The psychopharmacology of huperzine A: an alkaloid with cognitive enhancing and neuroprotective properties of interest in the treatment of Alzheimer's disease.
Huperzine A (HupA), extracted from a club moss (Huperzia serrata), is a sesquiterpene alkaloid and a powerful and reversible inhibitor of acetylcholinesterase (AChE). It has been used in China for centuries for the treatment of swelling, fever and blood disorders. It has demonstrated both memory enhancement in animal and clinical trials and neuroprotective effects. Recently it has undergone double-blind, placebo-controlled clinical trials in patients with Alzheimer's disease (AD), with significant improvements both to cognitive function and the quality of life. Most of the clinical trials are from China, but HupA and derivatives are attracting considerable interest in the West, where AD is a major and growing concern. Furthermore, both animal and human safety evaluations have demonstrated that HupA is devoid of unexpected toxicity. Other interesting aspects of HupA pharmacological profile relate to its neuroprotective properties: it has been shown in animal studies that HupA can be used as a protective agent against organophosphate (OP) intoxication and that it reduces glutamate-induced cell death.


Amyloid beta-protein precursor (APP) of cultured cells: secretory and non-secretory forms of APP.
Overproduction or aberrant catabolism of the predicted amyloid beta-protein precursor (APP) is suspected as the cause of amyloid deposition in Alzheimer's disease and Down's syndrome brains. For possible in vitro experiments of amyloid formation, we have examined the expression of APP in various cultured cells. We found two types of APP producing cell lines. PC12h (rat pheochromocytoma) and HL-60 (human acute promyelocytic leukemia) cells produce a secretory form that is released into the culture medium, while Bu-17 (human glioma) cells synthesize only a non-secretory form that accumulates at the cell surface. APP immunoreactivity on the latter cells was detected at the tips of cell processes or growth cones. These observations indicate that the nonsecretory form of APP may play a role in cell contact or adhesion.


The IL-6 family of cytokines modulates STAT3 activation by desumoylation of PML through SENP1 induction.
Post-translational modification by small ubiquitin-like modifier (SUMO) plays an important role in the regulation of different signaling pathways and is involved in the formation of promyelocytic leukemia (PML) protein nuclear bodies following sumoylation of PML. In the present study, we found that IL-6 induces desumoylation of PML and dissociation between PML and SUMO1 in hepatoma cells. We also found that IL-6 induces mRNA expression of SENP1, a member of the SUMO-specific protease family. Furthermore, wild-type SENP1 but not an inactive SENP1 mutant restored the PML-mediated suppression of STAT3 activation. These results indicate that the IL-6 family of cytokines modulates STAT3 activation by desumoylation and inactivation PML through SENP1 induction.


Insertion/Rearrangement Reactivity of a Lutetacyclopentadiene towards N,N'-Diphenylcarbodiimide: Cooperative Effect of the Metal Center, Concentration of LiCl, and Solvent.
The reactivity of lutetacyclopentadiene towards N,N'-diphenylcarbodiimide (DPC) was systematically investigated to efficiently construct three types of new N-containing fused cyclic complexes. The outcome of these reactions significantly depended on the the metal center, the concentration of LiCl, the number of equivalents of DPC, and the solvent. Thus, two unexpected reaction modes of amidinate were discovered for the first time, which were ascribed to an unusual κ(1) coordination mode of amidinate driven by a rigid seven-membered ring. These results are in striking contrast with the previously well-investigated zirconacyclopentadiene, which reacts with DPC to give azazirconacyclopentene and alkyne through β,β' CC bond cleavage. The difference in reactivity between lutetacyclopentadiene and zirconacyclopentadiene can be attributed to the highly ionic character of the LuC(sp(2) ) bonds. DFT calculations agreed well with the experimental results.


Neonatal pneumonia associated with medium-chain triglyceride feeding supplement.
The appearance of a similar pattern of multifocal pulmonary consolidation in four neonates receiving undiluted medium-chain triglyceride oil suggested a cause-and-effect relationship. This was supported by the demonstration in rabbits that the transtracheal injection of MCTO caused severe pneumonia. It is suggested that MCTO be mixed with formula before it is given to neonates.


[Epidemiological study on mental morbidity of the child at the age of latency].
A random sample of 300 9-year-old children in the canton of Vand were given a psychiatric examination. Boys showed psychopathology more often than girls, lower class children more than higher class children, children of foreign origin more than children of Swiss parents, children who had been separated from their families during their first three years of life more than children who had not been separated. On the other hand, the child psychiatric services were less well known by persons from those population groups, in which children showed psychopathologic findings more often. Questions concerning the intervention strategies that follow from these observations are discussed.


Cardio-oncology imaging tools at the translational interface.
Cardiovascular imaging is an evolving component in the care of cancer patients. With improved survival following prompt cancer treatment, patients are facing increased risks of cardiovascular complications. While currently established imaging modalities are providing useful structural mechanical information, they continue to develop towards increased specificity. New modalities, emerging from basic science and oncology, are being translated, targeting earlier stages of cardiovascular disease. Besides these technical advances, matching an imaging modality with the patients' individual risk level for a specific pathological change is part of a successful imaging strategy. The choice of suitable imaging modalities and time points for specific patients will impact the cardio-oncological risk stratification during surveillance and follow-up monitoring. In addition, future imaging tools are poised to give us important insights into the underlying cardiovascular molecular pathology associated with cancer and oncological therapies. This review aims at giving an overview of the novel imaging technologies that have the potential to change cardio-oncological science and clinical practice in the near future.


Silk fibroin/gelatin microcarriers as scaffolds for bone tissue engineering.
Microcarrier cell scaffolds have potential as injectable cell delivery vehicles or as building blocks for tissue engineering. The use of small cell carriers allows for a 'bottom up' approach to tissue assembly when moulding microparticles into larger structures, which can facilitate the introduction of hierarchy by layering different matrices and cell types, while evenly distributing cells through the structure. In this work, silk fibroin (SF), purified from Bombyx mori cocoons, was blended with gelatin (G) to produce materials composed of varying ratios of the two components (SF: G 25:75, 50:50, and 75:25). Cell compatibility to these materials was first confirmed in two-dimensional culture and found to be equivalent to standard tissue culture plastic, and better than SF or G alone. The mechanical properties of the blends were investigated and the blended materials were found to have increased Young's moduli over SF alone. Microcarriers of SF/G blends with defined diameters were generated in a reproducible manner through the use of an axisymmetric flow focussing device, constructed from off-the-shelf parts and fittings. These SF/G microcarriers supported adhesion of rat mesenchymal stem cells with high degrees of efficiency under dynamic culture conditions and, after culturing in osteogenic differentiation medium, cells were shown to have characteristics typical of osteoblasts. This work illustrates that microcarriers composed of SF/G blends are promising building blocks for osteogenic tissue engineering.


Microvascular basal lamina injury after experimental focal cerebral ischemia and reperfusion in the rat.
To define the location and extent of microvascular damage of the basal lamina after cerebral ischemia and reperfusion in rats, the authors subjected animals (n = 16) to 3 hours of focal cerebral ischemia and 24 hours of reperfusion using the suture middle cerebral artery occlusion model; sham-operated animals served as controls (n = 6). The Western blot technique was used to define the collagen type IV protein content in various brain regions, whereas immunohistochemistry identified microvascular basal lamina loss (anticollagen type IV staining). The extent of damage was quantified by automatic morphometric video-imaging analysis. Statistical analysis was based on the Mann-Whitney test and the paired Student's t-test. The ischemic hemisphere showed a reduction of the collagen type IV protein content after ischemia and reperfusion in the Western blot (reduction compared with the nonischemic side: total hemisphere, 33% +/- 6%; basal ganglia, 25% +/- 7%; cortex 49% +/- 4%; P < 0.01) [corrected]. There was also a decrease in the number of cerebral microvessels between the ischemic and nonischemic hemispheres (20% +/- 2%), cortical (8% +/- 3%), and basal ganglia areas (31% +/- 3%) (P < 0.001). Besides a reduction of the vessel number, there was also a loss in basal lamina antigen-positive stained area in ischemic areas (hemisphere, 16% +/- 3%; cortex, 14% +/- 3%; basal ganglia, 21% +/- 4%; P < 0.01) [corrected]. Cortical areas had a less pronounced basal lamina loss than basal ganglia (P < 0.05). For the first time, microvascular basal lamina damage, indicated by collagen type IV loss, is proven in rats by biochemical and morphometric analysis. These changes are comparable with those found in nonhuman primates. The authors report novel data regarding microvascular ischemic changes in the cortex. These data provide a basis for future experiments to determine the mechanisms of ischemic microvascular damage and to devise new therapeutic strategies.


Novel adenosine A(2A) receptor ligands: a synthetic, functional and computational investigation of selected literature adenosine A(2A) receptor antagonists for extending into extracellular space.
Growing evidence has suggested a role in targeting the adenosine A2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.


Bean's syndrome (blue rubber bleb nevus syndrome - BRBNS) as a gastrointestinal bleeding - case report and review of the literature.
BRBNS is a rare syndrome of vascular malformations caused by the TEK mutation associated with numerous lesions of the skin and gastrointestinal tract. We present a case report of 41 year old man with severe anemia with recurrent bleedings. The detailed clinical, endoscopical and histopathological description is given as a wide range of differential diagnosis of vascular lesions based on pathophysiology and updated classification of vascular lesions. Clinicopathological diagnosis and treatment options of BRBNS are discussed.


