hematologic neoplasia versus non-malignant hematologic diseases, OR=7.37, 95% CI 1.71-31.7) were independent predictors of non-response to vaccination. However, the positive predictive value of the model and the likelihood ratio for a positive result were low (PPV=76.6%, 95% CI 66.2-84.4%, LR(+)=1.41, 95% CI 1.08-1.86). We recommend determining the response to pneumococcal vaccine in these patients when possible.


Fish Oil Replacement by a Blend of Vegetable Oils in Diets for Juvenile Tench (Tinca tinca Linnaeus, 1758): Effects on Growth Performance and Whole-Body Composition.
Among freshwater species, tench (Tinca tinca Linnaeus, 1758) is considered as a promising species for the diversification of aquaculture, but the intensification of techniques is necessary to promote and consolidate its culture. Adequate feeding in early growth phases is essential to face further grow-out. Fish oil (FO) is the main source of lipids in fish diets, but its production is unsustainable, and thus, alternative oils should be considered. A 90-day experiment was performed to evaluate the effects of partial and total replacement of cod liver oil (FO) by a blend of vegetable oils (VO) in juvenile tench. Six isonitrogenous and isolipidic diets with different levels of a VO blend containing 30% linseed oil, 20% corn oil, and 50% olive oil were tested: 0% (control), 20%VO, 40%VO, 60%VO, 80%VO, and 100%VO. With all diets, survival was 100%, and there were not differences in growth performance (total length (TL); weight (W); specific growth rate (SGR); feed conversion ratio (FCR); and biomass gain (BG)). Compared to the control group, whole-body lipid content decreased significantly in the 100%VO group. No differences in total saturated (SFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids were found in the whole-body. The content of linolenic acid (ALA) in the whole-body increased as FO substitution did, being significantly higher with respect to control diet from 40% FO replacement diets. Nutritional indices, such as ΣPUFA/ΣSFA and Σn-6/Σn-3 ratios, tended to increase with increasing VO content, whereas the EPA + DHA showed an opposite trend. A total replacement of FO by the blend of VO did not affect the growth performance and fatty acid profile of juvenile tench. Further research on the effects of VO diet on nutritional quality in tench reared to commercial size should be performed.


Characterization of fatty acids, triacylglycerols, phytosterols and tocopherols in peony seed oil from five different major areas in China.
Peony (Paeonia lactiflora pall) is a unique plant in China, which is planted on a large scale in different areas. The study characterized the triacylglycerol (TAG), fatty acid (FA), phytosterol, and tocopherol in peony seed oil (PSO) from five cultivation areas in China. The FAs in PSO were mainly C18 fatty acyl chains, especially α-linolenic acid (C18:3n-3). The triacylglycerol of PSO was identified by UPLC-Q-ToF/MS, and the predominant TAGs were LnLnLn, LLnLn, LLLn, LnLO/LLL, and OOLn/OLL. As for the micronutrients, γ-tocopherol and β-sitosterol were main components of tocopherol and phytosterol, respectively. The obtained data were further analyzed by principal components analysis (PCA), which allowed differentiation of five PSOs by their cultivation areas. For the great potential in unsaturated fatty acid and micronutrients, PSO could be a good dietary resource of plant oil.


A general program for estimation of haplotype frequencies from population diploid data.
The program which is written in FORTRAN estimates haplotype frequencies in two-locus and three-locus genetic systems from population diploid data. It is based on the gene counting method which leads to maximum likelihood estimates, and can be used whenever the possible antigens (one or more) on each chromosome can be specified for each person and for each locus, i.e., ABO-like systems and inclusions are permitted. The number of alleles per locus may be rather large, and both grouped and ungrouped data can be used. Log likelihoods are calculated on the basis of various assumptions, so that likelihood ratio tests can be carried out.


Analysis of cellular expression of gangliosides by gene transfection. II: Rat 3Y1 cells transformed with several DNAs containing oncogenes (fes, fps, ras & src) invariably express sialosylparagloboside.
The transfection of several DNAs, containing oncogenes ras, src, fes or fps, into rat 3Y1 cells invariably induced the neosynthesis of sialosylparagloboside (SPG; IV3 alpha NeuAc nLcOse4Cer), with a concomitant decrease in GM3. All these oncogenes are 'extranuclear' type oncogenes, of which the products are expressed in the cytoplasm or on the cell surface membrane. These results are in striking contrast to those on the transfection of 'intranuclear' type oncogenes (ex., adeno E1) into the same 3Y1 cells, where GD3 neosynthesis was specifically brought about by the transfection.


Long-term outcome after management of pilocytic astrocytoma in the posterior fossa in a pediatric population.
To assess the impact of posterior fossa pilocytic astrocytoma (PA) removal in pediatric patients, with special focus on postoperative neurological outcome after repeated surgery for tumor remnants. Our institutional database was screened for patients with PA treated between 2000 and 2019. Patients ≤ 18 years of age with complete clinical records, preoperative contrast enhanced magnetic resonance imaging (MRI) and postoperative follow-up time of ≥ 6 months were suitable for study inclusion. Functional outcome was quantified with the modified Ranking Scale (mRS) score and assessed at admission, at discharge and at every follow-up investigation. Predictors of hydrocephalus, cranial nerve deficits and tumor recurrence were evaluated. A total of 57 pediatric patients with a mean age of 7.7 ± 4.8 years were included in the analysis. 27 (47.3%) children suffered from hydrocephalus at diagnosis, out of which 19 (33.3%) required a subsequent VP-Shunt. 22 (39.3%) patients had a partial resection, of which 9 (40.9%) went through second-look surgery. 2 patients with initially radiological confirmation of complete resection, had a tumor recurrence at FU and needed second-look surgery. Among the children requiring second-look surgery, 7 (63.6%) had a complete resection. Favorable outcome (mRS≤2) after initial and second-look surgery was observed in 52 patients (91.2%). Univariate analysis identified tumor location in the floor of the 4th ventricle (p = 0.030), and repeated surgery for tumor remnant removal (p = 0.043) as predictors for post-operative cranial nerve deficits. Multivariate analysis confirmed this independent association. The incidence of tumor recurrence occurred more often in patients with previous partial resection (p = 0.009) as well as in lesions located in the cerebellar peduncles (p = 0.043). Partial resection remained an independent predictor after multivariate logistic regression analysis (p = 0.045). Incomplete resection of posterior fossa PA is a risk factor for tumor recurrence and repeated surgery to remove tumor remnants increases the risk of new postoperative deficits. Thus, the risk of iatrogenic deterioration due to second look surgery should be implemented in the primary pre- and intraoperative decision-making.


[Substances inhibiting amine oxidases. III. Synthesis and amine oxidase inhibition of imidazoquinoline derivatives].
The activity of copper and FAD dependent amine oxidases was tested with some derivatives of 3H-imidazo[4,5-h]quinoline and its isomers 3H-imidazo[4,5-f]quinoline, the chemistry of which is described in the literature (1), and Ki calculated. The methyl derivative of 3H-imidazo[4,5-f]quinoline was found to activate the copper bovine serum enzyme, but inhibits the FAD mitochondrial enzyme.


Polishing methods for the lens capsule: histology and scanning electron microscopy.
Capsule opacification occurs when lens epithelial cells remains on the capsule after extracapsular cataract surgery. The cells divide and form fibers. The best way to prevent opacification is to remove all epithelial cells from the capsule. Our study compared the efficacy of different mechanical polishing methods in eyes in which cataracts were removed by endocapsular phacoemulsification through a miniature capsulorhexis. The capsular bag was polished using one of five techniques: metallic scrapers, silicone scrapers, Rentsch capsule curettes, irrigation/aspiration tip, or ultrasound irrigation/aspiration tip. Then a circular central portion of the anterior capsule was removed and processed for histology and scanning electron microscopy. A control group comprised unpolished central anterior capsules obtained by capsulorhexis before or after endophacoemulsification. The cleanest capsules were obtained by polishing with the ultrasound irrigation/aspiration tip.


Distinct functions of tissue-resident and circulating memory Th2 cells in allergic airway disease.
Memory CD4+ T helper type 2 (Th2) cells drive allergic asthma, yet the mechanisms whereby tissue-resident memory Th2 (Th2 Trm) cells and circulating memory Th2 cells collaborate in vivo remain unclear. Using a house dust mite (HDM) model of allergic asthma and parabiosis, we demonstrate that Th2 Trm cells and circulating memory Th2 cells perform nonredundant functions. Upon HDM rechallenge, circulating memory Th2 cells trafficked into the lung parenchyma and ignited perivascular inflammation to promote eosinophil and CD4+ T cell recruitment. In contrast, Th2 Trm cells proliferated near airways and induced mucus metaplasia, airway hyperresponsiveness, and airway eosinophil activation. Transcriptional analysis revealed that Th2 Trm cells and circulating memory Th2 cells share a core Th2 gene signature but also exhibit distinct transcriptional profiles. Th2 Trm cells express a tissue-adaptation signature, including genes involved in regulating and interacting with extracellular matrix. Our findings demonstrate that Th2 Trm cells and circulating memory Th2 cells are functionally and transcriptionally distinct subsets with unique roles in promoting allergic airway disease.


Dynamics of expression of apoptosis-regulatory proteins Bid, Bcl-2, Bcl-X, Bax and Bak during development of murine nervous system.
We have used immunohistochemistry and immunoblotting to examine the expression of Bid and four other Bcl-2 family proteins (Bcl-2, Bcl-X, Bax and Bak) in the developing and adult murine central nervous system (CNS). Bid protein is widespread in embryonic and postnatal brain, and its expression is maintained at a high level late into the adulthood. Bid is expressed both in the germ disc, early neural tube, proliferating stem cells of ventricular zones, and in postmitotic, differentiated neurons of the developing central and peripheral nervous system. As the differentiation proceeds, the neurons express higher levels of Bid than the stem cells of the paraventricular zone. Both in embryonic and postnatal life, Bid protein is present in the most vital regions of brain, such as the limbic system, basal ganglia, mesencephalic tectum, Purkinje cells in cerebellum, and the ventral columns of spinal cord. The p15 cleaved form of Bid was detectable in the brain specimens at fetal stages of development, consistent with caspase-mediated activation of this pro-apoptotic Bcl-2 family protein. Among the Bcl-2 family proteins only Bid and Bcl-XL continue to be expressed at high levels in the adult brain.


