Tailoring Active Sites via Synergy between Graphitic and Pyridinic N for Enhanced Catalytic Efficiency of a Carbocatalyst.
Because of the limited characterization methods of the structures and morphology of N-doped carbocatalysts that are available at the atomic level, the detailed promotion mechanism of the catalytic efficiency is unspecific and the particular active sites introduced by the N atoms require further evaluation. Herein, this challenging issue is tackled by extensive theoretical simulation. It is first proposed that the active sites, wherein O2 molecules become adsorbed and activated, be tailored by synergistic graphitic and pyridinic N atoms (GrN and PyN, respectively), which remarkably accelerate the generation of highly chemically reactive O-containing species. The boosted catalytic efficiency is essentially contributed by the electron donor and acceptor of the two active sites, which are induced by PyN and GrN, respectively. These active sites steer the electron transfer between O2 molecules, and the reaction centers in a one-way transmission manner along the PyN → O1 → O2 → C → GrN path. This work provides a feasible protocol for the modification of generally practical carbocatalysts and sheds new light on the understanding of the catalysis mechanism.


Halohydrocarbon synthesis by bromoperoxidase.
An enzyme extracted from marine red algae, Bonnemaisonia hamifera, is capable of incorporating bromine into a number of organic substrates in the pH range 5 to 8. At pH 7.3, incubation of partially purified preparations of bromoperoxidase with hydrogen peroxide, bromide ion, and 3-oxooctanoic acid leads to the formation of three volatile brominated hydrocarbons: dibromomethane, bromoform, and 1-pentyl bromide. The presence of significant quantities of halometabolites including volatile halohydrocarbons in marine organisms, ocean waters, and the upper atmosphere may result from peroxidase-catalyzed halogenation reactions.


Persistent Laplacian projected Omicron BA.4 and BA.5 to become new dominating variants.
Due to its high transmissibility, Omicron BA.1 ousted the Delta variant to become a dominating variant in late 2021 and was replaced by more transmissible Omicron BA.2 in March 2022. An important question is which new variants will dominate in the future. Topology-based deep learning models have had tremendous success in forecasting emerging variants in the past. However, topology is insensitive to homotopic shape evolution in virus-human protein-protein binding, which is crucial to viral evolution and transmission. This challenge is tackled with persistent Laplacian, which is able to capture both the topological change and homotopic shape evolution of data. Persistent Laplacian-based deep learning models are developed to systematically evaluate variant infectivity. Our comparative analysis of Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron BA.1, BA.1.1, BA.2, BA.2.11, BA.2.12.1, BA.3, BA.4, and BA.5 unveils that Omicron BA.2.11, BA.2.12.1, BA.3, BA.4, and BA.5 are more contagious than BA.2. In particular, BA.4 and BA.5 are about 36% more infectious than BA.2 and are projected to become new dominant variants by natural selection. Moreover, the proposed models outperform the state-of-the-art methods on three major benchmark datasets for mutation-induced protein-protein binding free energy changes. Our key projection about BA4 and BA.5's dominance made on May 1, 2022 (see arXiv:2205.00532) became a reality in late June 2022.


Nomograms for the Prediction of Survival for Patients with Pediatric Adrenal Cancer after Surgery.
Purpose: To develop and validate a nomogram to postoperatively evaluate overall survival (OS) and cancer-specific survival (CSS) in patients with pediatric adrenal cancer. Methods: In total, 847 eligible patients diagnosed between 1988 and 2015 form the Surveillance Epidemiology, and End Results (SEER) database were enrolled in this study according to the specified inclusion and exclusion criteria. They were divided into a training set (n = 661) and a validation set (n = 186). Multivariate Cox proportional hazards regression algorithm was used to identify the independent predictors of OS and CSS in the training set, and develop the predicting models, which were presented two nomograms. The performance of the nomograms (discrimination, calibration and clinical usefulness) was assessed in the training set and validated in the validation set. Results: Based on the multivariate Cox proportional hazards regression analyses, three independent predictors including age at diagnosis, tumor size and M stage were identified for both OS and CSS. Then, an OS nomogram and a CSS nomogram were developed incorporating these three predictors, respectively. The OS nomogram showed good calibration and discrimination in the training set (C-index [95% CI], 0.744 [0.711-0.777]), which was confirmed in the validation set (C-index [95% CI], 0.746 [0.656-0.836]). Favorable calibration and discrimination of the CSS nomogram were also observed in the training set (C-index [95% CI], 0.749 [0.715-0.783]) and validation set (C-index [95% CI], 0.789 [0.710-0.868]). Moreover, the nomograms successfully distinguished patients with high risk of all-cause and cancer-specific mortality in all patients and in the stratified analyses. Decision curve analysis demonstrated the usefulness of the nomograms. Conclusion: The presented nomograms show favorable predictive accuracy for OS and CSS in patients with pediatric adrenal cancer after surgery. Further validation is warranted prior to clinical implementation.


Cluster Randomized Trial: Sun Protection Intervention 'Clever in Sun and Shade for Preschools'-Effectiveness and Dissemination.
Skin cancer is one of the most common types of cancer and UV radiation is one of the main risk factors. Therefore, sun protection, especially in childhood, is strongly recommended. We examined the effectiveness of the 'Clever in Sun and Shade for Preschools' program (CLEVER) in promoting sun protection behavior among preschool staff (trial registration: DRKS00023468) and describe its dissemination. Within a cluster randomized trial with 24 preschools (n = 273 staff members) stating a high need for sun protection measures, an educational workshop for preschool staff and a project kit with materials applicable in preschool groups was provided. Staff members of preschools taking part in CLEVER report significantly stronger sun protection behavior to avoid the sun (effect size [ES] 0.70, 95% confidence interval [CI] 0.04 0.71, p < 0.05) and less perceived impediments to avoid the sun (ES -0.56, CI -0.82 -0.17, p < 0.01) after 12 months as well as higher self-efficacy to avoid the sun (ES 1.09, CI 0.39 1.07, p < 0.001) and to use sunscreen (ES 0.71, CI 0.03 0.88, p < 0.05) after 1 month. Compared to the control group, there was no significant effect on sunscreen use and further psychosocial outcomes. The effectiveness of CLEVER may be underrated due to a high drop-out rate. Within three years, an enhanced free-of-charge program kit, including a media-based workshop and materials, had reached over 4000 preschools, i.e., 7.1% of all daycare centers in Germany. The results show that CLEVER can strengthen sun protection, offer high-quality information at low cost, and is easily disseminable.


PERMANENT GENETIC RESOURCES: Twelve new microsatellite markers for the Chinese shrimp Fenneropenaeus chinensis.
Twelve new microsatellite markers were isolated by sequencing random clones from a genomic library of Fenneropenaeus chinensis. The number of alleles per locus ranged from five to 15. The polymorphism information content ranged from 0.568 to 0.898, and observed and expected heterozygosities from 0.344 to 0.882 and from 0.691 to 0.915, respectively. All loci except one conformed to Hardy-Weinberg equilibrium. These markers, described here for Chinese shrimp, will be further used to analyse the species' population genetics.


Sperm DNA integrity testing: big halo is a good predictor of embryo quality and pregnancy after conventional IVF.
Sperm DNA integrity is a sperm functional parameter of male fertility evaluation. Two parameters of sperm DNA integrity were observed: DNA damage expressed as DNA fragmentation index (DFI) and percentage of the DNA undamaged spermatozoa expressed as big halo. Halosperm test was used for sperm DNA integrity determination. The aim of this study was to evaluate which DNA integrity parameter is better as an embryo quality and pregnancy prognostic parameter after the conventional IVF. We evaluated two embryo groups (positive and negative group) according to the 3rd day cumulative embryo score. Big halo and DFI, as we expected, showed good correlation (r = -0.69; p < 0.001). Receiver operating characteristic (ROC) analyses show that DFI and big halo are significant (p < 0.001) as prognostic parameters of embryo quality. ROC curves comparison of DFI and big halo revealed the AUC value for big halo to be significantly higher (DFI AUC = 0.71 vs. big halo AUC = 0.83; p = 0.025) than for DFI. Big halo was found to be the only independent predictor of embryo quality. Sperm DNA integrity both parameters are good prognostic parameters of embryo quality after the conventional IVF where big halo seems to be better. ROC analyses show DFI and big halo as significant prognostic parameters for achieved pregnancy (AUC ± SE for DFI was 0.67 ± 0.06 and 0.75 ± 0.06 for big halo). To our knowledge, this is the first study demonstrating the correlation between sperm DNA undamaged rate expressed as big halo parameter and semen characteristics as well as the influence on fertilization rate, embryo quality and pregnancy in conventional IVF.


Update on the supply and use of allografts in locomotor system pathologies in France.
Allografts are increasingly used in orthopedics. The main aim of the present study was to map the use of locomotor system allografts in France between 2012 and 2016. The study hypothesis was that there are great differences in the distribution and activity of tissue banks and graft preservation procedure quality, failing to meet national requirements. Data from activity reports of the French Biomedicine Agency (ABM) were collected for the period 2012-2016. Existing viral inactivation procedures were described. Preliminary results from a study of allograft requirements by the French Society of Arthroscopy (SFA) were reported. Nineteen tissue banks were located. Four dealt exclusively with cryopreserved tissue, 3 exclusively with virus-inactivated bone, and 12 with both. Distribution analysis found wide disparities in geographic location and in type of activity. Viral inactivation is presently implemented only for femoral heads derived from hip replacement. Stocks of long bones, femoral heads and ligaments/tendons increased constantly over the study period, by 8.3%, 50.8% and 316.2% respectively. The SFA questionnaire confirmed a serious shortage of tissues, necessitating importation of allografts. Each tissue bank had its own specificities and specialization. They should probably be coalesced, so as to centralize both supply and demand and improve nationwide response to requirements. Locomotor system tissue harvesting also needs to be expanded to meet increasing demand.