Effect of mass media and Internet on sexual behavior of undergraduates in Osogbo metropolis, Southwestern Nigeria.
The influence of media portrayals of sexual attitudes and normative expectations of young people at a critical developmental stage is of public health concern. To examine the role of mass media and Internet utilization in shaping the sexual health attitudes and behaviors of young undergraduates in Osogbo metropolis, Osun State, Nigeria. In a descriptive cross-sectional study, 400 undergraduates were selected using a multistage random sampling technique. Four hundred and fifty pretested, semistructured questionnaires were distributed; of these, 400 were returned properly filled. Data were analyzed using SPSS statistical software version 16. Mean age of respondents ± standard deviation was 23.6±2.99 years. Most were aware of the various forms of mass media (>95%). Most (64.0%) respondents spent 1-5 hours watching television, daily, and most used the Internet often. About 38.3% and 24.2% of respondents used the Internet and radio/television, respectively, as sources of information on sexual issues. Most respondents used the Internet for school assignments (83.0%, n=332), electronic mail (89.0%, n=356), and for accessing sexually explicit materials (74.5%, n=298). Most of the respondents (73.5%) opined that the Internet has a bad influence on youths' sexual behavior, although accessing the Internet for sexual material or movies was acceptable to 25.3% of them. Of the 226 respondents who had ever had sex, 226 (100%), 37 (16.4%), 31 (13.7%), and 10 (4.4%) practiced coitus, oral sex, masturbation, and anal sex, respectively; 122 (54.0%) always used condoms, whereas 90 (40.0%) never used condoms during sexual activity; 33 (14.6%) had had sex with commercial sex workers. Further analysis showed that those who were yet to marry (single) were less likely to be sexually experienced than those who were married (adjusted odds ratio [AOR] =0.075, 95% confidence interval [CI] =0.008-0.679), and those who said accessing the Internet for sexual material is not acceptable to them were also less likely to be sexually experienced than those to whom it was acceptable (AOR =0.043, 95% CI =0.016-0.122). Predictors of having multiple sexual partners include the sex of the respondent and the frequency of Internet use, with females (AOR =0.308, 95% CI =0.113-0.843) and those who rarely use the Internet less likely to have multiple sexual partners. We conclude that uncontrolled exposure to mass media and Internet could negatively influence the sexual patterns and behavior of youths.


Alcohol-related consequences among women who want to lose weight.
Previous research has identified a positive relationship between disordered eating behaviors and heavy alcohol use, demonstrating that alcohol use is heavier among individuals with eating disorders or who demonstrate significant symptoms of disordered eating. The purpose of this study was to examine whether this relationship also exists among women displaying milder disordered eating attitudes, defined by a stated desire to lose weight despite maintaining a healthy body weight. Participants in this study were 255 female college students at a large public university in the northeast region of the United States who were either under- or of normal body weight. Results indicated that women who reported a desire to lose weight were significantly more likely to experience several negative alcohol-related consequences, including doing something later regretted and having forced intercourse than those without a desire to lose weight. Results also indicated that the use of protective behavioral strategies was associated with fewer alcohol-related problems among this group. Implications for interventions and future research studies are discussed.


Production of tagatose by a recombinant thermostable L-arabinose isomerase from Thermus sp. IM6501.
A gene (thaI) corresponding to L-arabinose isomerase from Thermus strain IM6501 was cloned by PCR. It comprised 1488 nucleotides and encoded a polypeptide of 496 residues with a predicted molecular weight of 56019 Da. The deduced amino acid sequence had 96.8% identity with the L-arabinose isomerase of Geobacillus stearothermophilus. Recombinant ThaI with N-terminal hexa-tistidine tags was over-expressed in Escherichia coli and purified by affinity chromatography using Ni-NTA resin. The purified ThaI was thermostable with maximal activity at 60 degrees C at pH 8 for 30 min of reaction. Zn2+ and Ni2+ inactivated the catalytic activity of ThaI, 5 mM Mn2+ enhanced the bioconversion yield by 90%. The bioconversion yield of 54% from D-galactose to D-tagatose was obtained by recombinant ThaI at 60 degrees C over 3 d.


Clinical and behavioral correlates of achieving and maintaining glycemic targets in an underserved population with type 2 diabetes.
In an underserved Latino area, we established a disease-management program and proved its effectiveness. However, many patients still remained above target. This study was designed to evaluate which factors are associated with reaching program goals. This was a randomized, prospective, observational study in which patients enrolled in our program were followed for 2 years with outcomes, measures, and questionnaires assessed at baseline and at 6, 12, and 24 months. Overall, A1C fell by 1%. Adherence to medication was the strongest predictor of reaching the target A1C of <8%; baseline A1C was also predictive. Knowledge scores increased in those who reached target, but the measures of self-efficacy and empowerment did not change for either group. Diabetes management is effective in a lower-income Latino population. However, adherence was suboptimal even when medications were provided on-site for free. Further research into barriers associated with medication adherence is needed.


Phytochemicals as PI3K/ Akt/ mTOR Inhibitors and Their Role in Breast Cancer Treatment.
Breast cancer is the predominant form of cancer in women; various cellular pathways are involved in the initiation and progression of breast cancer. Among the various types of breast cancer that differ in their growth factor receptor status, PI3K/Akt signaling is a common pathway where all these converge. Thus, the PI3K signaling is of great interest as a target for breast cancer prevention; however, it is less explored. The present review is aimed to provide a concise outline of the role of PI3K/Akt/mTOR pathway in breast carcinogenesis and its progression events, including metastasis, drug resistance and stemness. The review emphasizes the role of natural and synthetic inhibitors of PI3K/Akt/m- TOR pathway in breast cancer prevention. The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. PI3K/Akt/mTOR signaling plays an important role in human breast carcinogenesis; it acts on the initiation and progression events associated with it. Numerous molecules have been isolated and identified as promising drug candidates by targeting the signaling pathway. Results from clinical studies confirm their application in the treatment of human breast cancer alone and in combination with classical chemotherapeutics as well as monoclonal antibodies. PI3K/mTOR signaling blockers have evolved as promising anticancer agents by interfering breast cancer development and progression at various stages. Natural products and bioactive components are emerging as novel inhibitors of PI3K signaling and more research in this area may yield numerous drug candidates.


An overview of the toxic effect of potential human carcinogen Microcystin-LR on testis.
The worldwide occurrence of cyanobacterial blooms due to water eutrophication evokes extreme concerns. These blooms produce cyanotoxins which are hazardous to living organisms. So far among these toxins, Microcystin-LR (MC-LR) is the most toxic and the most frequently encountered toxin produced by the cyanobacteria in the contaminated aquatic environment. Microcystin-LR is a potential carcinogen for animals and humans, and the International Agency for Research on Cancer has classified Microcystin-LR as a possible human carcinogen. After liver, testis has been considered as one of the most important target organs of Microcystin-LR toxicity. Microcystin-LR crosses the blood-testis barrier and interferes with DNA damage repair pathway and also increases expression of the proto-oncogenes, genes involved in the response to DNA damage, cell cycle arrest, and apoptosis in testis. Toxicity of MC-LR disrupts the motility and morphology of sperm and also affects the hormone levels of male reproductive system. MC-LR treated mice exhibit oxidative stress in testis through the alteration of antioxidant enzyme activity and also affect the histopathology of male reproductive system. In the present review, an attempt has been made to comprehensively address the impact of MC-LR toxicity on testis.


Secondary Hyperparathyroidism.
Secondary hyperparathyroidism (SHPT) does not initiate as a primary dysfunction of parathyroid glands resulting from an intrinsic defect or disease but is the physiologic response of parathyroids to metabolic changes elsewhere in the body occurring over time. SHPT is a manifestation of a chronic condition that classically occurs from chronic kidney disease. In fact, given the relatively recent transition of populations from outside (agrarian) to indoor (industrial, information technology, and so forth) employment and a consequent reduction in sun exposure, combined with diets of highly processed food, vitamin D and calcium deficiencies are now the leading causes of SHPT.


Basal cell carcinomas of the scalp after radiotherapy for tinea capitis in childhood: A genetic and epigenetic study with comparison with basal cell carcinomas evolving in chronically sun-exposed areas.
Basal cell carcinoma (BCC) has been mostly associated with sun exposure, but ionizing radiation is also a known risk factor. It is not clear if the pathogenesis of BCC, namely at a genomic and epigenetic level, differs according to the underlying triggering factors. The present study aims to compare genetic and epigenetic changes in BCCs related to ionizing radiation and chronic sun exposure. Tumor samples from BCCs of the scalp in patients submitted to radiotherapy to treat tinea capitis in childhood and BCCs from sun-exposed areas were analysed through array comparative genomic hybridization (array-CGH) and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to detect copy number alterations and methylation status of specific genes. Genomic characterization of tumor samples revealed several copy number gains and losses in all chromosomes, with the most frequent gains observed at 2p, 6p, 12p, 14q, 15q, 18q, Xp and Yp, and the most frequent losses observed at 3q, 14q, 16p, 17q, 22q, Xp, Yp and Yq. We developed a statistical model, encompassing gains in 3p and 16p and losses in 14q and 20p, with potential to discriminate BCC samples with sporadic aetiology from BCC samples that evolve after radiotherapy in childhood for the treatment of tinea capitis, which presented statistical significance (P = 0.003). Few methylated genes were detected through MS-MLPA, most frequently RARB and CD44. Our study represents a step forward in the understanding of the genetic mechanisms underlying the pathogenesis of BCC and suggests potential differences according to the underlying ris k factors.


A human donor (cadaveric) observation study of three needle placements in the piriformis muscle.
To compare the safety and accuracy of three dry needling locations in the piriformis muscle using human donors. Observational dissection study of embalmed human donors. A licensed physical therapist of 17 years clinical experience and 5 years teaching dry needling placed three needles in a medial, midpoint, and lateral location of 14 piriformis muscles of seven embalmed human donors. Block dissection allowed for observation of tissues the needles traversed and recording of the structures that the needles pierced. The lateral needle pierced piriformis in 3/14 trials, and contacted sciatic nerve in 0/14 trials. The medial needle pierced both piriformis and sciatic nerve in 11/14 trials. The midpoint needle pierced the piriformis in 11/14 trials, and contacted sciatic nerve in 3/14 trials. Fisher's Exact test (p < 0.001) found a nonrandom association between dry needle placement, and dry needle contact. When dry needling the piriformis, a lateral approach can avoid the sciatic nerve, but cannot accurately pierce the piriformis tendon. Furthermore, while a midpoint and medial approach finds the piriformis muscle with the same accuracy, the midpoint location avoided the sciatic nerve more often.


Limbus-based versus fornix-based conjunctival flaps in trabeculectomy.
Forty consecutive trabeculectomies were performed by one surgeon, utilizing a limbus-based conjunctival flap in the first 20 eyes and a fornix-based flap in the remaining 20. A success rate of 90% was achieved in both groups, although eyes with limbus-based flaps had slightly better postoperative intraocular pressure control.