Application of polymaleimidostyrene as a convenient immobilization reagent of enzyme in biosensor.
Sulfhydryl groups of glucose oxidase (GOD) were reacted with maleimide groups of polymaleimidostyrene (PMS) which was coated onto the porous carbon sheet, and the carbon sheet immobilized by GOD was combined with an oxygen electrode to fabricate a glucose sensor. The activity of thiolated GOD immobilized to PMS is much larger than that of native GOD immobilized to PMS. The good linear relationship of glucose and oxygen current response was obtained in a concentration range from 0.1 to 2 mM and upper limit of linear range was found to be 3.0 mM. The immobilized GOD activity is highly dependent on pH at immobilization and the maximum activity was obtained at pH 5.5, probably because the SH groups of GOD that are indispensable for generation of enzyme activity is not exposed at this pH. It was found that PMS is very effective reagent to immobilize enzyme strongly via covalent bond, because high density of maleimide groups of PMS can catch not only exposed SH groups but also buried SH groups.


Determination of aeration rate and kinetics of composting some agricultural wastes.
This study aimed to determine the aeration rate and its kinetics in aerobic composting of agricultural wastes. For this aim compost materials were prepared by mixing grass trimmings, tomato, pepper, and eggplant wastes. Four vertical forced aeration type reactors and one vertical natural convection type reactor were manufactured to apply four different aeration rates. CO2 rate and temperature changes were recorded in three different places in the reactors. Moisture content, pH and organic material rate were recorded each day. While process-monitoring parameters (CO2, temperature, pH, moisture content) were used for interpretation of the process, organic material degradation was used for interpretation of the process success. The seven different kinetic models were applied for modeling decomposition rate to the experimental values. According to the results, four of these models were found applicable to this study. These models were analyzed with some statistical methods as root mean square error (RMSE), chi-square (chi2), and modeling efficiency (EF). According to the statistical results of these models, the best model was found as: [Formula: see text] where kT is the rate of decomposition (g VS/g VS day); T the process temperature (degrees C); Mc the daily moisture content (%wb); C the daily CO2 rate in composting reactor (%) and a, b, c, d are constants. According to the results, the highest organic matter degradation and temperature value were obtained at the aeration rate of 0.4 l air min(-1)kg(om)(-1). Thus, it could be applied to this mixed materials composting process.


Isolated and combined genetic tremor syndromes: a critical appraisal based on the 2018 MDS criteria.
The 2018 consensus statement on the classification of tremors proposes a two-axis categorization scheme based on clinical features and etiology. It also defines "isolated" and "combined" tremor syndromes depending on whether tremor is the sole clinical manifestation or is associated with other neurological or systemic signs. This syndromic approach provides a guide to investigate the underlying etiology of tremors, either genetic or acquired. Several genetic defects have been proven to cause tremor disorders, including autosomal dominant and recessive, X-linked, and mitochondrial diseases, as well as chromosomal abnormalities. Furthermore, some tremor syndromes are recognized in individuals with a positive family history, but their genetic confirmation is pending. Although most genetic tremor disorders show a combined clinical picture, there are some distinctive conditions in which tremor may precede the appearance of other neurological signs by years or remain the prominent manifestation throughout the disease course, previously leading to misdiagnosis as essential tremor (ET). Advances in the knowledge of genetically determined tremors may have been hampered by the inclusion of heterogeneous entities in previous studies on ET. The recent classification of tremors therefore aims to provide more consistent clinical data for deconstructing the genetic basis of tremor syndromes in the next-generation and long-read sequencing era. This review outlines the wide spectrum of tremor disorders with defined or presumed genetic etiology, both isolated and combined, unraveling diagnostic clues of these conditions and focusing mainly on ET-like phenotypes. Furthermore, we suggest a phenotype-to-genotype algorithm to support clinicians in identifying tremor syndromes and guiding genetic investigations.


Increasing growth with raised circulating somatomedin but normal immunoassayable growth hormone.
Two patients are described with elevation of circulating somatomedin A concentration but normal growth hormone levels. One,a young male, appeared clinically acromegalic; the other, a young female, was tall with kyphoscoliosis, and her appearance resembled Marfan's syndrome. In both patients plasma growth hormone concentration was suppressible by hyperglycaemia. It is suggested that their clinical syndromes resulted from excessive somatomedin activity.


[Adverse reproductive outcomes among women working in Colombian floriculture: a summary of the evidence through metaanalysis].
Workers in floriculture are exposed to pesticides and other risk factors. Work in these occupational environments is suspected to be associated with adverse reproductive outcomes. However, epidemiological studies in Colombia, a country that has a long tradition with this occupation, have not been consistent or conclusive. To quantify the effect of womens work in Colombian floriculture in the occurrence of spontaneous abortion, prematurity, and birth defects, using the results of two previous studies. The results of two previous studies among Colombian floriculture worker populations were summarized with metaanalysis techniques. A critical evaluation of each of the studies identified potential biases and methodological limitations. The pooled estimator of spontaneous abortion was 2.24 (95CI: 1.87-2.68); that of premature infant birth was 1.49 (95%CI: 0.91-2.43), and of birth defects 1.31 (95%CI: 1.95-1.64). The analyses suggested that work in floriculture is associated with a higher occurrence of spontaneous abortion and birth defects. However, these effects are not necessarily associated with pesticide exposure. Other risk factors requiring further study are levels of physical activity and high temperature in greenhouses. Data from countries which have initiated occupations in floriculture more recently will add valuable evidence for this controversial association.


High levels of hyaluronate in suction blister fluid from active psoriatic lesions.
Hyaluronate concentrations were measured in suction blister fluid from blisters raised on the abdominal skin of 12 healthy control subjects, on unaffected skin of 14 patients with psoriasis, and on lesional skin from 12 of these patients. The concentrations of hyaluronate in blister fluid from the controls and from the uninvolved skin of patients with psoriasis were within the same range (2.9-10.5 and 2.4-7.8 mg/l, respectively). Six of the patients had active, widespread, untreated psoriasis and in these cases the hyaluronate concentration in blister fluid from lesional skin was greatly increased (24-30 mg/l). Patients with stable or regressing psoriasis had no significant increase in hyaluronate levels in the blister fluid from lesional skin compared with the controls (range 4.6-12.4 mg/l). Patients with active psoriasis had significantly higher serum hyaluronate concentrations than the controls and those with inactive psoriasis.


Investigation of the applicability of silica-graphene hybrid materials as stationary phases for capillary liquid chromatography.
Graphene and graphene-derived substances are cutting-edge materials receiving increasing attention in the analytical chemistry field. Graphene oxide sheets bonded to amino silica particles functionalized with octadecyl (C18) groups and endcapped, also known as SiGO-C18ec, have been successfully employed as extraction phases and in analytical columns associated with conventional liquid chromatography (LC). In this work, SiGO-C18ec particles of 3, 5, and 10 µm nominal id were employed to pack capillary LC columns (100 mm long x 0.3 mm id), and their performance in the gradient mode was evaluated and compared. A 3 µm C18 capillary LC column (50 x 0.3 mm) was used as a reference column. Eight analytes having different polarities and topological surface areas were selected as a probe in this study: carbofuran clomazone, hexazinone, carbamazepine, citalopram, clomipramine, desipramine, and ochratoxin A. Studies about orthogonality were performed to investigate the orthogonality between the SiGO-C18ec and C18 phases. Among the SiGO-C18ec phases investigated, the column packed with 5 µm SiGO-C18ec particles presented the best peak capacity (29) in 15 min. Additionally, the performance of the columns packed with 5 µm SiGO-C18ec particles overcame the performance of the C18 columns used. Significant orthogonality was found between C18 and SiGO-C18ec packed columns; however, no significant differences were found between columns packed with SiGO-C18ec particles of different diameters.


Wafer-scale monolithic integration of full-colour micro-LED display using MoS2 transistor.
Large-scale growth of transition metal dichalcogenides and their subsequent integration with compound semiconductors is one of the major obstacles for two-dimensional materials implementation in optoelectronics applications such as active matrix displays or optical sensors. Here we present a novel transition metal dichalcogenide-on-compound-semiconductor fabrication method that is compatible with a batch microfabrication process. We show how a thin film of molybdenum disulfide (MoS2) can be directly synthesized on a gallium-nitride-based epitaxial wafer to form a thin film transistor array. Subsequently, the MoS2 thin film transistor was monolithically integrated with micro-light-emitting-diode (micro-LED) devices to produce an active matrix micro-LED display. In addition, we demonstrate a simple approach to obtain red and green colours through the printing of quantum dots on a blue micro-LED, which allows for the scalable fabrication of full-colour micro-LED displays. This strategy represents a promising route to attain heterogeneous integration, which is essential for high-performance optoelectronic systems that can incorporate the established semiconductor technology and emerging two-dimensional materials.


Treatment of aortic arch aneurysms with a modular transfemoral multibranched stent graft: initial experience.
To present initial experience with a new modular transfemoral multibranched stent graft for treating aortic arch aneurysms. Six patients, considered high risk for open surgery, were treated with custom made branched stent grafts. All patients had a staged left carotid subclavian bypass before the endovascular procedure. Each branched graft had a 12 mm side branch for the innominate artery and an 8 mm side branch for the left common carotid artery. Four patients out of six had uneventful placement of the prostheses, with successful exclusion of their aneurysms. One patient developed a type I endoleak that was managed successfully with coiling and gluing of the aneurysm sac. In one patient, cannulation of the innominate branch was unsuccessful and an extra-anatomic bypass was necessary to perfuse the right carotid and vertebral arteries. This patient developed a stroke, while one more suffered a right cerebellar infarct. We have demonstrated the technical feasibility of a modular transfemoral branched stent graft for treatment of aortic arch aneurysms. The method is relatively safe based on initial experience. More cases and long-term follow up are necessary to evaluate the efficacy and safety of this new device.


COVID19- clinical presentation and therapeutic considerations.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a pandemic infection in 2020 has presented many therapeutic challenges. Not least among these is the importance of abnormal host response to infection that is one of the main drivers of more severe disease. Despite significant research endeavours, very few effective therapies have been identified, in part related to the different pathogenic mechanisms underlying different stages of clinical COVID-19. This mini review summarises data related to current and potential future therapies for COVID-19 and highlights the many challenges inherent in developing effective therapeutic options for new pandemic infection.