A comparison of the quality of hypertension management in primary care between Shanghai and Shenzhen: a cohort study of 3196 patients.
Strong primary care is in urgent need for the management and control of hypertension. This study aimed to compare the quality of hypertensive care delivered by community health centers (CHCs) in Shanghai and Shenzhen. Multistage random sampling method was used to select 4 CHCs in each city as study settings. A cohort of hypertensive patients under the hypertensive management program in the CHCs was selected from the electronic information system by using a systematic random sampling method. Binary logistic regression models were constructed for comparison between the 2 cities. A total of 3196 patients' records were assessed. The proportions of hypertensive patients who received advice on smoking cessation (33.8 vs 7.7%, P < 0.001), increasing physical activity (52.4 vs 16.8%, P < 0.001), low-sodium diet (72.0 vs 64.1%, P < 0.001), and regular follow-up (37.8 vs 8.6%, P < 0.001) were higher in Shenzhen than in Shanghai. However, the drug treatment rate in Shenzhen was lower than that in Shanghai (74.2 vs 95.2%, P < 0.001). The hypertension control rate in Shenzhen was lower than that in Shanghai (76.3 vs 83.2%, P < 0.001). Better performance in the process of hypertensive care in terms of increasing physical activity advice, low-sodium diet advice, regular follow-up, and drug prescription was associated with a higher rate of hypertension control. The study indicates that primary care is effective in managing hypertension irrespective of management and operation models of CHCs in urban China. Our study suggests that improvements in the process of hypertensive care may lead to better hypertension control.


A single-layer wide-angle negative-index metamaterial at visible frequencies.
Metamaterials are materials with artificial electromagnetic properties defined by their sub-wavelength structure rather than their chemical composition. Negative-index materials (NIMs) are a special class of metamaterials characterized by an effective negative index that gives rise to such unusual wave behaviour as backwards phase propagation and negative refraction. These extraordinary properties lead to many interesting functions such as sub-diffraction imaging and invisibility cloaking. So far, NIMs have been realized through layering of resonant structures, such as split-ring resonators, and have been demonstrated at microwave to infrared frequencies over a narrow range of angles-of-incidence and polarization. However, resonant-element NIM designs suffer from the limitations of not being scalable to operate at visible frequencies because of intrinsic fabrication limitations, require multiple functional layers to achieve strong scattering and have refractive indices that are highly dependent on angle of incidence and polarization. Here we report a metamaterial composed of a single layer of coupled plasmonic coaxial waveguides that exhibits an effective refractive index of -2 in the blue spectral region with a figure-of-merit larger than 8. The resulting NIM refractive index is insensitive to both polarization and angle-of-incidence over a +/-50 degree angular range, yielding a wide-angle NIM at visible frequencies.


Magnetically driven in-plane modulation of the 3D orientation of vertical ferromagnetic flakes.
External magnetic fields are known to attract and orient magnetically responsive colloidal particles. In the case of 2D microplatelets, rotating magnetic fields are typically used to orient them parallel to each other in a brick-and-mortar fashion. Thanks to this microstructure, the resulting composites achieve enhanced mechanical and functional properties. However, parts with complex geometries require their microstructure to be specifically tuned and controlled locally in 3D. Although the tunability of the microstructure along the vertical direction has already been demonstrated using magnetic orientation combined with sequential or continuous casting, controlling the particle orientation in the horizontal plane in a fast and effective fashion remains challenging. Here, we propose to use rotating magnetic arrays to control the in-plane orientation of ferromagnetic nickel flakes distributed in curable polymeric matrices. We experimentally studied the orientation of the flakes in response to magnets rotating at various frequencies and precessing angles. Then, we used COMSOL to model the magnetic field from rotating magnetic arrays and predicted the resulting in-plane orientations. To validate the approach, we created composites with locally oriented flakes. This work could initiate reverse-engineering methods to design the microstructure in composite materials with intricate geometrical shapes for structural or functional applications.


Associations between state-level general population alcohol policies and drinking outcomes among women of reproductive age: Results from 1984 to 2020 National Alcohol Surveys.
Policies specific to alcohol use during pregnancy have not been found to reduce risks related to alcohol use during pregnancy. In contrast, general population alcohol policies are protective for the general population. Here, we assessed whether US state-level general population alcohol policies are related to drinking outcomes among women of reproductive age. We conducted secondary analyses of 1984-2020 National Alcohol Survey data (N = 13,555 women ≤44 years old). State-level policy exposures were government control of liquor retail sales, heavy beer at gas stations, heavy beer at grocery stores, liquor at grocery stores, Sunday off-premise liquor sales, and blood alcohol concentration (BAC) driving limits (no law, 0.10 limit, 0.05-0.08 limit). Outcomes were past 12-month number of drinks, ≥5 drink days, ≥8 drink days, and any DSM-IV alcohol abuse/dependence symptoms. Regressions adjusted for individual and state-level controls, clustering by state, and included fixed effects for survey month and year. Allowing Sunday off-premise liquor sales versus not was related to having 1.20 times as many drinks (95% CI: 1.01, 1.42), 1.41 times as many ≥5 drink days (95% CI: 1.08, 1.85), and 1.91 times as many ≥8 drink days (95% CI: 1.28, 2.83). BAC limits of 0.05-0.08 for driving versus no BAC limit was related to 0.51 times fewer drinks (95% CI: 0.27, 0.96), 0.28 times fewer days with ≥5 drinks (95% CI: 0.10, 0.75), and 0.20 times fewer days with ≥8 drinks (95% CI: 0.08, 0.47). US state-level policies prohibiting Sunday off-premise liquor sales and BAC limits of 0.05-0.08 for driving are related to less past 12-month overall and heavy drinking among women 18-44 years old.


Highlights on Drug and Ion Release and Recharge Capacity of Antimicrobial Removable Prostheses.
This article aimed to review the ion and drug release, recharge abilities, and antimicrobial properties of drug/ion-releasing removable prostheses, and to assess their capability in preventing and inhibiting denture stomatitis as well preventing caries and reversing carious lesions. Data was collected from published scientific papers listed in PubMed database from January 1975 to December 2021. English full-text articles, involving clinical or in vitro studies, focusing on removable prostheses and are concerned with drug/ion release and rechargeability as a way to prevent or inhibit denture stomatitis or dental caries were included. The relevant articles reported that ion- or drug-modified polymethylmethacrylate acts as a reservoir for these ions and drugs and is capable of releasing significant amounts with sustained release effect. Recharging of modified resin resulted in greater sustainability of ion and drug release, thus improving the long-term effects of protection against demineralization and reducing the adhesion of Streptococcus mutans and Candida albicans. Modifications of removable prostheses with rechargeable ions and drugs enhance remineralization, hinder demineralization, and reduce microbial adhesion in difficult-to-access areas. Selection of denture base for clinical use will consider its ability to act as an ion/drug reservoir that is capable of release and recharge.


Retroviral expression of connexins in embryonic chick lens.
To develop an in vivo model system in which exogenous proteins can be expressed in embryonic chick lens and to further understand the function of connexin-mediated gap junction intercellular communication in lens cell biology. RCAS(A) is a replication-competent chicken retrovirus that infects dividing cells. Retroviral constructs were prepared containing alkaline phosphatase (AP) and FLAG-tagged connexins. Chick lenses were infected in situ by injecting virus into the lumen of lens vesicles at stage 18, cultures were taken at various periods. The lenses were then dissected, and the expressed proteins were visualized by AP histochemical examination and immunostaining. Twenty-four hours after infection, alkaline phosphatase could be seen in epithelia and fibers. As lens fiber maturation progressed, however, the alkaline phosphatase staining was lost as the fibers matured, presumably because of the proteolytic removal of the enzyme. By 72 hours, alkaline phosphatase staining could still be observed in epithelial cells and in differentiating fibers in the bow region but not in the mature lens fibers. FLAG-tagged exogenous lens connexins were also abundantly expressed by viral infection. The exogenous connexins were localized at the cell surfaces in junctional maculae and showed the same cell-type specific distribution as that of their endogenous connexin counterparts. An in vivo model system has been developed in the chick that provides opportunities to study the expression of wild-type and mutant proteins during lens differentiation. Expression of wild-type connexins has revealed that the characteristic distribution of the three different lens connexins is maintained even when expression is driven by a viral promoter.


Genetic linkage of IgG autoantibody production in relation to lupus nephritis in New Zealand hybrid mice.
F1 hybrids of New Zealand black (NZB) and New Zealand white (NZW) mice are a model of human systemic lupus erythematosus. These mice develop a severe immune com-plex-mediated nephritis, in which antinuclear autoantibodies are believed to play the major role. We used a genetic analysis of (NZB x NZW)F1 x NZW backcross mice to provide insight into whether different autoantibodies are subject to separate genetic influences and to determine which autoantibodies are most important in the development of lupus-like nephritis. The results showed one set of loci that coordinately regulated serum levels of IgG antibodies to double-stranded DNA, single-stranded DNA, total histones, and chromatin, which overlapped with loci that were linked to the production of autoantibodies to the viral glycoprotein, gp70. Loci linked with anti-gp70 compared with antinuclear antibodies demonstrated the strongest linkage with renal disease, suggesting that autoantibodies to gp70 are the major pathogenic antibodies in this model of lupus nephritis. Interestingly, a distal chromosome 4 locus, Nba1, was linked with nephritis but not with any of the autoantibodies measured, suggesting that it contributes to renal disease at a checkpoint distal to autoantibody production.


Acute toxicity analysis of an inhibitor of BCL2, Disarib, in rats.
Apoptosis or programmed cell death is a highly regulated process, which eliminates unwanted and damaged cells. Inhibition of apoptosis is a hallmark of cancer cells. BCL2 family proteins are known to play a vital role in the regulation of apoptosis. Overexpression of BCL2, an antiapoptotic protein, provides the advantage of prolonged survival to cancer cells. Over the years, several BCL2 inhibitors have been investigated extensively for their anticancer potential. However, most of them were abolished before clinical use due to their side effects. Previously, we had identified and characterized a novel BCL2 inhibitor, Disarib, with the potential to eliminate tumor cells in a BCL2 specific manner leading to reduction in tumor burden in multiple mouse models. Notably, a head-to-head comparison of Disarib to ABT199, the only FDA approved BCL2 inhibitor revealed that Disarib is as potent as ABT199. Recent studies using mice revealed that Disarib did not invoke significant side effects in mice. In the present study, we have investigated the acute toxicity of Disarib in Wistar rats. The bioavailability studies following exposure of Disarib in Wistar rats revealed its maximum availability in serum at 24 h following oral administration. Acute toxicity analysis revealed that even a dose as high as 2000 mg/kg of Disarib did not cause significant toxicity in rats. There was no significant variation in blood parameters or kidney and liver functions following administration of Disarib. Histological analysis of different tissues from Disarib treated groups revealed standard architecture with no observable cellular damage. Importantly, exposure to Diasrib did not result in genotoxicity as determined by micronucleus assay. Further, solubility assays revealed that besides DMSO, Disarib is also soluble in alcohol. While the high acidic condition can increase the solubility of Disarib, even a lower percentage of alcohol with acidic conditions can improve its solubility. Thus, the toxicological profile in the current study revealed no significant side effects when Disarib was administered orally to rats.