Intra- and inter-rater reliability and agreement of stimulus electrodiagnostic tests in post-COVID-19 patients.
Background. COVID-19 patients may present sequelae, such as neuromuscular electrophysiological disorders (NED), that can be assessed using the stimulus electrodiagnostic test (SET). However, little is known about the reliability and agreement of the SET in post-COVID-19 patients.Objective. We aimed to verify the intra-inter-rater reliability and agreement of SET measurements in the rectus femoris, vastus medialis, vastus lateralis, tibialis anterior, and gastrocnemius lateralis (GL) in post-COVID-19 participants.Methods. We designed an observational prospective study to evaluate 20 (10 males and 10 females) post-COVID-19 patients, age: 44.95 ± 11.07 years, weight: 87.99 ± 19.08 kg, height: 1.69 ± 0.09 m. Two independent raters took two evaluations using the SET on selected muscles. The intra-class correlation coefficient (ICC) and 95% limits of the agreement defined the quality and magnitude of the measures.Results. For intra-rater reliability, all measurements presented correlations classified as high or very high (ICC: 0.71-1.0). For inter-rater reliability, the rheobase, chronaxie, accommodation, and accommodation index presented high or very high correlations, except for the accommodation index of the GL (ICC = 0.65), which was moderate.Conclusion. The reliability of the SET obtained by independent raters was very high, except for the GL accommodation, which presented moderate ICC. Therefore, the SET is a reliable tool for evaluating NED in post-COVID-19 patients.


Brewing and volatiles analysis of three tea beers indicate a potential interaction between tea components and lager yeast.
Green tea, oolong tea and black tea were separately introduced to brew three kinds of tea beers. A model was designed to investigate the tea beer flavour character. Comparison of the volatiles between the sample of tea beer plus water mixture (TBW) and the sample of combination of tea infusion and normal beer (CTB) was accomplished by triangular sensory test and HS-SPME GC-MS analysis. The PCA of GC-MS data not only showed a significant difference between volatile features of each TBW and CTB group, but also suggested some key compounds to distinguish TBW from CTB. The results of GC-MS showed that the relative concentrations of many typical tea volatiles were significantly changed after the brewing process. More interestingly, the behaviour of yeast fermentation was influenced by tea components. A potential interaction between tea components and lager yeast could be suggested.


Social support and life stress: a mental health consumers perspective.
This paper presents the results of an exploratory study of the relationship between two conceptualizations of social support and the experience of stress, frustrations and use of leisure time. A correlational study was conducted with over 200 clients of community support services in a large mid-western state. For these mental health consumers, no meaningful relationship was found between social support variables and the criterion variables. The long term mentally ill were found to have small social networks. The authors argue that reducing loneliness by itself is a valuable outcome of service for this population.


Using gastric emptying scintigraphy to evaluate antral contractions and duodenal bolus propagation.
Our aim was to investigate the feasibility of measuring antral contractions and duodenal bolus propagation (DBP) during dynamic antral contraction scintigraphy (DACS) as an assessment of antro-pyloro-duodenal coordination (APDC). Gastric emptying scintigraphy (GES) with DACS was performed with Tc-99m sulfur colloid (SC) using increasing doses of 74 MBq (2 mCi) for 10 subjects, 185 MBq (5 mCi) for 11, and 370 MBq (10 mCi) for 11. DACS was performed for 10 min after static images at 0, 30, 60, 120, 180, and 240 min in anterior and right anterior oblique (RAO) projections. Best projection and lowest dose of Tc-99m SC were assessed visually. DBP were quantified utilizing duodenal activity peaks from a region of interest in the first portion of the duodenum. DBP was better visualized in the RAO projection than anterior projection and using 185 MBq (5 mCi) and 370 MBq (10 mCi) compared with 74 MBq (2 mCi). DBP showed infrequent and irregular bolus transfers from the antrum to the duodenum. Antral activity peaks at 60 min averaged 2.91 ± 0.66 per minute and duodenum bolus peaks 0.36 ± 0.18 per minute (ratio 0.36/2.91 = 0.12). DBP activity peaks can be measured during GES with DACS but requires a 185-MBq (5 mCi) dose of Tc-99m SC radiolabeled test meal for adequate DBP signal detection and is better imaged in RAO than anterior projection. DBPs over the first 60 min postmeal ingestion are infrequent with only 12% of the antral contractions propagating into the duodenum. This methodology appears promising to assess APDC.NEW & NOTEWORTHY This study shows that duodenal bolus propagations after meal ingestion can be measured during gastric emptying scintigraphy using dynamic scintigraphy. Duodenal bolus propagation over the first 60 min postmeal ingestion are infrequent with only 12% of the antral contractions propagating into the duodenum. This methodology appears promising to assess antropyloroduodenal coordination in patients with unexplained symptoms of upper gastrointestinal dysmotility.


Proteomic and metabolomic analysis of earthworm Eisenia fetida exposed to different concentrations of 2,2',4,4'-tetrabromodiphenyl ether.
As a class of brominated flame-retardants (BFRs), polybrominated diphenyl ethers (PBDEs) are widely used in industrial products. PBDEs have been detected in local terrestrial biota from the Laizhou Bay in China. They can induce various toxicities, such as hepatotoxicity, neurotoxicity, cytotoxicity, genotoxicity and endocrine disrupting effects in animals. In this work, we characterized the dose-responsive effects of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) in earthworm Eisenia fetida using an integrated proteomic and metabolomic approach. Metabolic responses indicated that BDE 47 mainly caused disturbance in osmotic regulation and energy metabolism marked by differentially altered betaine, amino acids, ATP, glucose, maltose and succinate in E. fetida. Proteomic responses revealed that BDE 47 induced cell apoptosis (or injury), oxidative stress, disturbance in protein biosynthesis and energy metabolism in E. fetida in terms of differential proteomic biomarkers. Especially, the increased ATP was confirmed by up-regulated nucleoside diphosphate kinase A and ATP synthase in 1 and 100μg/L of BDE 47-treated groups, respectively. In addition, several metabolic biomarkers including betaine, glycine and 2-hexyl-5-ethyl-3-furansulfonate were relatively stable in all BDE 47-exposed groups. This work demonstrated that proteomics and metabolomics could partially validate one another and their combination could better understand toxicological effects of environmental pollutants. As a class of brominated flame-retardants (BFRs), polybrominated diphenyl ethers (PBDEs) are widely used in industrial products and have been detected in local terrestrial biota from the Laizhou Bay in China. Therefore a study on PBDE-induced toxicological effects is necessary. The earthworm E. fetida, a terrestrial sentinel animal, is the most frequently used bioindicator for terrestrial environmental contaminants. To our knowledge, however, very few studies have focused on the dose-dependent responses induced by PBDEs, in terrestrial sentinel animal at protein and metabolite levels. In the present study, an integrated metabolomic and proteomic approach was used to elucidate the dose-dependent toxicological effects of BDE 47 in E. fetida.


High-energy resolution X-ray, gamma and electron spectroscopy with cryogenic detectors.
Cryogenic detectors offer remarkably better energy resolutions than those achievable with conventional semiconductor or scintillation detectors. With the additional asset of a detection efficiency close to unity for low-energy X-ray photons and electrons, these detectors have the potential to perform X-ray, gamma and electron spectroscopy of a hitherto unknown quality, in particular at low energies. Two types of cryogenic detectors are described and the results of prototype detectors are presented.


The importance of GLU361 position in the reaction catalyzed by cholesterol oxidase.
Cholesterol oxidase stereospecifically isomerizes cholest-5-en-3-one to cholest-4-en-3-one. When the base catalyst for isomerization, Glu361, is mutated to Asp, the rate of deprotonation of cholest-5-en-3-one is not affected, but protonation of the dienolic intermediate becomes rate-limiting. This may be a consequence of the large distance between the catalytic base and carbon-6 of the intermediate in the mutant enzyme.


Pro-inflammatory cytokines, IL-1β and TNF-α, produce persistent compromise in tonic immobility defensive behaviour in endotoxemia guinea-pigs.
Sepsis has been associated with acute behavioural changes in humans and rodents, which consists of a motivational state and an adaptive response that improve survival. However, the involvement of peripheral cytokines synthesized during systemic inflammation as modulators of the tonic immobility (TI) defensive behaviour remains a literature gap. Our purposes were to characterize the TI defensive behaviour in endotoxemia guinea-pigs at acute phase and after recovery from the initial inflammatory challenge. Furthermore, we investigated whether peri-aqueductal grey matter (PAG) exists as a brain structure related to this behaviour and also pro-inflammatory cytokines, tumour necrosis factor (TNF)-α and interleukin (IL)-1β, act at this mesencephalic nucleus. Endotoxemia was induced by lipopolysaccharide (LPS) administration in guinea-pigs. The parameters evaluated included TI defensive behaviour, survival, cytokines production, as well as neuronal activation and apoptosis in the PAG. Endotoxemia guinea-pigs exhibited a reduction in the duration of TI episodes, starting at 2 h after LPS administration and persisting throughout the experimental period evaluated over 7 days. Moreover, endotoxemia increased the c-FOS immunoreactivity of neurones in the ventrolateral PAG (vlPAG), as well as the caspase-3 expression. The LPS microinjection into vlPAG reproduces the same compromise, that is a decrease in the duration of TI defensive behaviour, observed after the peripheral administration. The immunoneutralization against IL-1β and TNF-α into vlPAG reverts all the effects produced by peripheral LPS administration. Our findings confirm that vlPAG is an important brain structure involved in the behavioural alterations induced by endotoxemia, possibly changing the neuronal activity caused by pro-inflammatory cytokines produced peripherally.


Clinical aspects of renal prostaglandins and NSAID therapy.
Nonsteroidal antiinflammatory drugs (NSAIDs) can have a variety of effects on renal function. Excluding allergic phenomena, these are directly related to NSAID-induced inhibition of renal synthesis of prostaglandins (PGs). For the most part, renal PGs play important physiological roles only in certain pathologic conditions. Thus, patients without these diseases (such as cardiac, hepatic, or renal compromise) manifest no or only trivial effects on renal function when NSAIDs are administered. This feature is to the advantage of the clinician because it allows prospective identification of patients who are at risk for an adverse renal effect; hence, such effects can be minimized or avoided altogether. To do so requires an understanding of the various roles of PGs in the kidney and thereby the effects that one can observe from NSAIDs. This review focuses on these various roles of renal PGs and on identification of patient groups at risk for adverse renal effects of NSAIDs.