Bone marrow-derived cells in the healing burn wound--more than just inflammation.
Scarring after severe burn is a result of changes in collagen deposition and fibroblast activity that result in repaired but not regenerated tissue. Re-epithelialisation of wounds and dermal cell repopulation has been thought to be driven by cells in the periphery of the wound. However, recent research demonstrated that cells originating from the bone marrow contribute to healing wounds in other tissues and also after incisional injury. We investigated the contribution of bone marrow-derived cells to long-term cell populations in scar tissue (primarily fibroblasts and keratinocytes) after severe burn. Wild-type mice were lethally irradiated and then the bone marrow reconstituted by injection of chimeric bone marrow cells expressing EGFP marker protein. Mice with chimeric bone marrow were then given a burn, either an 1-cm diameter injury (to mimic minor injury) or 2-cm diameter (to mimic moderate injury). Wounds were analysed at days 1, 3, 7, 14, 21, 28, 56 and 120 using FACS and immunohistochemistry to identify the percentage and cell type within the wound originating from the bone marrow. The inflammatory cell infiltrate at the early time-points was bone marrow in origin. At later time-points, we noted that over half of the fibroblast population was bone marrow-derived; we also observed that a small percentage of keratinocytes appeared to be bone marrow in origin. These findings support the theory that the bone marrow plays an important role in providing cells not only for inflammation but also dermal and epidermal cells during burn wound healing. This increases our understanding of cell origins in the healing wound, and has the potential to impact on clinical practice providing a potential mechanism for intervention away from conventional topical treatments and directed instead to systemic treatments affecting the bone marrow response.


Differential expressions of cancer-associated genes and their regulatory miRNAs in colorectal carcinoma.
Colorectal cancer is one of the frequently seen malignancies in the world. To date, several oncogenes and tumor suppressor genes have been identified and linked to colorectal cancer pathogenesis. Although recent advances in the diagnosis and therapy of colorectal cancer are promising, identifying novel genetic contributors is still high priority. In the present study, expression profile of some cancer-related genes and their regulatory miRNA molecules were evaluated by using a high-throughput real-time PCR method. For the study, a total of 54 patients diagnosed with CRC and normal colon tissue samples of 42 healthy controls were included. For the expression analysis, total RNA was extracted from FFPE tissue samples and converted to cDNA. All expression analyses were assessed by using Fluidigm Microfluidic Dynamic Array chips for 96 samples and the reactions were held in Fluidigm BioMark™ HD System Real-Time PCR. As a result of the study, expression of the ADAMTS1, FHIT, RUNX1, RUNX3 and WWOX genes was shown to be significantly altered in CRC tissues in contrast to normal tissue samples. Moreover, miR-378a-3p, miR-155-5p, miR-193b-3p, miR-96-5p, miR-17-5p, miR-27a-3p, miR-133b, miR-203a, miR-205-5p, miR-34c-5p, miR-130a-3p, miR-301a-3p, miR-132-3p, miR-222-3p, miR-34a-5p, miR-21-5p, miR-29a-3p and miR-29b-3p were found to be significantly deregulated in CRC. Consequently, results of the current study strongly suggest the involvement of novel cancer-related genes and their regulatory miRNAs in CRC physiopathology.


Fusion Image-Guided and Ultrasound-Guided Fine Needle Aspiration in Patients With Suspected Hepatic Metastases.
The aim of this study was to compare the diagnostic adequacy of computed tomography (CT)-ultrasound (US) fusion image-guided fine needle aspiration (FNA) and US-guided FNA in patients with suspected hepatic metastases. Thirty consecutive patients of either sex with known or unknown primary malignancy suspected of having liver metastases on both US and CT, whose multiphasic contrast-enhanced computed tomography was performed using a 64-slice or a higher slice CT scanner, and who were referred for percutaneous FNA were included in this prospective study approved by the institutional review board of the study institute. CT-ultrasound fusion image-guided FNA of the largest lesion using electromagnetic tracking and with freehand ultrasound-guided FNA were performed in the same sitting. Value of fitness, which is a rough estimate of how well the fusion has been achieved, was recorded. Diagnostic adequacy of smears was assessed by a scoring system based on cellular material, background blood/clot, degree of cellular degeneration or trauma, and retention of architecture. The size of the lesions ranged from 1 to 10 cm, and the depth of location of the lesions ranged from 1.4 to 9.3 cm. The fusion fitness values ranged from 1.2 to 10 mm. The scores of the smears did not correlate with lesion size, depth of location, and fusion fitness value. Diagnostic adequacy was seen in 90% and 93.3% of lesions sampled by fusion image guidance and ultrasound guidance, respectively (p = 0.655). All the lesions that yielded inadequate smears by fusion guidance were deep-seated lesions (>5 cm). All the lesions that yielded inadequate smears by ultrasound guidance were small lesions (<3 cm). No complications were encountered in any of the patients. Fusion image-guided FNA is a safe procedure with a high diagnostic adequacy rate. Fusion image-guided FNA is not better than US-guided FNA for conspicuous hepatic lesions; however, it may be useful in inconspicuous lesions.


Quantitative Ultrasonography Measurements of the Phalanges in Adolescents: A Mixed Longitudinal Study.
This study examined the effect of pubertal development on Amplitude Dependent Speed of Sound (AD-SoS), accounting for the growth in stature among adolescents. A mixed-longitudinal design with 3 assessments across a 15-mo period in 439 adolescents (girls: 215; boys: 224) aged 9-16 y was used. Bayesian multilevel models were used to describe gender-specific AD-SoS variations among participants during pubertal years. Substantial increments in AD-SoS during pubertal years were observed in both genders. AD-SoS changes were positively related to stature, and the rate of stature growth per year. Quantitative ultrasonography was sensible to describe age-related changes of bone mass during pubertal development. It seemed clinically reliable to use AD-SoS in the study of bone growth and development.


Comparison and cost analysis of three protocols for mobilization and apheresis of haematopoietic progenitor cells.
Autologous bone marrow transplantation is a component of the malignant hemopathy therapy. The preferred mobilization and collection method is apheresis. The aim of this study is to compare three protocols analyzing the effect of plerixafor, higher dose of G-CSF and large volume leukapheresis (LVL). A retrospective cohort study including 119 patients referred for mobilization. Three protocols were compared: (a) G-CSF 10 μg/kg/day subcutaneous (sc) × 4 days mobilizing 1 to 1.5 blood volumes. (b) G-CSF 10 μg/kg/day sc × 4 days + plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 1 to 1.5 blood volumes. (c) G-CSF 20 μg/kg/day sc × 4 days ± plerixafor 0.24 mg/kg/day sc preventively or as a rescue agent mobilizing 3 to 4 blood volumes. The average number of days of apheresis was reduced to 1.37 with protocol 3. The average cost per patient was reduced by 67% compared with protocol 2 and increased by only 5% compared with protocol 1, reducing the failure rate to 0%. Adding preemptive or rescue plerixafor (protocol 2) to G-CSF 10 μg/kg/day alone (protocol 1) did not improve the days of apheresis nor the number of CD34+ cells collected but had higher cost and failure rate. Using LVL, plerixafor and G-CSF 20 μg/kg/day (protocol 3) decreased the number of sessions to 1.37, reduced the failure rate to 0% and led to a significant increase in the number of CD34+ cells collected without toxicity and with a similar cost to protocol 1.


[Anton-Babinski syndrome with recognition of the left upper limb on visualization in a mirror [author's transl)].
A patient presenting with an Anton-Babinski syndrome accompanied by a delusional conviction recognised her left upper limb with the aid of her right hand, but immediately denied its existence when she viewed it directly. In contrast, when placed in front of a mirror, she recognised this upper limb perfectly, recognition disappearing again when direct vision was associated with vision in the mirror. The authors suggest the possibility of a resurgence in adult life of the duality of the visual body image, direct or reflected, such as is normally experienced in childhood and, more prolonged, in identical twins.


Intraosseous venous malformation of the craniofacial region: diagnosis and management.
Vascular lesions mainly affect soft tissues, and less than 1% affect bone. In 1982, they were categorised by Mulliken and Glowacki as haemangiomas or vascular malformations, and an updated classification was subsequently published by the International Society for the Study of Vascular Anomalies. These lesions, however, continue to be termed haemangiomas and there is little attempt to differentiate between them. We report eight cases of intraosseous venous malformation that were inappropriately labelled as haemangioma by clinicians, pathologists, and radiologists. We highlight tailored management, and describe the clinical features, results of investigations to aid accurate designation (histological and immunohistochemical, including GLUT1 staining and cross-sectional imaging), and outcomes.


Survival of Escherichia coli in Airborne and Settled Poultry Litter Particles.
Airborne Escherichia coli (E. coli) in the poultry environment can migrate inside and outside houses through air movement. The airborne E. coli, after settling on surfaces, could be re-aerosolized or picked up by vectors (e.g., caretakers, rodents, transport trucks) for further transmission. To assess the impacts of airborne E. coli transmission among poultry farms, understanding the survivability of the bacteria is necessary. The objective of this study is to determine the survivability of airborne E. coli, settled E. coli, and E. coli in poultry litter under laboratory environmental conditions (22-28 °C with relative humidity of 54-63%). To determine the survivability of airborne E. coli, an AGI-30 bioaerosol sampler (AGI-30) was used to collect the E. coli at 0 and 20 min after the aerosolization. The half-life time of airborne E. coli was then determined by comparing the number of colony-forming units (CFUs) of the two samplings. To determine the survivability of settled E. coli, four sterile Petri dishes were placed on the chamber floor right after the aerosolization to collect settled E. coli. The Petri dishes were then divided into two groups, with each group being quantified for culturable E. coli concentrations and dust particle weight at 24-h intervals. The survivability of settled E. coli was then determined by comparing the number of viable E. coli per milligram settled dust collected in the Petri dishes in the two groups. The survivability of E. coli in the poultry litter sample (for aerosolization) was also determined. Results show that the half-life time of airborne E. coli was 5.7 ± 1.2 min. The survivability of E. coli in poultry litter and settled E. coli were much longer with the half-life time of 15.9 ± 1.3 h and 9.6 ± 1.6 h, respectively. In addition, the size distribution of airborne E. coli attached to dust particles and the size distribution of airborne dust particles were measured by using an Andersen impactor and a dust concentration monitor (DustTrak). Results show that most airborne E. coli (98.89% of total E. coli) were carried by the dust particles with aerodynamic diameter larger than 2.1 µm. The findings of this study may help better understand the fate of E. coli transmitted through the air and settled on surfaces and evaluate the impact of airborne transmission in poultry production.


p57Kip2 acts as a transcriptional corepressor to regulate intestinal stem cell fate and proliferation.
p57Kip2 is a cyclin/CDK inhibitor and a negative regulator of cell proliferation. Here, we report that p57 regulates intestinal stem cell (ISC) fate and proliferation in a CDK-independent manner during intestinal development. In the absence of p57, intestinal crypts exhibit an increased proliferation and an amplification of transit-amplifying cells and of Hopx+ ISCs, which are no longer quiescent, while Lgr5+ ISCs are unaffected. RNA sequencing (RNA-seq) analyses of Hopx+ ISCs show major gene expression changes in the absence of p57. We found that p57 binds to and inhibits the activity of Ascl2, a transcription factor critical for ISC specification and maintenance, by participating in the recruitment of a corepressor complex to Ascl2 target gene promoters. Thus, our data suggest that, during intestinal development, p57 plays a key role in maintaining Hopx+ ISC quiescence and repressing the ISC phenotype outside of the crypt bottom by inhibiting the transcription factor Ascl2 in a CDK-independent manner.