Leiomyogenic tumor of the spine: surgical treatments and long-term outcomes of 12 consecutive patients.
Leiomyogenic tumor of the spine is rare with limited published information. Here, the authors report the clinical features and long-term surgical outcomes and investigate the prognostic factors affecting disease-free survival (DFS). Twelve patients presented to the authors' institution for surgical treatment from January 2005 to December 2018. The clinical characteristics and outcomes were retrospectively reviewed, and the DFS rate was estimated using the Kaplan-Meier method. The log-rank test was used to identify the potential prognostic factors, with p < 0.05 considered statistically significant. The mean patient age was 49.7 ± 12.9 years (range 22-73 years). Four patients underwent marginal en bloc resection, and 8 patients underwent conventional piecemeal resection. Pathological diagnosis revealed leiomyosarcoma in 9 patients and leiomyoma in 3 patients. Three patients had tumor recurrence at a mean follow-up of 10.4 months (range 7.0-15.0 months), while 4 developed metastases at an average of 13.8 months (range 5.5-21.3 months) postoperatively. During the mean follow-up of 33.7 months (range 9.6-78.5 months), the estimated 1- and 5-year DFS rates were 66.7% and 38.2%, respectively. Albumin loss > 20 g/L after surgery, Ki-67 positivity > 10%, and piecemeal resection were correlated with worse DFS. Surgical management of spinal leiomyogenic tumors is challenging due to the high rate of recurrence and metastases. En bloc resection should be performed in eligible patients. Albumin loss > 20 g/L and the Ki-67 index may be independent factors affecting prognosis.


Comparison of recording of hepatitis B infection in the NSW Perinatal Data Collection with linked hepatitis B notifications.
Results of routine maternal antenatal hepatitis B (HBV) screening have been recorded in the New South Wales (NSW) Perinatal Data Collection (PDC) since January 2011. We evaluated the accuracy of this reporting in 2012, the first year that comprehensive data were available, by linking the PDC to HBV notifications. PDC records of mothers giving birth in 2012 were probabilistically linked to HBV notifications recorded in the NSW Notifiable Conditions Information Management System (NCIMS). Sensitivity and specificity of the PDC record of HBV status were determined using a linked HBV notification from the NCIMS database as the gold standard. Results were also examined according to health service (area health service, hospital level, public or private) and individual factors (maternal age, country of birth, Aboriginality, parity, timing of first antenatal visit). Among 99 510 records of women giving birth in NSW in 2012, positive HBV status was recorded for 0.69% of the women according to the PDC record and 0.90% from linked NCIMS records. The overall sensitivity of the HBV status variable in the PDC data was 65.5% (95% confidence interval [CI] 62.4, 68.7) and positive predictive value was 85.3% (95% CI 82.6, 87.9). In general, the low prevalence of HBV meant we had limited statistical power to assess differences between health service factors and maternal factors; however, sensitivity was significantly lower in PDC data for HBV in Australian-born non-Aboriginal women (37.0%; 95% CI 27.5, 46.7) than in overseas-born women (69.9%; 95% CI 66.6, 73.1; p < 0.001). PDC records of HBV status for women giving birth in 2012 had high specificity but poor sensitivity. Sensitivity varied across area health services and levels of maternal services, and by various maternal factors. Because the results of maternal HBV screening can be used to monitor HBV prevalence in adults, analysis of the PDC records in subsequent years is necessary to track whether sensitivity improves over time.


Adenoviral vector driven by a minimal Rad51 promoter is selective for p53-deficient tumor cells.
The full length Rad51 promoter is highly active in cancer cells but not in normal cells. We therefore set out to assess whether we could confer this tumor-selectivity to an adenovirus vector. Expression of an adenovirally-vectored luciferase reporter gene from the Rad51 promoter was up to 50 fold higher in cancer cells than in normal cells. Further evaluations of a panel of truncated promoter mutants identified a 447 bp minimal core promoter element that retained the full tumor selectivity and transcriptional activity of the original promoter, in the context of an adenovirus vector. This core Rad51 promoter was highly active in cancer cells that lack functional p53, but less active in normal cells and in cancer cell lines with intact p53 function. Exogenous expression of p53 in a p53 null cell line strongly suppressed activity of the Rad51 core promoter, underscoring the selectivity of this promoter for p53-deficient cells. Follow-up experiments showed that the p53-dependent suppression of the Rad51 core promoter was mediated via an indirect, p300 coactivator dependent mechanism. Finally, transduction of target cells with an adenovirus vector encoding the thymidine kinase gene under transcriptional control of the Rad51 core promoter resulted in efficient killing of p53 defective cancer cells, but not of normal cells, upon addition of ganciclovir. Overall, these experiments demonstrated that a small core domain of the Rad51 promoter can be used to target selective transgene expression from adenoviral vectors to tumor cells lacking functional p53.


Ultrastructure of peripheral blood granulocytes from patients with low serum cobalamin.
Peripheral blood granulocytes from ten patients with low serum cobalamin were studied using light and electron microscopic techniques. Six patients had classic neutrophil hypersegmentation using light microscopy, but three patients had an increase in band forms and rare hypersegmented cells. The electron microscope revealed nuclear appendages consisting of nuclear stalks, rings and blebs in neutrophils from all patients regardless of the degree of hypersegmentation but not from normal controls; these did not appear to result from sectioning artifact and their formation may be interrelated. Numerous cytoplasmic empty granules were seen in neutrophils from three patients. Another three showed what appeared to be granules in the shape of water-wings under low power, but on higher power were unique mitochondria. Some disorder of the eosinophil granule centrum was seen in all patients but was extreme in four patients; lipid cytoplasmic inclusions were also seen in these four and one other patient.


Clinical significance of telomerase activity in hepatocellular carcinoma.
Telomerase is a ribonucleoprotein enzyme that elongates telomeric DNA. It has been reported that most immortal cell lines express telomerase, whereas in adult normal tissues telomerase activity is not detected. So, in malignant tumors telomerase is thought to be activated to maintain their immortality. In this study, we examined telomerase activity in 12 cases of hepatocellular carcinoma (HCC) with the use of PCR-based assay and analyzed the relationship of telomerase activity to clinicopathological features. In 11 of 12 HCC nodules telomerase activity was detected, of which 9 cases showed strong activity. There was no significant correlation between telomerase activity and clinicopathological features of HCC. Telomerase activity among 6 well-differentiated HCCs was strong in 3 (50%), weak in 2 (33%), and undetected in 1 (17%). All of 6 moderately-differentiated HCCs (100%), however, showed strong activity. As regards tumor size, 4 of 5 HCCs (80%) less than 3 cm in diameter showed strong telomerase activity. On the other hand, weak telomerase activity was detected in only 2 of 12 (17%) noncancerous liver tissues surrounding HCC nodules. The assay of telomerase activity may be a useful diagnostic marker of HCC regardless of tumor size, and the activity may be expressed even at early stage.


European intergroup studies (MMT4-89 and MMT4-91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors.
Final results are presented from two consecutive European studies for patients with metastatic rhabdomyosarcoma (RMS) to identify prognostic variables and determine the value of high-dose chemotherapy (HDCT) in complete remission. A total of 174 patients aged 3 months to 18 years participated. From 1989 to 1991, patients received four cycles of intensive multiagent chemotherapy. From 1991 to 1995, patients achieving complete remission received consolidation with HDCT. All received local therapy (surgery, radiation therapy) according to response. At a median follow-up of 8 years, 5-year overall survival (OS) and event-free survival (EFS) for the whole group were 24% and 20%, respectively. No statistical difference was found between HDCT and standard chemotherapy (5-year OS, 36% v 27%; EFS 29% v 23%). Univariate analysis identified primary tumor in parameningeal, extremity, or other sites; age younger than 1 year and older than 10 years; bone or bone marrow metastases; multiple metastases; and multiple sites of metastases as unfavorable prognostic factors for OS and EFS. Multivariate analysis identified unfavorable site, bone or bone marrow involvement, and unfavorable age as independently unfavorable factors. Two subgroups were identified. Those with fewer than two unfavorable factors had 5-year EFS and OS of 40% and 47%, respectively. Patients with > or = two unfavorable factors had 5-year EFS and OS of 7.5% and 9%, respectively. A minority of patients with metastatic RMS have better survival than overall results for this population suggest. Those in the highest risk group have such poor survival that they are candidates for first-line novel therapies. There is no evidence that consolidation with HDCT improves outcome.


A web-based tool for rational screening of mutants libraries using ProSAR.
In directed evolution experiments, it is at stake to have methods to screen efficiently the mutant libraries. We propose a web-based tool that implements an established in silico method for the rational screening of mutant libraries. The method, known as ProSAR, attempts to link sequence data to activity. The method uses statistical models trained on small experimental datasets provided by the user. These can integrate potential epistatic interactions between mutations and be used in many diverse biological contexts. It drastically improves the search for leading mutants. The tool is freely available to non-commercial users at http://bo-protscience.fr/prosar/.