Quality of life and its socio-demographic and psychological determinants after bone marrow transplantation.
A host of medical, socio-demographic, and psychological factors that affect bone marrow transplantation (BMT) patients' quality of life (QOL) have been identified, but due to the methodological diversity of the studies, the findings have been contradictory. The aim of this study was to examine the influence of somatic status, social characteristics, and psychological symptoms on QOL in BMT patients. The study had a cross-sectional design. QOL was evaluated using the Hungarian version of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Anxiety and depression were assessed using Spielberger's State and Trait Anxiety Inventory (SSTAI) and the Beck Depression Inventory (BDI). A questionnaire designed for the study was used to record socio-demographic variables. One hundred and twenty-one patients formed the study sample. Patients' QOL was better in our sample than in another study with similar mean time after BMT. BDI scores indicated mild depression; SSTAI scores corresponded with healthy population levels. QOL was strongly influenced by psychological symptoms (depression P < 0.001; anxiety P = 0.001; psychiatric comorbidity P = 0.001), employment status (P = 0.042), and gender (P = 0.05). The somatic factors influenced only separate aspects of QOL; somatic comorbidity only affected cancer-associated QOL (P = 0.004). This is the first study on a Hungarian BMT sample that included economic factors in the assessment of QOL. Psychological variables were the strongest determinants of QOL in this study.


Binding Studies of Isoxsuprine Hydrochloride to Calf Thymus DNA Using Multispectroscopic and Molecular Docking Techniques.
In the present work, the interaction of Isoxsuprine (ISX) with Calf thymus DNA (ct-DNA) under physiological conditions (Tris-HCl buffer of pH 7.4) was investigated by using electronic absorption, circular dichroism, viscosity, electrochemical studies, fluorescence techniques, salt effect studies and computational studies. Competitive fluorimetric studies with Hoechst 33258 have shown that ISX exhibit the ability to displace the DNA-bound Hoechst 33258, indicating that it binds to ct-DNA in strong competition with Hoechst 33258 for the minor groove binding. Furthermore, the resulting data showed that ISX cannot displace methylene blue or acridine orange, which are the common intercalator molecules. The viscosity of ct-DNA solution was almost unchanged on addition of ISX and circular dichroism (CD) spectra of ct-DNA showed small changes in the presence of ISX which is in agreement with groove binding mode of interaction. Thus all above studies showed that the ISX drug binds to ct-DNA in a groove binding mode.The salt-effect studies showed the non-electrostatic nature of binding of ISX to ct-DNA. Moreover, molecular docking results support the above experimental data and suggest that ISX prefers to bind on the minor groove of ct-DNA.


A retrospective sero-epidemiological survey of bovine brucellosis on commercial and communal farming systems in Namibia from 2004 to 2018.
Cattle production is the major livestock production activity and the mainstay of Namibia's economy. Sustained beef exports are contingent on a sound sanitary environment where diseases such as brucellosis are under control. In this retrospective study, 49,718 bovine brucellosis testing results from 2004 to 2018 were analyzed to determine the proportion of sero-positive cattle and herds, and the spatial distribution of positive reactors from commercial and communal areas. In total, 244 positive reactors were identified based on the Rose Bengal Test (RBT) and the Complement Fixation Test (CFT) in series, giving an overall proportion of infected animals of 0.49% (244/49,718; 95% CI, 0.43-0.56%) and an overall proportion of infected herds of 9.26% (78/842; 95% CI, 7.49-11.41%). There was a higher proportion of sero-positive communal herds (33.09%) and cattle (10.27%) than commercial herds (4.67%) and cattle (0.24%; p < 0.05). Annually, the proportion of positive reactors was 0-1.37% in the commercial area and 0-52.38% in the communal areas, with a clear decline in positive reactors in the communal areas. Within the commercial sector, the proportion of positive reactor dairy, beef, and export cattle was 0.19% (51/27,067; 95% CI, 0.14-0.25%), 0.30% (48/16,098; 95% CI, 0.22-0.40%), and 0.33% (16/4811; 95% CI, 0.20-0.54%), respectively. Abortions were found to be the major reason for Brucella testing in the communal areas. About 12.65% (96/759) of abortion-linked sera tested positive in the communal areas, but none were positive in beef or dairy cattle. Widespread vaccination of cattle and robust planned surveillance is recommended to reduce the incidence of the disease, its associated production losses and public health risk.


Recurrence in Oral Squamous Cell Carcinoma Associated with Wide Field of Cancerization: Analysis of 93 Cases.
The late presentation of oral squamous cell carcinoma (OSCC) patients in the Sudan, with advanced stages and wide field of cancerization, have a negative impact on both the morbidity and the mortality of these patients. The present study aimed to investigate the clinicopathological behavior of OSCC and predictors of development of recurrence in these patients. This a prospective longitudinal study of 93 OSCC patients surgically treated at Khartoum Teaching Dental Hospital. Tumor's associated field of cancerization was identified. The patients were followed clinically on regular basis, for a year, for the development of recurrence. Out of the 93 patients, 57 (61.3%) were males and 36 (38.7%) were females. 82% of the patients presented with stage IV tumors, and 58 (62.4%) of the cases had nodal metastasis. Twenty-eight (30%) patients developed recurrence. Of them 17 (18.3%) had regional recurrence, eight (8.6%) had local recurrence and three (3.2%) had locoregional recurrence. Multivariate cox regression analysis showed that Toombak dipping (P.value = 0.001), tumor staging (P.value = 0.039) and presence of mucosal filed changes (P.value = 0.001) were independent predictors for local recurrence and positive pathological lymph nodes (P.value = 0.00) and extranodal extension (P.value = 0.040) were independent predictors for regional recurrence. The present study showed that OSCC patients in the Sudan present with advanced lesions, mostly associated with wide field of cancerization particularly Toombak dippers. Overall recurrences were identified in 30% of the cases, regional recurrence was the commonest type followed by local recurrence.


[Rheumatism and gastroenterology].
Gastroenterological and rheumatological diseases often have a systemic character, with disease manifestations beyond the area affected by the disease. Common disease-relevant pathophysiological pathways, e.g. chronic inflammation, may present primarily as rheumatological or gastroenterological disease. Knowledge of disease-specific symptoms and signs beyond one's own area of expertise my lead to an earlier and more precise diagnosis, with the chance of a more focused therapy. The aim of this overview is to sensitize orthopedists as well as rheumatologists to gastroenterological signs and symptoms and give them a clinical guide to approaching an interdisciplinary patient. Targeted, clinically relevant questions are discussed and common disease entities are presented.


Biomechanical characteristics of 3 pivot-shift maneuvers for the anterior cruciate ligament-deficient knee: in vivo evaluation with an electromagnetic sensor system.
A disadvantage of pivot-shift maneuvers is that the examiner has to subjectively evaluate the degree of pivot shift observed. It is unknown whether the various maneuvers are biomechanically identical. To compare biomechanical features of 3 clinical maneuvers for the anterior cruciate ligament (ACL)-deficient knee: the pivot-shift test, the jerk test, and the N-test. Controlled laboratory study. A total of 28 patients with an isolated ACL injury were examined by use of 3 pivot-shift maneuvers (pivot-shift test, jerk test, and N-test). An electromagnetic sensor system was used to evaluate the 3-dimensional knee kinematics of each patient's injured and uninjured knees during each maneuver. Peak coupled anterior tibial translation (pCAT) and maximal acceleration of posterior translation (APT) were measured relative to results during a flexion-extension motion in each test. The pCAT of the pivot-shift test was significantly greater than that of both the jerk test and the N-test (P = .0020 and P < .0001, respectively); there was no statistical difference in pCAT between the jerk test and the N-test. The APT of the N-test was significantly greater than that of both the pivot-shift test and the jerk test (P < .0001), while there was no statistical difference between the pivot-shift and the jerk tests. There was no correlation between pCAT and APT in each test. The pivot-shift test, jerk test, and N-test have different biomechanical characteristics to induce the pivot-shift phenomenon in the ACL-deficient knee. The pivot-shift test produced the largest side-to-side difference in pCAT, whereas the N-test provoked the largest side-to-side difference in APT. The biomechanical differences in pivot-shift maneuvers are caused by technical differences, and clinicians should understand these biomechanical differences while practicing the maneuvers. The electromagnetic sensor system is clinically useful for quantifying the pivot-shift phenomenon.


[Engineering and characterization of functional osteochondral replacement tissue].
Extensive osteochondral lesions require repair of the cartilage and underlying bone. We generated osteochondral repair tissue by tissue engineering. Standardized defects, 7 x 5 x 5 mm, were created in femoropatellar grooves of adult rabbits. Engineered cartilage, generated in vitro starting from chondrocytes and a biodegradable scaffold, was implanted using Collagraft as subchondral support. Cell-free implants, defects left empty, and unoperated knee joints served as controls. Explants were characterized morphologically and mechanically. Engineered cartilage implants were superior to cell-free implants and to natural healing of empty defects with respect to the histologic score and Young's modulus of the 6-month repair tissue. These data suggest that engineered cartilage can provide primary stability for the treatment of critical osteochondral defects.


Peptide-mediated delivery of CRISPR enzymes for the efficient editing of primary human lymphocytes.
CRISPR-mediated genome editing of primary human lymphocytes is typically carried out via electroporation, which can be cytotoxic, cumbersome and costly. Here we show that the yields of edited primary human lymphocytes can be increased substantially by delivering a CRISPR ribonucleoprotein mixed with an amphiphilic peptide identified through screening. We evaluated the performance of this simple delivery method by knocking out genes in T cells, B cells and natural killer cells via the delivery of Cas9 or Cas12a ribonucleoproteins or an adenine base editor. We also show that peptide-mediated ribonucleoprotein delivery paired with an adeno-associated-virus-mediated homology-directed repair template can introduce a chimaeric antigen receptor gene at the T-cell receptor α constant locus, and that the engineered cells display antitumour potency in mice. The method is minimally perturbative, does not require dedicated hardware, and is compatible with multiplexed editing via sequential delivery, which minimizes the risk of genotoxicity. The peptide-mediated intracellular delivery of ribonucleoproteins may facilitate the manufacturing of engineered T cells.


Outcome analysis of bilateral Cohen cross-trigonal ureteroneocystostomy.
The perioperative and long-term outcomes of children with vesicoureteral reflux (VUR) treated by cross-trigonal ureteroneocystostomy were ascertained. One hundred ten consecutive children with VUR who underwent bilateral cross-trigonal ureteroneocystostomy were studied retrospectively. Nineteen children with neurovesical dysfunction or megaureters requiring tapered reimplants were excluded. Outcome parameters of the remaining 91 children consisted of operative time, length of hospitalization, days of Foley catheter drainage perioperative complications, correction of reflux, subsequent morbidity, and parental satisfaction. Of 182 renal units, 11 (6%) had grade 0 VUR, 18 (10%) had grade I, 43 (24%) had grade II, 59 (32%) had grade III, 36 (20%) had grade IV, and 15 (8%) had grade V reflux. The mean operative and hospitalization times were 180 minutes and 5.6 days, respectively. No postoperative complications occurred. Three children were lost to follow-up, and the remaining 88 children had an extended mean follow-up in excess of 3 years. Voiding cystourethrogram documented a 98.3% (173 of 176 renal units) success rate. Sixteen children (18%) experienced nonfebrile clinically symptomatic cystitis episodes and 3 children (3%) experienced one febrile episode each. Telephone parental survey of overall surgical experience revealed a 94% very satisfied, 2% satisfied, and 3% dissatisified rate. Cross-trigonal ureteroneocystostomy is a safe and effective technique that is virtually complication free and has high parental satisfaction. The results of this study provide a baseline for comparison of non-operative treatment of reflux as well as laparoscopic and endoscopic techniques.