Varenicline enhances the survival of doxorubicin-treated mice.
Doxorubicin (DOX) is widely used to treat various types of cancer. However, DOX treatment increases oxidative stress and causes other undesirable effects, such as cardiotoxicity, cognitive impairment, and death. Nicotine has been shown to inhibit DOX-induced cytotoxicity in vitro by activating nicotinic acetylcholine receptors. This study aimed to investigate whether combined treatment with varenicline, a partial agonist of nicotinic acetylcholine receptors, increased the survival rate of DOX-treated mice. Forty male albino mice were divided into four groups of 10. Control-group mice received a single intraperitoneal (i.p.) injection of 0.9% saline. The DOX group received a single dose of DOX (20 mg/kg body weight, i.p.). The varenicline group received varenicline daily in their drinking water at 0.1 mg/mL. The DOX+varenicline group received a single dose of DOX (20 mg/kg body weight, i.p.) and daily administration of varenicline in their drinking water (0.1 mg/mL). Mice were observed daily to evaluate the survival rate, and their body weight was recorded on alternate days. All mice treated only with DOX died within 8 days. Co-administration of varenicline with DOX slightly improved the survival time and rate compared with the DOX-only group. Combined treatment with varenicline and DOX may be useful for improving survival relative to treatment with DOX alone. This may be because varenicline is an α7-nicotinic acetylcholine receptor agonist; however, further research into its precise mechanism of action is required.


Multitasking with molecular dynamics Typhoon: quantifying nucleic acids and autoradiographs.
With increased sensitivity and specificity, fluorescent assays are rapidly becoming the method of choice for nucleic acid quantification. The utility of the Typhoon scanner has now been extended to accurately measure low levels of DNA and RNA (5 ng ml(-1)) with PicoGreen and RiboGreen dyes. In addition, with a few simple modifications, autoradiographic film images can be scanned and quantified with the Typhoon series of scanners.


A conceptual model of posttraumatic growth of nursing students with a disabled parent.
To examine a conceptual model of posttraumatic growth (PTG) with the inclusion of family resilience as a mediator, and social support, individual resilience, maternal care, and family members' intimacy after trauma as protective factors. A cross-sectional questionnaire survey was carried out in a sample of 134 college nursing students who had a parent with a non-congenital disability. The Socio-demographic Information Questionnaire, the Chinese version of Perceived Social Support Scale (PSSS), 10-item Connor-Davidson Resilience Scale (CD-RISC10), Parental Bonding Instrument (PBI), Family Resilience Assessment Scale (FRAS) and the Posttraumatic Growth Inventory (PTGI) were used to collect data. Results showed that social support, individual resilience, maternal care, and family members' intimacy after trauma positively predicted family resilience (β = 0.41, 0.20, 0.20, 0.22, all P<0.01), respectively, and indirectly predicted PTG through family resilience. Family resilience positively predicted PTG (β = 0.25, P<0.01). Moreover, individual resilience directly positively predicted PTG (β = 0.25, P<0.001). Family resilience could facilitate PTG in nursing students in the face of parental disability. Interventions to promote PTG among college nursing students who have experienced parental disability should consider individual or family resilience-based intervention.


Going interactive: six strategies to meet the challenge of teaching electrosurgery to general dental practitioners.
Mandatory continuing professional development has resulted in a recent expansion in postgraduate dental teaching. One popular type of teaching is the practical 'hands-on' course that combines the explanation of theory with the acquisition of practical skills in small groups. The challenge to dental teachers is to provide the best level of teaching on these courses where the course participants bring varied expectations and different levels of knowledge, skill or interest. This paper presents a new teaching model that has been developed for the postgraduate teaching of Electrosurgery. The key components of this course include an interactive theory lecture using multimedia, followed by hands-on practical teaching. The emphasis throughout is on the use of facilitation and group learning rather than traditional didactic teaching. A series of strategies for the effective delivery of such a hands-on course together with evaluation of findings from 31 courses are considered.


Endoscopic retrograde cholangiopancreatography in the management of benign biliary strictures.
Several conditions may cause benign biliary stricture formation. Intraoperative bile duct injury, most often sustained during laparoscopic cholecystectomy, is the leading cause. Although surgical bypass procedure was the traditional treatment of choice for benign extrahepatic biliary strictures, therapeutic endoscopic retrograde cholangiopancreatography has recently come into favor; however, success rates have been variable and largely dependent on the underlying etiology. Because endoscopic therapy may be unsuccessful, a multidisciplinary approach to management, with surgical or radiological intervention if necessary, should be considered.


Anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes.
The effects of oral treatment of rats with streptozotocin-induced diabetes with a range of vanadium dipicolinate complexes (Vdipic) and derivatives are reviewed. Structure-reactivity relationships are explored aiming to correlate properties such as stability, to their insulin-enhancing effects. Three types of modifications are investigated; first, substitutions on the aromatic ring, second, coordination of a hydroxylamido group to the vanadium, and third, changes in the oxidation state of the vanadium ion. These studies allowed us to address the importance of coordination chemistry, and redox chemistry, as modes of action. Dipicolinate was originally chosen as a ligand because the dipicolinatooxovanadium(V) complex (V5dipic), is a potent inhibitor of phosphatases. The effect of vanadium oxidation state (3, 4 or 5), on the insulin-enhancing properties was studied in both the Vdipic and VdipicCl series. Effects on blood glucose, body weight, serum lipids, alkaline phosphatase and aspartate transaminase were selectively monitored. Statistically distinct differences in activity were found, however, the trends observed were not the same in the Vdipic and VdipicCl series. Interperitoneal administration of the Vdipic series was used to compare the effect of administration mode. Correlations were observed for blood vanadium and plasma glucose levels after V5dipic treatment, but not after treatment with corresponding V4dipic and V3dipic complexes. Modifications of the aromatic ring structure with chloride, amine or hydroxyl groups had limited effects. Global gene expression was measured using Affymetrix oligonucleotide chips. All diabetic animals treated with hydroxyl substituted V5dipic (V5dipicOH) and some diabetic rats treated with vanadyl sulfate had normalized hyperlipidemia yet uncontrolled hyperglycemia and showed abnormal gene expression patterns. In contrast to the normal gene expression profiles previously reported for some diabetic rats treated with vanadyl sulfate, where both hyperlipidemia and hyperglycemia were normalized. Modification of the metal, changing the coordination chemistry to form a hydroxylamine ternary complex, had the most influence on the anti-diabetic action. Vanadium absorption into serum was determined by atomic absorption spectroscopy for selected vanadium complexes. Only diabetic rats treated with the ternary V5dipicOH hydroxylamine complex showed statistically significant increases in accumulation of vanadium into serum compared to diabetic rats treated with vanadyl sulfate. The chemistry and physical properties of the Vdipic complexes correlated with their anti-diabetic properties. Here, we propose that compound stability and ability to interact with cellular redox reactions are key components for the insulin-enhancing activity of vanadium compounds. Specifically, we found that the most overall effective anti-diabetic Vdipic compounds were obtained when the compound administered had an increased coordination number in the vanadium complex.


Lymph node classification systems in cutaneous T-cell lymphoma. Evidence for the utility of the Working Formulation of Non-Hodgkin's Lymphomas for Clinical Usage.
This study was undertaken to compare three classification schemes used to evaluate lymph nodes (LN) obtained from patients with cutaneous T-cell lymphoma (CTCL): a modified Rappaport classification, the National Cancer Institute-Veterans Administration (NCI-VA) classification based on the relative numbers of cerebriform cells in the paracortical areas, and the Dutch classification based on the presence of cerebriform cells with large nuclei in mycosis fungoides (MF) and diffuse infiltration by cerebriform cells in Sézary syndrome. A study set of 195 LN obtained from patients with CTCL (MF, Sézary syndrome, and nonepidermotropic T-cell lymphomas) and 14 LN from patients with benign dermatoses was reviewed independently by three groups of pathologists familiar with each classification system. Each classification system provided useful prognostic information. However, contrary to prior reports, no significant difference in survival was apparent in patients with uneffaced LN when classified according to the NCI-VA (LN0-2 versus LN3) or Dutch (Gr0-1 versus Gr2) ratings. In addition, all classification systems demonstrated a poor survival time associated with effaced LN. By combining results from the modified Rappaport and Dutch classifications, three prognostic groups could be identified based on cell morphology: a low-grade category with a small cell histologic subtype (median survival time, 40 months); a high-grade immunoblastic subtype (median survival time, 9 months) composed of cells with an oval nucleus containing a large, usually solitary central nucleolus; and an intermediate-grade category composed of all cases without the distinctive small cell and immunoblastic morphologies (median survival time, 26 months). The authors propose that clearly involved LN in CTCL can be categorized on the basis of cell morphology into prognostic groups analogous to what has been proposed for the Working Formulation for Non-Hodgkin's Lymphomas for Clinical Usage.