Gustatory receptor 28b is necessary for avoiding saponin in Drosophila melanogaster.
Saponins function as a natural self-defense mechanism for plants to deter various insects due to their unpleasant taste and their toxicity. Here, we provide evidence that saponin from Quillaja saponaria functions as an antifeedant as well as an insecticide to ward off insects in both the larval and the adult stages. Using a behavioral screen of 26 mutant fly lines, we show that the Gr28b gene cluster plays a role in saponin avoidance in the labellum. The Gr28b mutant does not avoid saponin and exhibits increased lethality when fed saponin-mixed food. Tissue-specific rescue experiments with five different Gr28b isoforms revealed that only the Gr28b.c isoform is required for saponin sensation. We propose that in contrast to sensing many other bitter compounds, saponin sensing does not require the function of core taste receptors, such as GR32a, GR33a, and GR66a. Our results reveal a novel role for GR28b in taste. In addition, the ability of saponin to act as insecticides as well as antifeedants suggests its potential application in controlling insect pests.


Characterization of inflammatory (lymphoepithelioma-like) hepatocellular carcinoma: a study of 8 cases.
The World Health Organization has recently recognized lymphoepithelioma-like carcinoma, or inflammatory hepatocellular carcinoma, as a variant of hepatocellular carcinoma. To identify and characterize the inflammatory hepatocellular carcinomas in our institution from 1988 to the present. All cases of hepatocellular carcinoma in our institution from 1988 to the present were reviewed and reclassified as lymphoepithelioma-like carcinoma and were studied in comparison to appropriately matched controls. Among the 8 cases of lymphoepithelioma-like carcinoma identified, the male to female ratio was 1:3, the mean age was 68.5 years (range, 57-78 years), and all of the cases were seen in noncirrhotic livers. The average numbers of lymphocytes were significantly higher in the cases than in the controls. T cells were predominant, with a uniform distribution of CD4 and CD8 positive cells. Cholangiolar differentiation was seen by K19 positivity as focal in 1 case and diffuse in 2 cases. In situ hybridization for Epstein-Barr virus was negative in all of the cases. Diffuse overexpression of p16 (>75% of cells) was seen in 2 cases, both of which were negative for the presence of transcriptionally active human papilloma virus by in situ hybridization. In our series, 3 of 8 cases (37.5%) showed local recurrence, which was similar to the controls (6 of 18; 33%), P > .99. Although the rate of distant metastases was lower among the cases (12.5%) than the controls (22.2%), the difference was not statistically significant (P > .99). We present the first series of 8 cases of lymphoepithelioma-like carcinoma of the liver occurring in patients without cirrhosis and with a female preponderance and the absence of Epstein-Barr virus. Although clinical outcomes were similar to those of controls in our small series, additional data may be required for confirmation.


Where there is no doctor: can volunteer community health workers in rural Uganda provide integrated community case management?
Integrated community case management (iCCM) involves assessment and treatment of common childhood illnesses by community health workers (CHWs). Evaluation of a new Ugandan iCCM program is needed. The objectives of this study were to assess if iCCM by lay volunteer CHWs is feasible and if iCCM would increase proportions of children treated for fever, pneumonia, and diarrhoea in rural Uganda. This pre/post study used a quasi-experimental design and non-intervention comparison community. CHWs were selected, trained, and equipped to assess and treat children under five years with signs of the three illnesses. Evaluation included CHW-patient encounter record review plus analysis of pre/post household surveys. 196 iCCM-trained CHWs reported 6,276 sick child assessments (45% fever, 46% pneumonia, 9% diarrhoea). 93% of cases were managed according to algorithm recommendations. Absolute proportions of children receiving treatment significantly increased post-intervention: antimalarial for fever (+24% intervention versus +4% control) and oral rehydration salts/zinc for diarrhoea (+14% intervention versus +1% control). In our limited-resource, rural Ugandan setting, iCCM involving lay CHWs was feasible and significantly increased the proportion of young children treated for malaria and diarrhoea.


Environmental assessment of different advanced oxidation processes applied to a bleaching Kraft mill effluent.
Different advanced oxidation processes (AOPs) have been applied to remove the organic carbon content of a paper mill effluent originating from the Kraft pulp bleaching process. The considered AOPs were: TiO(2)-mediated heterogeneous photocatalysis, TiO(2)-mediated heterogeneous photocatalysis assisted with H(2)O(2), TiO(2)-mediated heterogeneous photocatalysis coupled with Fenton, photo-Fenton, ozonation and ozonation with UV-A light irradiation. The application of the selected AOPs all resulted in a considerable decrease in dissolved organic carbon (DOC) content with variable treatment efficiencies depending upon the nature/type of the applied AOP. A Life Cycle Assessment (LCA) study was used as a tool to compare the different AOPs in terms of their environmental impact. Heterogeneous photocatalysis coupled with the Fenton's reagent proved to have the lowest environmental impact accompanied with a moderate-to-high DOC removal rate. On the other hand, heterogeneous photocatalysis appeared to be the worst AOP both in terms of DOC abatement rate and environmental impact. For the studied AOPs, LCA has indicated that the environmental impact was attributable to the high electrical energy (power) consumption necessary to run a UV-A lamp or to produce ozone.


Slow wave heterogeneity within the circular muscle of the canine gastric antrum.
A cross-sectional preparation was designed in which multiple micro-electrodes can be precisely positioned to impale smooth muscle cells anywhere from the serosa to the submucosa. Intracellular electrical recordings were obtained from gastric antral circular muscle cells from the myenteric plexus to the submucosa. The resting membrane potential changed linearly as a function of distance from the myenteric plexus to the submucosa. Slow wave upstroke dV/dt, upstroke potential amplitude, and plateau potential amplitude changed linearly as a function of distance from the myenteric plexus to the submucosa. When slow waves were recorded simultaneously from a circular cell near the myenteric plexus and from a cell near the submucosa, the event always occurred first in the cell near the myenteric plexus. Electrical differences did not appear to be caused by electrotonic decay of slow waves as they propagated through the circular muscle. Electrical differences could not be explained on the basis of differences in intrinsic neural activity or prostaglandin synthesis. Membrane polarization could not explain the differences in slow waves between myenteric and submucosal circular muscle cells. The conclusion of this paper is that fundamental differences exist between the excitability mechanisms and/or passive membrane properties of cells near the myenteric plexus and the submucosa. These differences might be manifest in different motor performance of these two muscle cell populations.


Curcumin suppresses gastric tumor cell growth via ROS-mediated DNA polymerase γ depletion disrupting cellular bioenergetics.
Curcumin, as a pro-apoptotic agent, is extensively studied to inhibit tumor cell growth of various tumor types. Previous work has demonstrated that curcumin inhibits cancer cell growth by targeting multiple signaling transduction and cellular processes. However, the role of curcumin in regulating cellular bioenergetic processes remains largely unknown. Western blotting and qRT-PCR were performed to analyze the protein and mRNA level of indicated molecules, respectively. RTCA, CCK-8 assay, nude mice xenograft assay, and in vivo bioluminescence imaging were used to visualize the effects of curcmin on gastric cancer cell growth in vitro and in vivo. Seahorse bioenergetics analyzer was used to investigate the alteration of oxygen consumption and aerobic glycolysis rate. Curcumin significantly inhibited gastric tumor cell growth, proliferation and colony formation. We further investigated the role of curcumin in regulating cellular redox homeostasis and demonstrated that curcumin initiated severe cellular apoptosis via disrupting mitochondrial homeostasis, thereby enhancing cellular oxidative stress in gastric cancer cells. Furthermore, curcumin dramatically decreased mtDNA content and DNA polymerase γ (POLG) which contributed to reduced mitochondrial oxygen consumption and aerobic glycolysis. We found that curcumin induced POLG depletion via ROS generation, and POLG knockdown also reduced oxidative phosphorylation (OXPHOS) activity and cellular glycolytic rate which was partially rescued by ROS scavenger NAC, indiating POLG plays an important role in the treatment of gastric cancer. Data in the nude mice model verified that curcumin treatment significantly attenuated tumor growth in vivo. Finally, POLG was up-regulated in human gastric cancer tissues and primary gastric cancer cell growth was notably suppressed due to POLG deficiency. Together, our data suggest a novel mechanism by which curcumin inhibited gastric tumor growth through excessive ROS generation, resulting in depletion of POLG and mtDNA, and the subsequent disruption of cellular bioenergetics.


Analysis of pharmacokinetic parameters for assessment of dextromethorphan metabolic phenotypes.
In this study, the metabolic ratios of dextromethorphan to dextrorphan (DM/DX) in plasma were calculated at steady state after administering 2 dosage forms (Medicon) and Detusiv) of DM with different release rates. The urinary metabolic ratio for each subject was also determined based on the total drug concentration in the urine. An analysis of pharmacokinetic parameters for determining the DM metabolic phenotype was conducted. Results demonstrate that double logarithmic correlations between the metabolic ratios based on pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) for Medicon and Detusiv and the urinary metabolic ratios were all significant. Probit plots of the metabolic ratios based on these pharmacokinetic parameters revealed 2 clusters of distribution, representing extensive and intermediate metabolizers. An antimode of 2.0 for total drug based on these pharmacokinetic parameters was determined and correspondingly referred to an antimode of 0.02 for the urinary metabolic ratio to delineate extensive and intermediate metabolizers. This model was also verified to be appropriate when using total plasma concentrations of DM and DX at any time during the period of the dosing interval at steady state to calculate the metabolic ratio for identifying extensive and intermediate metabolizers. Therefore, the metabolic ratio based on the pharmacokinetic parameters of either AUC(0-tau,ss), C(max,ss), C(min,ss), or C(ave,ss) and plasma concentrations of DM and DX in a single blood sample at steady state are proposed as an alternative way to identify phenotypes of CYP2D6.


Biodegradation of pesticides using fungi species found in the aquatic environment.
Relatively limited attention has been given to the presence of fungi in the aquatic environment compared to their occurrence in other matrices. Taking advantage and recognizing the biodegradable capabilities of fungi is important, since these organisms may produce many potent enzymes capable of degrading toxic pollutants. Therefore, the aim of this study was to evaluate the potential ability of some species of filamentous fungi that occur in the aquatic environment to degrade pesticides in untreated surface water. Several laboratory-scale experiments were performed using the natural microbial population present in the aquatic environment as well as spiked fungi isolates that were found to occur in different water matrices, to test the ability of fungi to degrade several pesticides of current concern (atrazine, diuron, isoproturon and chlorfenvinphos). The results obtained in this study showed that, when spiked in sterile natural water, fungi were able to degrade chlorfenvinphos to levels below detection and unable to degrade atrazine, diuron and isoproturon. Penicillium citrinum, Aspergillus fumigatus, Aspergillus terreus and Trichoderma harzianum were found to be able to resist and degrade chlorfenvinphos. These fungi are therefore expected to play an important role in the degradation of this and other pollutants present in the aquatic environment.


Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance.
Macrophage infiltration in adipose tissue is strongly correlated with obesity. The exact role of macrophage in the development of obesity, however, has not been fully understood. In this study, using intraperitoneal injection of clodronate liposomes, we tissue-specifically depleted visceral adipose tissue macrophages (VATMs) and explored their roles in initiation and progression of obesity. Two sets of experiments were conducted, using mice on a high-fat diet as the animal model. Mice were injected with clodronate liposomes at the beginning of high-fat diet feeding to investigate the role of VATMs in the initiation of obesity. Treatment starting on week 5 was designed to explore the function of VATMs in the progression of weight gain. The results show that intraperitoneal injection of clodronate liposomes effectively depleted VATMs, which blocked high-fat diet-induced weight gain, fat accumulation, insulin resistance, and hepatic steatosis. Similarly, clodronate liposomes suppressed progression of weight gain in mice after being fed with a high-fat diet for 4 weeks and improved insulin sensitivity. Gene expression analysis showed that depletion of VATMs was associated with downregulation of the expression of genes involved in lipogenesis and gluconeogenesis including acc1, fas, scd1, and pepck, decreased expression of genes involved in chronic inflammation including mcp1 and tnfα, and suppressed expression of macrophage specific marker genes of f4/80 and cd11c in adipose tissue. Depletion of VATMs was associated with prevention of the formation of crown-like structures in white adipose tissue and the maintenance of a low level of blood TNF-α. Collectively, these data demonstrate that VATMs appeared to play a crucial role in the development of obesity and obesity-associated diseases and suggest that adipose tissue macrophages could be regarded as a potential target for drug development in prevention and therapy of obesity and obesity-associated complications.


Identification of genes associated with heat tolerance in Arctic charr exposed to acute thermal stress.
Arctic charr is an especially attractive aquaculture species given that it features the desirable tissue traits of other salmonids and is bred and grown at inland freshwater tank farms year round. It is of interest to develop upper temperature tolerant (UTT) strains of Arctic charr to increase the robustness of the species in the face of climate change and to enable production in more southern regions. We used a genomics approach that takes advantage of the well-studied Atlantic salmon genome to identify genes that are associated with UTT in Arctic charr. Specifically, we conducted an acute temperature trial to identify temperature tolerant and intolerant Arctic charr individuals, which were subject to microarray and qPCR analysis to identify candidate UTT genes. These were compared with genes annotated in a quantitative trait locus (QTL) region that was previously identified as associated with UTT in rainbow trout and Arctic charr and that we sequenced in Atlantic salmon. Our results suggest that small heat shock proteins as well as HSP-90 genes are associated with UTT. Furthermore, hemoglobin expression was significantly downregulated in tolerant compared with intolerant fish. Finally, QTL analysis and expression profiling identified COUP-TFII as a candidate UTT gene, although its specific role is unclear given the identification of two transcripts, which appear to have different expression patterns. Our results highlight the importance of using more than one approach to identify candidate genes, particularly when examining a complicated trait such as UTT in a highly complex genome for which there is no reference genome.


[Role of serodiagnosis in recognizing atypical forms of leptospirosis in Krasnodar Territory].
The work deals with the epidemiological situation with respect to Leptospira infections in the Krasnodar territory. The work demonstrates that, in comparison with 1960-ies characterized by the prevalence of diseases caused by L. pomona and L. grippotyphosa, in 1970-ies the increase of the specific proportion of infections caused by L. icterohaemorrhagiae was registered. In recent 5 years (1980-1984) this leptospirosis constituted 73.5-94.8% of the total morbidity rate in the territory. Such situation was caused by active prophylactic measures in cattle breeding, as well as by the increase of the number of leptospirosis foci, appearing as the result of human activities and providing favorable conditions for the life and multiplication of Norway rats, the main source of infection caused by L. icterohaemorrhagiae as indicated by the fact that up to 23.9% of the Norway rats examined in this study proved to be contaminated. The detection of cases of leptospirosis among febrile patients and mistakes in clinical diagnosis confirm the necessity of the serological examination of febrile patients with the acute onset of the disease with temperature reaching 38 degrees C and higher for 3-5 days and the clinical picture of the disease being unclear in order to find out patients presenting with the atypical clinical picture of leptospirosis.


Value of combined phenotypic markers in identifying inheritance of familial adenomatous polyposis.
Familial adenomatous polyposis is an autosomal dominant disease characterised by the development of hundreds of colorectal adenomas in young adults. Occult radio-opaque jaw lesions and pigmented ocular fundus lesions (formerly called congenital hypertrophy of the retinal pigment epithelium) are extraintestinal phenotypic markers for this disorder. We evaluated the usefulness of the combination of these markers for identifying patients who have inherited familial adenomatous polyposis. Forty three affected patients and 12 unaffected first degree relatives from 24 families with familial adenomatous polyposis, including four families without extraintestinal manifestations, were examined for both phenotypic markers. Thirty three of the 43 patients (77%) with familial adenomatous polyposis were positive for both markers, including patients from two families without extraintestinal manifestations. By contrast, only one of 12 (8%) unaffected first degree relatives over 35 years of age had both markers. The sensitivity of the combination of these markers in identifying patients who inherited familial adenomatous polyposis was 77%, the specificity 92%, the predictive value of a positive test 97%, the predictive value of a negative test 52%, and the efficacy 80%. The combined markers had improved efficacy over either marker alone (70% for occult radio-opaque jaw lesions and 67% for pigmented ocular fundus lesions). We conclude that the presence of both occult radio-opaque jaw lesions and pigmented ocular fundus lesions in a person at risk indicates a high probability of inheritance and expression of familial adenomatous polyposis.


[Clinico-geneaological study of paranoid schizophrenia].
On the basis of a comparative analysis of aggravated familial history in cases of paranoiac and neurosis-like schizophrenia (73 families in the main and control groups), the authors established accumulation of disturbances of "the paranoid spectrum" (delirious, paranoiac psychoses, paranoid anomalies of the personality) predominant in the families of the main group. This fact is interpreted in favour of a considerable role of constitutional and genetic factors in the genesis of paranoiac schizophrenia.


Inhibitory effects of interleukin 6 on immunity. Possible implications in burn patients.
Certain disease states are associated with abnormal increases in the monokine interleukin 6. Increased levels of interleukin 6 have been demonstrated in serum from patients with burns and are associated with systemic increases in endotoxin levels. Using a murine in vitro experimental model, we have studied the effects of interleukin 6 on various measures of immunity. Our data indicate that levels equivalent to the concentrations found in serum of burn victims inhibit T-cell proliferation. The inhibitory effect is dose and time dependent, is specific for T cells, is not due to impairment of interleukin 2 production or of interleukin 2 receptor expression, and is dependent on macrophages. These data suggest that extraordinary increases in interleukin 6 levels may be related to impaired T-cell responses and to an increased susceptibility to infection in the patient with burns.


Exploring donor and product factors and their impact on red cell post-transfusion outcomes.
The impact of donor characteristics, red cell age, and red cell processing methods on recipient outcomes is an emerging area of research. Knowledge generated from exploring this transfusion continuum has the potential to change the way donors are selected and how donations are processed and stored with important clinical and operational impact. Recently, donor characteristics including age, gender, donation frequency, genetics, and ethnicity have been shown to affect product quality and possibly recipient outcomes. The structural, biochemical and immunological changes that occur with red cell storage appear to not cause harm to blood recipients after 14 randomized clinical trials. However, both in vitro and clinical data are now beginning to question the safety of blood stored for a shorter duration. Whole blood filtration, a method of blood processing, has been linked to inferior recipient outcomes when compared to red cell filtration. Collectively, this emerging body of literature suggests that pre-transfusion parameters impact product quality and recipient outcomes and that no 2 units of red cells are quite the same. This review will summarize both the pre-clinical and clinical studies evaluating these associations.


The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.
Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well-defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 microg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre-exposure to Abeta25-35 and Abeta1-40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50-150 microM), a major peroxide possibly involved in mediating Abeta toxicity. Moreover, EGb 761 (10-100 microg/mL), and to a lesser extent CP 205 (10-50 microg/mL), completely blocked Abeta-induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Abeta-induced toxicity and cell death.


A numerical-experimental method to characterize the non-linear mechanical behaviour of human skin.
Human skin is a complex tissue consisting of several distinct layers. Each layer consists of various components with a specific structure. To gain a better insight into the overall mechanical behaviour of the skin, we wish to study the mechanical properties of the different layers. A numerical-experimental method was developed to characterize the non-linear mechanical behaviour of human dermis. Suction measurements at varying pressures were performed on the volar forearm skin of 10 subjects aged 19-24 years old. Deformation of dermis and fat during suction was measured using ultrasound. The experiment was simulated by a finite element model exhibiting extended Mooney material behaviour to account for the non-linear stress-strain relationship. An identification method is used to compare the experimental and numerical results to identify the parameters of the material model. C10, dermis was found to be 9.4 +/- 3.6 kPa and C11, dermis to be 82 +/- 60 kPa. A first rough estimate of C10, fat was 0.02 kPa. The resulting finite element model demonstrated its ability to describe the response of the skin to suction at various pressures. In the future, this method can be used to characterize the mechanical behaviour of different skin layers using various aperture sizes and to characterize the skin behaviour under various loading conditions.