Regional Overview on Maternal Nutrition and Examples of Health System Programme and Policy Responses: Asia and the Pacific.
The double burden of malnutrition in Asia and the Pacific is driving a renewed focus on maternal malnutrition. Though adverse consequences of maternal malnutrition have been long recognized, there is slow progress in addressing nutritional problems of women/adolescent girls. Coverage and quality of current maternal nutrition interventions, mostly delivered through antenatal care programmes vary across countries, and are often sub-optimum. Further, despite a marked increase in overweight and obesity in women of reproductive age, at present, most programmes are focused on under-nutrition and micronutrient deficiencies. Key Messages: The recent antenatal care recommendations released by World Health Organization provide a benchmark for countries to evaluate their programmes and identify gaps and challenges to improving maternal nutrition. Asian and Pacific countries need to address all forms of maternal malnutrition. For countries that historically focused on maternal under-nutrition, expanding their programmes to incorporate interventions to address overweight and obesity will be challenging. Innovative methods for nutrition counselling, both in terms of content and using novel channels of communication, are needed. Protocols and guidance on managing excessive weight gain as well as determining appropriate pregnancy weight gains are needed, while managing micronutrient deficiencies, particularly in settings where inherited disorders of red blood cells exist.


Acute toxicity of organophosphate pesticide profenofos, pyrethroid pesticide λ cyhalothrin and biopesticide azadirachtin and their sublethal effects on growth and oxidative stress enzymes in benthic oligochaete worm, Tubifex tubifex.
The present study was aimed to assess the acute toxicity of organophosphate pesticide, profenofos; synthetic pyrethroid pesticide, λ cyhalothrin and biopesticide, azadirachtin and their sublethal effects on growth rate and oxidative stress biomarkers in Tubifex tubifex in vivo. The results showed that 96 h LC50 value of profenofos, λ cyhalothrin and azadirachtin to Tubifex tubifex are 0.59, 0.13 and 82.15 mg L-1 respectively. Pesticide treated worms showed several behavioral abnormalities including increased mucus secretion, erratic movements, wrinkling activity and decreased clumping tendency during acute exposure. The percentage of autotomy increased significantly (p < 0.05) with the increasing concentration of the pesticides at 96 h of exposure. Sublethal concentrations of profenofos (0.059 and 0.118 mg L-1), λ cyhalothrin (0.013 and 0.026 mg L-1) and azadirachtin (8.2 and 16.4 mg L-1) caused significant alterations in growth rate and oxidative stress enzymes in T. tubifex during 14 days exposure period. The growth rate of the pesticide exposed worms decreased significantly (P < 0.05) in a concentration and duration-dependent manner. Superoxide dismutase (SOD), reduced glutathione (GSH), glutathione-s-transferase (GST) and glutathione peroxidase (GPx) demonstrated a noteworthy (p < 0.05) initial induction followed by a subsequent reduction, while catalase (CAT) and malondialdehyde (MDA) exhibited noteworthy induction (p < 0.05) all through the exposure time. Through principal component analysis, correlation matrix, and integrated biomarker response, the effects of profenofos, λ cyhalothrin and azadirachtin on T. tubifex were distinguished. These results indicate that exposure to profenofos, λ cyhalothrin and azadirachtin affect survivability, change the behavioral responses, reduce the growth rate and induce oxidative stress enzymes in T. tubifex.


Cybrid formation in mouse L cells: the influence of cytoplast-to-cell ratio.
The frequency of cybrid colony formation was measured in fusions between enucleated chloramphenicol (CAP)-resistant mouse cells and CAP-sensitive mouse cells in varying ratios. By labeling the CAP-resistant cytoplasts with polystyrene beads and then performing the same fusions with CAP-sensitive cells, the frequency of cybrid fusions could be measured. Comparison of the frequency of viable cybrids (cybrid colonies) with the frequency of cybrid fusions showed that, with increasing fusion ratios of cytoplasts to cells, the proportion of cells fused to cytoplasts increased. Further, the viability of cybrid fusions increased from about 1 in 500 to nearly 1 in 60 over the range of cytoplast-to-cell ratios studied.


Alternations in hepatic expression of fatty-acid metabolizing enzymes in ArKO mice and their reversal by the treatment with 17beta-estradiol or a peroxisome proliferator.
We generated aromatase gene knockout mice (ArKO mice) by targeting disruption of Cyp19, which encodes an enzyme responsible for conversion of androgens to estrogens. We found that ArKO males developed hepatic steatosis spontaneously with aging, indicating that the function of Cyp19 is required to maintain constitutive lipid metabolism in male mice. Plasma lipoprotein analysis using a gel permeation chromatography revealed that high density lipoprotein (HDL)-cholesterol levels were slightly higher in ArKO males than in wild-type males, whereas no other obvious alternations in the profiles were detected. Nevertheless, analysis of lipoprotein compositions by SDS-polyacrylamide gel electrophoresis demonstrated apparent reduction in the amounts of apolipoprotein E, functioning in receptor-mediated clearance of lipoproteins in the liver, in the IDL/LDL fraction of ArKO males as compared with that of wild-type males. Biochemical analysis on the ArKO livers revealed suppression of mRNA expression and activity of enzymes involved in fatty acid beta-oxidation. The impairment was reversed to the wild-type levels by treatment with 17beta-estradiol or bezafibrate, the latter is a synthetic peroxisome proliferator. These findings indicated a pivotal role of estrogen in supporting constitutive hepatic expression of genes involved in fatty acid beta-oxidation and in maintaining lipid homeostasis.


The end-tidal carbon dioxide detector. Assessment of a new method to distinguish oesophageal from tracheal intubation.
A new method to distinguish oesophageal from tracheal intubation using an end-tidal carbon dioxide detector was evaluated. In a prospective study on 50 healthy adult patients, the end-tidal carbon dioxide detector was reliably used to detect initial oesophageal intubation in 22 cases, and then to confirm tracheal intubation in all 50 patients. We conclude from this study that the end-tidal carbon dioxide detector is a reliable, rapid and easy method for the detection of oesophageal intubation.


An alternate-form instrument to assess vividness and controllability of mental imagery in seven modalities.
A review of the literature concerning assessment of the ability to produce mental images demonstrated that in both the clinical and research areas new instruments were needed. The problem was to produce an alternate-form measure that would enable simultaneous measurement of controllability and vividness on the same test items in seven modalities. The results seem to suggest that for the Survey of Mental Imagery alternate forms are strictly comparable, reliable, have a known factor structure, and combine simultaneous measurement of controllability and vividness in at least six sensory modalities.


Discovery and characterization of potent pan-variant SARS-CoV-2 neutralizing antibodies from individuals with Omicron breakthrough infection.
The SARS-CoV-2 Omicron variant evades most currently approved neutralizing antibodies (nAbs) and caused drastic decrease of plasma neutralizing activity elicited by vaccination or prior infection, urging the need for the development of pan-variant antivirals. Breakthrough infection induces a hybrid immunological response with potentially broad, potent and durable protection against variants, therefore, convalescent plasma from breakthrough infection may provide a broadened repertoire for identifying elite nAbs. We performed single-cell RNA sequencing (scRNA-seq) and BCR sequencing (scBCR-seq) of B cells from BA.1 breakthrough-infected patients who received 2 or 3 previous doses of inactivated vaccine. Elite nAbs, mainly derived from the IGHV2-5 and IGHV3-66/53 germlines, showed potent neutralizing activity across Wuhan-Hu-1, Delta, Omicron sublineages BA.1 and BA.2 at picomolar NT50 values. Cryo-EM analysis revealed diverse modes of spike recognition and guides the design of cocktail therapy. A single injection of paired antibodies cocktail provided potent protection in the K18-hACE2 transgenic female mouse model of SARS-CoV-2 infection.


[Individual megaspacers in two-stage revision of infected total hip arthroplasty-clinical and functional results after 2 years : Individual metal-endoskeleton cement spacer (iMECS)].
Large femoral defects in late periprosthetic infection (PPI) after total hip arthroplasty (THA) often require the use of large, individual metal endoskeleton-reinforced cement spacers (iMECS). The aim was to record the clinical, radiological and functional results (Harris Hip Score HHS) up to the 2 years after treatment of a PPI using an iMECS. Major patient-specific parameters were to be evaluated with regard to the treatment outcome. The collective of this single-center retrospective cohort study comprised 29 patients. The mean follow-up was 24.4 months (range: 23.0 to 27.6 months). The absence of infection after endoprosthetic hip joint reconstruction was rated as successful treatment. The two patient groups (successful (S)/not successful (nS)) were compared with regard to gender distribution, the Charlson comorbidity index (CCI), the number of previous septic changes, and the rate of polymicrobial and difficult-to-treat infections. The average CCI in the total collective was 6.4 points. Joint reconstruction was possible in 23 of 29 patients (79%); 2 years after PPI treatment 4 patients were not available for a follow-up examination (2 deceased, 2 unable to participate). At the time of the follow-up, 17 of the 29 patients had received a joint reconstruction and were free of infection, with an average HHS of 75 points. There were no iMECS-associated complications requiring revision. Only the initial CCI (S: 4.1 points; nS: 9.7 points) differed significantly between the patient groups (p < 0.05). In the case of large femoral defects, iMECS provide secure temporary stabilization. The chance of a successful joint reconstruction is closely related to the individual comorbidities profile.


CWLy-SVM: A support vector machine-based tool for identifying cell wall lytic enzymes.
Cell wall lytic enzymes, as an important biotechnical tool in drug development, agriculture and the food industry, have attracted more research attention. In this research, the accurate identification of cell wall lytic enzymes is one of the key and fundamental tasks. In this study, in order to eliminate the inefficiency of in vitro experiments, a support vector machine-based cell wall lytic enzyme identification model was constructed using bioinformatics. This machine learning process includes feature extraction, feature selection, model training and optimization. According to the jackknife cross validation test, this model obtained a sensitivity of 0.853, a specificity of 0.977, an MCC of 0.845 and an AUC of 0.915. These benchmark results demonstrate that the proposed model outperforms the state-of-the-art method and that it has powerful cell wall lytic enzyme identification ability. Furthermore, we comprehensively analyzed the selected optimal features and used the proposed model to construct a user friendly web server called the CWLy-SVM to identify cell wall lytic enzymes, which is available at http://server.malab.cn/CWLy-SVM/index.jsp.