Robotic spleen-preserving laparoscopic distal pancreatectomy: a single-centered Chinese experience.
Spleen-preserving laparoscopic distal pancreatectomy is technically challenging. New surgical robotic systems are now available and show promising outcomes but were very recently implemented in China. Seven patients underwent laparoscopic distal pancreatectomy using the da Vinci Robotic System (RDP) for benign or borderline malignant pancreatic tumors. Spleen preservation rate, blood loss, and operative complications were assessed. Mean age was 44.6 ± 13.7 years. Surgery was uneventful in all patients, without conversion to laparotomy. The surgical time (including anesthesia induction, robot docking, operation, and postoperative awaking time) was 460 ± 154 min, while the operation time was 368 ± 126 min. Blood losses were 200 ± 110 mL. The minor (Clavien I+II) complication rate was 14.3%, and the major (Clavien III+IV) complication rate was 14.3 %, including hemorrhage and pancreatic leakage. The spleen preservation rate was 100%. All complications were successfully managed and cured. Intraoperative laparoscopic ultrasound examination successfully identified the correct surgical resection margins. Mean postoperative hospitalization was 8.7 ± 6.6 days. No patient had to undergo a second pancreas surgery. Patients were followed up for a median of 6.8 months (range, 6 to 22 months). All patients survived and reported few discomforts. RDP is feasible and allows the preservation of the splenic vessels.


Long QT syndrome presenting as epileptic seizures in an adult.
A 50 year old woman with a previous diagnosis of epilepsy presented to the emergency department with a generalised seizure. Her admission ECG showed QT prolongation secondary to bradycardia and a subsequent seizure in the department demonstrated that these events were secondary to cerebral hypoperfusion during episodes of torsades de pointes. This case illustrates how long QT syndrome can masquerade convincingly as epilepsy, delaying treatment and exposing the patient to a high risk of sudden cardiac death. Careful ECG analysis is recommended for all patients presenting with seizures.


Identification of interleukin-8 as estrogen receptor-regulated factor involved in breast cancer invasion and angiogenesis by protein arrays.
With the goal of identifying key factors involved in human breast cancer progression, we applied human cytokine antibody arrays we have developed to screen cytokine expression levels in human breast cancer cell lines and identified interleukin (IL)-8 as a key factor involved in breast cancer invasion and angiogenesis. Elevated expression of IL-8 in breast cancer cells was associated with breast cancer invasiveness and angiogenesis. Neutralization of antibody against IL-8 specifically blocked IL-8-mediated tumor cell invasion and angiogenesis. Furthermore, IL-8 levels in human breast cancer cells were closely related to estrogen receptor (ER) status. ER positive cells expressed low levels of IL-8 whereas ER negative cells expressed high levels of IL-8. Expression of exogenous ERalpha substantially inhibited IL-8 expression. Our findings raise intriguing questions regarding the role of IL-8 in the development and progression of human breast cancer in association with ER status.


Anomalies of nanosecond ultrasonic relaxation in the lipid bilayer transition.
The frequency dependence of ultrasonic velocity as well as absorption in a suspension of sonicated dipalmitoylphosphatidylcholine vesicles was measured by a differential ultrasonic resonator. The frequency was scanned between 1.3 and 13 MHz and the temperature was varied from 25 to 47 degrees C. A pronounced relaxation was observed in the time range of 10 ns. The data were analyzed assuming a single relaxation which appeared to be a good approximation. The relaxation time as well as relaxation strength increased anomalously in the vicinity of the gel-to-liquid crystal transition of 41.5 degrees C. This result represents the first definite evidence of the critical slowing down in the lipid bilayer and is discussed in terms of the Landau theory of phase transition. The possible biological significance of the mechanical relaxation is also presented.


Increased diet-induced fatty streak formation in female mice with deficiency of liver-derived insulin-like growth factor-I.
The role of endocrine IGF-I for atherosclerosis is unclear. We determined the importance of circulating, liver-derived IGF-I for fatty streak formation in mice. Mice with adult, liver-specific IGF-I inactivation (LI-IGF-I(-/-) mice, serum IGF-I reduced by approximately 80 %) and control mice received an atherogenic (modified Paigen) diet between 6 and 12 months of age. At study end, Oil Red O staining of aortic root cryosections showed increased fatty streak area and lipid deposition in female but not in male LI-IGF-I(-/-) mice compared to controls. Mac-2 staining of aortic root and measurements of CD68 mRNA level in femoral artery revealed increased macrophage accumulation in proportion to the increased fatty streak area in female LI-IGF-I(-/-) mice. Moreover, female LI-IGF-I(-/-) mice displayed increased serum cholesterol and interleukin-6 as well as increased vascular cell-adhesion molecule 1 (VCAM1) mRNA levels in the femoral artery and elevated VCAM1 protein expression in the aortic root. Thus, increased diet-induced fatty streak formation in female LI-IGF-I(-/-) mice was associated with increased serum cholesterol and signs of systemic inflammation, endothelial activation, lipid deposition, and macrophage infiltration in the vascular wall.


False recognition of emotional stimuli is lateralised in the brain: An fMRI study.
We have investigated whether the left (LH) and right (RH) hemisphere play a different role in eliciting false recognition (FR) and whether their involvement in this memory illusion depends on the emotional content of stimuli. Negative and neutral pictures (taken from IAPS) were presented in the divided-visual field paradigm. Subjects task was to indicate whether the pictures had already been presented or not during the preceding study phase. FR rate was much higher for the RH than the LH presentations. In line, FR resulted in activations mainly in the right prefrontal cortex (PFC) for either RH or LH presentations. Emotional content of stimuli facilitated the formation of false memories and strengthened the involvement of the right PFC in FR induction.


Early childhood development when second-trimester ultrasound dating disagrees with last menstrual period: a prospective cohort study.
When an ultrasound-based estimate of gestational age (GA) is less (greater) than an estimate based on a definite last menstrual period, the fetus may grow slower (faster) than average. While the association between these discrepancies in GA estimates and adverse perinatal outcomes has been examined extensively, there is scant evidence about long-term effects, such as child neurodevelopment. Using data from a prospective cohort study titled, NICHD Study of Successive Small-for-Gestational Age Births, we examined if GA discrepancies in early second trimester of pregnancy (17 weeks' gestation) are associated with: (1) impaired motor and mental function at 13 months (measured using Bayley Scales of Infant Development (Bayley)), and (2) impaired cognitive development at five years (assessed by Wechsler Preschool and Primary Scale of Intelligence - Revised Intelligence Quotient (WPPSI-R)) in the infant. The study population consisted of 572 (30% of the overall sample of 1,945) women who presented for prenatal care in Norway and Sweden between 1986 and 1988. Our results showed that GA discrepancies in early second trimester are significantly associated with birthweight. We found no significant relationship, however, with the Bayley development scores at 13 months and with the WPPSI-R IQ measures at five years. GA discrepancies at 17 weeks' gestation are not associated child neurodevelopment. These discrepancies do, however, relate to birthweights, providing a basis for detecting fetal growth patterns early in the second trimester of pregnancy. Our study, however, was unable to evaluate the impact of first-trimester discrepancies on impaired neurodevelopment in the infant.


Amplitude of rippling in the P beta phase of dipalmitoylphosphatidylcholine bilayers.
We present x-ray diffraction results of dipalmitoylphosphatidylcholine (DPPC) multilayers in three structural phases. Using pure DPPC, precision temperature control, and high angular resolution methods, we have discovered splitting of the first diffraction order due to multilayering in the P(beta) phase. This splitting permits us to calculate the amplitude of ripples in this phase. The amplitude is large enough to suggest a structural mechanism for rippling.


Age-related differences of cholecystokinin receptor binding in the rat brain.
1. Cholecystokinin and benzodiazepine receptor binding was evaluated in 2-, 9- and 18-month old rats in the brain regions where cholecystokinin octapeptide and gamma-aminobutyric acid are known to coexist in common nerve cells (frontal cortex, hippocampus). 2. There was a regionally selective alteration of hippocampal 3H-CCK-8 binding in the oldest age group, if compared to both young and adult animals. Non-linear regression analysis of binding data revealed significantly lower apparent number of binding sites (Bmax), and twofold (but not statistically significantly) higher binding affinity for the radiolabelled ligand. No differences between any age groups in 3H-flunitrazepam binding to benzodiazepine receptors were found. 3. The results suggest that changes in cholecystokinin receptor characteristics might contribute to the behavioural impairments in aged rats.


Binding of an antiviral agent to a sensitive and a resistant human rhinovirus. Computer simulation studies with sampling of amino acid side-chain conformations. II. Calculation of free-energy differences by thermodynamic integration.
Thermodynamic-cycle perturbation theory and molecular dynamics simulations were used to calculate the difference in the free energy of binding of the antiviral compound WIN53338 to the wild-type human rhinovirus 14 and to a drug-resistant mutant of the virus in which valine 188 of the viral protein 1 is mutated to leucine. Because of the difficulty of achieving adequate sampling of all of the rotational isomers of amino acid side-chains in molecular dynamics simulations, an explicit treatment of the effects of the existence of multiple rotational isomers of residue 188 on the calculated free energies was used. The rotamers of residue 188 were first mapped by steric and energetic techniques as described in the accompanying article. Thermodynamic integration was then carried out during simulations of the virus, both with and without the antiviral compound bound, by mutating residue 188 while restraining its side-chain to one conformation. The contributions of the other rotamers of residue 188 to the free-energy changes for this mutation were then added to those calculated by thermodynamic integration as correction factors. Binding of WIN53338 to the wild-type virus was calculated to be favored over binding to the mutant virus by 1.7(+/- 3.0) kcal/mol. This is consistent with experimental data which, if differences in activity are assumed to be due to differences in binding, indicate that the binding affinity of WIN53338 for the wild-type virus is at least 0.15 to 1.7 kcal/mol greater than for the mutant virus. Thermodynamic integration was also performed in the conventional manner without restraints and was found to give less accurate results.


[Transureteral ureteronephrostomy--a possibility for palliative supravesical urinary diversion].
Unilateral retroperitoneal TUUN meets all the basic safety criteria for palliative supravesical drainage of urine. It is evaluated from the practical viewpoint and our own experience with 8 cases is given.