Chemical composition of essential oil and headspace-solid microextracts from fruits of Myrica gale L. and antifungal activity.
The essential oil and the volatile compounds of Myrica gale fruits were analysed by gas chromatography (GC) and GC-mass spectrometry (GC-MS). The volatile compounds were detected using two different fibres for headspace-solid phase microextraction (HS-SPME), Carboxen/PDMS and PDMS. Sixty two compounds were identified, which represented more than 90% of the total extracts. Major components of fruit essential oil are alpha-pinene (22.6%), 1,8-cineole (18.9%) and germacrone (14.2%), whereas they are germacrone (25.1%), alpha-pinene (12.2%), limonene (8.1%) and alpha-phellandrene (8.0%) for the leaf essential oil. Major volatile fruit compounds detected in HS-SPME were alpha-pinene, 1,8-cineole, p-cymene and eth-cadinene. As M. gale fruits are traditionally used in brewery for flavouring beer or as a spice in soups or stews, the antifungal properties of these essential oils were investigated on a panel of foodborne fungi, namely Aspergillus flavus, Cladosporium cladosporioides and Penicillium expansum. A complete antifungal activity was observed at 1000 ppm against C. cladosporioides. Both essential oil and entire fruits could thus be used as an additive in food or cosmetic preparations for their flavour, odour and their conservative properties.


Report: Evaluation of the scolicidal effects of Nectaroscordum tripedale extract and its acute toxicity in mice model.
Current scolicidal agents, which have been used for inactivation of protoscoleces during hydatid cyst surgery are associated with adverse side effects. This study aims to evaluate the in vitro scolicidal effects of Nectaroscordum tripedale L. leave extract against protoscoleces of hydatid cysts and its acute toxicity in mice model. Various concentrations of the extract (12.5-100 mg/mL) were used for 5 to 30 min. Viability of protoscoleces was confirmed using eosin exclusion test (0.1% eosin staining). In addition, the acute toxicity of N. tripedale extract was determined for 2 days in mice model. The results showed that the N. tripedale extract at the concentration of 100 mg/mL after 5 min of exposure killed 100% protoscoleces. Similarly, the mean of mortality rate of protoscoleces after 10 min of exposure to concentration of 50 mg/mL was 100%. The LD50 values of intraperitoneal injection of the N. tripedale extract was 3.36 g/kg body wt. and the maximum nonfatal doses were 2.98 g/kg body wt. The results showed the potential of N. tripedale extract as a natural source for the production of new scolicidal agent for use in hydatid cyst surgery.


S-100β and Antioxidant Capacity in Cerebrospinal Fluid during and after Thoracic Endovascular Aortic Repair.
Thoracic Endovascular Aortic Repair (TEVAR) has substantially decreased the mortality and major complications from aortic surgery. However, neurological complications such as spinal cord ischemia may still occur after TEVAR. S-100β is a biomarker of central nervous system injury, and oxidant injury plays an important role in neurological injury. In this pilot study, we examined the trends of S-100β and antioxidant capacity in the CSF during and after TEVAR. We recruited 10 patients who underwent elective TEVAR. CSF samples were collected through a lumbar catheter at the following time points: before the start of surgery (T0) and immediately (T1) and 24 (T2) and 48 hours (T3) after the deployment of the aortic stent. S-100β and CSF antioxidant capacity were analyzed with the use of commercially available kits. We observed that the level of S-100β in all of the subjects at 24 hours after the deployment of the aortic stent (T2) increased. However, the levels of S-100β at T1 and T3 were comparable to the baseline value. The antioxidant capacity remained unchanged. No patient had a clinical neurologic complication. Our observations may indicate biochemical/subclinical central nervous system injury attributable to the deployment of the aortic stent.


Bifunctional diatomic site catalysts supported by β12-borophene for efficient oxygen evolution and reduction reactions.
Efficient bifunctional catalysts for oxygen evolution and reduction reactions (OERs/ORRs) are of great importance for sustainable and renewable clean energy, especially for metal-air batteries. Herein, we investigated β12-borophene with double-hole sites capped with 3d transition metal atoms to explore its catalyst performance for hydrogen evolution reactions (HERs), OERs and ORRs. It was found that the borophene is a good platform for diatomic site catalysts (DASCs) due to their advantage of stability over the corresponding single-atom catalysts (SACs) or clusters. The HER performance of DASCs on β12-BM was further improved compared to the SAC case. Furthermore, the supported FeNi DASC exhibited good catalytic performance for both OERs and ORRs, the overpotentials for which were 0.43 and 0.55 V, respectively, better than those of the corresponding supported Ni or Fe SAC due to synergistic effects. We herein propose a novel descriptor involving the Bader charges of coordinated atoms explicitly, behaving much better than the d-band center and integrated crystal orbital Hamilton population (-ICOHP) for DASCs. The synergistic effect of Fe-Ni pairs balanced the too strong binding of OH and further activated OH to achieve better catalytic performance. The results of this study can provide theoretical guidance for the design of efficient bifunctional electrocatalysts.


Growth of CD34+ acute myeloblastic leukemia colony-forming cells in response to recombinant hematopoietic growth factors.
In order to minimize the interactions of clonogenic cells with accessory cells and characterize the direct effect of recombinant hematopoietic growth factors (HGF) on acute myelogenous leukemia colony-forming cells (AML-CFU), the response of CD34+ AML-CFU to individual or combined recombinant HGF, i.e., interleukin-1 (IL-1), interleukin-3 (IL-3), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and macrophage colony-stimulating factor (M-CSF), was studied in 10 patients and compared with the growth response obtained from unfractionated marrow cells. IL-3 and GM-CSF had a similar stimulating activity on AML-CFU growth. G-CSF resulted the most efficient stimulus for colony formation and was additive or synergistic with IL-3 and GM-CSF, M-CSF, used alone, had a negligible stimulating activity. When CD34+ cells were used, IL-1 by itself had a low stimulating activity and displayed little or no synergy with IL-3, GM-CSF, and G-CSF. On the contrary, when unfractionated cells were used, IL-1 was very effective in inducing AML-CFU formation and was markedly synergistic with IL-3 and GM-CSF. These results show that IL-1-induced leukemic colony formation is prevalently mediated by accessory cells. IL-6 supported AML-CFU growth in seven of 10 cases, thus showing a direct effect on CD34+ leukemic cells, and enhanced the growth of IL-3-(+47 to +167%) and GM-CSF-dependent (+60 to +110%) AML-CFU. Recloning studies of single colonies demonstrated that primary CD34+ AML-CFU, stimulated by IL-3 and GM-CSF, generated secondary and tertiary colonies, whereas primary AML-CFU stimulated by G-CSF and IL-6 failed to give rise to secondary colonies, thus indicating a complete suppression of self-renewal. Sequential recloning of colonies grown in the presence of IL-3 + IL-6 demonstrated that addition of IL-6 and IL-3-containing plates resulted in a nearly complete suppression of self-renewal. In conclusion, these results demonstrate the heterogeneity of the CD34+ leukemic cell fraction and indicate the existence of complex regulatory events at the level of CD34+ leukemic cells. Data obtained from recloning experiments are of therapeutic interest in view of the clinical application of HGFs in the treatment of myeloid leukemias.


Pulmonary complications in diabetes mellitus: the role of glycemic control.
Insulin deficiency induces an increase in blood glucose levels that, in long run, becomes toxic for many organs and systems. Microangiopathy and derangements in the immune function are known consequences of hyperglycemia, but the way in which these systemic alterations may affect pulmonary function has been scarcely investigated. Although confirmation from large clinical trials is still to come, the diabetic disease seems to hit the pulmonary microcirculation as any other organ by increasing vessel wall thickness and impairing gas exchange, which leads to a measurable loss of function and respiratory efficiency. In addition, a diabetic lung is more susceptible to low respiratory tract infections by atypical microorganisms and more likely to host severe episodes of pneumonia than a normal, non-diabetic lung. This is a review of current knowledge on the impact of diabetes mellitus in lung health. We have paid special attention to the role of metabolic control in preventing damage to the lung by sustained hyperglycemia.


Risk factors for very preterm delivery out of a level III maternity unit: The EPIPAGE-2 cohort study.
Regionalisation programmes aim to ensure that very preterm infants are born in level III units (inborn) through antenatal referral or transfer. Despite widespread knowledge about better survival without disability for inborn babies, 10%-30% of women deliver outside these units (outborn). To investigate risk factors associated with outborn deliveries and to estimate the proportion that were probably or possibly avoidable. We used a national French population-based cohort including 2205 women who delivered between 24 and 30+6 weeks in 2011. We examined risk factors for outborn delivery related to medical complications, antenatal care, sociodemographic characteristics and living far from a level III unit using multivariable binomial regression. Avoidable outborn deliveries were defined by pregnancy risk (obstetric history, antenatal hospitalisation) and time available for transfer. 25.0% of women were initially booked in level III, 9.1% were referred, 49.8% were transferred, and 16.1% had outborn delivery. Risk factors for outborn delivery were gestational age <26 weeks (adjusted relative risk (aRR) 1.37, 95% confidence interval (CI) 1.13, 1.66), inadequate antenatal care (aRR 1.39, 95% CI 1.10, 1.81), placental abruption (aRR 1.66, 95% CI 1.27, 2.17), and increased distance to the closest level III unit ((aRR 2.79, 95% CI 2.00, 3.92) in the 4th versus 1st distance quartile). Among outborn deliveries, 16.7% were probably avoidable, and 25.6% possibly avoidable, which could increase the proportion of inborn deliveries between 85.9% and 92.9%. Avoidable outborn deliveries were mainly associated with gestational age, intrauterine growth restriction, preterm premature rupture of membranes, and haemorrhage, but not distance. Our study identified some modifiable risk factors for outborn delivery; however, when regionalised care relies heavily on antenatal transfer, as it does in France, only some outborn deliveries may be prevented. Earlier referral of high-risk women will be needed to achieve full access to tertiary care.