First Report of Campylobacter hepaticus Isolation in Laying Hens and Broiler Breeders with Spotty Liver Disease in Costa Rica.
Poultry producers in Costa Rica have informally reported a spotty liver disease-like syndrome for more than 20 yr. However, despite many attempts, the infectious agent responsible for this syndrome had not been identified. Therefore, following current knowledge of spotty liver disease diagnosis, we invited veterinarians and poultry producers to submit samples to the diagnostic laboratories of the Veterinary Medicine School, Universidad Nacional, to identify the infectious agent of this syndrome. Veterinarians and poultry producers were instructed to collect gallbladders and livers aseptically and send them for pathology examinations and bacterial cultures in less than 24 hr after collection. Samples were processed for standard histopathologic studies and cultured under aerophilic, anaerobic, and microaerophilic conditions. Campylobacter-like colonies were isolated and identified by biochemical and PCR tests. Here we report for the first time the isolation, biochemical characterization, and molecular confirmation of Campylobacter hepaticus in laying hens and broiler breeders with spotty liver disease in Costa Rica.


A theoretical study of ultrasonic wave transmission through a fluid-solid interface.
This article develops a model for the study of the transient ultrasonic waves radiated by a transducer in a liquid and transmitted into a solid through a plane interface. The method is an extension to the transient case, of the angular spectrum method previously developed for the monochromatic case. It is based on the decomposition of the ultrasonic field, in impulse plane waves. The radiated waveform is calculated at any point in the field by a simple summation of these impulse plane waves, where the propagation delay and the refraction have been taken into account. These plane waves are, first of all, delayed by an amount of time corresponding to the travel time up to the considered field point. The transmission through the plane interface is taken into account by using Snell refraction laws and transmission coefficients. In the obtained results all the waves previously described by other authors are highlighted: direct wave, edge waves, head waves as well as subsurface waves with a clear resolution between compression and shear waves.


RNA-binding protein CCDC137 activates AKT signaling and promotes hepatocellular carcinoma through a novel non-canonical role of DGCR8 in mRNA localization.
RNA binding proteins (RBPs)-regulated gene expression play a vital role in various pathological processes, including the progression of cancer. However, the role of RBP in hepatocellular carcinoma (HCC) remains much unknown. In this study, we aimed to explore the contribution of RBP CCDC137 in HCC development. We analyzed the altered expression level and clinical significance of CCDC137 in database and HCC specimens. In vitro cell assays and in vivo spontaneous mouse models were used to assess the function of CCDC137. Finally, the molecular mechanisms of how CCDC137 regulates gene expression and promotes HCC was explored. CCDC137 is aberrantly upregulated in HCC and correlates with poor clinical outcomes in HCC patients. CCDC137 markedly promoted HCC proliferation and progression in vitro and in vivo. Mechanistically, CCDC137 binds with FOXM1, JTV1, LASP1 and FLOT2 mRNAs, which was revealed by APOBEC1-mediated profiling, to increase their cytoplasmic localization and thus enhance their protein expressions. Upregulation of FOXM1, JTV1, LASP1 and FLOT2 subsequently synergistically activate AKT signaling and promote HCC. Interestingly, we found that CCDC137 binds with the microprocessor protein DGCR8 and DGCR8 has a novel non-canonical function in mRNA subcellular localization, which mediates the cytoplasmic distribution of mRNAs regulated by CCDC137. Our results identify a critical proliferation-related role of CCDC137 and reveal a novel CCDC137/DGCR8/mRNA localization/AKT axis in HCC progression, which provide a potential target for HCC therapy.


Upgrading the biogas production from raw landfill leachate using O3/H2O2 pretreatment process: Modeling, optimization and anaerobic digestion performance.
Here, a combined pretreatment oxidation process (O3/H2O2) was investigated to enhance the biodegradability of raw landfill leachate (RLL) and biomethane potential (BMP) in anaerobic reactors. The central composite design (CCD) and response surface methodology (RSM) were employed to optimize the operational parameters influencing on RLL bioavailability in O3/H2O2 process: pH, Oxygen Flow rate, Reaction Time, and H2O2 concentration. The findings revealed that the O3/H2O2 increased biodegradability index (BOD5/COD) of RLL from 0.41 to 0.68 under optimized condition (pH=8, Oxygen flow= 0.25 L.min-1, Reaction Time= 25 min, H2O2 concentration= 2.5 g.L-1). Furthermore, the effects of O3/H2O2 process on BMP of RLL were surveyed under mesophilic anaerobic reactors (Temperature: 37 ± 1 °C) in viewpoints of operational performance and methane yield in a batch mode for incubation period of 24 days. The results showed that O3/H2O2 process simultaneously improve the BMP by 2.99 times higher in a shorter lag-phase period (5 days) compared with control. The pretreatment O3/H2O2 and mesophilic anaerobic digestion process revealed a feasible and efficient method for enhance BMP of RLL.


CYP2C19 genotype and S-mephenytoin 4'-hydroxylation phenotype in a Chinese Dai population.
To investigate the incidence of the CYP2C19 polymorphism in the Chinese Dai population. One hundred and ninety-three healthy Chinese Dai volunteers were identified with respect to CYP2C19 by genotype and phenotype analyses. A polymerase chain reaction-restriction fragment length polymorphism method was performed for genotyping procedures. The 4'-hydroxymephenytoin (4'-OH-MP) and S/R-mephenytoin ( S/R-MP) excreted in the urine were determined by high-performance liquid chromatography and gas chromatography, respectively. Eighteen subjects were identified as poor metabolisers (PMs). The frequency of PMs in the Chinese Dai subjects was 9.3% (95% confidence interval 5.2, 13.4), which is lower than that in the Chinese Han population ( P<0.05). Chinese Dai subjects had a higher frequency of the mutant CYP2C19*2 allele (0.303) and a lower frequency of the mutant CYP2C19*3 allele (0.034). These two mutant alleles could explain all deficiencies of CYP2C19 activity in the Chinese Dai subjects. The frequency of the CYP2C19*3 allele is significantly lower than that in the Chinese Han population ( P<0.05). The mean S/R ratio was lower in the homozygous extensive metabolisers (EMs) compared with that in heterozygous EMs ( P<0.01), and the latter was lower than that in the PMs ( P<0.01). Furthermore, the mean S/R ratio in CYP2C19*3/ CYP2C19*2 heterozygous PMs was possibly lower than that in the CYP2C19*2/ CYP2C19*2 homozygous PMs ( P<0.05). The frequencies of PMs and CYP2C19*3 allele in the Chinese Dai population are significantly lower than those in the Han population. The CYP2C19 genotype analysis is largely consistent with the mephenytoin phenotype analysis. The variability of S/R ratios in EMs and PMs shows a gene-dosage effect.


Partial purification of a major type of rat prostatic growth factor: characterization as an epidermal growth factor-related mitogen.
The dorsolateral prostate of rats contains a mitogen that shares several properties with epidermal growth factor (EGF), which was designated as prostatic EGF-related mitogen (PEM). PEM was purified about 2,100-fold using molecular-sieve and ion-exchange chromatography. Final preparation stimulated DNA synthesis in BALB/c 3T3 cells at a concentration as low as 1.5 ng/ml and competed with 125I-EGF for binding to cell surface receptors. PEM had a molecular weight of about 14,000 and an isoelectric point of about 4.5, being heat- and acid-stable but inactivated by dithiothreitol. The primary cultured rat dorsolateral prostate epithelial cells required EGF for maximum growth. Partially purified PEM fully substituted for EGF in the primary culture system at a concentration as low as 90 ng/ml. However, the activity of PEM was hardly suppressed by antimouse EGF antiserum. These findings suggest that PEM is a member of the EGF family but has a higher molecular weight (high molecular weight EGF).


ER-Stress-Induced Differentiation Sensitizes Colon Cancer Stem Cells to Chemotherapy.
Colon cancer stem cells (colon-CSCs) are more resistant to conventional chemotherapy than differentiated cancer cells. This subset of therapy refractory cells is therefore believed to play an important role in post-therapeutic tumor relapse. In order to improve the rate of sustained response to conventional chemotherapy, development of approaches is warranted that specifically sensitize colon-CSCs to treatment. Here, we report that ER-stress-induced activation of the unfolded protein response (UPR) forces colon-CSCs to differentiate, resulting in their enhanced sensitivity to chemotherapy in vitro and in vivo. Our data suggest that agents that induce activation of the UPR may be used to specifically increase sensitivity of colon-CSCs to the effects of conventional chemotherapy.


Effects of adrenergic stimulating and blocking agents on the eccrine sweat secretion in atopic dermatitis and psoriasis.
Quantitative measurements of eccrine sweat secretion following stimulation with adrenaline and terbutaline sulphate, a beta-stimulator, have been performed in patients with atopic dermatitis and psoriasis by means of the electrolytic water analyzer, "Meeco". Seasonal variations were demonstrated, the values being lower in the late autumn. The response to adrenaline could be blocked by phentolamine, an alpha-inhibitor, while propranolol, a beta inhibitor, had no effect.--The response to terbutaline was blocked by atropine and partly by practolol, a beta-inhibitor. Terbutaline induced a larger sweat response than isoprenaline, another beta-stimulator. A beta-receptor mechanism, in some way related to cholinergic receptors, is suggested.