Predictors of bone density in ambulatory patients on antiepileptic drugs.
Antiepileptic drugs are associated with bone loss and fractures. Data in children is scarce and the impact of new therapies and of low vitamin D is not clear. This study assessed predictors of bone mineral density (BMD) in 225 ambulatory patients with epilepsy. BMD and detailed clinical information were obtained from 137 adults mean age of 31 years, on therapy for a mean of 11.7 years, and 88 children mean age of 13 years, on therapy for an average of 4.7 years. Hypovitaminosis D was common in epileptic patients. BMD was reduced in adults but not children with epilepsy, by 0.3-0.6 SD depending on the skeletal site measured, compared to controls. Duration of treatment, but not vitamin D levels, was negatively correlated with BMD at the hip in adults. Bone density was reduced with the use of both enzyme and non-enzyme-inducing drugs, with both mono- and polytherapy, and was most severely reduced at the spine and hip with the use of enzyme-inducing drugs. In the multivariate analyses, polytherapy in children and duration of therapy and enzyme-inducing drugs in adults were independent predictors of BMD. Antiepileptic drug therapy is associated with low bone density at clinically relevant skeletal sites, projecting into a possible doubling of fracture risk. Age, therapy duration, polypharmacy and the use of enzyme-inducing drugs were risk factors. Newer drugs may be associated with deleterious effects on bone. Skeletal monitoring with varying intervals, depending on the individual risk profile, is indicated.


A unified brain system of orientation and its disruption in Alzheimer's disease.
To investigate whether a unified brain system manages one's orientation to different places, events and people in one's environment, and test the hypothesis that failure of this system (disorientation) is an early sign of Alzheimer's disease (AD). A total of 46 participants (patients along the AD continuum and cognitively normal control subjects) were tested in a personalized, ecologically valid task of orientation relating to the participant's own world in space, time and person under high-density electroencephalography. As a first step, we used evoked potential mapping to search for brain topography correlated with participants' performance in orientating themselves to different places (space), events (time) and people (person) (Experiment 1). We then compared behavioral and electrophysiological changes in patients along the AD continuum (Experiment 2). We identified a specific brain topography ("orientation map") that was active for orientation in space, time and person in correlation to participants' performance. Both performance and the map's strength gradually decreased from health to mild cognitive impairment (MCI) and from MCI to AD. Another map, immediately preceding the orientation map, showed the longest activity in patients with MCI, significantly more than both patients with AD and cognitively normal controls. Our findings demonstrate that the same brain topography accounts for orientation in the different domains of space, time and person and provide a nexus between deterioration in patients' orientation with the aggravation of Alzheimer's disease.


Latent Trajectories of Fluid Balance Are Associated With Outcomes in Cardiac and Aortic Surgery.
Fluid overload is common in critically ill patients and is associated with worse outcomes. The trends in fluid balance have not been investigated previously. This study used trajectory analysis to investigate the impact of fluid balance trends on patients who had undergone cardiac or aortic surgery. We analyzed patients who underwent cardiac or aortic surgery between August 2005 and March 2015. We excluded patients who died within the first 72 postoperative hours or received chronic dialysis before the surgery. Trajectories of urine and input-output during the first 3 postoperative days were analyzed using a latent class growth model. The primary outcomes were any stage of acute kidney injury (AKI) by Kidney Disease Improving Global Outcomes definition and de novo dialysis. The in-hospital mortality was 6.6% (70 of the 1063 patients included). The fluid input-output balance trajectories had better association with the primary outcome than urine output trajectories did. The risk of AKI and de novo dialysis were highest in the group with progressively positive fluid balance adjusted by preoperative body weight (AKI: adjusted odds ratio, 7.10; 95% confidence interval, 2.02-24.93; de novo dialysis: odds ratio, 4.54; 95% confidence interval, 1.12-18.38). A progressively positive fluid balance is associated with AKI and de novo dialysis in patients undergoing cardiac or aortic surgery.


Controlling drug effects through improved oral formulations. The pharmacokinetics of the prazosin gastrointestinal therapeutic system.
Influences that determine a drug's effects include pharmacokinetic factors (the serum concentrations of drug as determined by the drug dose, absorption, distribution, and excretion) and pharmacodynamic factors (the intensity of drug effect). Most assessments of drug effect focus on the therapeutic range, i.e., the serum concentrations below which therapeutic effects are unlikely and above which toxic effects may be seen. A goal for many treatment regimens is to maintain serum drug concentrations within the therapeutic range. Maintenance of drug concentrations within the therapeutic range can be difficult with many traditional oral dosage formulations. Soon after administration of standard tablets, capsules, or liquids, a pronounced peak level is observed in serum. At the end of a dosage interval, serum concentrations are frequently below those needed to exert therapeutic effect. One reason for the wide range in serum concentrations with standard oral formulations is that these products usually exhibit first-order drug absorption, in which the rate of absorption from the gastrointestinal tract continually varies following a dose (from high to low) and is directly determined by the amount of drug remaining in the gastrointestinal tract. First-order absorption, therefore, results in changing absorption rates, wide swings in serum drug concentrations, a relatively short duration of action, and often, inconsistent drug effects over a dosage interval. One way to address the problems with standard oral products that have first-order absorption is to produce products that control drug release and absorption. A large number of controlled-release oral products are now on the market and use a variety of technologies. The ideal controlled-release formulation would result in zero-order drug absorption, in which the rate of drug absorption from the gastrointestinal tract would be constant and not determined by the amount of drug in the gastrointestinal tract. Zero-order absorption, therefore, results in an unchanging absorption rate, consistent serum levels, a longer duration of action, and more steady drug effect. Zero-order absorption is particularly preferable in situations that require a consistent, long-term therapeutic effect, e.g., in patients with hypertension, asthma, or arrhythmias. Of all the controlled-release preparations on the market, however, very few exhibit zero-order absorption; most can be categorized somewhere between first- and zero-order kinetics. An advanced-technology tablet has been invented to produce zero-order drug absorption for prazosin and nifedipine.(ABSTRACT TRUNCATED AT 400 WORDS)


Safety and clinical outcomes in endovascular treatment for symptomatic cerebral venous thrombosis: a single-center experience with meta-analysis.
The role of mechanical thrombectomy (MT) in cerebral venous sinus thrombosis (CVT) is ambiguous. This study aims to share our experience with MT in CVT, supplemented by a meta-analysis on this treatment. All patients who had MT for CVT at our institution, between 2016 and 2021, were retrospectively reviewed for treatment indications, the technique used, success and complication rates, and clinical outcomes. A meta-analysis was performed for clinical and safety outcomes from published literature with > 10 patients. A total of 15 patients were included in this study. All had a venous hemorrhage or deteriorating despite anticoagulation. MT was performed using aspiration (with wide bore catheters) in 7 patients: aspiration with stent retriever in 5 and transjugular Fogarty-balloon thrombectomy in 3 patients. Adjunctive intra-sinus thrombolysis (IST) was used in 4 cases and venoplasty in 3. Technical success (restoring antegrade venous flow on arterial injection) was 100% with no procedure-related major complication. The direct transjugular approach was cheaper and faster. At 3-month follow-up, 86% of patients had good outcomes (MRS < 2). Meta-analysis of clinical and safety outcomes from 22 and 20 studies, respectively, demonstrated a positive association between MT and good outcomes as well as no significant association with hazardous periprocedural events. EVT via mechanical means for CVT is feasible in our series and meta-analysis. From our experience, trans-jugular Fogarty balloon embolectomy seems to be a potential cost-saving option, at least in a certain part of the world.


Molecular characterization of the gyrB region of the oral spirochete, Treponema denticola.
The nucleotide (nt) sequence of the Treponema denticola (Td) DNA gyrase beta-subunit gene (gyrB) has been determined. Southern blot analysis of Td chromosomal DNA indicated that gyrB is present as a single copy. Approximately 3.2kb of the nt sequence 5' and 0.7kb of nucleotide sequence 3' of gyrB were obtained. Analysis of the deduced amino acid (aa) sequence revealed two complete open reading frames (ORFs) (ORF1 and ORF3) and a truncated ORF (ORF4'). ORF1 has no homology to sequences in the databases, whereas ORF3 and ORF4' have significant homology to several bacterial DnaA (replication initiator) and DnaE (DNA polymerase III) proteins respectively. RT-PCR data showed that orf1-gyrB are co-transcribed, while dnaA-dnaE are co-transcribed but in the opposite direction. These data indicated that the gene organization of the Td gyrB region is unique compared with that of other bacteria. Eighteen putative DnaA boxes with several AT-rich regions were identified in the dnaA-dnaE intergenic region, and three putative DnaA boxes were identified in the gyrB-dnaA intergenic region. Spontaneous coumermycin A(1)-resistant Td mutants were isolated and characterized. The mutants have a >20-fold higher resistance to coumermycin A(1) than wild-type Td. A single point mutation in gyrB that changed GyrB Lys(136) to Glu or Thr appears to be responsible for the coumermycin A(1) resistance.


The non-competitive N-methyl-D-aspartate-antagonist memantine does not affect segmental mono- and polysynaptic reflexes in man.
Studies in rats have shown that the polysynaptic flexor reflex (FR) but not the monosynaptic reflexes are affected by N-methyl-D-aspartate (NMDA) receptor antagonists. Theoretically, the suppression of FR might be caused by an alteration of the spinal nociceptive neurons. To investigate, whether the non-competitive NMDA receptor antagonist memantine interferes with nociception in man, we studied both its effect on pain perception and on FR. In a double-blind study 14 male subjects were randomly assigned to either placebo or memantine (30 mg p.o.) treatment. H-reflex (HR) and FR as well as pain and tolerance threshold were determined prior to and 6 h after drug intake. Contrary to expectations, there were no differential treatment effects either on FR threshold and magnitude or on pain and tolerance thresholds or the HR amplitude.


Cicletanine attenuates overdrive pacing-induced global myocardial ischemia in rabbits: possible role of cardiac cyclic nucleotides.
This study examined whether cicletanine, an antihypertensive drug with cGMP phosphodiesterase inhibitory effect, could alleviate ventricular overdrive pacing-induced myocardial ischemia in chronically instrumented rabbits. An electrode-catheter implanted into the right ventricle was used for pacing (500 bpm over 5 min) and for measuring intracavital ST-segment elevation and ventricular effective refractory period (VERP). PQ and QT intervals were measured in the chest-lead ECG, and dP/dtmax as well as left ventricular end-diastolic pressure (LVEDP) were recorded through a left intraventricular catheter. In separate groups, mean arterial blood pressure (MABP) was monitored from the right carotid artery. Experiments were performed on conscious rabbits after a week of convalescence. In anesthetized, open-chest rabbits, samples were taken from the left ventricle before and after drug treatment and/or overdrive pacing for determination of cGMP and cAMP contents by radioimmunoassay. Intravenous cicletanine, 30 mg/kg body weight, did not change resting MABP, dP/dtmax, and LVEDP, but it did reduce heart rate and prolonged PQ and QT intervals and VERP. Overdrive pacing produced intracavital ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. Cicletanine administered 15 minutes before pacing significantly attenuated ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. In anesthetized animals, cicletanine itself slightly increased cardiac cGMP and cAMP contents. Overdrive pacing moderately increased cGMP and profoundly elevated cAMP, and in overpaced rabbits, cicletanine further increased cGMO and markedly attenuated cAMP content increased by overdrive pacing. These results suggest that in correlation with alterations of cardiac cycle nucleotide contents, cicletanine protects the heart against pacing-induced myocardial ischemia.