The effects of exercise on cognitive function and brain plasticity - a feasibility trial.
Exercise-mediated cognitive improvements can be at least partly attributed to neuroplastic changes in the nervous system, and may be influenced by the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene. Transcranial magnetic stimulation (TMS) can be used to assess mechanisms of plasticity in humans noninvasively. To assess the feasibility of evaluating the effects of short-term regular exercise on cognitive performance, and to evaluate the relationship between these effects, TMS measures of plasticity, and BDNF Met carrier status in young healthy sedentary adults. Of the 19 participants who enrolled in the study, 14 sedentary adults (12 females, age mean±SD, 27±12.3 yr), with less than two sessions of physical exercise in the preceding 2 months, completed an aerobic exercise regimen including four 30-min daily sessions per week for 4 weeks (for a total of 16 sessions) delivered at 55-64% of age-predicted maximal heart rate. Prior to and following the exercise regimen, participants performed a neuropsychological test battery and an intermittent theta-burst TMS plasticity protocol. All participants completed the various measures and adhered to the exercise regimen. There were no complications and the results obtained were reliable. The feasibility of the approach is thus well established. Between-group comparisons of pre-post change revealed trends toward increased performance on the Stroop and faster reaction times in the CPT detectability in the Val66Val subgroup (p = 0.07 and p = 0.08), and a reduction in TBS-induced modulation of TMS responses in Met carriers (p = 0.07). Acute exercise interventions in sedentary adults can be meaningfully conducted along with cognitive and neurophysiologic measures to assess behavioral and neurobiological effects and assessment of BDNF polymorphism. TMS measures of plasticity can be used to evaluate the effects of exercise on brain plasticity, and relate them to neuropsychological measures of cognition.


Involvement of brain monoamines in the delta-9-tetrahydrocannabinol-induced reduction of hippocampal choline uptake.
The role of monoamines in the transsynaptic reduction of neuronal activity produced by delta 9-tetrahydrocannabinol (delta 9-THC) in the septal-hippocampal cholinergic pathway has been investigated. Serotonergic afferents were chemically lesioned by unilateral infusion of 5,7-dihydroxytryptamine. Noradrenergic and dopaminergic inputs were selectively deleted by unilateral infusion of 6-hydroxydopamine into appropriate anatomic sites. Although removal of serotonergic and noradrenergic input did not alter hippocampal choline uptake relative to the contralateral control side, dopaminergic input reduction produced a significant elevation. After administration of delta 9-THC (20 mg/kg), reduction of choline uptake into lesioned hippocampi was not significantly different from that for the controls. These results indicate that monoaminergic afferents do not play a major role in the effect of delta 9-THC on cholinergic activity in the rat hippocampus.


Acute admissions to a community hospital: experiences from Hallingdal sjukestugu.
Acute admissions to anywhere other than general hospitals are uncommon in Norway, but at Hallingdal sjukestugu, a community hospital in a rural district, this has been practiced for years. This article presents experiences from this practice. Materials and Hallingdal sjukestugu is a decentralized, specialist healthcare service, under the administration and funding of Ringerike sykehus, the nearest general hospital, which is 170 km away. General practitioners under telephone supervision of the hospital specialists run the inpatient department. Six municipalities with 20,000 inhabitants make use of the community hospital. Statistics were obtained from the patient administration systems and from manual statistics continuously registered in 2009-10. In 2009-10 the inpatient department, an intermediate care unit with 14 beds, had an average of 605 admissions a year, with a mean length of stay of 6.3 days. There were 455 acute admissions to Hallingdal sjukestugu. Forty per cent of these patients were younger than 67 and 36% were older than 80 years of age. Half were admitted for observation and half for treatment. The main diagnostic groups were infections, injuries and palliative care. Seventeen per cent of the acute admitted patients were later transferred to the general hospital for further work-up or treatment; 70% were discharged to their homes. The experiences from Hallingdal sjukestugu indicate that it is feasible to give a selected group of patients an alternative to acute admissions to a general hospital.


In silico studies in probing the role of kinetic and structural effects of different drugs for the reactivation of tabun-inhibited AChE.
We have examined the reactivation mechanism of the tabun-conjugated AChE with various drugs using density functional theory (DFT) and post-Hartree-Fock methods. The electronic environments and structural features of neutral oximes (deazapralidoxime and 3-hydroxy-2-pyridinealdoxime) and charged monopyridinium oxime (2-PAM) and bispyridinium oxime (Ortho-7) are different, hence their efficacy varies towards the reactivation process of tabun-conjugated AChE. The calculated potential energy surfaces suggest that a monopyridinium reactivator is less favorable for the reactivation of tabun-inhibited AChE compared to a bis-quaternary reactivator, which substantiates the experimental study. The rate determining barrier with neutral oximes was found to be ∼2.5 kcal/mol, which was ∼5.0 kcal/mol lower than charged oxime drugs such as Ortho-7. The structural analysis of the calculated geometries suggest that the charged oximes form strong O(…)H and N(…)H hydrogen bonding and C-H(…)π non-bonding interaction with the tabun-inhibited enzyme to stabilize the reactant complex compared to separated reactants, which influences the activation barrier. The ability of neutral drugs to cross the blood-brain barrier was also found to be superior to charged antidotes, which corroborates the available experimental observations. The calculated activation barriers support the superiority of neutral oximes for the activation of tabun-inhibited AChE compared to charged oximes. However, they lack effective interactions with their peripheral sites. Docking studies revealed that the poor binding affinity of simple neutral oxime drugs such as 3-hydroxy-2-pyridinealdoxime inside the active-site gorge of AChE was significantly augmented with the addition of neutral peripheral units compared to conventional charged peripheral sites. The newly designed oxime drug 2 appears to be an attractive candidate as efficient antidote to kinetically and structurally reactivate the tabun-inhibited enzyme.


A systematic approach toward stabilization of CagL, a protein antigen from Helicobacter pylori that is a candidate subunit vaccine.
An important consideration in the development of subunit vaccines is the loss of activity caused by physical instability of the protein. Such instability often results from suboptimal solution conditions related to pH and temperature. Excipients can help to stabilize vaccines, but it is important to screen and identify excipients that adequately contribute to stabilization of a given formulation. CagL is a protein present in strains of Helicobacter pylori (H. pylori) that possess type IV secretion systems. It contributes to bacterial adherence via α5β1 integrin, thereby making it an attractive subunit vaccine candidate. We characterized the stability of CagL in different pH and temperature conditions using a variety of spectroscopic techniques. Stability was assessed in terms of transition temperature with the accumulated data, and then incorporated into an empirical phase diagram (EPD) that provided an overview of CagL physical stability. These analyses indicated maximum CagL stability at pH 4-6 up to 40°C in the absence of excipient. Using this EPD analysis, aggregation assays were developed to screen a panel of excipients with some found to inhibit CagL aggregation. Candidate stabilizers were selected to confirm their enhanced stabilizing effect. These analyses will help in the formulation of a stable vaccine against H. pylori.


Electronic health record training in undergraduate medical education: bridging theory to practice with curricula for empowering patient- and relationship-centered care in the computerized setting.
While electronic health record (EHR) use is becoming state-of-the-art, deliberate teaching of health care information technology (HCIT) competencies is not keeping pace with burgeoning use. Medical students require training to become skilled users of HCIT, but formal pedagogy within undergraduate medical education (UME) is sparse. How can medical educators best meet the needs of learners while integrating EHRs into medical education and practice? How can they help learners preserve and foster effective communication skills within the computerized setting? In general, how can UME curricula be devised for skilled use of EHRs to enhance rather than hinder provision of effective, humanistic health care?Within this Perspective, the authors build on recent publications that "set the stage" for next steps: EHR curricula innovation and implementation as concrete embodiments of theoretical underpinnings. They elaborate on previous calls for maximizing benefits and minimizing risks of EHR use with sufficient focus on physician-patient communication skills and for developing core competencies within medical education. The authors describe bridging theory into practice with systematic longitudinal curriculum development for EHR training in UME at their institution, informed by Kern and colleagues' curriculum development framework, narrative medicine, and reflective practice. They consider this innovation within a broader perspective-the overarching goal of empowering undergraduate medical students' patient- and relationship-centered skills while effectively demonstrating HCIT-related skills.


Effects of Experiential Learning Programmes on Adolescent Prosocial Behaviour, Empathy, and Subjective Well-being: A Systematic Review and Meta-Analysis.
Introduction: Effective adolescent learning programmes can positively influence adolescent development and curb risky behaviour. By immersing learners in an experience, experiential learning motivates learners to reflect on the experience to transform and create new skills, attitudes and ways of thinking. However, evidence of its effectiveness in learning programs facilitating positive youth development is still lacking. The objective of this study is to (a) identify the effect of adolescent learning programmes on prosocial behaviour, empathy and subjective well-being, (b) compare the effectiveness of experiential learning programmes and non-experiential learning programmes on improving these three outcomes, and (c) evaluating the effects of age on the outcomes of adolescent learning programmes. Methods: This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomised controlled trials of learning programmes for typically developing adolescents aged 8-25 in the past 15 years were identified, and assessed for quality with the Physiotherapy Evidence Database (PEDRO) scale. One thousand ninety-six records were screened with the inclusion and exclusion criteria, and 20 studies were adopted for this meta-analysis. The standardised mean difference and 95% confidence interval (CI) of the effect of experiential learning program on empathy, prosocial behaviour, and subjective well-being were examined. Sub-group analysis based on age was conducted to examine the effects of experiential learning on adolescents in different stages of life. Results: Experiential learning programmes were more effective than non-experiential learning programmes in improving empathy [d = 0.65 (0.07, 1.23)] and subjective well-being [d = 0.46 (0.33, 0.59)]. The effect sizes of the three outcomes in non-experiential learning programmes were non-significant. Studies conducted on older adolescents had the most significant improvements in the three outcomes. Conclusions: Results suggest the broader application of experiential learning in adolescent learning programmes for older adolescents in the future to promote positive youth development.


Apolipoprotein E genotype and outcome in infants with hypoxic-ischemic encephalopathy.
Adults with the apolipoprotein E (APOE) gene alleles e4 and e2 are at high risk of poor neurological outcome after brain injury. The e4 allele has been associated with cerebral palsy (CP), and the e2 allele has been associated with worse neurological outcome with congenital heart disease. This study was done to test the hypothesis that the APOE genotype is associated with outcome among neonates who survive after hypoxic-ischemic encephalopathy (HIE). We conducted a cohort study of infants who survived HIE and had 18-22 mo standardized neurodevelopmental evaluations to assess associations between disability and the APOE genotypes e3/e3, e4/-, and e2/-. A total of 139 survivors were genotyped. Of these, 86 (62%) were of the e3/e3, 41 (29%) were of the e4/-, and 14 (10%) were of the e2/- genotypes. One hundred and twenty-nine infants had genotype and follow-up data; 26% had moderate or severe disabilities. Disability prevalence was 30 and 19% among those with and without the e3/e3 genotype, 25 and 26% among those with and without the e2 allele, and 18 and 29% among those with and without the e4 allele, respectively. None of the differences were statistically significant. CP prevalence was also similar among genotype groups. Disability was not associated with the APOE genotype in this cohort of HIE survivors.