[Use of drug reimbursement as markers of disease for epidemiological and cost analysis: The case of severe epilepsy in France].
Population characteristics of epileptic patients remain poorly documented in France. Health Insurance claims database may be useful to perform cost and epidemiological studies provided that patients' diagnosis could be identified especially through drugs used as markers. This study explored the possibility to use the French Sickness Fund (FSF) database to determine the prevalence and direct cost of epilepsy. The "FSF" reimbursement database is a 1/97 representative sample of the population covered under the French General Scheme. Only the fraction of patients fully covered for epilepsy may be identified by a diagnosis in the database. Others can only be identified through their claims for antiepileptic drugs (AEDs) with the limitation that, among the 19 AEDs used, some are not specific for epilepsy. An algorithm was built to select patients to get a range of prevalence estimates whereas medical expenses of patients were derived on the fully covered sub-population. Only patients treated in polytherapy (≥2 AEDs) were deemed to be identified in a relevant way by an algorithm based on drug usage. The prevalence of epilepsy in this sub-group in 2009 was estimated between 1.83 and 2.79‰ (93,000-142,000 patients). A proportion of 70.1 to 71.6% were fully covered for their expenses, with epilepsy alone as a cause in only 27 to 33% of them. The most frequent other co-morbidities were psychiatric disorders and invalidating stroke. The annual per capita expenses were in the range 6.696-6.601€ in patients in polytherapy. Inpatient care and drug costs represented about 50 and 27% of overall expenses, respectively. The increase by 24.4% of polytherapy patients mean costs as compared to monotherapy raised to 72% (IC 95: 44-106%) after adjustment for age, gender and presence of severe co-morbidity. In France, in 2009, 93,000 to 142,000 epileptic patients have been treated for epilepsy with a polytherapy. About one out of three patients only benefited from a full coverage of their medical expenses for epilepsy but half of them were fully covered for another disease. This resulted from the frequent presence of a severe co-morbidity especially psychiatric or due to a history of an invalidating stroke. Conversely, about 30% of epileptic patients in polytherapy, fully eligible to a full coverage did not benefit from it, which suggested an important sub-declaration of severe epilepsy.


The spectrum of primary cutaneous elastolytic granulomas and their distinction from granuloma annulare: a clinicopathological analysis.
Actinic granuloma (AG) and annular elastolytic giant cell granuloma (AEGCG) are terms commonly applied to cutaneous lesions characterized by elastolysis, elastophagocytosis and a multinucleated cell infiltrate. The aim of this study was to clarify the relationship of these lesions to granuloma annulare (GA) which they resemble clinically. The clinicopathological data of 20 patients whose biopsies showed the histology of elastolytic granuloma as well as those of previously published cases with identical tissue changes were analysed to assess differences between AG, AEGCG and GA. The tissue changes of AG and AEGCG are identical and differ substantially from GA because of the predominant elastolysis and elastophagocytosis in the absence of necrobiosis and palisading granuloma. Actinic and/or thermal injury could be elicited frequently in the patient's history, but not always. AG may be considered as an aetiopathological subdivision of AEGCG. Patients with biopsies showing both GA and AEGCG are occasionally encountered. AEGCG is easily differentiated from incidental elastolysis which may be seen in a variety of aetiologically unrelated processes.


Early treatment with laronidase improves clinical outcomes in patients with attenuated MPS I: a retrospective case series analysis of nine sibships.
Enzyme replacement therapy (ERT) with laronidase, (recombinant human α-L-iduronidase; Aldurazyme) is the primary treatment option for patients with attenuated mucopolysaccharidosis type I (MPS I). This study examined the effect of early ERT on clinical manifestations. This multinational, retrospective case series abstracted data from records of 20 patients with Hurler-Scheie syndrome within nine sibships that included older siblings treated with laronidase after the development of significant clinical symptoms, and younger siblings treated before significant symptomatology. Median age at diagnosis was 5.6 and 0.5 years for older and younger siblings, respectively. Median age at ERT initiation was 7.9 and 1.9 years for older and younger siblings, respectively. Improvement or stabilization of somatic signs and symptoms was more notable in younger siblings. Organomegaly present at onset of ERT improved in the majority of both older and younger siblings. Analysis of physician-rated symptom severity demonstrated that cardiac, musculoskeletal, and cognitive symptoms, when absent or mild in younger siblings at ERT initiation, generally did not develop or progress. The majority of older siblings had height/length Z-scores greater than two standard deviations below the mean (less than -2) at both time points. In general, Z-scores for younger siblings were closer to the sex- and age-matched means at follow-up. These findings suggest early initiation of laronidase, prior to the onset of symptoms in patients with attenuated MPS I, can slow or prevent the development of severe clinical manifestations.


Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats.
The present study examined the protective effect of sulindac on bleomycin-induced lung fibrosis in rats. Animals were divided into saline group, bleomycin group (single intra-tracheal instillation of bleomycin) and bleomycin+sulindac (orally from day 1 to day 20). Bleomycin administration reduced the body weight, altered antioxidant status (such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione) while it increased the lung weight, hydroxyproline content, collagen deposition and lipid peroxidation. However, simultaneous administration of sulindac improved the body weight, antioxidant status and decreased the collagen deposition in lungs. Moreover, the levels of inflammatory cytokine tumour necrosis factor-α increased in bleomycin-induced group, whereas, on treatment with sulindac the levels of tumour necrosis factor-α were found reduced. Finally, histological evidence also supported the ability of sulindac to inhibit bleomycin-induced lung fibrosis. The results of the present study indicate that sulindac can be used as an agent against bleomycin-induced pulmonary fibrosis.


Fetal and neonatal cerebral blood velocity in the normal fetus and neonate: a longitudinal Doppler ultrasound study.
In a longitudinal Doppler ultrasound study fetal and early neonatal cerebral blood flow velocities were assessed in the middle cerebral artery in 40 uncomplicated pregnancies during the third trimester of pregnancy and in 22 neonates born from these pregnancies. Peak systolic (PSFV), temporal mean (TMFV), and end diastolic flow velocities (EDFV) were determined and pulsatility index (PI = (PSFV - EDFV)/TMFV) and Pourcelot's resistance index (RI = (PSFV - EDFV)/PSFV) calculated. PSFV, TMFV and EDFV increased during the third trimester of pregnancy and were significantly higher from 36 weeks of gestation onward as compared to values obtained at 28 weeks of gestation, suggesting an increase in actual cerebral blood flow. PI and RI of the MCA did not differ significantly during this period. Immediately after birth PSFV, TMFV and EDFV decreased significantly and remained lower during the first 5 postnatal days compared to fetal values. PI and RI of the MCA tended to decrease during the first postnatal day, but stabilized afterwards.


Expression of alanine:glyoxylate aminotransferase gene from Saccharomyces cerevisiae in Ashbya gossypii.
Two plasmids containing an autonomously replicating sequence from Saccharomyces cerevisiae were constructed. Using these vectors, the AGX1 gene encoding alanine:glyoxylate aminotransferase (AGT) from S. cerevisiae, which converts glyoxylate into glycine but is not present in Ashbya gossypii, was expressed in A. gossypii. Geneticin-resistant transformants with the plasmid having the kanamycin resistance gene under the control of the translation elongation factor 1 alpha (TEF) promoter and terminator from A. gossypii were obtained with a transformation efficiency of approximately 10-20 transformants per microgram of plasmid DNA. The specific AGT activities of A. gossypii pYPKTPAT carrying the AGX1 gene in glucose- and rapeseed-oil-containing media were 40 and 160 mU mg-1 of wet mycelial weight, respectively. The riboflavin concentrations of A. gossypii pYPKTPAT carrying AGX1 gene in glucose- and rapeseed-oil-containing media were 20 and 150 mg l-1, respectively. In the presence of 50 mM glyoxylate, the riboflavin concentration and the specific riboflavin concentration of A. gossypii pYPKTPAT were 2- and 1.3-fold those of A. gossypii pYPKT without the AGX1 gene.


Parallel Post-Polyketide Synthase Modification Mechanism Involved in FD-891 Biosynthesis in Streptomyces graminofaciens A-8890.
To isolate a key polyketide biosynthetic intermediate for the 16-membered macrolide FD-891 (1), we inactivated two biosynthetic genes coding for post-polyketide synthase (PKS) modification enzymes: a methyltransferase (GfsG) and a cytochrome P450 (GfsF). Consequently, FD-892 (2), which lacks the epoxide moiety at C8-C9, the hydroxy group at C10, and the O-methyl group at O-25 of FD-891, was isolated from the gfsF/gfsG double-knockout mutant. In addition, 25-O-methyl-FD-892 (3) and 25-O-demethyl-FD-891 (4) were isolated from the gfsF and gfsG mutants, respectively. We also confirmed that GfsG efficiently catalyzes the methylation of 2 and 4 in vitro. Further, GfsF catalyzed the epoxidation of the double bond at C8-C9 of 2 and 3 and subsequent hydroxylation at C10, to afford 4 and 1, respectively. These results suggest that a parallel post-PKS modification mechanism is involved in FD-891 biosynthesis.


Industry Funding Is Correlated With Publication Productivity of US Academic Radiation Oncologists.
Industry payments to physicians are financial conflicts of interest and may influence research findings and medical decisions. We aim to (1) characterize industry payments within radiation oncology; and (2) explore the potential correlation between receiving disclosed industry payments and academic productivity. CMS database was used to extract 2015 industry payments. For academic radiation oncologists, research productivity was characterized by h- and m-indices, as well as receipt of National Institutes of Health (NIH) funding, which is not an industry payment. Logistic regression models were used to determine whether publication metrics (m-index, h-index) and other study characteristics such as gender, PhD status, NIH institution funding status, were associated with the endpoints, research and general payments. Associations between the amount of payments (if any) and publication metrics were further studied using linear regression models. A total of 22,543 individual payments totaling $25,532,482 to 2,995 radiation oncologists were included. Among the 1,189 academic radiation oncologists, 75% received less than $167; on the other hand, 10 (<1%) individuals received $6,425,728 (51%) of payments. On multiple logistic regression, research payments were significantly associated with the m-index, odds ratio 2.86 (95% confidence interval, 1.84-4.45, p-value <0.0001); as well as with the h-index, odds ratio 1.03 (95% confidence interval, 1.01-1.05, p-value <0.0001). The linear regression model shows that both m-index and h-index were significantly positively associated with the amount of general payments (p-values <0.0001). There is an association between disclosed payment from the industry and increased individual research productivity metrics. Further research to find the cause behind this association is warranted.


A Nitrate-Sensing Domain-Containing Chemoreceptor Is Required for Successful Entry and Virulence of Dickeya dadantii 3937 in Potato Plants.
Nitrate metabolism plays an important role in bacterial physiology. During the interaction of plant-pathogenic bacteria with their hosts, bacteria face variable conditions with respect to nitrate availability. Perception mechanisms through the chemosensory pathway drive the entry and control the colonization of the plant host in phytopathogenic bacteria. In this work, the identification and characterization of the nitrate- and nitrite-sensing (NIT) domain-containing chemoreceptor of Dickeya dadantii 3937 (Dd3937) allowed us to unveil the key role of nitrate sensing not only for the entry into the plant apoplast through wounds but also for infection success. We determined the specificity of this chemoreceptor to bind nitrate and nitrite, with a slight ligand preference for nitrate. Gene expression analysis showed that nitrate perception controls not only the expression of nitrate reductase genes involved in respiratory and assimilatory metabolic processes but also the expression of gyrA, hrpN, and bgxA, three well-known virulence determinants in Dd3937.