Sensitive median-ulnar motor comparative techniques in carpal tunnel syndrome.
We describe two modified methods for median-to-ulnar motor conduction comparison in the diagnosis of median neuropathy at the wrist: the median-thenar to ulnar-thenar latency difference (TTLD), and the median-thenar to ulnar-hypothenar latency difference (THLD). We also describe an F-wave ulnar-to-median comparative test, the F-wave latency difference (FWLD). The abnormal cutoffs based upon 34 normal controls are: TTLD, 0.8 ms; THLD, 1.2 ms; FWLD, 0.6 ms. In 50 patients (79 hands) with clinically defined carpal tunnel syndrome and electrophysiological evidence of median neuropathy at the wrist (based upon a prolonged median nerve palm-wrist latency), the diagnostic sensitivities were: 95-98%, 85-88%, and 75-78%, respectively. These tests are therefore highly sensitive. They are easily performed and require minimal additional effort to incorporate into commonly used clinical electrodiagnostic routines. They may be advantageous when a concomitant polyneuropathy is present, and they may also help avoid technical pitfalls and aid in identification of anatomic variants.


The stressful life events schedule for children and adolescents: development and validation.
The development and psychometric properties of the Stressful Life Events Schedule (SLES), an interview instrument to assess stressors in children and adolescents, are described. Children (< or =12 years) and adolescents (>12 years) with psychopathology (n=30) and non-psychiatric controls (n=30) were interviewed with the SLES about the occurrence of stressful life events during the prior year. To examine concurrent validity of the SLES, all subjects also completed the self-report Life Events Checklist (LEC) and half the sample completed the Life Events and Difficulties Schedule (LEDS). To examine informant validity, the parent/guardian also reported on stressful life events occurring to their child during the year prior to interview. Test-retest reliability of the SLES was examined by re-assessing all children approximately one week after the initial interview. Subjects rated subjectively how stressful an event was on a 4-point scale. Additionally, panel ratings of objective stress and behavior-dependence/independence were made on 4-point scales. The SLES was found to have substantial inter-rater consensus reliability for objective threat (kappa=0.67) and almost perfect reliability for event behavior-dependence/independence (kappa=0.84). Similarly, the test-retest reliability of the SLES was also found to be substantial at the level of specific event comparisons (kappa=0.68). The SLES discriminated between children with and without psychopathology on all measures of stressful life events. Total stressful life events assessed with the SLES concurred well with those assessed by the LEC (ICC=0.83) and the LEDS (kappa=0.77) although, as expected, examination of specific events showed much smaller overlap between the SLES and the LEC (kappa=0.26). Child-parent agreement for the occurrence of severe events was substantial (kappa=0.73) but tended to be only moderate when all events were examined (kappa=0.48). The results of this study indicate that the SLES has good psychometric properties. The SLES is a useful, cost-effective tool for assessing stressful life events in children and adolescents.


The Gq signalling pathway inhibits brown and beige adipose tissue.
Brown adipose tissue (BAT) dissipates nutritional energy as heat via the uncoupling protein-1 (UCP1) and BAT activity correlates with leanness in human adults. Here we profile G protein-coupled receptors (GPCRs) in brown adipocytes to identify druggable regulators of BAT. Twenty-one per cent of the GPCRs link to the Gq family, and inhibition of Gq signalling enhances differentiation of human and murine brown adipocytes. In contrast, activation of Gq signalling abrogates brown adipogenesis. We further identify the endothelin/Ednra pathway as an autocrine activator of Gq signalling in brown adipocytes. Expression of a constitutively active Gq protein in mice reduces UCP1 expression in BAT, whole-body energy expenditure and the number of brown-like/beige cells in white adipose tissue (WAT). Furthermore, expression of Gq in human WAT inversely correlates with UCP1 expression. Thus, our data indicate that Gq signalling regulates brown/beige adipocytes and inhibition of Gq signalling may be a novel therapeutic approach to combat obesity.


Trappc9 deficiency in mice impairs learning and memory by causing imbalance of dopamine D1 and D2 neurons.
Genetic mutations in the gene encoding transport protein particle complex 9 (trappc9), a subunit of TRAPP that acts as a guanine nucleotide exchange factor for rab proteins, cause intellectual disability with brain structural malformations by elusive mechanisms. Here, we report that trappc9-deficient mice exhibit a broad range of behavioral deficits and postnatal delay in growth of the brain. Contrary to volume decline of various brain structures, the striatum of trappc9 null mice was enlarged. An imbalance existed between dopamine D1 and D2 receptor containing neurons in the brain of trappc9-deficient mice; pharmacological manipulation of dopamine receptors improved performances of trappc9 null mice to levels of wild-type mice on cognitive tasks. Loss of trappc9 compromised the activation of rab11 in the brain and resulted in retardation of endocytic receptor recycling in neurons. Our study elicits a pathogenic mechanism and a potential treatment for trappc9-linked disorders including intellectual disability.


Tuberculosis treatment intermittency in the continuation phase and mortality in HIV-positive persons receiving antiretroviral therapy.
Some tuberculosis (TB) treatment guidelines recommend daily TB treatment in both the intensive and continuation phases of treatment in HIV-positive persons to decrease the risk of relapse and acquired drug resistance. However, guidelines vary across countries, and treatment is given 7, 5, 3, or 2 days/week. The effect of TB treatment intermittency in the continuation phase on mortality in HIV-positive persons on antiretroviral therapy (ART), is not well-described. We conducted an observational cohort study among HIV-positive adults treated for TB between 2000 and 2018 and after enrollment into the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet; Brazil, Chile, Haiti, Honduras, Mexico and Peru). All received standard TB therapy (2-month initiation phase of daily isoniazid, rifampin or rifabutin, pyrazinamide ± ethambutol) and continuation phase of isoniazid and rifampin or rifabutin, administered concomitantly with ART. Known timing of ART and TB treatment were also inclusion criteria. Kaplan-Meier and Cox proportional hazards methods compared time to death between groups. Missing model covariates were imputed via multiple imputation. 2303 patients met inclusion criteria: 2003(87%) received TB treatment 5-7 days/week and 300(13%) 2-3 days/week in the continuation phase. Intermittency varied by site: 100% of patients from Brazil and Haiti received continuation phase treatment 5-7 days/week, followed by Honduras (91%), Peru (42%), Mexico (7%), and Chile (0%). The crude risk of death was lower among those receiving treatment 5-7 vs. 2-3 days/week (HR = 0.68; 95% CI = 0.51-0.91; P = 0.008). After adjusting for age, sex, CD4, ART use at TB diagnosis, site of TB disease (pulmonary vs. extrapulmonary), and year of TB diagnosis, mortality risk was lower, but not significantly, among those treated 5-7 days/week vs. 2-3 days/week (HR 0.75, 95%CI 0.55-1.01; P = 0.06). After also stratifying by study site, there was no longer a protective effect (HR 1.42, 95%CI 0.83-2.45; P = 0.20). TB treatment 5-7 days/week was associated with a marginally decreased risk of death compared to TB treatment 2-3 days/week in the continuation phase in multivariable, unstratified analyses. However, little variation in TB treatment intermittency within country meant the results could have been driven by other differences between study sites. Therefore, randomized trials are needed, especially in heterogenous regions such as Latin America.


Differential expression dynamics of Growth differentiation factor9 (GDF9) and Bone morphogenetic factor15 (BMP15) mRNA transcripts during in vitro maturation of buffalo (Bubalus bubalis) cumulus-oocyte complexes.
The present study has evaluated the association of growth differentiation factor9 (GDF9) and bone morphogenetic protein15 (BMP15) mRNA expression in cumulus-oocyte complexes (COCs) of buffalo ovary during in vitro maturation (IVM). GDF9 and BMP15 are expressed specifically in mammalian oocytes and also participate in cumulus-oocyte crosstalk. Quantitative real-time polymerase chain reaction (qRT-PCR) technique was applied to investigate the relative abundance (RA) of GDF9 and BMP15 mRNA transcripts throughout the IVM process. Relative mRNA expression pattern of these specific genes were assessed in oocytes and cumulus cells at 0, 6, 12 and 24 h of in vitro culture. Our results revealed that RA of GDF9 during different hours of IVM showed significant reduction between 0 h and 24 h of maturation in oocytes and BMP15 transcript increased significantly (P<0.05) between 6 h and 12 h and decreased again between 12 h and 24. In cumulus cells, GDF9 remained stable during IVM upto 12 h of maturation and decreased significantly between 12 h and 24 h of maturation. Conversely, significant reduction of BMP15 was observed between 0 h and 6 h, stayed stable upto 12 h and became undetectable at 24 h of maturation. In conclusion, these two genes were differentially expressed during the period of oocyte maturation process and notably, BMP15 expression pattern is associated specifically with the period of cumulus cell expansion.


Out-patient operation of inguinal hernia in children.
A retrospective review is presented of 496 children with a median age of 4 years (range 0-13 years) on whom a total of 527 hernia repairs were performed as out-patients. No wound infections were observed, and the rate of early surgical complications was 1.5 per cent. There were 15 (3.7 per cent) known recurrences. No complications from the anaesthetic were recorded. Owing to the negligible infection rate and the low surgical complication and recurrence rates it is concluded that children with inguinal hernia would benefit from operation as out-patients, and that they should be operated on immediately after diagnosis, irrespective of age. Besides probably minimizing the children's psychological trauma, out-patient surgery provided considerable savings to the health service in the present study.