Insight into chloroplast genome structural variation of the Mongolian endemic species Adonis mongolica (Ranunculaceae) in the Adonideae tribe.
Adonis mongolica is a threatened species that is endemic to Mongolia. It is a medicinal plant from the Adonis genus and has been used to treat heart diseases. However, the genomics and evolution of this species have not been thoroughly studied. We sequenced the first complete plastome of A. mongolica and compared it with ten Adonideae species to describe the plastome structure and infer phylogenetic relationships. The complete plastome of A. mongolica was 157,521 bp long and had a typical quadripartite structure with numerous divergent regions. The plastomes of Adonideae had relatively constant genome structures and sizes, except for those of Adonis. The plastome structure was consistent across Adonis. We identified a 44.8 kb large-scale inversion within the large single-copy region and rpl32 gene loss in the Adonis plastomes compared to other members of the Adonideae tribe. Additionally, Adonis had a smaller plastome size (156,917-157,603 bp) than the other genera within the tribe (159,666-160,940 bp), which was attributed to deletions of intergenic regions and partial and complete gene losses. These results suggested that an intramolecular mutation occurred in the ancestor of the Adonis genus. Based on the phylogenetic results, Adonis separated earlier than the other genera within the Adonideae tribe. The genome structures and divergences of specific regions in the Adonis genus were unique to the Adonideae tribe. This study provides fundamental knowledge for further genomic research in Mongolia and a better understanding of the evolutionary history of endemic plants.


The anatomy of the female reproductive tract of the springbok (Antidorcas marsupialis).
The anatomy of the female reproductive tract of the springbok is described, using material of 25 ewes collected at the S.A. Lombard Nature Reserve and 300 ewes collected at the De Beers farm Benfontein. No difference in the length of left and right fallopian tubes (104 +/- 24 mm) was observed, and from the funnel to the isthmus it narrows considerably from 15 mm to 1,25 mm. A distinct flexure is formed by the utero-tubal juncture. A complete ovarian bursa with a ventral orifice occurs. The reproductive tract increases in mass from 9.2 g in infants to 38,0 g in adults. The right uterine horn of the bicornuate tract is consistently longer. Caruncles are more numerous in the right (60,2 +/- 9,37) than the left (45,8 +/- 10,18) uterine horn. The intricate cervical lumen consisting of four to six valves in non-pregnant ewes becomes a simple S-shaped canal with advanced pregnancy.


Midface membranous bone lengthening: A one-year histological and morphological follow-up of distraction osteogenesis.
Midface bone lengthening was performed on three young, adult sheep using distraction osteogenesis following osteotomy of the maxilla and mounting of an extraoral fixation device. The midface was gradually distracted, 2 mm/day, for 21 days, up to approximately 40 mm. A marked midface advancement was noted. Following a further 6 weeks of retention, the device was removed and the animals were followed for 1 year. Biopsies specimens were taken from the distracted area at the end of the distraction period, after the additional 6 weeks of retention, and finally 1 year later. A nondistracted area of the maxillary bone served as control. The specimens were analyzed histologically, histochemically, and by scanning electron microscopy for the ultrastructural pattern, mineralization, mineral content, and approximate Ca2+ concentration. Clinically and radiographically, all sheep fully bridged the experimental gap. Histologically, at the completion of distraction, collagen bundles and slender bone trabeculae oriented in the direction of the distraction could be seen. At the end of the retention period, the trabeculae thickened noticeably and were partially replaced by mature lamellar bone. At the end of 1 year and after completion of the process of remodeling, the pattern of the distracted area resembled the control area. The mineralization, as reflected by quantitative calcium analysis, compared with the nondistracted area, demonstrated a low rate of mineralization after 3 weeks of lengthening, increased 6 weeks later, and after 1 year became nearly the same as in the nondistracted area. In conclusion, distraction osteogenesis provides satisfactory quantitative and structural new bone.


Zonal organization of olivocerebellar projections to the uvula in rabbits.
Olivocerebellar projections to the uvula were studied by means of retrograde axonal transport of horseradish peroxidase (HRP) in pigmented rabbits. The distribution pattern of labeled cells in the inferior olive was compared among cases following large- and microinjections of HRP into the uvula. Findings indicate topographically organized projections to longitudinally oriented zones. There are at least 6 zones in the rabbit's uvula. The caudal part of the nucleus beta projects contralaterally to a most medially located zone (caudal beta zone). The rostral part of the nucleus beta projects to a little more laterally located zone (rostral beta zone) at a distance of about 1 mm from the midline of the uvula. The caudolateral part of the MAO projects to a zone (caudolateral MAO zone) located laterally to the rostral beta zone. The dorsomedial cell column projects to a zone (dorsomedial cell column zone) located in the intermediate part of the uvula at about 2 mm from the midline. The rostrolateral part of the MAO projects to the most lateral zone (rostrolateral MAO zone) of the uvula. Finally, the ventral lamella of the PO projects to a zone (ventral lamella of PO zone) located between the rostrolateral MAO zone and the dorsomedial cell column zone.


[Gene-enzyme alcohol dehydrogenase system and adaptability in Drosophila melanogaster].
As follows from the experiments on the genotypic related populations of Drosophila melanogaster with different frequency of ADH allozymes selection for postponement of ageing and resistance to hypothermia lead to saturation of population with S-allozyme ADH, and genotypic adaptation to ethanol-to increasing of frequency of F-allozyme. It is supposed that genotypic adaptation is realized by selection of specimens with the most favourable alleles of genes. At the same time ontogenetic adaptation is accompanied by biochemical modification of existing allozymes.


Techniques of Mucilage and Gum Modification and their Effect on Hydrophilicity and Drug Release.
The manuscript aims to describe the techniques of modification of gums and mucilages and their effect on hydrophilicity and drug release. The interest is increased in the fields of polymers which are obtained from natural origin and used in the preparation of pharmaceuticals. Mucilage and gum are natural materials widely used in the preparation of novel dosage and conventional dosage forms. They are used in the pharmaceutical industry for various purposes like suspending, emulsifying, bio-adhesive, binding, matrix-forming, extended release and controlled release agent. Gum and mucilage are biodegradable, less toxic, cheap and easily available. Moreover, mucilage and gum can be changed to acquire tailored materials for the delivery of drugs and allow them to compete with commercially available synthetic products. These polysaccharides have unique swellability in an aqueous medium that can exert a retardant effect on drug release or act as a super disintegrant, depending on the concentration utilized in the preparation. Drug release mechanism from hydrophilic matrices consisting of gums and mucilages is based on solvent penetration-induced polymer relaxation, diffusion of entrapped drug followed by degradation or erosion of the matrix. The present manuscript highlights the advantages, modifications of gum and mucilage, their effects on hydrophilicity and drug release as well as aspects of the natural gums which can be assumed to be bifunctional excipient because of their concentration-dependent effect on drug release and their high degree of swellability.


Ductular expression of autoantigens in primary biliary cirrhosis.
The role of biliary epithelial cell (BEC) antigens in immune recognition and damage of biliary epithelium in primary biliary cirrhosis (PBC) is unknown. The major autoantigen in PBC (the mitochondrial enzyme pyruvate dehydrogenase dihydrolipoamide acetyltransferase [PDC-E2]) is abnormally distributed in the biliary epithelium of patients with PBC relative to controls. The antigen is not only present in mitochondria but also associated with the BEC plasma membrane. This atypical distribution of PDC-E2 is present both in early (stages I-II) and advanced (stages III-IV) disease, suggesting a role for the antigen in progression and/or etiology of PBC. The identity of the plasma membrane antigen remains unknown, but there is evidence to suggest that it is an antigen that cross reacts with antibodies to PDC-E2. Use of BEC purified from human liver may help in deciphering the possible importance of BEC plasma membrane antigens in immune recognition and toxicity toward BEC in PBC.


Analysis of Adherence to Acute Inpatient Rehabilitation in Patients with Cancer.
Importance: The need for cancer rehabilitation is expected to continue to dramatically increase with the aging population and increasing number of cancer survivors. These survivors experience a wide range of physical limitations and symptoms that negatively affect their health and quality of life. Research is needed to determine the rate of adherence, reasons for non-adherence, and interventions to improve adherence to acute inpatient rehabilitation among patients with cancer. Objective: To evaluate the rate of adherence and reasons for non-adherence to acute inpatient rehabilitation in patients with cancer. Design, Setting, and Participants: This was a secondary analysis of a retrospective study that assessed medical complications in 165 patients with cancer who had a median length of stay of 11 days (interquartile range of 8-14) in acute inpatient rehabilitation. We reviewed the records of all consecutive patients who underwent acute inpatient rehabilitation from September 1, 2017 through February 28, 2018 at a large academic, quaternary National Cancer Institute-designated Cancer Center. Main Outcomes and Measures: We calculated the rehabilitation session adherence rate and descriptively summarized the reasons for non-adherence. Results: There were 78/165 (47%) patients that had 1 or more incomplete rehabilitation sessions due to medical complications. These patients had a median of 2 (interquartile range of 1-4) incomplete rehabilitation sessions. We noted other reasons for incomplete rehabilitation sessions in 146/165 (89%) patients, who had a median of 3 (interquartile range of 2-4) incomplete rehabilitation sessions. The median total number of days with incomplete rehabilitation sessions in the entire cohort was 2 (interquartile range 1-3). Conclusion and Relevance: Among patients with cancer undergoing acute inpatient rehabilitation, the adherence rate to 1-hour long intensive rehabilitation sessions were low due to medical complications and other reasons. This in turn affected compliance with the 3 hours of rehabilitation a day requirement for acute inpatient rehabilitation. Patients with cancer undergoing acute inpatient rehabilitation are medically complex and further research at multiple institutions with larger cohorts may be beneficial in further assessing adherence rates and reasons for non-adherence to improve participation in acute inpatient rehabilitation.