Impact of aortic stiffness on the frequency of paroxysmal atrial fibrillation recurrences.
The relationship between arterial stiffness (AS) and atrial fibrillation (AF) incidence is well-known. In this study we aimed to investigate the relationship between AS parameters and AF occurence as well as AF recurrence post catheter ablation (CA) in patients with paroxysmal AF (PAF). We enrolled 103 patients with PAF diagnosis and 103 control subjects with similar demographic characteristics. We measured AS parameters and central aortic pressure (CAP) parameters by an oscillometric device in both groups. In the patient group 51 patients underwent CA for AF and recurrence rates at 3 and 6 months postprocedurally were recorded. AS parameters were compared between patients with and without AF recurrence. In the PAF patient group central systolic pressure, central diastolic pressure, central pulse pressure, augmentation pressure, augmentation index, and pulse wave velocity were significantly higher than in the control group (for each listed parameter P<0.05). AS parameters were not associated with AF recurrence post CA. Left atrial size (LAS) was found as an independent predictor for recurrence in multivariate analysis (0: 2.30; P = 0.02; OR: 9.97; 95% CI [1.28-77.48]). Increased AS is associated with PAF occurence. Nevertheless, LAS, a traditional risk factor, was the most powerful predictor for recurrence post CA; whereas AS or CAP were not associated with recurrence.


Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF).
To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion. Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos. Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase. A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient.


[Research on substances with antiviral activity. X. 1-substituted-2-(methylamino) naphtho/2,1-b/furan hydrochlorides].
Some 2-(methylamino)naphtho [2,1-b] furans hydrochlorides 1-substituted were synthetized and investigates for antiviral activity in vitro against Herpes simplex virus type I (VHS-I) and parainfluenza virus type 3 HA-I/CR-8 stock.


Relationship between cardiac output and the end-tidal carbon dioxide tension.
To further define the relationship between cardiac output (CO) and end-tidal carbon dioxide tension (ETCO2) at various levels of systemic flow. Prospective, controlled laboratory investigation. Animal laboratory. Fourteen anesthetized, intubated sheep weighing 23 to 47 kg. One hundred seventy-two simultaneous measurements of thermodilution CO and ETCO2 were made during controlled arterial hemorrhage. After a 30-minute baseline control period, CO was sampled from approximately 0.6 to more than 8.0 L/min during a 60- to 90-minute period of controlled hemorrhage. Thermodilution CO; arterial pressure using fluid-filled plastic 14-gauge catheters; ETCO2 using an infrared analyzer. A plot of CO versus ETCO2 suggested that the relationship was logarithmic rather than linear. Linear regression showed that ETCO2 was significantly related (r = .91; P less than .001) to a logarithmic transformation of the CO. The relationship between CO and ETCO2 is logarithmic. Decreased presentation of CO2 to the lungs is the major, rate-limiting determinant of the ETCO2 during low flow. As the CO increases during resuscitation from shock or cardiac arrest, respiration becomes the rate-limiting controller of the ETCO2 (after the tissue washout of CO2 has occurred). Under such conditions, the ETCO2 provides useful information about the adequacy of ventilation provided that there is little ventilation/perfusion mismatch.


Three new aliphatic glycosides from the leaves of Antidesma japonicum Sieb. et Zucc.
From the 1-BuOH-soluble fraction of an MeOH extract of leaves of Antidesma japonicum, three new aliphatic glycosides, α-L-arabinofuranosyl-(1 → 6)-β-D-glucopyranosides of (6R,9R)-megastigma-4,7-dien-9-ol-3-one, (Z)-hex-3-en-1-ol, and methyl 2-hydroxy-2-(1'-hydroxyethyl)pentanoate 1'-O-β-D-glucopyranoside, were isolated, along with seven known compounds.


Fusing Carborane Carboxylic Acids with Alkynes: 3D Analogues of Isocoumarins via Regioselective B-H Activation.
An iridium-catalyzed alkenylation/annulation sequence between monocarba-closo-dodecaborate carboxylic acids and diarylacetylenes is reported. Regioselective activation of the B2 position, followed by B-C bond formation and ring closure, affords 3D bora-analogues of isocoumarins. The reaction tolerates a variety of functional groups on the aromatic rings and can be extended to B12-substituted derivatives. Furthermore, subsequent alkenylation of the B4 vertex has been achieved in high yields.


Ambulatory blood pressure and drug treatment for orthostatic hypotension as predictors of mortality in patients with multiple system atrophy.
Multiple system atrophy (MSA) is a rare fatal neurodegenerative disease characterized by parkinsonism, cerebellar ataxia and autonomic failure. This study was aimed at investigating possible associations between mortality, 24-h blood pressure (BP) level and variability, and drug treatments for orthostatic hypotension (OH) in MSA patients. A total of 129 patients followed at the French Reference Center for MSA who underwent routine 24-h ambulatory BP monitoring were included. Unified MSA Rating Scale (UMSARS) scores, drug treatments and the occurrence and cause of death were recorded. Seventy patients died during follow-up (2.9 ± 1.8 years), mainly from terminal illness, pulmonary or sudden death. Multivariate Cox regression analysis, after adjustment for gender, disease duration and severity (UMSARS I+II score), showed that increased daytime systolic BP variability, OH severity and OH drug treatment were independently correlated with mortality. OH treatment was associated with the risk of cardiac causes and/or sudden death (p = 0.01). In a fully adjusted model, male gender [(female vs. male) hazard ratio (HR) 0.56, 95% CI 0.34-0.94, p = 0.03], UMSARS I+II score (HR 1.04, 95% CI 1.02-1.06, p < 0.01), systolic BP daytime variability (HR 3.66, 95% CI 1.46-9.17, p < 0.01) and OH treatment (HR: 2.13, 95% CI 1.15-3.94, p = 0.02) predicted mortality. Increased daytime BP variability and OH treatment were predictive of mortality in patients with MSA, independently from disease severity. Further studies are required to assess if these associations are explained by more severe autonomic dysfunction or if OH treatment exposes per se to a specific risk in this population.


Analytical approaches to evaluating hypertensive disorders of pregnancy.
Data from the A Randomized Trial of Induction Versus Expectant Management study suggested that low-risk pregnant patients randomized to expectant management at term had a higher risk for developing hypertensive disorders of pregnancy than pregnant patients randomized to elective induction at 39 weeks. In addition, hypertensive disorders of pregnancy were reported to decrease with advancing gestational age when comparing outcomes by gestational age at delivery. This study aimed to verify these contrasting findings by evaluating the relationship between hypertensive disorders of pregnancy at term and gestational age at delivery. This was a secondary analysis of a multicenter, prospective cohort study of nulliparous pregnant patients with singleton gestations (from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be). Pregnant patients who delivered ≥37+0 weeks' gestation were included. Patients were excluded if they did not provide consent for data release in subsequent studies or if they had missing outcome data. The primary outcome was hypertensive disorders of pregnancy, defined as gestational hypertension or preeclampsia with or without severe features according to the American College of Obstetricians and Gynecologists guidelines. Descriptive statistics were used to evaluate hypertensive disorders of pregnancy in the following 2 ways: analysis (1), incidence of hypertensive disorders of pregnancy by gestational age week among all ongoing pregnancies and analysis (2), the incidence of hypertensive disorders of pregnancy by gestational age week among deliveries at that gestational age week. It was assumed that hypertensive disorders of pregnancy were not expectantly managed at term. Of the 8011 pregnant patients included in this analysis, 1003 (12.5%) had hypertensive disorders of pregnancy: 162 (24.5%) delivered at 37+0 to 37+6 weeks' gestation, 232 (18%) delivered at 38+0 to 38+6 weeks, 310 (12.1%) delivered at 39+0 to 39+6 weeks, 207 (8.7%) delivered at 40+0 to 40+6 weeks, and 92 (8.1%) delivered at ≥41+0 weeks. In analysis 1, the incidence of hypertensive disorders of pregnancy increased with advancing gestational age among all ongoing pregnancies with a hypertensive disorder of pregnancy (2.0% at 37 weeks and 8.1% at 41 weeks). In analysis 2, the incidence of hypertensive disorders of pregnancy decreased with advancing gestational age among deliveries at that gestational age week alone (24.5% at 37 weeks and 8.1% at 41 weeks). Our results confirm the findings from the A Randomized Trial of Induction Versus Expectant Management study showing that the risk for hypertensive disorders of pregnancy increases with advancing gestational age, but hypertensive disorders of pregnancy is more common among deliveries at earlier gestational ages. These key differences illustrate how important the study design and analytical approach are to accurately interpret results and apply findings clinically.


Nck influences preosteoblastic/osteoblastic migration and bone mass.
Migration of the cells in osteoblastic lineage, including preosteoblasts and osteoblasts, has been postulated to influence bone formation. However, the molecular bases that link preosteoblastic/osteoblastic cell migration and bone formation are incompletely understood. Nck (noncatalytic region of tyrosine kinase; collectively referred to Nck1 and Nck2) is a member of the signaling adaptors that regulate cell migration and cytoskeletal structures, but its function in cells in the osteoblastic lineage is not known. Therefore, we examined the role of Nck in migration of these cells. Nck is expressed in preosteoblasts/osteoblasts, and its knockdown suppresses migration as well as cell spreading and attachment to substrates. In contrast, Nck1 overexpression enhances spreading and increases migration and attachment. As for signaling, Nck double knockdown suppresses migration toward IGF1 (insulin-like growth factor 1). In these cells, Nck1 binds to IRS-1 (insulin receptor substrate 1) based on immunoprecipitation experiments using anti-Nck and anti-IRS-1 antibodies. In vivo, Nck knockdown suppresses enlargement of the pellet of DiI-labeled preosteoblasts/osteoblasts placed in the calvarial defects. Genetic experiments indicate that conditional double deletion of both Nck1 and Nck2 specifically in osteoblasts causes osteopenia. In these mice, Nck double deficiency suppresses the levels of bone-formation parameters such as bone formation rate in vivo. Interestingly, bone-resorption parameters are not affected. Finally, Nck deficiency suppresses repair of bone injury after bone marrow ablation. These results reveal that Nck regulates preosteoblastic/osteoblastic migration and bone mass.