Changes in objectively-measured physical capability over 4-year, risk of diabetes, and glycemic control in older adults: The China Health and Retirement Longitudinal study.
High physical capability reduces risk of diabetes, but the association of its changes with risk of diabetes and glycemic control is unclear in older adults. This study aimed to quantify their association. A total of 1,667 participants without diabetes and aged ≥ 60 years from the China Health and Retirement Longitudinal Study were included and followed over 4 years. Physical capability was objectively measured at baseline and 4-year later. Logistic regression models were used to assess the association of changes in physical capability with risk of diabetes. During follow-up, 160 participants developed diabetes. None of the changes in physical capability expressed in continuous scales or in tertiles was associated with risk of diabetes in unadjusted or adjusted models (all P > 0.05), and no favorable joint effects were observed. Changes in physical capability were not associated with changes in fasting plasma glucose or hemoglobin A1c. Yet increases in walking speed or grip strength were related to reduced metabolic score for insulin resistance (both P ≤ 0.03). Increases in objectively-measured physical capability were not associated with reduced risk of diabetes but may ameliorate insulin resistance in older adults. Studies with longer follow-up periods are required to confirm these findings.


Efficacy of Cognitive-Behavioral Therapy Targeting Severe Fatigue Following Coronavirus Disease 2019: Results of a Randomized Controlled Trial.
Severe fatigue following coronavirus disease 2019 (COVID-19) is prevalent and debilitating. This study investigated the efficacy of cognitive-behavioral therapy (CBT) for severe fatigue following COVID-19. A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (N = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post-CBT or CAU (T1), and after 6 months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms, and problems concentrating between CBT and CAU. Patients were mainly nonhospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8 [95% confidence interval {CI}, -11.9 to -5.8]); P < .001), representing a medium Cohen's d effect size (0.69). The between-group difference in fatigue severity was present at T1 (-9.3 [95% CI, -13.3 to -5.3]) and T2 (-8.4 [95% CI, -13.1 to -3.7]). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded. Among patients, who were mainly nonhospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at 6-month follow-up. Netherlands Trial Register NL8947.


Effect of Broad-Spectrum Hemp Extract on Neurobehavioral Activity on the Immobilization Stress-Induced Model in Sprague Dawley Rats.
Broad-spectrum hemp extract is expected to be a promising new intervention for managing stress and anxiety. Research has shown that the cannabinoids found in Cannabis sativa, such as cannabidiol (CBD), tetrahydrocannabinol (THC), and cannabigerol (CBG), possess anxiolytic properties that can positively impact mood and stress. In the current study, a broad-spectrum, nondetectable THC hemp extract with other minor cannabinoids (broad-spectrum hemp extract) was administered at 28 mg/kg·bw to evaluate its anxiolytic properties. This was performed using various behavioural models and biomarkers for oxidative stress. In addition, a 300 mg/kg·bw of Ashwagandha root extract was also incorporated to compare its effects on relieving stress and anxiety. The decreased levels of lipid peroxidation were measured in broad-spectrum hemp extract (36 nmol/ml), Ashwagandha (37 nmol/ml), and induction control (49 nmol/ml) treated groups of animals. The levels of 2-AG decreased in the broad-spectrum hemp extract (1.5 ng/ml), Ashwagandha (1.2 ng/ml), and induction control (2.3 ng/ml) treated groups of animals. The levels of FAAH decreased in broad-spectrum hemp extract (1.6 ng/ml), Ashwagandha (1.7 ng/ml), and induction control (1.9 ng/ml) treated groups of animals. The levels of catalase increased in broad-spectrum hemp extract (35 ng/ml), Ashwagandha (37 ng/ml), and induction control (17 ng/ml) treated groups of animals. Similarly, increased levels of glutathione were found in broad-spectrum hemp extract (30 ng/ml), Ashwagandha (27 ng/ml), and induction control (16 ng/ml) treated groups of animals. Based on the results of this study, it can be concluded that broad-spectrum hemp extract inhibited the biomarkers for oxidative stress. Also, certain behavioural parameters showed improvements with respect to both the ingredient administered groups.


Inhibitors of p38 mitogen-activated protein kinase enhance proliferation of mouse neural stem cells.
The p38 mitogen-activated protein kinase (MAPK) is induced in response to environmental stress. Although p38 MAPK has been implicated in diverse cellular processes, including cell proliferation, differentiation, and survival of differentiated cells in the central nervous system (CNS), the expression profile and roles of p38 MAPK in the developing brain remain largely unknown. In the present study, we demonstrate that p38 MAPK is expressed predominantly in nestin-positive cells in the cerebral cortex in embryonic day 10 (E10) brain and that expression of the protein decreases gradually during development. To investigate the roles of p38 MAPK in the embryonic brain, two selective p38 MAPK inhibitors, SB202190 and SB203580, were added to the primary neuronal cultures from E10-E14 brains. After 7 days of exposure to these inhibitors, but not SB202474, a negative analog of SB203580, numerous large neurospheres were present. MAPK inhibitors also selectively increased the growth rate of neural stem cells (NSCs) purified from secondary neurospheres and the number of bromodeoxyuridine-positive NSCs. Thus, p38 MAPK inhibitors are potent stimulators of NSC proliferation, and p38 MAPK may be an intrinsic negative regulator of NSC proliferation during early brain development.


Do serine proteases degrade amyloid A fibrils?
Human serum contains enzyme(s) able to degrade serum amyloid A protein (SAA) and amyloid A (AA) fibrils. On the basis of inhibition tests these enzymes are regarded as serine proteases, but further characterization of the enzymes has, however, so far not been done. Chymotrypsin, trypsin, elastase, collagenase and kallikrein, when added to SAA-containing serum, all degraded SAA to peptides within 2 h at 37 degrees C. With the exception of collagenase these enzymes also destroyed the Sirius-Red-binding ability of amyloidotic tissue and that of isolated AA fibrils. Hence, they altered the conformation of the beta-pleated structure and possibly also degraded the fibrils. These results suggest that any of these serine proteases could be responsible of the degradation of SAA in serum. The enzyme concentrations needed to degrade amyloid fibrils, however, were much higher than normally found in serum. Thus, it is unlikely that the amyloid-fibril-degrading activity in serum could be due to any of these enzymes.


Incidence of influenza virus infection in early infancy: a prospective study in South Asia.
We evaluated infant sera from an immunization trial in Bangladesh to assess influenza hemagglutination inhibition antibody titer increases in 131 unimmunized infants from birth to 6 months. We detected 31 serologically defined infections. Combined with 10 additional rapid test-proven influenza cases, the minimal estimated incidence was 31 of 100 infants (95% CI: 24-41). These data suggest a high burden of influenza in young infants in tropical South Asia.


The development, implementation, evaluation, and future directions of a chronic disease prevention program for children: the "Know Your Body" studies.
In 1975, the American Health Foundation initiated the development, implementation, and evaluation of a school-based, teacher-delivered program of the primary prevention of heart disease, cancer, and stroke. The aims of this program, entitled "Know Your Body," are to modify favorably the population distributions of risk factors for chronic disease through changes in diet, physical activity, and cigarette smoking. After more than a decade of investigation, this program has been found to be feasible and acceptable to school personnel, students, and parents, and appears to have had favorable effects on prevention-related knowledge, dietary intake, obesity, blood cholesterol levels, and the rate of initiation of cigarette smoking among diverse populations of school children in the New York City area. If these findings can be replicated, the widespread implementation of such programs has the potential to reduce the population risk for the future development of the nation's leading causes of premature mortality.


Obstetric outcome of in vitro fertilized pregnancies complicated by severe ovarian hyperstimulation syndrome: a multicenter study.
To assess the outcome of pregnancies conceived with the use of IVF that are complicated by severe ovarian hyperstimulation syndrome (OHSS). A retrospective nationwide multicenter study. Sixteen of 19 tertiary care medical centers in Israel. All patients undergoing IVF who were hospitalized for severe OHSS between January 1987 and December 1996. Pregnancy rate (PR) and rates of multiple gestation, miscarriage, ectopic pregnancy, obstetric complications, and intervention. A total of 163 patients who had severe OHSS after IVF treatment were identified, of whom 142 (87.1%) had undergone ET. The clinical PR was 73.2%; 42.3% were singletons, 33.6% were twins, 17.3% were triplets, and 6.7% were quadruplets. The miscarriage rate was 29.8%, whereas the incidence of ectopic pregnancy was 1.9%. Forty-four percent of all births were premature, and 62.1% of all newborns had low birth weight. The most common antenatal complications were pregnancy-induced hypertension (13.2%), gestational diabetes (5.9%), and placental abruption (4.4%). The rate of cesarean section was 44.1%. Among patients who have severe OHSS after IVF treatment, the pregnancy rate and the rates of multiple gestation, miscarriage, prematurity, low birth weight, pregnancy-induced hypertension, gestational diabetes, and placental abruption are significantly higher than those reported previously for pregnancies conceived with the use of assisted reproductive techniques.


Effect of ozone exposure on the foraging behaviour of Bombus terrestris.
Tropospheric ozone (O3) mixing ratios have increased substantially since preindustrial times and high O3 peaks are increasingly common. Plant-pollinator interactions are central to natural ecosystem functioning and food production systems but could be negatively affected by unfavourable environmental conditions such as elevated O3. Ecosystem functioning is threatened by O3, which can degrade floral volatile organic compounds (VOCs) used by pollinators as olfactory cues during foraging. It can also exert oxidative stress on VOC-emitting plants and receiving organisms, potentially disturbing the sending and receiving of VOC signals. The aim of this study was to determine the effects of elevated ozone on the foraging behaviour of Bombus terrestris on three species of the Brassicaceae, with a particular focus on bumblebee choices and the mechanisms underpinning differences observed. Moreover, the study was designed to fill a gap between observations in small-scale laboratory experiments and large-scale modelling through empirical observations in polytunnels that represent a medium-large-scale artificial environment. Using 10 × 3 × 2 m polytunnels the effects of O3 on pollinator foraging parameters on Sinapis alba, Sinapis arvensis and Raphanus raphanistrum were assessed. Significant effects of elevated O3 (100 ± 10 ppb) on the time taken for the first bee to alight on a flower and the cumulative amount of time spent on flowers was observed. To further investigate the underlying mechanisms, a laboratory test was conducted to determine the effects of ozone on the VOC blend composition of S. alba flowers. Synthetic VOC blends representing O3-altered and unaltered profiles were reconstituted and utilized in polytunnel and olfactometry experiments. The results indicated that a reduction of olfaction-mediated orientation, probably via VOC-degradation or direct effects of O3 on bees, was responsible for the altered foraging parameters of B. terrestris, suggesting that the presence of elevated O3 could have negative effects on the foraging efficiency of important pollinator species.